Clinical Gastrointestinal Endoscopy [3rd Edition] 9780323547925

Table of contents :
SECTION I: EQUIPMENT AND GENERAL PRINCIPLES OF ENDOSCOPY

1. The History of Gastrointestinal Endoscopy

2. Setting Up an Endoscopy Facility

3. How Endoscopes Work

4. Cleaning and Disinfecting Gastrointestinal Endoscopy Equipment

5. Tissue Sampling, Specimen Handling, and Chromoendoscopy

6. Electrosurgery in Therapeutic Endoscopy

7. Sedation and Monitoring in Endoscopy

8. Patient Preparation and Pharmacotherapeutic Considerations

9. Bowel Preparation for Colonoscopy

10. Reporting, Documentation, and Risk Management

11. Small-Caliber Endoscopy

12. Postsurgical Endoscopic Anatomy

13. Endoscopic Simulators

SECTION II: LUMINAL GASTROINTESTINAL DISORDERS

Part 1: Gastrointestinal Bleeding

14. Nonvariceal Upper Gastrointestinal Bleeding

15. Portal Hypertensive Bleeding

16. Lower Gastrointestinal Bleeding

17. Mid-gut Gastrointestinal Bleeding

18. Occult and Unexplained Chronic Gastrointestinal Bleeding

Part 2: Esophageal Disorders

19. Esophageal Motility Disorders

20. Endoscopic Diagnosis and Management of Zenker’s Diverticula

21. Benign Esophageal Strictures

22. Ingested Foreign Objects and Food Bolus Impactions

23. Eosinophilic Esophagitis

24. Gastroesophageal Reflux Disease

25. Barrett's Esophagus

26. Screening for Esophageal Squamous Cell Carcinoma

27. Endoscopic Treatment of Early Esophageal Neoplasia

28. Palliation of Malignant Dysphagia and Esophageal Fistulas

Part 3: Gastric Disorders

29. Gastroparesis

30. Gastric Polyps and Thickened Gastric Folds

31. Subepithelial Tumors of the Esophagus and Stomach

32. Diagnosis and Treatment of Superficial Gastric Neoplasms

33. Palliation of Gastric Outlet Obstruction

Part 4: Duodenal Disorders

34. Duodenal and Papillary Adenomas

Part 5: Colonic Disorders

35. Acute Colonic Pseudo-Obstruction

36. Colorectal Cancer Screening and Surveillance

37. Polypectomy, Mucosal Resection, and Submucosal Dissection

38. Endoscopic Diagnosis and Staging of Inflammatory Bowel Disease

39. Dysplasia Surveillance in Inflammatory Bowel Disease

40. Colonic Strictures

Part 6: Miscellaneous

41. Infections of the Luminal Digestive Tract

42. Techniques in Enteral Access

43. Endoscopic Techniques for Weight Loss

44. Management of Post-Bariatric Complications

45. Intramural and Transmural Endoscopy

46. Endoscopic Full Thickness Resection of Subepithelial Lesions of the GI Tract

47. Extraintestinal Endosonography

SECTION 3: PANCREATOBILIARY DISORDERS

Part 1: General Considerations and Techniques

48. Preparation for Pancreaticobiliary Endoscopy

49. Choloangiography and Pancreatography

50. Cannulation and Sphinctertomy

51. Endoscopic Ultrasound and FNA for Pancreatic and Biliary Disorders

52. Endoscopic Ultrasound-Guided Access and Drainage of the Pancreaticobiliary Ductal Systems

Part 2: Benign Biliary Disorders

53. Gallstone Disease: Choledocholithiasis, Cholecystitis, and Gallstone Pancreatitis

54. Postoperative Biliary Strictures and Leaks

55. Infections of the Biliary Tract

56. Sphincter of Oddi Disorders

Part 3: Benign Pancreatic Disorders

57. Recurrent Acute Pancreatitis

58. Pancreatic Fluid Collections and Leaks

59. Chronic Pancreatitis

Part 4: Neoplastic Pancreaticobiliary Disorders

60. The Indeterminate Biliary Stricture

61. Pancreatic Cystic Lesions

62. Evaluation and Staging of Pancreaticobiliary Malignancy

63. Palliation of Malignant Pancreaticobiliary Obstruction

Citation preview

CLINICAL GASTROINTESTINAL ENDOSCOPY

CLINICAL GASTROINTESTINAL ENDOSCOPY TTHIRD H I R D EEDITION DITION

Vinay Chandrasekhara, MD Senior Associate Consultant Division of Gastroenterology & Hepatology Mayo Clinic Rochester, Minnesota

B. Joseph Elmunzer, MD, MSc The Peter B. Cotton Endowed Chair in Endoscopic Innovation Associate Professor of Internal Medicine Division of Gastroenterology and Hepatology Medical University of South Carolina Charleston, South Carolina

Mouen A. Khashab, MD Associate Professor of Medicine Director of Therapeutic Endoscopy Division of Gastroenterology and Hepatology Johns Hopkins Hospital Baltimore, Maryland

V. Raman Muthusamy, MD, MAS Director of Endoscopy, UCLA Health System Professor of Clinical Medicine Vatche and Tamar Manoukian Division of Digestive Diseases David Geffen School of Medicine at UCLA Los Angeles, California

1600 John F. Kennedy Blvd. Ste 1800 Philadelphia, PA 19103-2899

CLINICAL GASTROINTESTINAL ENDOSCOPY, THIRD EDITION

ISBN: 978-0-323-41509-5

Copyright © 2019 by Elsevier, Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).

Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. With respect to any drug or pharmaceutical products identified, readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of practitioners, relying on their own experience and knowledge of their patients, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Previous editions copyrighted 2012 and 2005. Library of Congress Cataloging-in-Publication Data Names: Chandrasekhara, Vinay, editor. | Elmunzer, B. Joseph, editor. | Khashab, Mouen, editor. | Muthusamy, V. Raman, editor. Title: Clinical gastrointestinal endoscopy / [edited by] Vinay Chandrasekhara, B. Joseph Elmunzer, Mouen A. Khashab, V. Raman Muthusamy. Description: Third edition. | Philadelphia, PA : Elsevier, [2019] | Includes bibliographical references and index. Identifiers: LCCN 2017056974 | ISBN 9780323415095 (hardcover : alk. paper) Subjects: | MESH: Endoscopy, Gastrointestinal | Gastrointestinal Diseases–therapy | Biliary Tract Diseases–therapy | Pancreatic Diseases–therapy Classification: LCC RC804.E64 | NLM WI 190 | DDC 616.3/407545–dc23 LC record available at https://lccn.loc.gov/2017056974

Executive Content Strategist: Dolores Meloni Senior Content Development Specialist: Rae Robertson Publishing Services Manager: Catherine Jackson Project Manager: Tara Delaney Design Direction: Renee Duenow

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CONTRIBUTORS James L. Achord, MD

John Baillie, MD

Stas Bezobchuk, MD

Professor Emeritus University of Mississippi Medical Center Jackson, Misssissippi 1: The History of Gastrointestinal Endoscopy

Professor Division of Gastroenterology and Hepatology Department of Medicine Virginia Commonwealth University School of Medicine Richmond, Virginia 3: How Endoscopes Work

Institute of Gastroenterology, Hepatology, and Nutrition Emek Medical Center Afula, Israel 17: Middle Gastrointestinal Bleeding

Michelle J. Alfa, BSc, MSc, PhD Principal Investigator St. Boniface Research Centre; Professor Department of Medical Microbiology University of Manitoba Winnipeg, Manitoba, Canada 4: Cleaning and Disinfecting Gastrointestinal Endoscopy Equipment

Mohammad Al-Haddad, MD, MSc, FASGE, FACG, AGAF Associate Professor of Medicine Division of Gastroenterology and Hepatology Indiana University School Medicine Indianapolis, Indiana 62: Evaluation and Staging of Pancreaticobiliary Malignancy

Alan N. Barkun, MD, MSc Division of Gastroenterology McGill University Health Center Montreal, Québec, Canada 14: Nonvariceal Upper Gastrointestinal Bleeding

Todd H. Baron, MD, FASGE Professor of Medicine Division of Gastroenterology and Hepatology University of North Carolina Chapel Hill, North Carolina 20: Endoscopic Diagnosis and Management of Zenker’s Diverticula

Kenneth F. Binmoeller, MD Director, Interventional Endoscopy Services Paul May and Frank Stein Interventional Endoscopy Center California Pacific Medical Center San Francisco, California 58: Pancreatic Fluid Collections and Leaks

Sarah Blankstein, AB, JD Boston, Massachusetts 10: Legal Concepts for Gastroenterologists

Daniel Blero, MD, PhD Department of Gastroenterology Chu Charleroi Charleroi, Belgium; Hôpital Erasme Brussels, Belgium 43: Endoscopic Techniques for Weight Loss

Omer Basar, MD Andrea Anderloni, MD, PhD Digestive Endoscopy Unit Division of Gastroenterology Humanitas Research Hospital Milan, Italy 28: Palliation of Malignant Dysphagia and Esophageal Fistulas

Joseph C. Anderson, MD Associate Professor of Medicine Department of Veterans Affairs Medical Center White River Junction, Vermont; The Geisel School of Medicine at Dartmouth Hanover, New Hampshire; Division of Gastroenterology and Hepatology University of Connecticut School of Medicine Farmington, Connecticut 36: Colorectal Cancer Screening and Surveillance

Anna Baiges, MD Hepatic Hemodynamic Laboratory Liver Unit, Hospital Clínic Barcelona, Spain 15: Portal Hypertensive Bleeding

Pancreas Biliary Center, Gastrointestinal Unit Massachusetts General Hospital Boston, Massachusetts; Professor of Medicine Department of Gastroenterology Hacettepe University Ankara, Turkey 61: Pancreatic Cystic Lesions

Mark Benson, MD Assistant Professor Division of Gastroenterology and Hepatology University of Wisconsin School of Medicine and Public Health Madison, Wisconsin 22: Ingested Foreign Objects and Food Bolus Impactions

Lyz Bezerra Silva, MD, MSC Associate Professor of Surgery Department of Surgery Federal University of Pernambuco Recife, Brazil 45: Intramural and Transmural Endoscopy

Michael J. Bourke, BSc, MD Department of Gastroenterology and Hepatology Westmead Hospital Sydney, Australia 34: Duodenal and Papillary Adenomas

William R. Brugge, MD Chief Division of Gastroenterology Mount Auburn Hospital Cambridge, Massachusetts 61: Pancreatic Cystic Lesions

Marco J. Bruno, MD, PhD Department of Gastroenterology and Hepatology Erasmus Medical Center University of Rotterdam Rotterdam, The Netherlands 63: Palliation of Malignant Pancreaticobiliary Obstruction

Anna M. Buchner, MD, PhD Assistant Professor of Medicine Division of Gastroenterology University of Pennsylvania Philadelphia, Pennsylvania 38: Endoscopic Diagnosis and Staging of Inflammatory Bowel Disease

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CONTRIBUTORS

Andrés Cárdenas, MD, MMSc, PhD, AGAF, FAASLD Faculty Member/Consultant Institute of Digestive Diseases and Metabolism Hospital Clinic University of Barcelona Barcelona, Spain 15: Portal Hypertensive Bleeding 54: Postoperative Biliary Strictures and Leaks

David Carr-Locke, MD, FRCP, FASGE, AGAF, NYSGEF Clinical Director Center for Advanced Digestive Care Gastroenterology & Hepatology Weill Cornell Medical College Cornell University New York, New York 55: Infections of the Biliary Tract

Guido Costamagna, MD, FACG

Jeffrey J. Easler, MD

Digestive Endoscopy Unit Catholic University Gemelli University Hospital Rome, Italy 54: Postoperative Biliary Strictures and Leaks

Assistant Professor of Medicine Division of Gastroenterology and Hepatology Indiana University School of Medicine; Richard L. Roudebush VA Medical Center Indianapolis, Indiana 49: Cholangiography and Pancreatography

Peter B. Cotton, MD, FRCS, FRCP Professor of Medicine Digestive Disease Center Medical University of South Carolina Charleston, South Carolina 56: Sphincter of Oddi Disorders

Amit P. Desai, MD Texas Digestive Diseases Consultants Texas Health Presbyterian Hospital Dallas, Texas 47: Extraintestinal Endosonography

Kenneth Chang, MD Professor and Chief Division of Gastroenterology and Hepatology University of California—Irvine Orange, California 51: Endoscopic Ultrasound and Fine-Needle Aspiration for Pancreatic and Biliary Disorders

Saurabh Chawla, MD, FACG Director of Endoscopy Grady Memorial Hospital; Assistant Professor of Medicine Emory University School of Medicine Atlanta, Georgia 48: Preparation for Pancreaticobiliary Endoscopy

John O. Clarke, MD Clinical Associate Professor Department of Medicine Stanford University Stanford, California 19: Esophageal Motility Disorders 29: Endoscopic Approaches for Gastroparesis

Jonathan Cohen, MD Clinical Professor Department of Medicine New York University Langone School of Medicine New York, New York 13: Endoscopic Simulators

Andrew P. Copland, MD Assistant Professor of Medicine Division of Gastroenterology and Hepatology University of Virginia Health Systems Charlottesville, Virginia 40: Colonic Strictures

Jacques Devière, MD, PhD Professor of Medicine Chairman, Department of Gastroenterology, Hepatopancreatology, and Digestive Oncology Erasme Hospital Université Libre de Bruxelles Brussels, Belgium 43: Endoscopic Techniques for Weight Loss

Christopher J. DiMaio, MD Director of Therapeutic Endoscopy Associate Professor of Medicine Division of Gastroenterology Icahn School of Medicine at Mount Sinai New York, New York 53: Gallstone Disease: Choledocholithiasis, Cholecystitis, and Gallstone Pancreatitis

Gary W. Falk, MD, MS Professor of Medicine Department of Medicine, Division of Gastroenterology University of Pennsylvania Perelman School of Medicine Philadelphia, Pennsylvania 25: Barrett’s Esophagus: Diagnosis, Surveillance, and Medical Management

Francis A. Farraye, MD, MSc Clinical Director Section of Gastroenterology Boston Medical Center; Professor of Medicine Department of Medicine Boston University School of Medicine Boston, Massachusetts 39: Dysplasia Surveillance in Inflammatory Bowel Disease

Andrew Feld, MD, JD Program Chief, Group Health Cooperative Clinical Professor University of Washington Seattle, Washington 10: Legal Concepts for Gastroenterologists

Kayla Feld, JD Quinn Emanuel Urquhart & Sullivan Washington, D.C. 10: Legal Concepts for Gastroenterologists

Peter Draganov, MD Professor of Medicine Department of Internal Medicine University of Florida Gainesville, Florida 37: Colonoscopic Polypectomy, Mucosal Resection, and Submucosal Dissection

Paul Fockens, MD, PhD, FASGE

Jérôme Dumortier, MD

Evan L. Fogel, MD, MSc, FRCP(C)

Department of Hepatogastroenterology and Digestive Endoscopy Edouard Herriot Hospital Lyon, France 11: Small-Caliber Endoscopy

Professor of Medicine Department of Gastroenterology and Hepatology Indiana University School of Medicine Indianapolis, Indiana 49: Cholangiography and Pancreatography

Professor and Chair Department of Gastroenterology and Hepatology Academic Medical Center Amsterdam, The Netherlands 33: Palliation of Gastric Outlet Obstruction

CONTRIBUTORS

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Kyle J. Fortinsky, MD, BSc

Ian M. Gralnek, MD, MSHS, FASGE

Douglas A. Howell, MD

Division of Gastroenterology University of Toronto Toronto, Ontario, Canada 14: Nonvariceal Upper Gastrointestinal Bleeding

Clinical Associate Professor of Medicine/ Gastroenterology Rappaport Faculty of Medicine Technion Israel Institute of Technology; Chief, Institute of Gastroenterology, Hepatology and Nutrition Emek Medical Center Afula, Israel 17: Middle Gastrointestinal Bleeding

Director, Advanced Interventional Endoscopy Fellowship Director, Pancreaticobiliary Center Maine Medical Center Portland, Maine; Associate Clinical Professor Tufts University School of Medicine Boston, Massachusetts 60: The Indeterminate Biliary Stricture

Frank G. Gress, MD

Chin Hur, MD, MPH

Professor of Medicine Chief, Interventional Endoscopy Division of Digestive & Liver Diseases Columbia University Medical Center New York, New York 47: Extraintestinal Endosonography

Associate Director, Institute for Technology Assessment Director, GI Health Outcomes Research Massachusetts General Hospital; Associate Professor of Medicine Harvard Medical School Boston, Massachusetts 26: Screening for Esophageal Squamous Cell Carcinoma

Martin L. Freeman, MD Professor of Medicine Division of Gastroenterology, Hepatology, and Nutrition University of Minnesota Minneapolis, Minnesota 57: Recurrent Acute Pancreatitis

Juan Carlos García-Pagán, MD, PhD Head Barcelona Hepatic Hemodynamic Lab; Senior Consultant in Hepatology Associate Professor University of Barcelona; Liver Unit, Hospital Clínic Barcelona, Spain 15: Portal Hypertensive Bleeding

Hans Gerdes, MD Attending Physician Department of Medicine Memorial Sloan Kettering Cancer Center; Professor of Clinical Medicine Weill Cornell Medical College of Cornell University New York, New York 30: Gastric Polyps and Thickened Gastric Folds

Robert H. Hawes, MD Professor Department of Medicine University of Central Florida College of Medicine; Medical Director Florida Hospital Institute for Minimally Invasive Therapy Florida Hospital Orlando Orlando, Florida 59: Chronic Pancreatitis

Gregory G. Ginsberg, MD Professor of Medicine Department of Medicine, Division of Gastroenterology Hospital of the University of Pennsylvania Philadelphia, Pennsylvania 50: Difficult Cannulation and Sphincterotomy

Marc Giovannini, MD Head, Gastroenterology and Endoscopy Department Paoli-Calmettes Institute Marseille, France 52: Endoscopic Ultrasound-Guided Access and Drainage of the Pancreaticobiliary Ductal Systems

Professor of Medicine Department of Medicine Division of Gastroenterology and Hepatology Stanford University Stanford, California 6: Electrosurgery in Therapeutic Endoscopy

Virginia Hernández-Gea, MD, PhD

Maite Betés Ibáñez, PhD, MD

Hepatic Hemodynamic Laboratory Liver Unit, Hospital Clínic Barcelona, Spain 15: Portal Hypertensive Bleeding

Department of Gastroenterology University Clinic of Navarra Pamplona, Navarra, Spain 18: Occult and Unexplained Chronic Gastrointestinal Bleeding

Joanna A. Gibson, MD, PhD Assistant Professor of Pathology Yale University School of Medicine New Haven, Connecticut 5: Tissue Sampling, Specimen Handling, and Laboratory Processing

Joo Ha Hwang, MD, PhD

Ikuo Hirano, MD Professor of Medicine Department of Medicine, Division of Gastroenterology Northwestern University Feinberg School of Medicine; Director, Northwestern Esophageal Center Northwestern Medicine Chicago, Illinois 23: Eosinophilic Esophagitis

Takao Itoi, MD, PhD, FASGE, FACG

Juergen Hochberger, MD, PhD

Prasad G. Iyer, MD, MS

Chairman Department of Gastroenterology Vivantes Klinikum im Friedrichshain Berlin, Germany 50: Difficult Cannulation and Sphincterotomy

Professor and Consultant Department of Gastroenterology and Hepatology Mayo Clinic Rochester, Minnesota 27: Endoscopic Treatment of Early Esophageal Neoplasia

Chair and Professor Department of Gastroenterology and Hepatology Tokyo Medical University Tokyo, Japan 52: Endoscopic Ultrasound-Guided Access and Drainage of the Pancreaticobiliary Ductal Systems

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CONTRIBUTORS

David A. Johnson, MD, MACG, FASGE, FACP Professor of Medicine and Chief Division of Gastroenterology and Hepatology Department of Internal Medicine Eastern Virginia Medical School Norfolk, Virginia 9: Bowel Preparation for Colonoscopy

Sreeni Jonnalagadda, MD Professor of Medicine Director of Therapeutic and Biliary Endoscopy Saint Luke’s Hospital University of Missouri—Kansas City Kansas City, Missouri 12: Postsurgical Endoscopic Anatomy

Charles J. Kahi, MD, MS, FACP, FACG, AGAF, FASGE Professor of Clinical Medicine Indiana University School of Medicine; Gastroenterology Section Chief Richard L. Roudebush VA Medical Center Indianapolis, Indiana 36: Colorectal Cancer Screening and Surveillance

Tonya Kaltenbach, MD, MAS Associate Professor of Clinical Medicine Division of Gastroenterology, Department of Medicine University California San Francisco; Director of Advanced Endoscopy San Francisco Veterans Affair Medical Center San Francisco, California 37: Colonoscopic Polypectomy, Mucosal Resection, and Submucosal Dissection

Michael L. Kochman, MD

Michael Levy, MD

Wilmott Family Professor of Medicine Division of Gastroenterology, Department of Medicine Perelman School of Medicine University of Pennsylvania Philadelphia, Pennsylvania 21: Benign Esophageal Strictures

Professor of Medicine Division of Gastroenterology and Hepatology Mayo Clinic Rochester, Minnesota 62: Evaluation and Staging of Pancreaticobiliary Malignancy

Divyanshoo R. Kohli, MD

David Lichtenstein, MD

Division of Gastroenterology and Hepatology Department of Medicine Virginia Commonwealth University School of Medicine Richmond, Virginia 3: How Endoscopes Work

Director of Endoscopy Department of Gastroenterology Boston Medical Center Boston University School of Medicine Boston, Massachusetts 4: Cleaning and Disinfecting Gastrointestinal Endoscopy Equipment

Andrew Korman

Gary R. Lichtenstein, MD

Division of Gastroenterology and Hepatology Saint Peter’s University Hospital New Brunswick, New Jersey 55: Infections of the Biliary Tract

Professor of Medicine Director, Center for Inflammatory Bowel Disease Division of Gastroenterology University of Pennsylvania Philadelphia, Pennsylvania 38: Endoscopic Diagnosis and Staging of Inflammatory Bowel Disease

Wilson T. Kwong, MD, MS Assistant Professor Department of Gastroenterology University of California San Diego La Jolla, California 16: Lower Gastrointestinal Bleeding

Ryan Law, DO Clinical Lecturer Division of Gastroenterology and Hepatology University of Michigan Ann Arbor, Michigan 20: Endoscopic Diagnosis and Management of Zenker’s Diverticula

Leila Kia, MD Assistant Professor of Medicine Department of Medicine, Division of Gastroenterology Northwestern University Feinberg School of Medicine Chicago, Illinois 23: Eosinophilic Esophagitis

David A. Leiman, MD, MSHP Assistant Professor of Medicine Division of Gastroenterology Duke University School of Medicine Durham, North Carolina 24: Gastroesophageal Reflux Disease

Franciscan Digestive Care Associates Gig Harbor, Washington 35: Acute Colonic Pseudo-Obstruction

Amir Klein, MD Department of Gastroenterology and Hepatology Rambam Health Care Campus Haifa, Israel 34: Duodenal and Papillary Adenomas

Gastroenterology Fellow Department of Gastroenterology University of Missouri—Kansas City Kansas City, Missouri 12: Postsurgical Endoscopic Anatomy

Jimmy K. Limdi, MBBS, FRCP, FRCPE, FACG Consultant Gastroenterologist Department of Gastroenterology The Pennine Acute Hospitals NHS Trust; Honorary Senior Lecturer Institute of Inflammation and Repair University of Manchester Manchester, United Kingdom 39: Dysplasia Surveillance in Inflammatory Bowel Disease

Gianluca Lollo, MD Anne Marie Lennon, MB, PhD, FRCPI

Michael B. Kimmey, MD

Alisa Likhitsup, MD

Benjamin Baker Scholar Associate Professor of Medicine and Surgery The Johns Hopkins Hospital Baltimore, Maryland 61: Pancreatic Cystic Lesions

Department of Surgical Oncology and Gastroenterological Sciences University of Padua Padua, Italy 28: Palliation of Malignant Dysphagia and Esophageal Fistulas

CONTRIBUTORS

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Fauze Maluf-Filho, MD, PhD, FASGE

Marcia L. Morris, MS

Nicholas Nickl, MD

Professor Department of Gastroenterology Medical School of University of São Paulo; Chief Endoscopy Unit Institute of Cancer of Univeristy of São Paulo 63: Palliation of Malignant Pancreaticobiliary Obstruction

Electrosurgery Consultant St. Paul, Minnesota 6: Electrosurgery in Therapeutic Endoscopy

Professor of Medicine University of Kentucky Medical Center Lexington, Kentucky 31: Subepithelial Tumors of the Esophagus and Stomach

Jennifer Maranki, MD, MSc Associate Professor of Medicine Director of Endoscopy Division of Gastroenterology and Hepatology Penn State Hershey Medical Center Hershey, Pennsylvania 46: Endoscopic Full-Thickness Resection of Subepithelial Lesions of the GI Tract

Richard W. McCallum, MD, FACP, FRACP (Aust), FACG, AGAF Professor of Medicine and Founding Chair Department of Internal Medicine Texas Tech University El Paso, Texas; Honorary Professor University of Queensland Queensland, Australia 29: Endoscopic Approaches for Gastroparesis

Stephen A. McClave, MD Professor of Medicine Department of Medicine University of Louisville School of Medicine Louisville, Kentucky 42: Techniques in Enteral Access

Klaus Mergener, MD, PhD, MBA Partner Digestive Health Specialists Tacoma, Washington 2: Setting Up an Endoscopy Facility

David C. Metz, MD Professor of Medicine Division of Gastroenterology Perelman School of Medicine University of Pennsylvania Philadelphia, Pennsylvania 24: Gastroesophageal Reflux Disease

Volker Meves, MD Department of Gastroenterology Vivantes Klinikum im Friedrichshain Berlin, Germany 50: Difficult Cannulation and Sphincterotomy

Daniel K. Mullady, MD Associate Professor of Medicine Director, Interventional Endoscopy Department of Gastroenterology Washington University in St. Louis School of Medicine St. Louis, Missouri 53: Gallstone Disease: Choledocholithiasis, Cholecystitis, and Gallstone Pancreatitis

Satoru Nonaka, MD, PhD Endoscopy Division National Cancer Center Hospital Tokyo, Japan 32: Diagnosis and Treatment of Superficial Gastric Neoplasms

Ichiro Oda, MD Miguel Muñoz-Navas, PhD, MD Professor of Medicine University of Navarra School of Medicine; Director Department of Gastroenterology University of Navarra Clinic Pamplona, Navarra, Spain 18: Occult and Unexplained Chronic Gastrointestinal Bleeding

V. Raman Muthusamy, MD, MAS Director of Endoscopy, UCLA Health System Professor of Clinical Medicine Vatche and Tamar Manoukian Division of Digestive Diseases David Geffen School of Medicine at UCLA Los Angeles, California 1: The History of Gastrointestinal Endoscopy

Endoscopy Division National Cancer Center Hospital Tokyo, Japan 32: Diagnosis and Treatment of Superficial Gastric Neoplasms

Robert D. Odze, MD, FRCPC Professor of Pathology Department of Pathology Brigham and Women’s Hospital Boston, Massachusetts 5: Tissue Sampling, Specimen Handling, and Laboratory Processing

Edward C. Oldfield IV, MD Department of Internal Medicine Eastern Virginia Medical School Norfolk, Virginia 9: Bowel Preparation for Colonoscopy

Zaheer Nabi, MD, DNB

Parth J. Parekh, MD

Consultant Gastoenterologist Asian Institute of Gastroenterology Hyderabad, India 55: Infections of the Biliary Tract

Department of Internal Medicine Division of Gastroenterology and Hepatology Tulane University New Orleans, Louisiana 9: Bowel Preparation for Colonoscopy

Andrew Nett, MD Paul May and Frank Stein Interventional Endoscopy Center California Pacific Medical Center; Department of Medicine University of California San Francisco San Francisco, California 58: Pancreatic Fluid Collections and Leaks

Nam Q. Nguyen, MBBS (Hons), FRACP, PhD Associate Professor Head, Education and Research Department of Gastroenterology and Hepatology Royal Adelaide Hospital University of Adelaide Adelaide, South Australia, Australia 8: Patient Preparation and Pharmacotherapeutic Considerations

Patrick R. Pfau, MD Professor of Medicine, Chief of Clinical Gastroenterology Division of Gastroenterology and Hepatology University of Wisconsin School of Medicine and Public Health Madison, Wisconsin 22: Ingested Foreign Objects and Food Bolus Impactions

Mathieu Pioche, MD, PhD Department of Hepatogastroenterology and Digestive Endoscopy Edouard Herriot Hospital Lyon, France 11: Small-Caliber Endoscopy

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CONTRIBUTORS

Heiko Pohl, MD

Marvin Ryou, MD

Pari M. Shah, MD, MSCE

Associate Professor of Medicine Geisel School of Medicine at Dartmouth Hanover New Hampshire; Department of Gastroenterology Veterans Affair Medical Center White River Junction, Vermont 37: Colonoscopic Polypectomy, Mucosal Resection, and Submucosal Dissection

Division of Gastroenterology, Hepatology, and Endoscopy Brigham and Womens’ Hospital; Instructor Harvard Medical School Boston, Massachusetts 44: Management of Post-Bariatric Complications

Assistant Attending Physician Department of Medicine Memorial Sloan Kettering Cancer Center; Assistant Professor of Clinical Medicine Weill Cornell Medical College of Cornell University New York, New York 30: Gastric Polyps and Thickened Gastric Folds

Thierry Ponchon, MD, PhD

Yutaka Saito, MD, PhD, FASGE, FACG

Department of Hepatogastroenterology and Digestive Endoscopy Edouard Herriot Hospital Lyon, France 11: Small-Caliber Endoscopy

Chief, Director Endoscopy Division National Cancer Center Hospital Tokyo, Japan 32: Diagnosis and Treatment of Superficial Gastric Neoplasms

Robert J. Ponec, MD Consulting Gastroenterologist and Therapeutic Endoscopist Department of Gastroenterology and Hepatology Salem Gastroenterology Consultants Salem, Oregon 35: Acute Colonic Pseudo-Obstruction

Michael W. Rajala, MD, PhD Assistant Professor of Clinical Medicine Division of Gastroenterology, Department of Medicine Perelman School of Medicine University of Pennsylvania Philadelphia, Pennsylvania 21: Benign Esophageal Strictures

Jason B. Samarasena, MD Associate Clinical Professor of Medicine Division of Gastroenterology and Hepatology University of California—Irvine Orange, California 51: Endoscopic Ultrasound and Fine-Needle Aspiration for Pancreatic and Biliary Disorders

Stuart Sherman, MD Glen A. Lehman Professor of Gastroenterology Professor of Medicine Division of Gastroenterology and Hepatology Indiana University School of Medicine Indianapolis, Indiana 49: Cholangiography and Pancreatography

Uzma D. Siddiqui, MD Center for Endoscopic Research and Therapeutics University of Chicago School of Medicine Chicago, Illinois 59: Chronic Pancreatitis

Thomas J. Savides, MD

Vikesh K. Singh, MD, MSc

Professor of Clinical Medicine Division of Gastroenterology University of California San Diego La Jolla, California 16: Lower Gastrointestinal Bleeding

Director, Pancreatitis Center Associate Professor of Medicine John Hopkins University School of Medicine Baltimore, Maryland 48: Preparation for Pancreaticobiliary Endoscopy

Nageshwar Reddy, MBBS, MD, DM

Mark Schoeman, MBBS, PhD, FRACP

Chairman and Chief of Gastroenterology Asian Institute of Gastroenterology Hyderabad, India 55: Infections of the Biliary Tract

Head, Gastrointestinal Investigation Unit Department of Gastroenterology and Hepatology Royal Adelaide Hospital Adelaide, South Australia, Australia 8: Patient Preparation and Pharmacotherapeutic Considerations

Roy Soetikno, MD, MS

Allison R. Schulman, MD, MPH

Stavros N. Stavropoulos, MD, FASGE

Physician Division of Gastroenterology, Hepatology, and Endoscopy Brigham and Women’s Hospital; Harvard Medical School Boston, Massachusetts 44: Management of Post-Bariatric Complications

Chief, GI Endoscopy Director, Program in Advanced GI Endoscopy (P.A.G.E.) Winthrop University Hospital Mineola, New York; Adjunct Professor of Clinical Medicine Columbia University New York, New York 46: Endoscopic Full-Thickness Resection of Subepithelial Lesions of the GI Tract

Alessandro Repici, MD Professor of Gastroenterology Director of Endoscopy Humanitas Research Hospital & Humanitas University Milan, Italy 28: Palliation of Malignant Dysphagia and Esophageal Fistulas

Jérôme Rivory, MD Department of Hepatogastroenterology and Digestive Endoscopy Edouard Herriot Hospital Lyon, France 11: Small-Caliber Endoscopy

Amrita Sethi, MD, MSc Associate Professor of Medicine Director of Pancreaticobiliary Endoscopy Services Columbia University Medical Center New York, New York 60: The Indeterminate Biliary Stricture

Veterans Affairs Palo Alto Health Care System Stanford University School of Medicine Palo Alto, California 37: Colonoscopic Polypectomy, Mucosal Resection, and Submucosal Dissection

CONTRIBUTORS Tyler Stevens, MD

Emo E. van Halsema, MD

Associate Professor Department of Gastroenterology and Hepatology Cleveland Clinic Cleveland, Ohio 57: Recurrent Acute Pancreatitis

Department of Gastroenterology and Hepatology Academic Medical Center Amsterdam, The Netherlands 33: Palliation of Gastric Outlet Obstruction

Jeanin E. van Hooft, MD, PhD, MBA Christina Surawicz, MD Professor Division of Gastroenterology Department of Medicine University of Washington Seattle, Washington 41: Infections of the Luminal Digestive Tract

Department of Gastroenterology and Hepatology Academic Medical Center Amsterdam, The Netherlands 33: Palliation of Gastric Outlet Obstruction

John Joseph Vargo II, MD, MPH

Chief Executive Officer Physicians Endoscopy Jamison, Pennsylvania 2: Setting Up an Endoscopy Facility

Vice Chair, Digestive Disease Institute Chair Department of Gastroenterology and Hepatology Cleveland Clinic Cleveland, Ohio 7: Sedation and Monitoring in Endoscopy

Paul Tarnasky, MD

Kavel Visrodia, MD

Digestive Health Associates of Texas Dallas, Texas 56: Sphincter of Oddi Disorders

Fellow Department of Internal Medicine, Division of Gastroenterology and Hepatology Mayo Clinic Rochester, Minnesota 27: Endoscopic Treatment of Early Esophageal Neoplasia

Barry Tanner, CPA

Christopher C. Thompson, MD, MSc, FACG, FASGE, AGAF Director of Therapeutic Endoscopy Division of Gastroenterology, Hepatology, and Endoscopy Brigham and Women’s Hospital; Assistant Professor of Medicine Harvard Medical School Boston, Massachusetts 44: Management of Post-Bariatric Complications

Vaibhav Wadhwa, MD Clinical Fellow Department of Gastroenterology and Hepatology Cleveland Clinic Florida Weston, Florida 7: Sedation and Monitoring in Endoscopy

Mark Topazian, MD

Kristian Wall, MD

Professor of Medicine Division of Gastroenterology & Hepatology Mayo Clinic Rochester, Minnesota 51: Endoscopic Ultrasound and Fine-Needle Aspiration for Pancreatic and Biliary Disorders

Fellow Division of Digestive Diseases and Nutrition University of Kentucky Lexington, Kentucky 31: Subepithelial Tumors of the Esophagus and Stomach

George Triadafilopoulos, MD, DSc

Catharine M. Walsh, MD, MEd, PhD, FAAP, FRCPC

Clinical Professor of Medicine Stanford Multidimensional Program for Innovation and Research in the Esophagus (S-MPIRE) Division of Gastroenterology and Hepatology Stanford University School of Medicine Stanford, California 19: Esophageal Motility Disorders

Division of Gastroenterology, Hepatology, and Nutrition and the Learning and Research Institutes Department of Paediatrics Hospital for Sick Children; The Wilson Centre University of Toronto Toronto, Ontario, Canada 13: Endoscopic Simulators

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Andrew Y. Wang, MD, AGAF, FACG, FASGE Associate Professor of Medicine Chief, Section of Interventional Endoscopy Division of Gastroenterology and Hepatology University of Virginia Health System Charlottesville, Virginia 40: Colonic Strictures

Kenneth K. Wang, MD Kathy and Russ VanCleve Professor of Gastroenterology Research Department of Gastroenterology and Hepatology Mayo Clinic Rochester, Minnesota 27: Endoscopic Treatment of Early Esophageal Neoplasia

Sachin Wani, MD Associate Professor of Medicine Department of Medicine, Division of Gastroenterology University of Colorado School of Medicine Aurora, Colorado 25: Barrett’s Esophagus: Diagnosis, Surveillance, and Medical Management

C. Mel Wilcox, MD, MSPH Director Division of Gastroenterology and Hepatology University of Alabama at Birmingham Birmingham, Alabama 41: Infections of the Luminal Digestive Tract

Field F. Willingham, MD, MPH, FASGE Director of Endoscopy Associate Professor of Medicine Emory University School of Medicine Atlanta, Georgia 48: Preparation for Pancreaticobiliary Endoscopy

Patrick S. Yachimski, MD, MPH, FASGE Associate Professor of Medicine Vanderbilt University School of Medicine Nashville, Tennessee 26: Screening for Esophageal Squamous Cell Carcinoma

Ricardo Zorron, MD, PhD Professor of Surgery, University UNIRIO, UENF; Director, Center for Innovative Surgery-ZIC, Center for Bariatric and Metabolic Surgery; Department of Surgery, Campus Charité Mitte/Campus Virchow-Klinikum Charité-Universitätsmedizin Berlin Berlin, Germany 45: Intramural and Transmural Endoscopy

P R E FAC E Welcome to the third edition of Clinical Gastrointestinal Endoscopy. Gastrointestinal endoscopy is a continuously evolving field with the advent of new technologies, refined techniques, and new applications. The prior editions of this book have been universally regarded as a comprehensive guide to the latest endoscopic techniques. Understanding and adoption of such practices leads to optimal outcomes with endoscopy. This text is unique because of the breadth of topics covered by experts in every discipline of gastrointestinal endoscopy from across the globe. Clinical Gastrointestinal Endoscopy has been an essential resource for anyone interested in learning about endoscopic procedures, as one can access a variety of topics in succinct, easily understood chapters from content specialists. This edition marks the transition to a new editorial team and builds on the success of the two prior editions. The previous editions achieved great accolade due to the efforts of the editorial board lead by Gregory Ginsberg and coedited by Michael Kochman, Ian Norton, and Christopher Gostout. The new editorial team was selected due to their expertise in gastrointestinal endoscopy, enthusiasm for disseminating best practices to a worldwide audience, and diverse background of training and experience from different premiere institutions. Commensurate with the change in the editors, we were excited to invite a new set of content experts who share their insights into recent advances in endoscopy and the impact these innovations have had on improving patient care. This has led to an exciting, comprehensive textbook from today’s most prestigious specialists. Clinical Gastrointestinal Endoscopy, third edition, is divided into three main sections covering Equipment and General Principles of Endoscopy, Luminal Gastrointestinal Disorders,

and Pancreaticobiliary Disorders. Section I elegantly describes the history of gastrointestinal endoscopy and then provides primers on how endoscopes, endoscopic devices, and endoscopy units function. There are many applicable practice-changing pearls of wisdom in this section. Section II: Luminal Gastrointestinal Disorders covers both benign and malignant disorders as well as emerging endoscopic areas. Section III: Pancreaticobiliary Disorders details standard and advanced techniques in ERCP and EUS for the diagnosis and management of benign and malignant disorders of the pancreaticobiliary systems. Each chapter has been meticulously crafted to present relevant updates to the topic in a manner that is easy to read and readily retained. These chapters are filled with tips that will help deliver optimal care for your patients. In addition, the content has been enhanced with new images and illustrations to highlight recent major advances in endoscopic techniques and applications for the latest technologies. These images and pictures can be downloaded from the book’s website so that you can use them in your presentations. Furthermore, most topics have accompanying videos demonstrating the diagnostic and therapeutic endoscopic procedures. This media platform allows the reader to experience endoscopic procedures firsthand when accessing the content from their handheld device or computer. Each video clip has been meticulously edited to maximize the educational value. The authors and editors draw upon their collective experience to provide you with the most current, authoritative, and impactful content for the sole purpose of enhancing the education of gastrointestinal endoscopy for years to come. Vinay Chandrasekhara, MD

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D E D I C AT I O N To my parents Bina and Kota and my sister Sheila, who provided a nurturing environment and encouraged me to dream big. The values that you instilled from an early age will forever remain with me. To my wife Meghana and our children Siddhant and Adya, who have allowed me to pursue my dreams even if it meant being away from home. Every professional accomplishment is only possible because of your love and support. To my colleagues, friends, trainees, and professional acquaintances: I appreciate everything you have taught me over the years. I am especially ever grateful to Drs. Gregory Ginsberg and Michael Kochman for providing me with unbelievable opportunities, including serving as an editor for this textbook. —Vinay Chandrasekhara To my parents, Carol and Hadi, for showing me the right path and to my wife, Alli, for taking it with me. To our patients, without whom there would be no progress. —B. Joseph Elmunzer

This book is dedicated to my family, trainees, nurses, colleagues and mentors. It took a tremendous effort and commitment to put this comprehensive endoscopy book together. I am grateful to both my personal family and my work family who allowed me to have the focus, dedication, and time to be a coeditor of this book. —Mouen A. Khashab I dedicate this book to my teachers, colleagues, and trainees who continue to challenge me to question what is felt to already be known. To my patients for their inspiration in motivating me to continually improve on the care we deliver. To my entire family, I thank you for your constant love and support. Specifically, to my mother, who has always encouraged me to follow my own path, and to my father, who left a medical school faculty position in India 45 years ago to start over as a resident in the USA with nothing other than $20 in his pocket and the American Dream, for the many opportunities I have had in my life and to whom I owe everything. Finally, to my wife Nanda and daughter Sonali for your substantial patience, compassion, warmth, and most importantly for bringing so much joy and laughter into my life. —V. Raman Muthusamy

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VIDEO CONTENTS SECTION I Equipment and General Principles of Endoscopy 3 How Endoscopes Work Video 3.1

Distinguishing Colonic Pathology

11 Small-Caliber Endoscopy Video 11.1 Transnasal Endoscopy

SECTION II Luminal Gastrointestinal Disorders 14 Nonvariceal Upper Gastrointestinal Bleeding Video 14.1 Endoscopic Clipping of Actively Bleeding Peptic Ulcer

15 Portal Hypertensive Bleeding Video 15.1 Endoscopic Band Ligation

16 Lower Gastrointestinal Bleeding Video 16.1 Contact Thermal Therapy for a Colonic Arteriovenous Malformation Video 16.2 Combination Therapy for Delayed Postpolypectomy Bleeding I Video 16.3 Combination Therapy for Delayed Postpolypectomy Bleeding II

17 Middle Gastrointestinal Bleeding Video 17.1 Video 17.2 Video 17.3 Video 17.4 Video 17.5 Video 17.6 Video 17.7 Video 17.8 Video 17.9 Video 17.10 Video 17.11 Video 17.12 Video 17.13 Video 17.14 Video 17.15 Video 17.16 Video 17.17

VCE With Fresh Blood VCE With Suspected Celiac Disease VCE With Angioectasia VCE With Suspected Crohn’s Disease (1) VCE With Suspected Crohn’s Disease (2) VCE With Ulcerated Small Bowel Mass Lesion VCE With GIST VCE With Large Submucosal Mass Lesion VCE With NSAID Enteropathy (1) VCE With NSAID Enteropathy (2) Double-Balloon Enteroscopy With Ulcerated Jejunal GIST Double-Balloon Enteroscopy With Ileal Hemangioma Double-Balloon Enteroscopy With Small Bowel Angioectasia Double-Balloon Enteroscopy With Metastatic Melanoma Double-Balloon Enteroscopy With Polypectomy in Peutz-Jehger’s Disease Double-Balloon Enteroscopy With Balloon Dilatation of Crohn’s Stricture Spiral Enteroscopy

19 Esophageal Motility Disorders Video 19.1 Video 19.2 Video 19.3 Video 19.4

Peroral Endoscopic Myotomy in Achalasia (1) Peroral Endoscopic Myotomy in Achalasia (2) Peroral Endoscopic Myotomy in Achalasia (3) Peroral Endoscopic Myotomy in Achalasia (4)

20 Endoscopic Diagnosis and Management of Zenker’s Diverticula Video 20.1 Endoscopic Management of Zenker’s Diverticulum

23 Eosinophilic Esophagitis Video 23.1 Felinization Video 23.2 Fixed Rings and Stenoses Characteristic of EoE Video 23.3 Salient Endoscopic Features of EoE

24 Gastroesophageal Reflux Disease Video 24.1 Endoscopic Evaluation of a Surgical Nissen Fundoplication

25 Barrett’s Esophagus: Diagnosis, Surveillance, and Medical Management Video 25.1 Barrett’s Esophagus Inspection Technique

26 Screening for Esophageal Squamous Cell Carcinoma Video 26.1 Esophageal Squamous Cell Carcinoma With Verrucous Features Video 26.2 Long Segment Esophageal Squamous Cell Carcinoma In Situ

27 Endoscopic Treatment of Early Esophageal Neoplasia Video 27.1 Cap-Assisted Endoscopic Mucosal Resection Video 27.2 Band Endoscopic Mucosal Resection

29 Endoscopic Approaches for Gastroparesis Video 29.1 Gastric Peroral Endoscopic Pyloromyotomy

31 Subepithelial Tumors of the Esophagus and Stomach Video 31.1 Endoscopic Ultrasonography of Subepithelial Lesion: Gastrointestinal Stromal Tumor Video 31.2 Endoscopic Ultrasonography of Submucosal Lesion: Lipoma Video 31.3 Endoscopic Ultrasonography of Extramural Lesion: Hepatic Hemangioma

32 Diagnosis and Treatment of Superficial Gastric Neoplasms Video 32.1 Systematic Examination of Endoscopic Images Video 32.2 Endoscopic Submucosal Dissection Using IT Knife for Early Gastric Cancer—Greater Curvature of Lower Gastric Body Video 32.3 Endoscopic Submucossal Dissection Using IT Knife for Early Gastric Cancer—Lesser Curvature of the Lower Gastric Body

33 Palliation of Gastric Outlet Obstruction Video 33.1 Self-Expandable Metal Stent Placement for Malignant Gastric Outlet Obstruction

34 Duodenal and Papillary Adenomas Video 34.1 Endoscopic Mucosal Resection of a Duodenal Adenoma Video 34.2 En-Bloc Papillectomy Video 34.3 Endoscopic Resection of a Lateral Spreading Lesion of the Papilla

37 Colonoscopic Polypectomy, Mucosal Resection, and Submucosal Dissection Video 37.1 Cold Snare Polypectomy Video 37.2 Hot Snare Polypectomy Video 37.3 Endoscopic Mucosal Resection of a Laterally Spreading Tumore-Granular Type Lesion in the Ascending Colon

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VIDEO CONTENTS

38 Endoscopic Diagnosis and Staging of Inflammatory Bowel Disease Video 38.1 Ulcerative Colitis With Pseudopolyp Formation Video 38.2 Crohn’s Colitis With Aphthous Ulcerations, Mild Hyperemia Video 38.3 Ulcerative Colitis With Severe Left-Sided Colitis

39 Dysplasia Surveillance in Inflammatory Bowel Disease Video 39.1 Flat Dysplasia Seen at Chromoendoscopy Video 39.2 Dysplastic Polyp With HGD in the Rectum

40 Colonic Strictures Video 40.1 Endoscopic Balloon Dilation of a Benign Colonic Stricture Video 40.2 Fully-Covered Metal Stenting of a Refractory Benign Colonic Stricture Video 40.3 Through-the-Scope Placement of a Fully-Covered Metal Stent for a Benign Colonic Stricture as an Alternative to Surgery Video 40.4 Palliative Metal Stenting of a Patient With Obstruction From Incurable Sigmoid Colon Cancer

43 Endoscopic Techniques for Weight Loss Video 43.1 Spatz Balloon Insertion Video 43.2 Endomina Device Platform Explanation (Ex-Vivo) Video 43.3 Endomina Device Use in Human Stomach

45 Intramural and Transmural Endoscopy Video 45.1 Natural Orifice Transluminal Endoscopic Surgery Transvaginal Cholecystectomy Video 45.2 Intragastric Single-Port Surgery Resection of a Dieulafoy Lesion

47 Extraintestinal Endosonography Video 47.1 EUS Staging for Lung Cancer

51 Endoscopic Ultrasound and Fine-Needle Aspiration for Pancreatic and Biliary Disorders Video 51.1 Radial Echoendoscope Examination Video 51.2 Linear Echoendoscope Examination

52 Endoscopic Ultrasound–Guided Access and Drainage of the Pancreaticobiliary Ductal Systems Video 52.1 EUS-Guided Choledochoduodenostomy Using a Tubular Metal Stent Video 52.2 EUS-Guided Hepaticogastrostomy Using a PartiallyCovered Metal Stent

53 Gallstone Disease: Choledocholithiasis, Cholecystitis, and Gallstone Pancreatitis Video 53.1 Gallbladder Drainage, Lumen-Apposing Metallic Stent Video 53.2 Gallbladder Drainage, Electrocautery-Enhanced Lumen-Apposing Metallic Stent Video 53.3 Endoscopic Retrograde Cholangiography With Large Balloon Sphincteroplasty

54 Postoperative Biliary Strictures and Leaks Video 54.1 Benign Biliary Strictures and Complex Leaks Video 54.2 Cystic Duct Stump Leak and Treatment

56 Sphincter of Oddi Disorders Video 56.1 Sphincter of Oddi Manometry

57 Recurrent Acute Pancreatitis Video 57.1 Endoscopic Techniques for Pancreas Divisum Therapy Video 57.2 Endoscopic Ultrasound for Diagnosis of Pancreas Divisum Video 57.3 Endoscopic Ultrasound Findings in Autoimmune Pancreatitis

58 Pancreatic Fluid Collections and Leaks Video 58.1 AXIOS Cystgastrostomy + Direct Endoscopic Necrosectomy

59 Chronic Pancreatitis Video 59.1 Pancreatic Duct Stone Extraction

SECTION III Pancreaticobiliary Disorders 49 Choloangiography and Pancreatography Video 49.1 Snare-Over-The-Wire Biliary Stent Exchange Video 49.2 Occlusion Cholangiogram

50 Difficult Cannulation and Sphincterotomy Video 50.1 Reshaping of an Endoscopic Retrograde Cholangiopancreatography (ERCP) Guidewire Tip Video 50.2 Steering of an Angled Guidewire Tip Using a Torque Aid Video 50.3 “Clip and Line” Technique

60 The Indeterminate Biliary Stricture Video 60.1 SMASH Protocol Video 60.2 SpyDS-Intraductal Lesion and Mapping

62 Evaluation and Staging of Pancreaticobiliary Malignancy Video 62.1 Metastasis to the Pancreatic Tail From Renal Cell Carcinoma Video 62.2 EUS Exam of a Cholangiocarcinoma

63 Palliation of Malignant Pancreaticobiliary Obstruction Video 63.1 Palliation of Malignant Biliary Obstruction with Self-Expanding Metallic Stent

1 The History of Gastrointestinal Endoscopy James L. Achord and V. Raman Muthusamy

CHAPTER OUTLINE Introduction, 2 Sequential History of Endoscopy, 2 Rigid Gastrointestinal Endoscopes, 2 Semiflexible Gastroscopes, 4 Biopsy, 5 Fiberoptics, 6 Endoscopic Retrograde Cholangiopancreatography (ERCP), 7

Photography, 8 Sigmoidoscopy and Colonoscopy, 8 Digital Endoscopy (Videoendoscopy), 8 Endoscopic Ultrasonography (EUS), 9 Capsule Endoscopy (Wireless Endoscopy), 10 Enteroscopy, 10

INTRODUCTION The role of the physician is to observe, detect anatomic abnormalities or disease, and conceive ways and means by which discovered deficiencies in function can be corrected or ameliorated. To extend the physical examination to areas hidden from external view, such as within body orifices, presents a problem of safe and effective access. In insatiable attempts to accomplish these goals, there is no human orifice along with its recesses that has not been inspected, probed, prodded, and otherwise examined over the centuries. It was a compelling necessity to develop safe, nonsurgical methods to accomplish this purpose. Before the 20th century, numerous attempts to access these hidden cavities were plagued by instrumentation that was inadequate and dangerous. The history of every science or technical development is invariably a series of small discoveries or innovations, often in fields remote from those under investigation. Small improvements, each resulting in incremental gains, lead toward the idealized goal. Often, changes that appear to be an advance are found to be an impediment by further discoveries, and we recognize that a different way is better. Therefore, the task is never ending. The term endoscopy comes from the Greek prefix endo(“within”) and the verb skopein (“to view or observe”). In this chapter, we summarize major developments over the years in gastrointestinal (GI) endoscopy to the present. As in any summary, the contributions of some individuals inevitably are not cited, and we offer our apologies to these individuals.

SEQUENTIAL HISTORY OF ENDOSCOPY The visual exploration and examination of body orifices date to at least Egyptian and later Greco-Roman times, during which

2

Natural Orifice Transluminal Endoscopic Surgery (NOTES) and Peroral Endoscopy Myotomy (POEM), 10 Summary, 11

mechanical specula for viewing the vagina and anus were developed and used to a limited extent. Further progress was delayed by lack of sufficiently strong metals and the ability to form them into usable instruments, as well as the lack of adequate illumination. These initial efforts were directed at the genitourinary (GU) tract, with cavities that were only a short and relatively straight distance from the exterior. Bozini (1805) is credited with the earliest known attempt to visualize the interior of a body cavity with a primitive endoscope (Fig. 1.1).1–3 Bozini devised a tin tube illuminated by a candle from which light was reflected by a mirror; this was a device he called a lichtleiter (light conductor). He used this device to examine the urethra, urinary bladder, and vagina, but it was an impractical instrument that never gained wide acceptance. Although there were multiple attempts to develop more usable instruments, all directed toward the GU tract, none were widely used. The most notable efforts were by Segalas in France in 1826 and Fisher in Boston in 1827,2 both using straight metal tubes, but the lack of a satisfactory light source remained a major impediment. The next significant development was the instrument of Desormeaux in France.2 Desormeaux’s contribution in 1855 was a better, although still inadequate, light source using a lamp fueled with alcohol and turpentine (“gazogene”) (Fig. 1.2). His instrument was based on that of Segalas. Others continued with efforts to improve the light source and the means to deliver it, but the devices were unsatisfactory for the more inaccessible areas of the GI tract.

Rigid Gastrointestinal Endoscopes Kussmaul is credited as being the first to perform a gastroscopy in 1868, using a straight rigid metal tube passed over a flexible obturator and a cooperative sword swallower (Fig. 1.3).1–4 For a light source, he used a mirror reflecting light from the

CHAPTER 1 The History of Gastrointestinal Endoscopy

2.e1

Abstract

Keywords

The development of endoscopy is a testimony to human ingenuity. Instruments have evolved from dangerous straight tubes, illuminated by light reflected from candles, to more flexible and safer instruments with an image transmitted through a series of prism lenses and illumination by an electric light bulb, to images transmitted through fiberoptic bundles with illumination transmitted by fiber bundles from an external source, to our present remarkably safe electronic instruments with digital images transmitted to a video screen through wires and processed by computers. Most recently, we can visualize the lumen of the gut without touching the patient. Now we not only can visualize, biopsy tissue, and perform procedures within the hidden cavities of the body, but also directly and indirectly see beneath the mucosa and into immediately adjacent organs. The evolution of gastrointestinal endoscopy is a truly remarkable story, and advances in the diagnostic and therapeutic capabilities of these instruments continue to be made at a rapid pace. To know and understand what has occurred previously lends strength to efforts toward achieving what is to come.

gastrointestinal endoscopes fiberoptics videoendoscopy capsule endoscopy gastroscopy sigmoidoscopy colonoscopy endoscopic retrograde cholangiopancreatography (ERCP) endoscopic ultrasonography (EUS) enteroscopy

CHAPTER 1 The History of Gastrointestinal Endoscopy

3

FIG 1.3 Kussmaul’s gastroscope, 1868. (From Edmonson JM: History of the instruments for gastrointestinal endoscopy. Gastrointest Endosc 37[Suppl 2]:S27–S56, 1991.)

FIG 1.1 Bozzini’s lichtleiter, 1805. (From Edmonson JM: History of the instruments for gastrointestinal endoscopy. Gastrointest Endosc 37[Suppl 2]:S27–S56, 1991.)

FIG 1.2 Desormeaux’s endoscope, 1853. (From Edmonson JM: History of the instruments for gastrointestinal endoscopy. Gastrointest Endosc 37[Suppl 2]:S27–S56, 1991.)

Desormeaux device but found it inadequate. He also quickly discovered that gastric secretions were a problem, despite using a flexible tube he had developed earlier to empty the stomach before the procedure. The value of his efforts was the demonstration that the curves and bends of the esophagus and esophago-

gastric junction could be traversed with careful manipulation and that the gastric pouch could be visualized. Kussmaul apparently demonstrated his “gastroscope” several times, but the illumination was too poor to allow a clinically useful image,4 and he abandoned his efforts. Encouraged by the efforts of Kussmaul, others switched their attention to developing esophagoscopes because the esophagus is much easier to visualize, and a less complex design than the gastroscope was required. The problems of perforation, at that time usually fatal, and of illumination, remained major obstacles. Before the late 19th century, illumination of light reflected by a mirror into a straight metal tube continued to be used. As noted earlier, several light sources were developed, but the intensity left much to be desired. Several innovations were developed to solve this problem, including a burning magnesium wire, which produced a brilliant light but unacceptable heat and smoke. The most promising device seemed to be the brilliant light from a loop of platinum wire charged with direct current, introduced simultaneously by Bruck in Breslau and Milliot of Paris in 1882.2 Although the illumination was adequate, major difficulties were encountered with the considerable heat generated, necessitating a water cooling system and the cumbersome batteries used for a power source. Nevertheless, the platinum wire device was an encouraging development and was used in several instruments that saw relatively widespread use. These instruments were made obsolete just a few years later by Edison’s incandescent electric light bulb, introduced in 1879. In 1886, Leiter, an instrument maker, was the first to use the electric incandescent light bulb in a cystoscope just 7 years after Edison introduced it. With a few short-lived exceptions, all instruments used Edison’s invention after 1886. Working with Leiter, von Mikulicz developed an unsuccessful gastroscope but a practical esophagoscope that he used extensively until distracted by his many other medical interests. At the turn of the 20th century, Jackson, an otolaryngologist, also examined the esophagus and the stomach using a straight rigid tube and a distal electric light bulb, but few could match

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SECTION I

Equipment and General Principles of Endoscopy

his talents in the GI tract. Under his influence, esophagoscopy was considered the exclusive province of ear, nose, and throat (ENT) departments in many community hospitals in the United States as late as the 1950s. The design of the esophagoscope remained a straight rigid tube, usually with a rubber finger-tipped obturator to make insertion safer. With the later addition of a 4 × power lens on the proximal end and a distal incandescent bulb, various models were popular until the introduction of fiberoptics in 1961. The Eder-Hufford rigid esophagoscope (Fig. 1.4), introduced in 1949, was popular and still in use in the early 1960s. It was not until after 1900 that persistent efforts to develop a usable gastroscope were successful. All attempts to build a flexible instrument using a multiplicity of lenses were designed to be straightened after introduction and were fragile, easily damaged, and cumbersome. Straight tubes with simpler optics were useful, but perforations were still a problem.1 In 1911, Elsner introduced a rigid gastroscope with an outer tube through which a separate inner optical tube with a flexible rubber tip and sideviewing portal could be passed (Fig. 1.5). The rubber tip, previously used in the esophagoscope obturator, was more crucial than it might appear, for it seemed to be, along with the later

FIG 1.4 Eder-Hufford esophagoscope, the result of multiple attempts to develop a clinically useful instrument, 1949.

FIG 1.5 Elsner’s gastroscope, 1911. (From Edmonson JM: History of the instruments for gastrointestinal endoscopy. Gastrointest Endosc 37[Suppl 2]:S27–S56, 1991.)

addition of a flexible metal coil proximal to it, the single feature that reduced the rate of perforation. Elsner’s instrument worked as designed and was widely used, especially by Schindler, then in his native Germany, who called it the “mother of all instruments until 1932.”5 In 1922, Schindler introduced his own version of the Elsner gastroscope, the major innovation of which was the important addition of an air channel to clear the lens of secretions. With the Elsner gastroscope, Schindler examined the stomachs of several hundred patients and meticulously recorded his findings in each procedure. He published Lehrbuch und Atlas der Gastreoskopie in 1923, with descriptions and remarkably accurate drawings. He trained others in the technique and was responsible for wide acceptance of gastroscopy. The procedure began with emptying the stomach using a nasogastric tube, followed by sedation. The patient was placed on the left side, and an assistant held the head rigidly extended to produce a straight path into the esophagus and the stomach (the “sword swallower’s technique”). The role of the assistant was crucial. Schindler’s effort was impressive and convinced many of the value of an expert examination of the stomach.

Semiflexible Gastroscopes It became apparent that straight, rigid tubes were not ideal for examination of the stomach. Fatal perforations continued to the detriment of acceptance of the procedure. Visualization of the surface of the stomach was incomplete at best, with many consistent blind spots. These problems stimulated investigation of methods to manufacture safer, “flexible” instruments. The use of the term flexible here is problematic in view of what we think of today as flexible instruments. Although these early instruments were not flexible by our standards, they were more flexible than the straight, rigid instruments that came before. Semiflexible, with passive angulation of the distal portion of 34 degrees and sometimes more, was a more appropriate term. In 1911, Hoffman showed that an image could be transmitted through a curved line by linking several short-focus prisms. Using this principle, several instruments were constructed, but these were unsatisfactory or were not widely accepted. Schindler, working with Wolf, the renowned instrument maker, constructed a semiflexible instrument with a rigid proximal portion and a distal portion made elastic by coiled copper wire and terminating with first a rubber finger and later a small rubber ball. Illumination was with a distal incandescent light bulb. Air insufflation was made possible with a rubber bulb, expanding the stomach wall to beyond the focal length of the prisms, which were manufactured by Zeiss. In 1932, the sixth and final version was patented. This instrument, known as the Wolf-Schindler gastroscope, greatly improved the safety and efficacy of gastroscopy and was used throughout the world (Fig. 1.6). Thanks to the published meticulous work and enthusiasm of Schindler, whose designation as the “father of gastroscopy” is well deserved, the procedure was finally widely accepted as a valuable extension of the physical examination. The era of the semiflexible gastroscope from 1932 to 1957 has been called the Schindler era. Schindler was chiefly responsible for transforming gastroscopy from a dangerous and seldom used procedure to one that was relatively safe and indispensable for evaluation of known or suspected disease of the stomach. He insisted that all clinicians who planned to use the instrument be properly trained and that “… no manipulation inside of the body is without danger; therefore no endoscopic examination should be done

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CHAPTER 1 The History of Gastrointestinal Endoscopy

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FIG 1.7 Benedict operating gastroscope.

FIG 1.6 Wolf-Schindler “flexible” gastroscope (top) being used by Schindler (bottom) with his wife as the head holder. (From Edmonson JM: History of the instruments for gastrointestinal endoscopy. Gastrointest Endosc 37[Suppl 2]:S27–S56, 1991.)

without reasonable indication.”6 In today’s vernacular, the risk approaches infinity if the benefit approaches zero. Schindler was born in Berlin in 1888. He gained considerable experience as an Army physician in World War I, where he became convinced that gastritis, then an often-disparaged cause of symptoms, was a bona fide disease. His interest in gastritis lasted throughout his career and undoubtedly stimulated his interest in gastroscopy. The Wolf-Schindler endoscope of 1932 and Schindler’s publications with drawings further enhanced what thereafter rapidly became a discipline. His enthusiasm for and talent in using the gastroscope led to what has been called his gospel of gastroscopy, which he and others spread throughout academia and to the community of practicing physicians. Because of his Jewish background, Schindler was put in “protective custody” by the Nazis, but with the help of the physicians Ortmeyer and Palmer and philanthropists in Chicago, he was able to immigrate to the United States in 1934.1–4,7 Chicago became the hub of GI endoscopy, and it was here, in Schindler’s home, that the first discussions were held about forming a new organization for GI endoscopy, now known, after several name changes, as the American Society of Gastrointestinal Endoscopy. In 1943, just 9 years after his arrival in the United States, Schindler left Chicago for Loma Linda University. In 1958, he accepted an appointment as Professor of Medicine at the

University of Minas Gerais in Belo Horizone, Brazil. He came back to the United States in 1960 because of an eventually fatal illness of his wife and returned to his native Berlin in 1964, where he died in 1968 at the age of 80.1 Despite his acclaim in endoscopy, Schindler insisted that one must be a physician first and an endoscopist second. He was very knowledgeable in the field of general gastroenterology and published, without coauthors, a synopsis of the entire field in 1957.6 The Wolf-Schindler endoscope was introduced into the United States by Benedict, Borland, and many others. Schindler’s immigration to Chicago inspired a surge of interest in the United States, but with the outbreak of war in Europe, the German source of instruments disappeared. Several US companies working with Schindler and others produced many popular gastroscopes that were significant variations on the Wolf-Schindler model, including Cameron Co., which produced its first instrument in 1940.8 The Eder-Hufford semiflexible gastroscope followed in 1946,9 and American Cystoscope Makers, Inc. (ACMI) produced a gastroscope in 1950. A combination of the Eder-Hufford esophagoscope with a semiflexible gastroscope to be passed through it was the Eder-Palmer transesophagoscopic flexible gastroscope produced by the Eder Company in 1953. Each gastroscope had its proponents.

Biopsy With the availability of instruments for visualization, it became apparent that tissue must be obtained to identify the nature of the observed abnormalities. Instruments for blind biopsies were used early on, but a device was needed that would allow the operator to obtain a biopsy specimen of abnormal tissue directly when seen at endoscopy. The Benedict Operating Gastroscope was produced in 1948 based on a 1940 model by Kenamore (Fig. 1.7).10 The Benedict instrument was a popular instrument that was widely used. In the debates about the necessity for biopsy, Benedict, a surgeon who switched entirely to endoscopy, stated that gastroscopy was not a routine procedure and should be reserved for those with a complex differential diagnosis, but “gastroscopic examination is not complete unless the gastroscopist has some means of biopsy readily available.”11 It soon became clear that the correlation between histology and a diagnosis based on visualization alone was often widely discrepant, and certain diagnoses could not be reliably made without tissue examination.

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Efforts such as wash and brush cytology continued and have persisted in various forms to the present time.

Fiberoptics By the 1950s, the ideal of a totally flexible GI endoscope with good visualization that could withstand the rigors of clinical use had not been realized, although the semi-flexible instruments with their biopsy capabilities were satisfactory for most clinical purposes. In fact, these instruments were not rapidly abandoned by all with the introduction of the remarkably flexible fiberscope. The development of the science of fiberoptics and its application to endoscopes truly revolutionized the diagnostic and, later, the therapeutic abilities of endoscopy. Its importance in the development of this field cannot be overstated. The principle of internal reflection of light along a conduction pathway was used by Lamm in October 1930.1 The image was severely degraded by light escaping from the thin fibers of quartz he used, although the potential for total flexibility was present. Lamm could not interest Schindler or others in his efforts, and the experiment was discontinued. Almost 25 years later, in 1954, Hirschowitz, in fellowship training at the University of Michigan, visited Hopkins and Kapany in London to review their work12 with glass fibers, which totally confirmed the work of Lamm and his predecessors. Hirschowitz became convinced that application of this principle could be used to develop a totally new and superior endoscope. He began work with a graduate student, Curtiss, who developed a technique of coating glass fibers with glass of a different optical density, preventing the escape of light and degradation of the image. This was the critical discovery that made the principle of internal reflection through glass fibers workable. In 1957, Hirschowitz demonstrated his fiberscope, and he published his work in 1958 (Fig. 1.8).13 His audience was not impressed, and it took another 3 years, working with ACMI, to produce a marketable scope, which he called the Hirschowitz

FIG 1.8 Hirschowitz examining the stomach of an outpatient. (From Hirschowitz BI: Endoscopic examination of the stomach and duodenal cap with the fiberscope. Lancet 277[7186]:1074– 1078, 1961.)

Gastroduodenal Fiberscope. This was a very flexible side-viewing instrument with an electric light on its distal end, an air channel, and an adjustable focusing lens proximally. The tip lacked what was by then the “obligatory” rubber finger, and this omission was a source of criticism; one was added on a later model. Although some individuals criticized the quality of the image, most believed the size and brightness were superior to the semiflexible scopes. This model, the ACMI 4990, was introduced to the market late in 1960 after being tested by Hirschowitz on himself and numerous patients. In 1961, the senior author of this chapter was in a gastroenterology fellowship at the Emory University Clinic with Schroder. He vividly recalls Schroder’s reaction after the first use of the new fiberscope around March 1962 (Fig. 1.9). Upon finishing the initial examination using the new device, he turned to him and said, “Anybody want to buy a used Benedict operating scope?” The senior author does not recall it ever being used again, as the Hirschowitz Gastroduodenal Fiberscope was clearly superior in his view, and he finished his training with that instrument. There were problems with the fiberscope noted by users. The distal light source would become so heated that thermal injury to the gastric mucosa was possible unless the tip was continuously moved. In prolonged procedures, protein in gastric secretions would coagulate on the bulb and the adjacent visualizing port, totally obscuring the lens. As the number of procedures with a single instrument increased, some glass fibers would break, producing small black dots in the visual field. This was a persistent problem with fiberscopes during their entire history and especially apparent in training programs where a single scope was used by several trainees on many patients. The side-viewing lens prevented visualization of the esophagus, and the scope had to be passed blindly through the pharyngeal orifice. The previous semiflexible scopes in use shared this problem, and it was not considered a defect at the time. The flexibility itself resulted in some difficulty in advancing because attempts to push the instrument through the pylorus and into the gut resulted in more bowing in the gastric pouch (Fig. 1.10). Although one could sometimes visualize the duodenum, this was done by overinflating the stomach and looking through the pylorus without actually entering it. If one managed to introduce the tip into the duodenum, as occasionally happened, the visual field was inside the focal length of the instrument, and only a “red-out” was observed.4

FIG 1.9 ACMI fiberscope, 1962.

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CHAPTER 1 The History of Gastrointestinal Endoscopy

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FIG 1.11 LoPresti forward-viewing esophagogastroscope. (From advertisement in Gastrointest Endosc 16:79, 1970.)

FIG 1.10 Visualization of duodenum was sometimes obtained by overinflating the stomach.

Many clinicians did not believe the additional expense of replacing the older, beloved instruments with which they had been successful for many years was warranted. Even ACMI officials did not see the fiberscope as totally replacing the instruments with a lens system.2 Despite reservations, comparison and experiential studies showed the advantages of the new fiberscopes.14–17 Following the flagship ACMI model 4990, several models of the fiberscope were introduced by ACMI and other companies, each with significant improvements, including the controllable tip in the side-viewing ACMI model 5004. Visualization of the gastric pouch, including retroflexed views of the cardia, was now complete. The major objection to these instruments was the inability to pass the instrument under direct vision and examine the esophagus; in addition, the area beyond the pylorus could not be consistently examined. Most clinicians were already fully trained in use of the EderHufford esophagoscope, and in the absence of a forward-viewing fiberscope, use of the Eder-Hufford esophagoscope continued. A forward-viewing scope was mandatory. LoPresti modified the tip of the fiberscope to create the foroblique fiberoptic esophagoscope in 1964.18 Passing the instrument under direct vision was possible, and clinicians immediately discovered that they could examine not only the esophagus, but also a large portion of the proximal stomach. At a length of 90 cm, however, one could not reach the duodenum. Working with ACMI, LoPresti produced the longer Panview Mark “87” gastroesophageal endoscope in 1970. By about 1971, the instrument had been lengthened to 105 cm with a four-way controllable tip capable of 180 degrees of deflection (Fig. 1.11).

The aptly named panendoscope was now a reality. Japanese and American manufacturers began to produce new models with such rapidity that endoscopists hardly had time to become thoroughly familiar with one before another, significantly improved (and more expensive) model was on the market. Patient comfort was greatly improved, and the relative safety of the fiberoptic endoscopes rapidly became apparent. By 1970, most gastroscopic examinations were done with fiberscopes. The development of a “teaching head” fiberoptic bundle with a light splitter and attached eyepiece and attachment to the eyepiece of the scope allowed two people to visualize the image. Dividing the light from the endoscope considerably diminished the brightness of the image, however, to both the operator and the observer. This device saw limited use and was utilized primarily in teaching institutions.

Endoscopic Retrograde Cholangiopancreatography (ERCP) With access to the duodenum, the ampulla of Vater became visible. It followed that one should be able to inject contrast material into the bile and pancreatic ducts and increase diagnostic capabilities. Initial attempts in 1968 by McCune et al19 to modify an existing scope were only partially successful, but did show that endoscopic visualization by injection of radiologic contrast agents into ducts was possible. In 1970, Machida and Olympus in Japan produced usable, side-viewing scopes with controllable tips and elevators to move the injection tube to the ampulla. Japanese endoscopists20 developed the technique of endoscopic retrograde cholangiopancreatography (ERCP) with an 80% success rate. Vennes and Silvis21 showed the utility of ERCP in the United States and taught many physicians to use it.4 It was immediately apparent that if clinicians could visualize the biliary and pancreatic ducts endoscopically (i.e., nonsurgically), they should be able to apply by some means long-established surgical techniques for treatment of choledocholithiasis and pancreatitis, such as sphincterotomy and stone removal. In 1974, just 4 years after the demonstration of the diagnostic utility of the new ERCP

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scopes, Kawai et al in Japan22 and Classen and Demling in Germany23 independently developed methods of endoscopic electrosurgical sphincterotomy for extraction of biliary calculi in the common duct. This procedure requires great skill; in 1976, Geenen24 reported that only 62 operative procedures had been done by four endoscopists, and seven of the procedures were failures. In 1983, Schuman4 reported that several thousands of patients had undergone ERCP, and by now, hundreds of thousands of ERCP procedures have been done. Because of advances in radiologic techniques, ERCP is now seldom used for purely diagnostic purposes.

Photography It is one thing to describe to others what one may see through any device and another to be able to show them. The large impact of Schindler’s early publications was related, in part, to the excellent color drawings he presented. Early on, neither cameras nor photographic films were advanced enough to allow good color reproduction or sharp, accurate images in relatively poor lighting. Such documentation is essential for widespread appreciation of endoscopy by individuals who do not perform the procedure. The first clinically useful photography came with improvements in film by Kodak and the construction of an external integrated camera by Segal and Watson in 1948.25,26 Although these authors reported that approximately 61% of the images were of good quality, this was not the experience of all clinicians.4 Although an intragastric camera was developed as early as 1848 by Lange and Meltzung, a clinically useful device was not available until 1950, when Uji, Sugiura, and Fukami, working with Olympus Corp. (Center Valley, PA),27 developed the Gastrocamera with synchronized flash, which took good intragastric pictures and had a controllable distal portion. By following a prescribed pattern of rotation and flexion, a series of pictures was obtained that included the entire surface of the stomach. The big disadvantage was that the operator could not see through the instrument and had to await development of the very narrow (5-mm) film before the results could be seen. Photographs for demonstration required additional time in the photo laboratory while enlargements were made. After the introduction of fiberoptic scopes in 1961, Olympus introduced a combination Gastrocamera fiberscope (GTF-A) in 1964, but, as Schuman4 commented, “it was just a gastroscope” and never attained popularity. Simultaneously, rapid development and physician acceptance of fiberscopes with the ability to use technically advanced 35-mm cameras with an external adapter made the Gastrocamera obsolete, and it was abandoned.

Sigmoidoscopy and Colonoscopy The problems presented by examination of the anus and rectum were relatively easy. Straight metal tubes were used and found in the ruins of Pompeii.2 The basic design of the anoscope has not changed in the past century or more except that it is now made of disposable plastic. It remains a tapering short tube with an obturator that is removed after introduction through the anal sphincter. Examination of the rectum and sigmoid required a longer tube, but no truly satisfactory device was available until 1894, when Kelly28 at Johns Hopkins developed a 30-cm rigid tube with light reflected down the tube from a head lamp. Tuttle29 incorporated a distal light source in his proctosigmoidoscope of 25 cm in 1903. These instruments have remained the basic design for the past 100 years. For the past 25 years or so, disposable

clear plastic tubes have been widely used. These are essentially a plastic version of the Kelly and Tuttle tubes with a distal electric light source, but visualization is possible through the clear plastic. With the application of fiberoptics to sigmoidoscopy in the late 1960s, examination of the sigmoid colon became not only satisfactory, but also much more comfortable for the patient. Overholt,30 who later went on to be the principal developer of colonoscopy using similar technology, presented his results of flexible sigmoidoscopy in 250 patients in 1968. Although early flexible sigmoidoscopes were made in variable lengths, the current length of 60 cm came to be the preferred one. Examination of the colon above the sigmoid presents obvious additional problems of multiple curves and angulations amenable only to highly flexible instruments and trained operators. Attempts, all unsuccessful, were made using semiflexible instruments, and these are reviewed by Edmonson.2 Satisfactory examination of the length of the colon was impossible until the introduction of the flexible fiberscope. Attempts to use forward-viewing gastroscopes were not technically satisfactory, although several clinicians tried. Turell31 presented his attempts in 1967 using a modified gastroscope, but he concluded that the instrument was not ready for routine clinical use. By 1970, several manufacturers produced instruments specifically designed for colonoscopy, including ACMI working with Overholt in the United States and Olympus Corporation in Japan. The primary problem with regularly completing examinations to the cecum was not the instruments so much as it was the techniques necessary for passage of the scopes into the more proximal portions of the colon. Earlier pioneers in developing successful techniques still in use include, among others, Overholt, Wolf, Shinya, and Waye in the United States; Niwa and colleagues in Japan; Salmon and Williams in England; and Dehyle in Germany.4 Many of these early efforts were accomplished with the guidance of fluoroscopy to negotiate the more difficult turns and to identify the actual area being observed, but, as experience was gained, fluoroscopy was no longer required. Learning under expert guidance and experience continues to be more necessary in colonoscopy (and ERCP) than in upper endoscopy. By 1971, the diagnostic advantage of fiberoptic colonoscopy over singlecontrast barium enema was firmly established,32 and the efficacy and safety of polypectomy were established by 1973.33

Digital Endoscopy (Videoendoscopy) In 1984, barely 20 years after introduction of the endoscopic fiberscope, Welch Allyn, Inc. (Skaneateles Falls, NY), replaced the coherent fiberoptic image bundle in a colonoscope with a light-sensitive computer chip or charge-coupled device on which the image was focused by a small lens (see Chapter 3).34 The digital signal was fed to a video processor, which generated an image to a television monitor. The image did not occupy the entire screen, leaving space for information to be typed in by a keyboard. The resolution of the image was at least equal to that of the fiberscope. It was unnecessary to change the basic mechanics of the fiberscope. The fiberoptic light bundle remained unchanged, as did water, suction, and biopsy channels; in addition, the deflection and locking mechanisms were the same. The basic elements of the videoendoscope have not changed, although a magnified image is now available. Since the original introduction of the videoendoscope by Welch Allyn, which no longer produces the Video Endoscope, the market has been supplied by Olympus, Pentax, and Fujinon. The technology was rapidly adapted to

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CHAPTER 1 The History of Gastrointestinal Endoscopy

A

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B

FIG 1.12 Fujinon fiberoptic panendoscope (top) and its successor, the Videopanendoscope (bottom), 1990, showing the two kinds of operating heads. (From advertisement in Gastrointest Endosc 36:240–241, 1990.)

all endoscopes, used not only in gastroenterology but also in other fields. Advantages of the electronic instruments include an image that can be seen not only by the operator, but also by anyone with access to a connected monitor in the same or another room. This feature greatly enhanced the ability to teach others about the procedure and to inform other interested physicians about the findings in the individual patient. If desired, recording of procedures could be accomplished with videotape machines, and good-quality pictures of individual frames could be made immediately with externally integrated digital equipment. Individual endoscopists found that no adjustment of techniques was necessary when videoendoscopes were used, although they had to become accustomed to looking at the monitor screen rather than through an optical system with one eye (Fig. 1.12). This feature added to the useful length of the instrument because the whole scope could be held at the waist rather than being brought to eye level. More recent innovations in colonoscopy instruments by Olympus include the ability to make a portion less flexible to facilitate navigation of difficult bends and turns. In addition, an enlarged image is now available that is an improvement in vision and ease of manipulation. A major disadvantage of videoendoscopes is cost. Fiberoptic endoscopes, when they were still in use, could be purchased for less than $6000 and did not require processors or monitors, whereas the latest videoendoscopes are priced at more than $20,000, and initial purchase of the entire package of endoscope, processing computer, monitors, and attachments may exceed $30,000. Initially, many questioned the wisdom of this added cost, which is passed on to the patient and their insurance companies.

Endoscopic Ultrasonography (EUS) Although the improvements in GI endoscopy are remarkable in the synthesis of diverse but complementary technologies, the information gained remains confined to what one can see from

C

D

FIG 1.13 A to D, Ultrasonic endoscope system, model IV, made by Olympus Corp., 1986. (From Yasuda K, Mukai H, Fujimoto S, et al: The diagnosis of pancreatic cancer by endoscopic ultrasonography. Gastrointest Endosc 34:1–8, 1988.)

within the lumen of the gut. Simultaneous with these developments were those of computed tomography and external ultrasonographic tomograms. Conceptually, it was not only logical but also compelling to look beneath the mucosa of the gut by incorporating miniaturized models of ultrasonographic transducers already in use into GI endoscopes. The ability to noninvasively explore tissue and organs in proximity to the gut had exciting implications for diagnosis and therapy. In Germany in 1976, working with Siemens Co., (Berlin, Germany) Lutz and Rosch35 reported the use of a 1-cm ultrasonographic 4-MHz probe that could be passed through the biopsy channel of an Olympus TGF. They used it in two patients to successfully differentiate between pancreatic pseudocysts and tumors.7 In 1980, Classen’s group in Germany36 and DiMagno et al37 at the Mayo Clinic reported EUS devices that were incorporated onto the tip of conventional fiberscopes, one using a 5-MHz transducer and the other using a 10-MHz transducer. These probes had good resolution at an acoustic focus depth of 3 cm. Others incorporated the transducer in the distal shaft of fiberoptic scopes and primarily explored the gut wall.33,38 By 1985, ultrasonic transducers with variable frequencies incorporated into videoendoscopes were readily available, although expensive (> $100,000 for initial setup) (Fig. 1.13). It was immediately apparent that this procedure could accurately evaluate known or suspected intramural lesions of the gut,39,40 and it was rapidly expanded to include the esophagus; problems

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of diagnosis and recurrence of neoplasia, especially in the pancreas; portal hypertension; the colon and rectum; and bile ducts.41 In 1991, Wiersema et al42,43 showed that EUS could be used to obtain fine-needle aspiration cytology of mediastinal nodes and of nodes and lesions of the upper and lower GI tract. The addition of Doppler technology has now made possible the study of the flow through various structures, including the thoracic duct and blood vessels. EUS is increasingly being used to provide therapy, leading to the development of “interventional EUS.” EUS-guided interventions include celiac plexus block/ neurolysis, placement of fiducial markers to facilitate radiotherapy, direct injection of alcohol or chemotherapeutic agents for the treatment of tumors or cystic lesions, drainage of the pancreatic or biliary ductal systems, and the creation of gastrojejunal anastomoses using lumen-apposing metal stents. The techniques of using EUS instruments differ only slightly from using videoendoscopes, but dedicated training is necessary to interpret the sonographic images obtained accurately. EUS is not amenable to self-instruction. EUS training centers have been established in academic centers, but retraining of practicing physicians is challenging due to the duration of training necessary to achieve competence.44

Capsule Endoscopy (Wireless Endoscopy) In 2000, Iddan et al45 reported the development of a capsule containing a tiny CMOS camera that could be swallowed, obtain images (at 2 frames per second), and transmit the images over 7 hours to a receiving digital storage unit worn by the patient as he or she goes about his or her normal activities. These frames are downloaded to a computer from which they are projected onto a monitor at a rate that can be controlled by the observer. Pictures can be printed of areas of interest. Gastroenterologists in Israel conducted randomized trials comparing the efficacy of the wireless capsule with push enteroscopy and obtained superior results with the capsule.46–48 Wireless capsule endoscopy caught the imagination of gastroenterologists over the world, and capsule endoscopy has been adopted as a part of standard practice for small bowel imaging. The findings are virtually unanimous in demonstrating better results in identifying lesions in the small bowel with capsule endoscopy when compared to push enteroscopy.49 The capsule avoids the discomfort and need for sedation inherent with push enteroscopy. In addition to lack of biopsy capability, an additional disadvantage is the time needed to review the study, but this has been overcome by a variety of methods including software advancements, improved training techniques, and utilizing non-physician personnel to initially review the obtained images. The major use of the capsule to date has been in elucidating the cause of occult bleeding from small bowel sources, where it seems to be superior to other methods. Future applications, such as in the colon, are continuing to be investigated in large, multicenter comparative studies. The future of wireless capsule endoscopy is bright. It will be interesting to see how the principle of wireless endoscopy is incorporated into videoendoscopes, such as the potential for a wireless connection between the endoscope and the image processor.

Enteroscopy The small intestine has traditionally been regarded as the final frontier of GI endoscopy. Although capsule endoscopy provides remarkable images of the small bowel mucosa, tissue acquisition

and therapy with a capsule-based instrument is many years away. Surgically assisted small bowel enteroscopy may be performed via either the transoral or anal route or via a mid–small bowel enterotomy incision. The disadvantage of this technique is its invasive nature.50 Endoscopic examination of the small intestine has remained technically difficult. The many loops of the small intestine prevent progression of the instrument tip by simple pushing. This problem was overcome initially with the use of the Sonde enteroscope,51 which is a very fine, floppy instrument with a balloon at the tip. The Sonde enteroscope progressed through much of the small bowel under peristalsis, and then the proceduralist would slowly withdraw the instrument, assessing the mucosa while pulling back. This technique was thought to visualize 50% to 70% of the mucosal surface.52 However, the procedure was uncomfortable, time-consuming, and did not permit therapeutics, all of which limited its use. The concept of small bowel enteroscopy was revolutionized by Yamamoto with the introduction of the double-balloon enteroscope in 2001.53 This technique uses traction between a balloon at the tip of the enteroscope and another balloon on a flexible overtube to fix the loops of small bowel and provide traction for forward movement. The procedure requires peroral and anal procedures to examine the entire small intestine, and even then only in a minority of Western patients is the whole small bowel visualized. Nonetheless, double-balloon–assisted enteroscopy permits endoscopic therapeutics to most of the small bowel without the need for surgical assistance. A single balloon version is also available.

Natural Orifice Transluminal Endoscopic Surgery (NOTES) and Peroral Endoscopy Myotomy (POEM) A new development in endoscopy is natural orifice transluminal endoscopic surgery (NOTES), in which the endoscope is inserted into the abdominal cavity via an incision in an accessible organ. The first report appeared in 2002. Incisions have been made in the stomach, vagina, and colon with successful tubal ligation, liver biopsies, biopsy of peritoneal metastases, oophorectomy, cholecystectomy, and nephrectomy procedures having been performed. Most published articles report experimental use in animals, but more recent reports have described the simultaneous use of NOTES with laparoscopic techniques. Comparative studies are ongoing. A difficulty with the technique has been overcoming the lack of instrument “triangulation”; that is, approaching a surgical site from two or more directions to create countertraction, tie sutures, and so forth. Although NOTES is an exciting development, its remarkable potential will have to await the development of new instruments and the acquisition of additional expertise. At a minimum, it appears the development of NOTES will result in marked improvements in mucosal and transmural closure devices. Recently, flexible endoscopes have also been used to tunnel into the submucosal space of the esophagus and perform a myotomy, resulting in a treatment for achalasia termed peroral endoscopy myotomy, or POEM. First performed by Inoue in 2008 and reported by Inoue in 2010, this procedure has gained widespread popularity worldwide and has been performed thousands of times to date with impressive short- and long-term results and an excellent safety profile.54,55 Additional applications of “submucosal” endoscopy include performing a similar procedure in the antrum to treat gastroparesis (G-POEM) and to perform resection of intramural lesions of the GI tract.56,57

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CHAPTER 1 The History of Gastrointestinal Endoscopy

SUMMARY The development of endoscopy is a testimony to human ingenuity. Instruments have evolved from dangerous straight tubes illuminated by light reflected from candles, to more flexible and safer instruments with an image transmitted through a series of prism lenses and illumination by an electric light bulb, to images transmitted through fiberoptic bundles with illumination transmitted by fiber bundles from an external source, to our present remarkably safe electronic instruments with digital images transmitted to a video screen through wires and processed by computers. Most recently, we can visualize the lumen of the gut without touching the patient. Now we can not only visualize, biopsy tissue, and perform surgical procedures within the hidden cavities of the body, but also directly and indirectly see beneath the mucosa and into immediately adjacent organs. The evolution of gastrointestinal endoscopy is a truly remarkable story, and advances in the diagnostic and therapeutic capabilities of these instruments continue to be made at a rapid pace. To know and understand what has occurred previously lends strength to efforts toward achieving what is to come.

KEY REFERENCES 1. Modlin IM: A brief history of endoscopy, Milano, 2000, MultiMed. 2. Edmonson JM: History of the instruments for gastrointestinal endoscopy. Gastrointest Endosc 37:S27–S56, 1991. 6. Schindler R: Synopsis of gastroenterology, Philadelphia, 1957, Grune & Stratton. 7. Kirsner JB: American gastroscopy—yesterday and today. Gastrointest Endosc 37:643–648, 1991. 11. Benedict EB: Gastroscopic biopsy. Gastroenterology 37:447–448, 1959. 12. Hopkins HH, Kapany NS: A flexible fiberscope using static scanning. Nature 173:39–41, 1954. 13. Hirschowitz BI, Curtiss LE, Pollard HM: Demonstration of the new gastroscope, the “fiberscope.” Gastroenterology 35:50–53, 1958. 15. Burnett W: An evaluation of the gastroduodenal fibrescope. Gut 3:361–365, 1962. 20. Takagi K, Ikeda S, Nakagawa Y, et al: Retrograde pancreatography and cholangiography by fiber duodenoscope. Gastroenterology 59:445–452, 1970.

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21. Vennes JA, Silvis SE: Endoscopic visualization of bile and pancreatic ducts. Gastrointest Endosc 18:149–152, 1972. 22. Kawai K, Akasaka Y, Murakami K, et al: Endoscopic sphincterotomy of the ampulla of Vater. Gastrointest Endosc 20:148–151, 1974. 25. Segal HL, Watson JS: Color photography through the flexible gastroscope. Gastroenterology 10:575–585, 1948. 32. Wolff WI, Shinya H: Colonofiberoscopy. JAMA 217:1509–1512, 1971. 33. Wolff WI, Shinya H: Polypectomy via the fiberoptic colonoscope: Removal of neoplasms beyond the reach of the sigmoidoscope. N Engl J Med 288:329–332, 1973. 35. Lutz H, Rosch W: Transgastroscopic ultrasonography. Endoscopy 8:203–205, 1976. 37. DiMagno EP, Buxton JL, Regan PT, et al: Ultrasonic endoscope. Lancet 1:629–631, 1980. 42. Wiersema MJ, Hawes RH, Wiersema LM, et al: Endoscopic ultrasonography as an adjunct to fine needle aspiration cytology of the upper and lower gastrointestinal tract. Gastrointest Endosc 38:35–39, 1992. 43. Rex RK, Tarver RD, Wiersema M, et al: Endoscopic transesophageal fine needle aspiration of mediastinal masses. Gastrointest Endosc 37:465–468, 1991. 45. Iddan G, Meron G, Glukhovsky A, et al: Wireless capsule endoscopy. Nature 405:417, 2000. 47. Appleyard M, Glukhovsky A, Swain P, et al: Wireless-capsule diagnostic endoscopy for recurrent small-bowel bleeding. N Engl J Med 344: 232–233, 2001. 53. Yamamoto H, Sekine Y, Saito Y: Total enteroscopy with a non-surgical, steerable double-balloon method. Gastrointest Endosc 53:216–220, 2001. 54. Inoue H, Minami H, Kobayashi Y, et al: Peroral endoscopic myotomy (POEM) for esophageal achalasia. Endoscopy 42:265–271, 2010. 55. ASGE Technology Committee, Pannala R, Abu Dayyeh BK, et al: Per-oral endoscopic myotomy (with video). Gastrointest Endosc 83(6):1051–1060, 2016. 56. Khashab MA, Stein E, Clarke JO, et al: Gastric peroral endoscopic myotomy for refractory gastroparesis: first human endoscopic pyloromyotomy (with video). Gastrointest Endosc 78(5):764–768, 2013. 57. Xu MD, Cai MY, Zhou PH, et al: Submucosal tunneling endoscopic resection: a new technique for treating upper GI submucosal tumors originating from the muscularis propria layer (with videos). Gastrointest Endosc 75(1):195–199, 2012.

A complete reference list can be found online at ExpertConsult .com

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CHAPTER 1 The History of Gastrointestinal Endoscopy

REFERENCES 1. Modlin IM: A brief history of endoscopy, Milano, 2000, MultiMed. 2. Edmonson JM: History of the instruments for gastrointestinal endoscopy. Gastrointest Endosc 37:S27–S56, 1991. 3. Haubrich WS: Gastrointestinal endoscopy. In Kirsner JB, editor: The growth of gastroenterologic knowledge during the twentieth century, Philadelphia, 1994, Lea & Febiger, pp 474–490. 4. Schuman B: The development of the endoscope. In DiMarino AJ, Jr, Benjamin SB, editors: Gastrointestinal disease an endoscopic approach, vol I, Malden, MA, 1997, Blackwell Science, pp 9–24. 5. Schindler R: Gastroscopy. The endoscopic study of gastric pathology, Chicago, 1950, University of Chicago Press. 6. Schindler R: Synopsis of gastroenterology, Philadelphia, 1957, Grune & Stratton. 7. Kirsner JB: American gastroscopy—yesterday and today. Gastrointest Endosc 37:643–648, 1991. 8. Schindler R: An American built gastroscope. Am J Dig Dis 7:256–257, 1940. 9. Hufford AR: A new light weight, extra flexible gastroscope. Rev Gastroenterol 13:381, 1946. 10. Kenamore B: A biopsy forceps for the flexible gastroscope. Am J Dig Dis 7:539, 1940. 11. Benedict EB: Gastroscopic biopsy. Gastroenterology 37:447–448, 1959. 12. Hopkins HH, Kapany NS: A flexible fiberscope using static scanning. Nature 173:39–41, 1954. 13. Hirschowitz BI, Curtiss LE, Pollard HM: Demonstration of the new gastroscope, the “fiberscope.” Gastroenterology 35:50–53, 1958. 14. Weisinger BB, Cramer AB, Zacharis LC: Comparative accuracy of the fiberscope and standard gastroscope in the diagnosis of gastric lesions: Preliminary report. Gastroenterology 44:858A, 1963. 15. Burnett W: An evaluation of the gastroduodenal fibrescope. Gut 3:361–365, 1962. 16. Cohen NN, Hughes RW, Manfredo HE: Experience with 1000 fibergastroscopic examinations of the stomach. Am J Dig Dis 11:943–950, 1966. 17. Paulson M, Gladsden ES: Esophagoscopy, gastroscopy, gastroenteroscopy, and proctosigmoidoscopy. In Paulson M, editor: Gastroenterologic medicine, Philadelphia, 1969, Lea & Febiger, p. 217–258. 18. LoPresti PA, Hilmi AM: Clinical experience with a new foroblique fiber optic esophagoscope. Am J Dig Dis 9:690–697, 1964. 19. McCune WS, Shorb PE, Moscovitz H: Endoscopic cannulation of the ampulla of Vater: A preliminary report. Ann Surg 167:753–755, 1968. 20. Takagi K, Ikeda S, Nakagawa Y, et al: Retrograde pancreatography and cholangiography by fiber duodenoscope. Gastroenterology 59:445–452, 1970. 21. Vennes JA, Silvis SE: Endoscopic visualization of bile and pancreatic ducts. Gastrointest Endosc 18:149–152, 1972. 22. Kawai K, Akasaka Y, Murakami K, et al: Endoscopic sphincterotomy of the ampulla of Vater. Gastrointest Endosc 20:148–151, 1974. 23. Classen M, Demling L: Endoskopische sphinckterotomie der papilla Vateri und steinextraktion aus dem ductus choledochus. Dtsch Med Wochenschr 99:496–497, 1974. 24. Geenen JE: Endoscopic papillotomy. In Demling L, Classen M, editor: Endoscopic sphincterotomy of the papilla of vater, Stuttgart, 1978, Georg Thieme. 25. Segal HL, Watson JS: Color photography through the flexible gastroscope. Gastroenterology 10:575–585, 1948. 26. Segal HL: The history of gastroscopic color photography. Bull Gastrosc Esophagosc 7:7, 1960. 27. Ashizawa S, Sakai Y: Gastrocamera: Its past and future. In Berry HL, editor: Gastrointestinal panendoscopy, Springfield, IL, 1974, Charles C. Thomas, pp 223–229. 28. Kelly HA: A new method of examination and treatment of diseases of the rectum and sigmoid flexure. Ann Surg 21:468–478, 1895. 29. Tuttle JP: A treatise on diseases of the anus, rectum, and pelvic colon, New York, 1903, S. Appleton & Co.

11.e1

30. Overholt B: Flexible fiberoptic sigmoidoscopes. CA Cancer J Clin 19:80–84, 1969. 31. Turell R: Fiber optic sigmoidoscopes: Up to date developments. Am J Surg 113:305–307, 1967. 32. Wolff WI, Shinya H: Colonofiberoscopy. JAMA 217:1509–1512, 1971. 33. Wolff WI, Shinya H: Polypectomy via the fiberoptic colonoscope: Removal of neoplasms beyond the reach of the sigmoidoscope. N Engl J Med 288:329–332, 1973. 34. Sivak, Jr MV, Fleischer DE: Colonoscopy with a VideoEndoscope: Preliminary experience. Gastrointest Endosc 30:1–5, 1984. 35. Lutz H, Rosch W: Transgastroscopic ultrasonography. Endoscopy 8:203–205, 1976. 36. Strohm WD, Phillip J, Hagenmuller F, et al: Ultrasonic tomography by means of an ultrasonic fiberendoscope. Endoscopy 12:241–244, 1980. 37. DiMagno EP, Buxton JL, Regan PT, et al: Ultrasonic endoscope. Lancet 1:629–631, 1980. 38. Gordon SJ, Rifkin B, Goldberg RB: Endoscopic evaluation of mural abnormalities of the upper gastrointestinal tract. Gastrointest Endosc 32:193–198, 1986. 39. Kawai K, Tanaka Y, Yasuda K: Clinical evaluation of endoscopic ultrasonography (EUS). Gastrointest Endosc 29:183A, 1983. 40. Sivak MV, George C: Endoscopic ultrasonography: Preliminary experience. Gastrointest Endosc 29:187A, 1983. 41. Symposium: Endoscopic ultrasonography. Gastrointest Endosc 36:S1–S46, 1990. 42. Wiersema MJ, Hawes RH, Wiersema LM, et al: Endoscopic ultrasonography as an adjunct to fine needle aspiration cytology of the upper and lower gastrointestinal tract. Gastrointest Endosc 38:35–39, 1992. 43. Rex RK, Tarver RD, Wiersema M, et al: Endoscopic transesophageal fine needle aspiration of mediastinal masses. Gastrointest Endosc 37:465–468, 1991. 44. Hoffman BJ, Hawes RH: Endoscopic ultrasound and clinical competence. Gastrointest Endosc Clin N Am 5:879–884, 1995. 45. Iddan G, Meron G, Glukhovsky A, et al: Wireless capsule endoscopy. Nature 405:417, 2000. 46. Appleyard M, Fireman Z, Glukhovsky A, et al: A randomized trial comparing wireless-capsule endoscopy with push enteroscopy for detection of small bowel lesions. Gastroenterology 119:1431–1438, 2000. 47. Appleyard M, Glukhovsky A, Swain P, et al: Wireless-capsule diagnostic endoscopy for recurrent small-bowel bleeding. N Engl J Med 344:232– 233, 2001. 48. Scapa E, Jacob H, Lewkowicz S, et al: Initial experience of wirelesscapsule endoscopy for evaluating occult gastrointestinal bleeding and suspected small bowel pathology. Am J Gastroenterol 97:2776–2779, 2002. 49. Ell C, Remke S, May A, et al: The first prospective controlled trial comparing wireless capsule endoscopy with push enteroscopy in chronic gastrointestinal bleeding. Endoscopy 34:685–689, 2002. 50. Greenberg G, Phillips M, Tovee E, et al: Fibreoptic endoscopy during laparotomy in the diagnosis of small intestinal bleeding. Gastroenterology 71:133–135, 1976. 51. Tada M, Kawai K: Small bowel endoscopy. Scand J Gastroenterol 19(Suppl 102):39–52, 1984. 52. Lewis BS, Waye JD: Total small bowel enteroscopy. Gastrointest Endosc 33:435–438, 1987. 53. Yamamoto H, Sekine Y, Saito Y: Total enteroscopy with a non-surgical, steerable double-balloon method. Gastrointest Endosc 53:216–220, 2001. 54. Inoue H, Minami H, Kobayashi Y, et al: Peroral endoscopic myotomy (POEM) for esophageal achalasia. Endoscopy 42:265–271, 2010. 55. ASGE Technology Committee, Pannala R, Abu Dayyeh BK, et al: Per-oral endoscopic myotomy (with video). Gastrointest Endosc 83(6):1051–1060, 2016. 56. Khashab MA, Stein E, Clarke JO, et al: Gastric peroral endoscopic myotomy for refractory gastroparesis: first human endoscopic pyloromyotomy (with video). Gastrointest Endosc 78(5):764–768, 2013. 57. Xu MD, Cai MY, Zhou PH, et al: Submucosal tunneling endoscopic resection: a new technique for treating upper GI submucosal tumors originating from the muscularis propria layer (with videos). Gastrointest Endosc 75(1):195–199, 2012.

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2 Setting Up an Endoscopy Facility Klaus Mergener and Barry Tanner

CHAPTER OUTLINE Introduction, 12 Exploring Possibilities, 12 Type of Facility, 12 Business Plan, 13 Regulatory and Certification Issues, 13 General Federal Health-Related Laws, 13 State Licensure, 14 Medicare Certification, 14 Third-Party Accreditation, 14

Physician Credentialing, 14 Payer Requirements, 14 Choosing a Site, 14 Facility Planning and Design, 15 Planning, 15 Scope of Activities, 15 Equipment, 16 Physical Environment, 16 Flow, 16 Designing the Endoscopy Facility, 17

INTRODUCTION The safe and efficient performance of gastrointestinal (GI) endoscopy has the following requirements: }
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CHAPTER 2 Setting Up an Endoscopy Facility

Abstract

Keywords

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12.e1

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200 V; see Table 6.2) or blended (37% to 70% duty cycle; see Table 6.2) current. The use of a cut current results in a more rapid incision with less edema of surrounding tissues, but less hemostasis. Elta43 et al (1998) first demonstrated that the use of a cut current in lieu of a blended coag waveform (25% duty cycle) resulted in a lower rate of pancreatitis. As would be expected with less coagulation, increased mild hemorrhage is seen, but this does not translate into clinically significant bleeding.44 However, because of the potential for less control of a rapid incision with a nonfractionated cut current, great care must be taken with this current output. As mentioned earlier, most new generators have waveform selections that automatically fractionate or interrupt (pulse) the cut current during the course of the incision. As with colonic polypectomy, excessive tissue desiccation should be avoided because this may lead to stalling of the incision. Needle-Knife Sphincterotomy Needle-knife sphincterotomy employs a fine, stiff wire projecting approximately 5 mm beyond the tip of a catheter. This type of sphincterotomy is used to cut a pathway into the bile duct and is usually reserved for cases of failed cannulation in which biliary access is of particular importance. Complications of Sphincterotomy—Link With Electrosurgery Common complications of endoscopic sphincterotomy include pancreatitis, hemorrhage, and perforation. Each complication may be influenced by the type of current used. Pancreatitis. Acute pancreatitis is the most common complication of endoscopic sphincterotomy, occurring in at least 5% of cases.45,46 Development of pancreatitis may be partly a function of iatrogenic trauma to the periampullary region (this trauma results in edema and obstruction to pancreatic flow) or to patient factors such as the presence of Sphincter of Oddi dysfunction. Most current research indicates that generator waveform choice has little effect on post-ERCP pancreatitis as long as a coagulation or blended coagulation waveform with a 25% duty cycle or lower is avoided (see Table 6.2).15 Hemorrhage. Hemorrhage during endoscopic sphincterotomy is due in part to inadequate coagulation effect of tissue during the incision. Mild oozing at the sphincterotomy site at the time of endoscopic sphincterotomy is common, settles spontaneously, and is of no clinical significance. Minor bleeding at the time of sphincterotomy may be more common with pure cut technique. Significant hemorrhage occurs in 1% to 3% of patients47 with an associated mortality of less than 1%.48 This hemorrhage is due to incision of a significant vessel, which is partly “bad luck” and sometimes due to poor orientation of the incision, cutting into a diverticulum or overcutting the incision. Arterial bleeding is not prevented by one electrosurgical output versus another. It is believed, however, that a half-incised vessel (the ends of which cannot retract) bleeds much more than a fully cut one, implying that cutting a little more may be useful in this situation. Perforation. Duodenal perforation during endoscopic sphincterotomy is usually the result of a poorly aligned or too-long incision beyond the boundaries of the intramural common bile duct. Clinically significant perforation occurs in less than 1% of sphincterotomies.49,50 The risk of perforation may be 8% in patients with a small papilla and patients with papillary stenosis.51

Asymptomatic perforation may be more common, possibly occurring in 15% of sphincterotomies.52 Duodenal perforation may occur during a rapid, uncontrolled cut of the sphincter (zipper cut). The occurrence of this type of rapid incision is a function of current delivery to the tissue and operator experience. The use of a pulsed or interrupted advance type of waveform has been shown to reduce this risk.53

Polypectomy Polypectomy is most commonly used to remove colonic polyps, either in one piece or piecemeal. Polypectomy and other thermal ablative techniques such as hot biopsy and ablation have the potential to cause transmural damage, resulting in either serosal inflammation (post-polypectomy syndrome) or perforation. The risk of perforation with all colonoscopies has been estimated to be one perforation in a range between 1000 to 2000 colonoscopies.54 Serositis without perforation occurs in 1% of polypectomies55 and manifests 6 hours to 5 days after the procedure with pain, fever, and leukocytosis. The right side of the colon is particularly at risk because of its thinner wall. Immediate hemorrhage occurs in approximately 1% of polypectomies, and delayed bleeding may occur in 2% of polypectomies.56 Significant hemorrhage is much more likely when cutting through a thick stalk. Delayed bleeding may occur anytime up to 2 weeks after the procedure. From the preceding discussion, it can be seen that sphincterotomy and polypectomy complications may be related partly to either an overrapid, poorly controlled incision or an overdesiccated, poorly progressed incision. Modern generators use microprocessor-controlled feedback to help produce predictable tissue results in spite of changes in tissue resistance. However, there are patient factors and operator technique that cannot be accounted for by the generator’s algorithm (see Fig. 6.1). Bleeding risk, for example, is greatly influenced by patient factors such as anticoagulant use. Dobrowolski et al (2006)57 reported variance in bleeding rates with polyp size, morphology, and malignant state, whereas Watabe et al (2006)58 also noted that hypertension puts patients at risk for a delayed post-polypectomy hemorrhage. It is at this intersection of electrosurgery fundamentals and the characteristics of the particular patient presenting for treatment that the physician well schooled in both will consistently experience the best outcomes.

Hot Biopsy Forceps HBF have been a popular means of removing diminutive polyps for many years.59 HBF employs monopolar circuitry. Blended or coagulation current should be used at a relatively low setting and applied only until blanching of the tissue occurs (1 to 2 seconds). The bowel should be deflated before power application, and care must be taken not to touch other parts of the bowel wall with the cups while coagulating. Post-polypectomy syndrome, perforation, and significant bleeding have all been reported after removal of diminutive polyps using HBF.19,58 This technique is also relatively poor at removing all polyp tissue.60

Endoscopic Mucosal Resection EMR is a method of removing sessile or flat neoplasms involving the mucosal layer of the GI tract. Several methods of EMR exist including injection, cap, and ligation-assisted techniques.61 All forms of EMR utilize snares to perform the resection. The resection is typically performed using either some form of a

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CHAPTER 6 Electrosurgery in Therapeutic Endoscopy

79

blended-cut current (crest factors of approximately 2.5 to 5.5 [see Table 6.2]) or a coagulation mode similar to that used to perform polypectomy (i.e., broad power curve with a crest factor of approximately 6 [see Table 6.2]). Potential complications associated with EMR include hemorrhage (immediate and delayed) and perforation/full thickness resection.

produce a cutting effect along with coagulation. Large vessels and active bleeding can be managed using coagulation graspers using a continuous coagulation current less than 200 V (see Table 6.2).

Endoscopic Submucosal Dissection

There are a variety of indications for electrosurgery throughout the gastrointestinal tract for cutting or ablating tissue. All these techniques involve manageable risks of perforation or hemorrhage. New accessory devices, techniques, and generators intended to reduce these risks do not replace the responsibility of the clinician to have a working knowledge of the principles underlying the tools in use.

ESD is a method for resecting neoplastic lesions en bloc. In performing ESD, the perimeter of the margin is typically marked using a needle-knife or snare tip using a low-voltage contact coagulation current (100% duty cycle, < 200 V; see Table 6.2). The submucosa is then injected with a solution (typically salinebased) followed by incision of the mucosa around the perimeter of the initial markings. The incision is made using an electrosurgical knife with an ESU setting that delivers a blended current capable of both cutting and coagulation. Following the mucosal incision of the perimeter of the lesion, dissection of the submucosa can be performed with various electrosurgical knives (discussed in detail in Chapters 32 and 37). Various ESU settings will allow the endoscopist to perform the dissection. In selecting the appropriate ESU setting for performing the dissection, factors such as the vascularity and extent of fibrosis need to be considered and often need to be modified during the procedure depending on what is encountered during the resection. If a large vessel or active bleeding is encountered during the resection, the vessel should be coagulated using coagulation graspers with a soft coagulation current (100% duty cycle, < 200 V; see Table 6.2). As previously mentioned in this chapter, the specific ESU settings used for the various aspects of ESD depend on the technique used by the endoscopist, with the tissue effect being largely impacted by the technique and accessory used (see Fig. 6.1). Therefore, a physician performing ESD should have a thorough understanding of electrosurgical principles and the specific operating characteristics of their ESU.

Peroral Endoscopic Myotomy POEM is a method to treat achalasia and other esophageal motility disorders by performing a myotomy endoscopically.62 The procedure and indications are discussed in detail in Chapters 19 and 45. In regard to electrosurgical principles for performing POEM, the procedure utilizes similar devices and techniques to ESD. A submucosal injection is performed proximal to where the myotomy is performed. This is followed by a longitudinal mucosal incision (approximately 2 cm in length) using an electrosurgical knife with ESU setting similar to that for performing the mucosal incision in ESD. The submucosal space is then entered through the mucosal incision. A submucosal tunnel is then created by performing a series of injections into the submucosal space followed by dissection of the submucosa. Various electrosurgical knives and ESU settings can be used for performing the dissection of the submucosal space. The use of “spray coag” (high voltage, high crest factor, short duty cycle current; see Table 6.2) has been reported to be used successfully for dissecting the submucosal space.62 However, other ESU settings (e.g., blended cut currents or coagulation current with a crest factor of approximately 6; see Table 6.2) can also be utilized to perform the submucosal dissection. Following the creation of the submucosal tunnel past the gastroesophageal junction, the myotomy is then performed using an electrosurgical knife. Again, the choice of ESU setting is dependent on the accessory used, tissue factors, and the operator technique. The setting should

SUMMARY

KEY REFERENCES 5. Wong Kee Song LM, Gostout CJ, Tucker RD, et al: Electrosurgery in gastrointestinal endoscopy: terminology matters. Letters to the Editor, Gastrointest Endosc 83:271–273, 2016. 11. Tucker RD, Hudrlik TR, Silvis SE, et al: Automated impedance: a case study in microprocessor programming, Comput Biol Med 11(3):153–160, 1981. 13. Laine L, Long GL, Bakos GJ, et al: Optimizing bipolar electrocoagulation for endoscopic hemostasis: assessment of factors influencing energy delivery and coagulation, Gastrointest Endosc 67:502–508, 2008. 14. Fahrtash-Bahin F, Holt B, Jayasekeran V, et al: Snare tip soft coagulation achieves effective and safe endoscopic hemostasis during wide-field endoscopic resection of large colonic lesions, Gastrointest Endosc 78(1): 158–163, 2013. 15. ASGE Technology Committee, Tokar JL, Barth BA, et al: Electrosurgical generators, Gastrointest Endosc 78(2):197–208, 2013. 16. Norton ID, Petersen BT, Bosco J, et al: A randomized trial of endoscopic biliary sphincterotomy using pure cut versus combined cut and coagulation waveforms, Clin Gastroenterol Hepatol 3(10):1029–1033, 2005. 17. Morris ML, Bowers WJ: Math, myth and the fundamentals of electrosurgery, J Hepatol Gastroenterol 1(1):1–5, 2016. 18. Munro MG: Fundamentals of electrosurgery part I: principles of radiofrequency energy for surgery. In Feldman LS, Fuchshuber P, Jones DB, editors: The SAGES manual on the fundamental use of surgical energy (FUSE), New York, 2012, Springer. 19. Morris ML, Tucker RD, Baron TH, et al: Electrosurgery in in gastrointestinal endoscopy: principles to practice, Am J Gastroenterol 104(6):1563–1574, 2009. 20. Singh N, Harrison M, Rex DK: A survey of colonoscopic polypectomy practices among clinical gastroenterologists, Gastrointest Endosc 60(3): 414–418, 2004. 21. Rey JF, Bellenhoff U, Dumonceau JM: ESGE Guideline: the use of electrosurgical units, Endoscopy 42:764–771, 2010. 24. Nelson G, Morris ML: Electrosurgery in the gastroenterology suite, Gastroenterol Nurs 38:430–439, 2015. 27. Ginsberg G, Barkun AN, Bosco J, et al: Technology status evaluation report: the argon plasma coagulator, Gastrointest Endosc 55(7):807–810, 2002. 29. Eickhoff A, Jakobs R, Schilling D, et al: Prospective nonrandomized comparison of two modes of argon beamer (APC) tumor desobstruction: effectiveness of the new pulsed APC versus forced APC, Endoscopy 39(7):637–642, 2007. 32. Eickhoff A, Hartmann D, Eickhoff JC, et al: Pain sensation and neuromuscular stimulation during argon plasma coagulation in gastrointestinal endoscopy, Surg Endosc 22(7):1701–1707, 2008. 33. Manner E, May A, Faerber M, et al: Safety and efficacy of a new high power argon plasma coagulation system (hp-APC) in lesions of the upper gastrointestinal tract, Dig Liver Dis 38(7):471–478, 2006.

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35. Association of periOperative Registered Nurses (AORN): Recommended practices for electrosurgery. In Perioperative standards and recommended practices, Denver, 2010, AORN, pp 105–125. 41. Manner H, Plum N, Pech O, et al: Colon explosion during argon plasma coagulation, Gastrointest Endosc 67:1123–1127, 2008. 43. Elta GH, Barnett JL, Wille RT, et al: Pure cut electrocautery current for sphincterotomy causes less post procedure pancreatitis than blended current, Gastrointest Endosc 47:149–153, 1998. 50. Freeman ML: Adverse outcomes in ERCP, Gastrointest Endosc 56:S273–S282, 2002. 54. Fyock CJ, Draganov PV: Colonoscopic polypectomy and associated techniques, World J Gastroenterol 16(29):3630–3637, 2010.

58. Watabe H, Yamaji Y, Okamoto M, et al: Risk assessment for delayed hemorrhagic complication of colonic polypectomy: polyp related factors and patient related factors, Gastrointest Endosc 64:73–78, 2006. 61. ASGE Technology Committee, Hwang JH, Konda V, et al: Endoscopic mucosal resection, Gastrointest Endosc 82(2):215–226, 2015. 62. Inoue H, Minami H, Kobayashi Y, et al: Peroral endoscopic myotomy (POEM) for esophageal achalasia, Endoscopy 42(4):265–271, 2010.

A complete reference list can be found online at ExpertConsult .com

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CHAPTER 6 Electrosurgery in Therapeutic Endoscopy

REFERENCES 1. Shinya H, Wolff WI: Polypectomy via the fibreoptic colonoscope, N Engl J Med 288:328–332, 1973. 2. Blackwood WD, Silvis E: Gastroscopic electrosurgery, Gastroenterology 61:305–314, 1971. 3. Vilos GA, Rajakumar C: Electrosurgical generators and monopolar and bipolar electrosurgery, J Minim Invasive Gynecol 20:279–287, 2013. 4. Munro M, Abbott JA, Vilos GA, Brill A: Radiofrequency electrical energy guidelines for authors: What’s in a name? J Minim Invasive Gynecol 22:1–2, 2015. 5. Wong Kee Song LM, Gostout CJ, Tucker RD, et al: Electrosurgery in gastrointestinal endoscopy: terminology matters. Letters to the Editor, Gastrointest Endosc 83:271–273, 2016. 6. Tucker RD: Principles of electrosurgery. In Sivak MV, editor: Gastroenterologic endoscopy, 2nd ed, Philadelphia, 2000, Saunders, pp 125–135. 7. Honig WM: The mechanism of cutting in electrosurgery, IEEE Trans Biomed Eng 22:58–62, 1975. 8. Curtis LE: High frequency currents in endoscopy: a review of principles and precautions, Gastrointest Endosc 20:9–12, 1993. 9. Lin HJ, Tsai YT, Lee SD, et al: Heater probe therapy for severe hemorrhage from a peptic ulcer with a visible vessel, Endoscopy 20:131–133, 1988. 10. Barlow DE: Endoscopic applications of electrosurgery: a review of basic principles, Gastrointest Endosc 28:73–76, 1982. 11. Tucker RD, Hudrlik TR, Silvis SE, et al: Automated impedance: a case study in microprocessor programming, Comput Biol Med 11(3):153–160, 1981. 12. Jutabha R, Jensen DM, Machicado G, et al: Randomized controlled studies of injection gold probes compared with monotherapies for hemostasis of bleeding canine gastric ulcers, Gastrointest Endosc 48:598–605, 1998. 13. Laine L, Long GL, Bakos GJ, et al: Optimizing bipolar electrocoagulation for endoscopic hemostasis: assessment of factors influencing energy delivery and coagulation, Gastrointest Endosc 67:502–508, 2008. 14. Fahrtash-Bahin F, Holt B, Jayasekeran V, et al: Snare tip soft coagulation achieves effective and safe endoscopic hemostasis during wide-field endoscopic resection of large colonic lesions, Gastrointest Endosc 78(1):158–163, 2013. 15. ASGE Technology Committee, Tokar JL, Barth BA, et al: Electrosurgical generators, Gastrointest Endosc 78(2):197–208, 2013. 16. Norton ID, Petersen BT, Bosco J, et al: A randomized trial of endoscopic biliary sphincterotomy using pure cut versus combined cut and coagulation waveforms, Clin Gastroenterol Hepatol 3(10):1029–1033, 2005. 17. Morris ML, Bowers WJ: Math, myth and the fundamentals of electrosurgery, J Hepatol Gastroenterol 1(1):1–5, 2016. 18. Munro MG: Fundamentals of electrosurgery part I: principles of radiofrequency energy for surgery. In Feldman LS, Fuchshuber P, Jones DB, editors: The SAGES manual on the fundamental use of surgical energy (FUSE), New York, 2012, Springer. 19. Morris ML, Tucker RD, Baron TH, et al: Electrosurgery in in gastrointestinal endoscopy: principles to practice, Am J Gastroenterol 104(6):1563–1574, 2009. 20. Singh N, Harrison M, Rex DK: A survey of colonoscopic polypectomy practices among clinical gastroenterologists, Gastrointest Endosc 60(3): 414–418, 2004. 21. Rey JF, Bellenhoff U, Dumonceau JM: ESGE Guideline: the use of electrosurgical units, Endoscopy 42:764–771, 2010. 22. Norton ID, Wang L, Levine SA, et al: Submucosal saline injection limits the depth of colonic thermal injury, Gastrointest Endosc 56:95–100, 2002. 23. Mitsuhiro F, Shinya K, Satoshi O, et al: Submucosal injection of normal saline can prevent unexpected deep thermal injury of argon plasma coagulation in the in vivo porcine stomach, Gut Liver 2(2):95–98, 2008. 24. Nelson G, Morris ML: Electrosurgery in the gastroenterology suite: knowledge is power, Gastroenterol Nurs 38:430–439, 2015.

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25. Manner H: Argon plasma coagulation therapy, Curr Opin Gastroenterol 24:612–616, 2008. 26. Roman S, Saurin JC, Dumortier J, et al: Tolerance and efficacy of argon plasma coagulation for controlling bleeding in patients with typical and atypical manifestations of watermelon stomach, Endoscopy 35:1024–1028, 2003. 27. Ginsberg G, Barkun AN, Bosco J, et al: Technology status evaluation report: the argon plasma coagulator, Gastrointest Endosc 55(7):807–810, 2002. 28. Zlatanic J, Waye JD, Kim PS, et al: Large sessile colonic adenomas: use of argon plasmacoagulator to supplement piecemeal snare polypectomy, Gastrointest Endosc 49:731–735, 1999. 29. Eickhoff A, Jakobs R, Schilling D, et al: Prospective nonrandomized comparison of two modes of argon beamer (APC) tumor desobstruction: effectiveness of the new pulsed APC versus forced APC, Endoscopy 39(7):637–642, 2007. 30. Norton ID, Wang L, Levine S, et al: In vivo characterization of colonic thermal injury caused by argon plasma coagulation, Gastrointest Endosc 55:631–636, 2002. 31. Hoyer N, Thouet R, Zellweger U: Massive pneumoperitoneum after endoscopic argon plasma coagulation, Endoscopy 30:S44–S45, 1998. 32. Eickhoff A, Hartmann D, Eickhoff JC, et al: Pain sensation and neuromuscular stimulation during argon plasma coagulation in gastrointestinal endoscopy, Surg Endosc 22(7):1701–1707, 2008. 33. Manner E, May A, Faerber M, et al: Safety and efficacy of a new high power argon plasma coagulation system (hp-APC) in lesions of the upper gastrointestinal tract, Dig Liver Dis 38(7):471–478, 2006. 34. Goulet CJ, Disario JA, Emerson L, et al: In vivo evaluation of argon plasma coagulation in a porcine model, Gastrointest Endosc 65(3):457– 462, 2007. 35. Association of periOperative Registered Nurses (AORN): Recommended practices for electrosurgery. In Perioperative standards and recommended practices, Denver, 2010, AORN, pp 105–125. 36. Morris ML: Electrosurgery in the gastroenterology suite: principles, practice, and safety, Gastroenterol Nurs 29(2):126–134, 2006. 37. Fiek M, Dorwarth U, Durchlaub I, et al: Application of radiofrequency energy in surgical and interventional procedures: Are there interactions with ICD’s? Pacing Clin Electrophysiol 27(3):293–298, 2004. 38. Madigan JD, Asim F, Choudhri BS, et al: Surgical management of the patient with an implanted cardiac device, Ann Surg 230(5):639–647, 1999. 39. Avgerinos A, Kalantzis N, Rekoumis G, et al: Bowel preparation and the risk of explosion during colonoscopic polypectomy, Gut 25(4):361–364, 1984. 40. Strocchi A, Bond JH, Ellis C, et al: Colonic concentrations of hydrogen and methane following colonoscopic preparation with an oral lavage solution, Gastrointest Endosc 36(6):580–582, 1990. 41. Manner H, Plum N, Pech O, et al: Colon explosion during argon plasma coagulation, Gastrointest Endosc 67:1123–1127, 2008. 42. Nurnberg D, Pannwitz H, Burkhardt KD, et al: Gas explosion caused by argon plasma coagulation of colonic angiodysplasias, Endoscopy 39(S1):E182, 2007. 43. Elta GH, Barnett JL, Wille RT, et al: Pure cut electrocautery current for sphincterotomy causes less post procedure pancreatitis than blended current, Gastrointest Endosc 47:149–153, 1998. 44. Stefanidis G, Karamanolis G, Viazis N, et al: A comparative study of postendoscopic sphincterotomy complications with various types of electrosurgical current in patients with choledocholithiasis, Gastrointest Endosc 57:192–197, 2003. 45. Freeman ML: Complications of endoscopic biliary sphincterotomy: a review, Endoscopy 29:288–297, 1997. 46. Gottlieb K, Sherman S: ERCP and biliary endoscopic sphincterotomyinduced pancreatitis, Gastrointest Endosc Clin N Am 8:87–114, 1998. 47. Sherman S, Uzer MF, Lehman GA: Wire-guided sphincterotomy, Am J Gastroenterol 89:2125–2129, 1994. 48. Ferrari AP, Slivka A, Lichtenstein DR: Factors affecting ERCP complications: looking backwards and forwards. 10th World Congress of Gastroenterology, 1994. A1866.

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49. Foutch PG, Harlan JR, Hoefer M: Endoscopic therapy for patients with a post-operative biliary leak, Gastrointest Endosc 39:416–421, 1993. 50. Freeman ML: Adverse outcomes in ERCP, Gastrointest Endosc 56:S273– S282, 2002. 51. Leese T, Neoptolemos JP, Carr-Locke DL: Successes, failures, early complications and their management following endoscopic sphincterotomy: results in 394 consecutive patients from a single centre, Br J Surg 72:215–219, 1985. 52. de Vries JH, Duijm LE, Dekker W, et al: CT before and after ERCP: detection of pancreatic pseudotumor, asymptomatic retroperitoneal perforation and duodenal diverticulum, Gastrointest Endosc 45:231–235, 1997. 53. Kohler A, Maier M, Benz C, et al: A new HF current generator with automatically controlled system (Endocut Mode) for endoscopic sphincterotomy-preliminary experience, Endoscopy 30:351–355, 1998. 54. Fyock CJ, Draganov PV: Colonoscopic polypectomy and associated techniques, World J Gastroenterol 16(29):3630–3637, 2010. 55. Waye JD, Lewis BS, Yessayan S: Colonoscopy: a prospective report of complications, J Clin Gastroenterol 15:347–351, 1992.

56. Sorbi D, Norton I, Conio M, et al: Postpolypectomy lower GI bleeding: descriptive analysis, Gastrointest Endosc 51:690–696, 2000. 57. Dobrowolski S, Dobosz M, Babicki A, et al: Blood supply of colorectal polyps correlates with risk of bleeding after colonoscopic polypectomy, Gastrointest Endosc 63:1004–1009, 2006. 58. Watabe H, Yamaji Y, Okamoto M, et al: Risk assessment for delayed hemorrhagic complication of colonic polypectomy: polyp related factors and patient related factors, Gastrointest Endosc 64:73–78, 2006. 59. Gilbert DA, DiMarino AJ, Jensen DM, et al: Status evaluation: hot biopsy forceps. American Society for Gastrointestinal Endoscopy. Technology Assessment Committee, Gastrointest Endosc 38:753–756, 1992. 60. Peluso F, Goldner F: Follow-up of hot biopsy forceps treatment of diminutive colonic polyps, Gastrointest Endosc 37:604–606, 1991. 61. ASGE Technology Committee, Hwang JH, Konda V, et al: Endoscopic mucosal resection, Gastrointest Endosc 82(2):215–226, 2015. 62. Inoue H, Minami H, Kobayashi Y, et al: Peroral endoscopic myotomy (POEM) for esophageal achalasia, Endoscopy 42(4):265–271, 2010.

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7 Sedation and Monitoring in Endoscopy Vaibhav Wadhwa and John Joseph Vargo II

CHAPTER OUTLINE Introduction, 81 Patient Evaluation, Preparation, and Risk Stratification, 82 Procedural Monitoring, 82 Level of Consciousness, 82 Pulse Oximetry, 82 Pulmonary Ventilation, 83 Hemodynamic Measurements, 83 Supplemental Oxygen, 83 Intravenous Access, 83 Sedation and Consent, 83 Staffing Levels and Training, 83 Postprocedural Monitoring, 84 Drugs for Sedation, 84 Propofol and Deep Sedation, 85

Newer Agents, 85 Sedation Providers, 85 SEDASYS, 86 Patient-Controlled Sedation (PCS), 86 Gastroenterologist-Directed Propofol Sedation, 86 Sedation in Different Patient Populations, 86 Endoscopy in Patients With Cirrhosis, 86 Endoscopy Without Sedation, 86 Endoscopy and Pregnancy, 86 Endoscopy in Obese Patients, 87

INTRODUCTION Sedation is regularly used to facilitate the performance of endoscopic procedures. Sedation practices have noticeably changed over the past decade, with a shift from no or moderate sedation to monitored anesthesia care (MAC) for gastrointestinal (GI) endoscopy.1 Sedation during an endoscopic procedure helps in two ways; first, by decreasing procedural pain, thereby making the patient more comfortable, and second, by decreasing any untimely patient movements, thereby reducing complications.2 Both these factors affect the overall quality and safety of endoscopic procedures. Sedation is associated with its own potential problems. Sedation-related complications, such as aspiration, oversedation, hypoventilation, and airway obstruction, make up more than half of all reported endoscopic complications.3,4 Sedation use requires additional monitoring and recovery, and therefore has implications in the form of time, cost, and staffing. Due to these issues, some prior studies have advocated for the use of unsedated endoscopy5–7; however, the rate of use of unsedated endoscopy remains very low in the United States.8 The main reason for that is unpredictable patient tolerability during the endoscopic procedures. Several studies have shown that even though patients agree to undergo the procedure without sedation initially, the need for sedation later in the procedure causes significant delays in procedure completion

Sedation for Different Endoscopic Procedures, 87 Standard Endoscopic Procedures, 87 Propofol Use in Complex Endoscopic Procedures, 87 Pharyngeal Anesthesia in Sedation, 87 Management of Oversedation, 87 Review of Specific Drugs, 88 Benzodiazepines, 88 Opioid Analgesics, 88 Propofol, 89 Flumazenil, 89 Naloxone, 89

when compared to patients who are sedated throughout the procedure.9,10 The length and complexity of procedures and the comorbidities of the patient are the most important factors for sedation use. These factors may influence the choice of sedative, the level of sedation, and the need for an anesthesiologist during the procedure. Patients also vary in their sensitivity to sedation and their tolerance of endoscopy. The American Society of Anesthesiologists (ASA) defines the level of sedation on a spectrum of four recognizable levels, from minimal sedation to general anesthesia11 (Table 7.1). The most commonly used level in endoscopic procedures is moderate sedation, wherein the patient demonstrates purposeful response to visual or tactile stimuli. This level of sedation can be achieved with a benzodiazepine alone or combined with an opiate. Due to the increased use of MAC, propofol use to target balanced propofol sedation (concurrent use with midazolam and/or fentanyl) is being increasingly used for mild to moderate sedation and is associated with improved patient outcomes.12,13 This chapter focuses on all aspects of sedation and patient safety. Patient evaluation and risk assessment, presedation preparation, patient monitoring during sedation, sedation providers, sedation in high-risk populations, and issues of consent are discussed. The attributes of commonly used sedative drugs are discussed in the context of level of sedation and monitoring required.

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CHAPTER 7 Sedation and Monitoring in Endoscopy

Abstract

Keywords

Sedation practices have noticeably changed over the past decade as the utilization of esophagogastroduodenoscopy and colonoscopy has steadily risen. Over time, we have seen a dramatic shift from no or moderate sedation to monitored anesthesia care (MAC) for gastrointestinal endoscopy. This shift has led anesthesiologists into the endoscopy suite with newer sedative medications and increased safety concerns. The consequence of this change in sedation practices requires an endoscopist to have a strong foundation regarding many sedation-related issues, including depth of sedation, appropriate patient selection, choice of sedative medications, methods of sedation delivery, patient monitoring, recovery from sedation, and patient outcomes. With the changing landscape of the health care system, the challenges of quality and cost warrant us to provide the best possible care for our patients in the most efficient manner possible. The endoscopy suite is a unique sedation environment, and the purpose of this chapter is to review all aspects pertaining to current sedation practices in gastrointestinal endoscopy.

gastrointestinal endoscopy propofol moderate sedation deep sedation anesthesiology

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TABLE 7.1

Equipment and General Principles of Endoscopy

Levels of Sedation

Level 1: Minimal sedation

Drug-induced state, during which patient responds normally to verbal commands. Cognitive function and coordination may be impaired. Ventilatory and cardiovascular function are unaffected

Level 2: Conscious sedation

Drug-induced depression of consciousness, during which patient responds purposefully to verbal commands, either alone or accompanied by light tactile stimulation. Patent airway is maintained without help. Spontaneous ventilation is adequate, and cardiovascular function is usually maintained

Level 3: Deep sedation

Level 4: General anesthesia

Drug-induced depression of consciousness, during which patient cannot be easily aroused but responds purposefully to repeated or painful stimulation. Patient may require assistance maintaining an airway. Spontaneous ventilation may be inadequate, and cardiovascular function is maintained Patient is not able to be aroused even by painful stimuli. Patient often requires assistance in maintaining patent airway. Positive-pressure ventilation may be required owing to respiratory depression or neuromuscular blockade. Cardiovascular function may be impaired

From Bryson HM, Fulton BR, Faulds D: Propofol: an update of its use in anesthesia and conscious sedation. Drugs 50(3):513–559, 1995.

PATIENT EVALUATION, PREPARATION, AND RISK STRATIFICATION The risk of adverse outcomes can be reduced by appropriate preprocedural evaluation of the patient’s history and physical findings. The clinicians responsible for sedation should familiarize themselves with specific and relevant aspects of the medical history, including abnormalities of major organ systems, previous adverse experience with sedation and analgesia, current medications and drug allergies, time of the last oral intake, and history of alcohol or recreational drug use. A thorough physical examination should be done, particularly to assess the heart and lungs, in addition to assessing the airway anatomy. It may be useful to consider the patient in terms of the ASA status classification (Table 7.2), as increasing number and severity of comorbidities are associated with an increased incidence of cardiopulmonary unplanned events. Patients undergoing sedation should be informed of the benefits, risks, and limitations associated with sedation and possible alternatives. This should be completed as part of the patient consent. Patients undergoing sedation should be stratified according to the risk for sedation-related complications to receive either moderate sedation or MAC. The Stratifying Clinical Outcomes Prior to Endoscopy score (the SCOPE score) is a validated score that can be used to predict difficult moderate sedation for endoscopy based on several factors.14 The purpose of the risk stratification is to reduce the incidence of sedation-related adverse events.

PROCEDURAL MONITORING Patients should have continuous monitoring while undergoing endoscopic procedures and also before, during, and after the

Definition of American Society of Anesthesiologists Status TABLE 7.2 Class 1

Patient has no organic, physiologic, biochemical, or psychiatric disturbance. Pathologic process for which operation is to be performed is localized and does not entail systemic disturbance

Class 2

Mild to moderate systemic disturbance caused either by the condition to be treated surgically or by other pathophysiologic processes

Class 3

Severe systemic disturbance or disease from whatever cause; it may be impossible to define degree of disability with finality

Class 4

Severe systemic disorders that are already life-threatening, not always correctable by operation

Class 5

Moribund patient who has little chance of survival but is submitted to operation in desperation

administration of sedative agents. Standard monitoring procedures include electrocardiography, pulse oximetry, blood pressure measurement, and capnography. Monitoring should be discontinued only when the patient is fully awake. According to the ASA guidelines, it is recommended that continuous recording of the patient’s level of consciousness, respiratory function, and hemodynamics reduces the risk of sedation-related adverse outcomes.11 Close monitoring helps in early detection of adverse events induced by sedatives, such as apnea, hypoxemia, hypotension, and arrhythmias, which allows for early intervention to prevent any life-threatening complications. Each of the monitored parameters is addressed in the following sections.

Level of Consciousness Alteration in the level of consciousness while under sedation serves as a guide to the depth of sedation the patients. With a decrease in level of consciousness being associated with a loss of reflexes that normally protect the airway and prevent hypoventilation, it is important to assess patient response to commands during sedation (see Table 7.1). Verbal responses also provide information indicating that the patient is breathing. In procedures where verbal responses are impossible, such as upper GI endoscopy, nonverbal responses such as hand movements, finger squeezing, toe wiggling, etc., should be sought. A lack of response to verbal or tactile stimuli suggests a higher depth of sedation and should be managed accordingly.

Pulse Oximetry A common noninvasive method of measuring oxygen saturation is pulse oximetry, which uses a light signal transmitted through tissue and takes into account the pulsatile volume changes that occur. The pulse oximeter measures the pulsatile signals across perfused tissue at two distinct wavelengths: the infrared band, which corresponds to oxyhemoglobin, and the red band, which corresponds to reduced hemoglobin. However, the sole use of pulse oximetry is inadequate for detecting alveolar hypoventilation in patients undergoing endoscopy.15 This is demonstrated by the oxyhemoglobin dissociation curve. A high oxyhemoglobin concentration is preserved despite a decrease in partial pressure of oxygen in the blood (Pao2) until the Pao2 falls below 60 mm Hg, at which point the pulse oximeter reading reflects the decreasing Pao2 with a rapid

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CHAPTER 7 Sedation and Monitoring in Endoscopy

83

decrease in oxygen saturation. Therefore, alveolar hypoventilation is detected earlier with the use of capnography (described later) than pulse oximetry.16

cardiac rhythm, cardiomyopathies, or ischemic heart disease. The requirement for ECG monitoring has not been evaluated in clinical trials.

Pulmonary Ventilation

Supplemental Oxygen

Respiratory depression in the form of transient hypoxemia is not uncommon with sedation use and is usually trivial. It is also encountered in unsedated procedures. Extended periods of hypoxemia, however, can cause tachycardia and coronary ischemia. Therefore, respiratory monitoring is very important to reduce the risk of adverse outcomes. Direct observation of respiratory movement or direct pulmonary auscultation is the simplest way to monitor ventilator function. A noninvasive method for measuring arterial carbon dioxide is transcutaneous carbon dioxide monitoring (PtCO2), which entails placing a heated electrode on the skin, causing the microcirculation to “arterialize.” The eventual production of carbonic acid due to diffusion of carbon dioxide into an electrolyte solution provides a pH reading by using the Henderson-Hasselbalch equation, which allows for calculation of the arterial carbon dioxide level. The use of this technique was validated by Nelson et al (2000), who demonstrated significantly more CO2 retention in patients with standard monitoring than those with standard monitoring coupled with PtCO2 monitoring in patients undergoing endoscopic retrograde cholangiopancreatography (ERCP).17 Capnography is the gold standard for respiratory monitoring. It works by measuring the CO2 indirectly by virtue of light absorption in the infrared region of the electromagnetic spectrum. CO2 retention is identified as an early event on capnography and is a sign of ventilation compromise. It serves as a qualitative method for detection of CO2 levels in nonintubated patients undergoing endoscopy, as the exact measurement of CO2 is inaccurate unless the breathing system is a closed circuit, such as in intubated patients. There have been several studies that have demonstrated that use of capnography detects significantly more hypoxemia in patients undergoing GI endoscopy than standard monitoring.16,18 However, a 2016 trial did not demonstrate any reduction in the incidence of hypoxemia events in healthy individuals undergoing routine endoscopy targeting moderate sedation.19 Bispectral index (BIS) monitors are often used in the operating room to assess the adequacy of the depth of anesthesia while under a general anesthetic in patients undergoing surgical procedures. However, the BIS monitor has significant overlap of scores across sedation levels when it is used to detect deep sedation, resulting in an overall lower accuracy rate.20

Supplemental oxygen administered via nasal cannulas or a mask has been shown to reduce the incidence of desaturation during endoscopy performed under sedation21,22 and hence it should be given to all patients receiving sedation. However, as supplemental oxygen may delay the onset of hypoxemia in sedated patients with decreased pulmonary ventilation, it is essential not to rely solely on pulse oximetry to monitor ventilation but to employ additional techniques, such as capnography or a BIS monitor.

Hemodynamic Measurements Hemodynamic complications, such as hypotension, arrhythmias, and cardiovascular response to stress, are some of the mild direct effects of sedative agents and analgesics that may happen during sedation. Regular measurements of pulse and blood pressure can help detect these changes, which may represent responses to hypoxemia, oversedation, or possibly patient distress to procedure-induced pain. Although no evidence shows that blood pressure monitoring during endoscopy influences morbidity and mortality, it has been recommended that both regular blood pressure measurements and pulse be monitored throughout procedures performed under sedation.1 Continuous electrocardiogram (ECG) monitoring should be considered in high-risk patients, such as patients with known disturbances in

INTRAVENOUS ACCESS Intravenous access should be maintained throughout the procedure until the patient is no longer at risk from cardiopulmonary or respiratory depression. It facilitates the immediate availability of vascular access in the event of oversedation for administration of reversal agents or for using emergency drugs in the event of cardiopulmonary compromise. In patients who are receiving sedatives via nonintravascular routes (e.g., pediatric patients undergoing endoscopic procedures), intravenous access should also be obtained if the likelihood of any cardiopulmonary depression is high.

SEDATION AND CONSENT There are a couple of important things to keep in mind when it comes to consent and sedation. First and foremost, the patient should be fully informed of the indications, risks, and alternatives to sedation before he or she consents to the procedure. The second important issue is whether a patient, while under sedation, can withdraw consent for the procedure. If a sedated patient indicates during endoscopy that he or she wishes to have the procedure stopped, should the endoscopist stop or complete the procedure, bearing in mind that it would be in the patient’s best interests to complete it? A study from the United Kingdom researched this issue and found that 88% of gastroenterologists stated that they would only stop after repeated requests by the sedated patient, and only 45% of gastroenterologists thought patients were capable of making rational decisions while under sedation.23 When looked at from the patient’s perspective, the study found that opinion was evenly divided into terminating the procedure immediately or completing it.23

STAFFING LEVELS AND TRAINING Adequate patient monitoring during sedation is difficult for a clinician performing the procedure. There should be additional individuals available to monitor the patient’s status in terms of level of consciousness, ventilatory function, and hemodynamic parameters. The presence of another individual is likely to improve patient comfort and satisfaction. Several areas of expertise are required while managing sedated patients, including knowledge of administered drugs and management of adverse events. All staff members administering sedative drugs should be made familiar with the pharmacology of all drugs used prior to their involvement. Particularly, staff members should be aware of the basics such as the time to onset of action, elimination half-life,

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84

SECTION I

Equipment and General Principles of Endoscopy

Appropriate Emergency Equipment to Have Available When Using Sedative or Analgesic Drugs Capable of Causing Cardiorespiratory Depression BOX 7.1

Appropriate emergency equipment should be available whenever sedative or analgesic drugs capable of causing cardiorespiratory depression are administered. The following lists should be used as a guide, which should be modified depending on the individual practice circumstances. Items in brackets are recommended when infants or children are sedated.

Intravenous Equipment } } } } } } } }

Gloves Tourniquets Alcohol wipes Sterile gauze pads Intravenous catheters [24–22-gauge] Intravenous tubing [pediatric “microdrip” (60 drops/mL)] Intravenous fluid Assorted needles for drug aspiration, intramuscular injection (intraosseous bone marrow needle) } Appropriately sized syringes [1-mL syringes] } Tape

Basic Airway Management Equipment } Source of compressed oxygen (tank with regulator or pipeline supply with flowmeter) } Source of suction } Suction catheters [pediatric suction catheters] } Yankauer-type suction } Face masks [infant/child] } Self-inflating breathing bag-valve set [pediatric] } Oral and nasal airways [infant/child-sized] } Lubricant

Advanced Airway Management Equipment (for practitioners with intubation skills) } } } }

Laryngeal mask airways [pediatric] Laryngoscope handles (tested) Laryngoscope blades [pediatric] Endotracheal tubes } Cuffed 6.0, 7.0, 8.0 mm ID } [Uncuffed 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0 mm ID] } Stylet (appropriately sized for endotracheal tubes)

Pharmacologic Antagonists } Naloxone } Flumazenil

Emergency Medications } } } } } } } } } } }

Epinephrine Ephedrine Vasopressin Atropine Nitroglycerin (tablets or spray) Amiodarone Lidocaine Glucose, 50% [10% or 25%] Diphenhydramine Hydrocortisone, methylprednisolone, or dexamethasone Diazepam or midazolam

ID, internal diameter. From American Society of Anesthesiologists Task Force on Sedation and Analgesia by Non-Anesthesiologists: Practice guidelines for sedation and analgesia by non-anesthesiologists. Anesthesiology 96(4):1004–1017, 2002.

interactions, adverse reactions, contraindications, and pharmacology of appropriate antagonists. Individuals monitoring sedated patients should be able to recognize complications associated with the sedative drugs. Since most of the complications associated with sedatives are cardiopulmonary in nature, at least one individual should be familiar with advanced airway and ventilation management. Guidelines recommend an advanced resuscitation provider be immediately available in the event of an emergency.11 Resuscitation equipment should be readily available and must include a cardiac defibrillator, advanced airway and positive-pressure ventilation equipment, and all the appropriate drugs, including sedative antagonists (Box 7.1).

POSTPROCEDURAL MONITORING The patients remain at risk of sedative-related complications even after completion of the procedure. The risk of upper airway obstruction and hypoxemia after significant moderate sedation for ERCP seems to be greatest immediately after removal of the endoscope. Monitoring of the patient should be continued until the patient has reached an acceptable level of consciousness, with normal ventilation, oxygenation, and hemodynamic parameters. Before discharging the patient, it should be recognized that there may be a prolonged period of amnesia with impairment of cognition and judgment, even though the patient’s conscious level may appear normal. Patients may also be mildly dehydrated,

especially after colonoscopy, and fluid replacement should be addressed before discharge planning. After an outpatient procedure, the following instructions should apply for at least 24 hours after discharge: }
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DRUGS FOR SEDATION An ideal sedative agent should have the following characteristics: }
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CHAPTER 7 Sedation and Monitoring in Endoscopy }
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PART THREE Benign Pancreatic Disorders

57 Recurrent Acute Pancreatitis Tyler Stevens and Martin L. Freeman

CHAPTER OUTLINE Introduction, 661 Definitions, 661 Epidemiology, 661 Causes, 662 Biliary Microlithiasis, 662 Pancreas Divisum, 663

Sphincter of Oddi Disorders, 665 Ampullary and Pancreatic Neoplasms, 667 Autoimmune Pancreatitis, 667 Choledochocele, 667

INTRODUCTION Acute pancreatitis (AP) has an excellent prognosis if the severity is limited, and if the underlying cause can be identified and treated. However, AP may recur if the underlying causes are not eliminated or modified. Patients with recurrent AP (RAP) endure frequent emergency room (ER) visits and hospitalizations, costly testing, potentially risky interventions, and may eventually develop chronic pancreatitis (CP) and related functional impairment. Thus, RAP has a detrimental impact on quality of life and places a tremendous cost burden on health care systems. The central clinical objective is to evaluate and treat the causes of RAP to interrupt the disease process. In this chapter, the evaluation and treatment of RAP are reviewed, with an emphasis on the appropriate role of endoscopy.

DEFINITIONS The diagnosis of AP can be established based on two of the following: (1) typical pancreatic pain, (2) elevation in serum lipase and/or amylase levels to greater than 3 times the upper limit of normal, and (3) confirmatory imaging findings.1 The term RAP is found in the literature dating back seven decades.2 RAP is defined as “two or more episodes of AP.” Reasonable stipulations have been imposed on this basic definition, including full resolution of symptoms between attacks,3 the absence of imaging changes indicating CP, and a period of at least 3 months between the initial and recurrent episode(s).4 The latter criterion is used to distinguish true recurrence from a complication from the initial attack or an exacerbation related to dietary advancement. The term idiopathic RAP (IRAP) is used when the cause is not immediately recognized based on history, physical

Evaluation and Treatment, 667 Primary Evaluation, 668 Secondary Evaluation, 669 Tertiary Evaluation, 673

examination, basic laboratory testing (e.g., serum triglyceride and calcium), and imaging tests (transabdominal ultrasound [TAUS] and/or computed tomography [CT] scan).5 Patients with IRAP are at risk for further attacks and progression to CP. In efforts to find obscure causes and cure the disease, they may undergo second-line imaging tests, endoscopic retrograde cholangiopancreatography (ERCP), and genetic testing. Even after these advanced tests have been performed and thousands of dollars have been spent, the cause may remain unexplained or unmodifiable, and attacks or persistent intractable pain may persist with or without morphologic evidence of CP. The term true idiopathic recurrent acute pancreatitis (TIRAP) has been coined for such unfortunate patients.6 An axiom of RAP and CP is that the symptom burden, especially chronic pain, correlates poorly with morphologic changes.7,8 Some patients with frequent attacks or intractable pain between attacks even undergo total pancreatectomy with autologous islet cell transplantation as a last resort, despite the absence of morphologic or functional evidence of CP.9

EPIDEMIOLOGY The incidence of AP ranges from 13 to 45/100,000.10 In 2012, AP accounted for 330,561 ER visits and 275,170 hospitalizations, with a related aggregate cost of $2.6 billion.11 Multiple observational studies have included consecutive patients followed after an index bout of AP to ascertain the rates of RAP and progression to CP. A 2015 meta-analysis showed a pooled recurrence rate of 22% (95% confidence interval [CI] 18%–26%) in 11 studies.12 The pooled rate of progression from RAP to CP was 36% (CI 20%–53%) in five studies. The prevalence rates of RAP and CP were higher in alcohol-related compared to biliary pancreatitis.

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CHAPTER 57 Recurrent Acute Pancreatitis

Abstract

Keywords

Recurrent acute pancreatitis (RAP) is a painful and debilitating condition for patients, and poses several challenges for clinicians. The primary management goal is to uncover the causes of RAP to prevent recurrent episodes and progression to chronic pancreatitis. Endoscopists have much to offer in the management of RAP, but endoscopic methods should be employed thoughtfully within the framework of a careful history, laboratory and genetic testing, and noninvasive imaging tests. In this chapter, the various causes of RAP will be discussed, with emphasis on the diagnostic and therapeutic role of endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic ultrasound (EUS).

acute pancreatitis endoscopic ultrasound ERCP pancreas divisum microlithiasis sphincter of Oddi dysfunction

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661.e1

662

SECTION III

Pancreaticobiliary Disorders

The results for other etiologies and idiopathic pancreatitis are not always reported. However, some studies have shown higher recurrence and progression rates in those with idiopathic compared to biliary etiology.13,14

CAUSES The causes of RAP and CP overlap, and have been categorized as toxic and metabolic, genetic, autoimmune, and obstructive (Table 57.1).15 Several etiologies particularly relevant to endoscopists are discussed in the following sections.

Biliary Microlithiasis Biliary microlithiasis is a common cause of IRAP in patients who have an intact gallbladder, particularly those with risk factors such as pregnancy, rapid weight loss, critical illness, prolonged fasting, ceftriaxone use, octreotide use, bone marrow or organ transplant, and prolonged fasting.16 Microlithiasis refers to small gallstones (e.g., < 3 mm)17 that are not easily visible on TAUS but may easily traverse the cystic duct and impact at the ampulla of Vater. Recurrent passage of small stones may produce an inflammation and fibrosis cycle resulting in ampullary stenosis, which increases susceptibility to obstructive AP episodes. Though microlithiasis is “invisible” on TAUS, it may coincide with the presence of biliary

TABLE 57.1

sludge, which is more easily seen on TAUS, repeat TAUS,18 and endoscopic ultrasound (EUS). Biliary sludge is a mixture of particulate matter, mucous, and bile, and is visible as nonshadowing echogenic material that forms layers in the dependent portion of the gallbladder.16 Sludge visible on EUS may not always contain stones, but may be a reasonable biomarker to guide treatment. Two studies showed high rates of sludge or biliary crystals (67%–74%) in patients with IRAP and intact gallbladders.18,19 In general, we consider both findings of microlithiasis or sludge visible on TAUS/EUS or the presence of crystals in the bile to indicate biliary pancreatitis, caused by passage of particulate material that causes transient ampullary obstruction. The diagnostic workup for microlithiasis and the threshold for an empiric cholecystectomy have been sources of some controversy. EUS may be more sensitive for detecting sludge and microlithiasis than TAUS, CT, and magnetic resonance cholangiopancreatography (MRCP)20,21 (Fig. 57.1). Some use cholecystokinin stimulation with endoscopic collection of expressed bile and polarized microscopy to check for crystals.22 This method is performed infrequently because of questionable specificity and reproducibility. Cholecystectomy is the definitive and currently preferred treatment for suspected microlithiasis. A practical approach advocated by many experts is to proceed to empiric cholecystectomy in those

TIGAR-O* Classification of Causes of Pancreatitis

Etiology

Clinical Clues/Risk Factors

Toxic

Alcohol Cigarette smoking Cannabis

Heavy regular or binge alcohol consumption

Metabolic

Hypertriglyceridemia

Familial lipid disorders, poorly controlled diabetes, obesity, excess estrogen, hypothyroidism, alcohol abuse Hyperparathyroidism

Hypercalcemia Obstructive

Cholelithiasis/choledocholithiasis Microlithiasis Sphincter of Oddi dysfunction IPMN Pancreatic cancer Chronic pancreatitis Upper GI Crohn’s disease Pancreas divisum Duodenal duplication cyst Juxtapapillary diverticulum

Rapid weight loss/gain, pregnancy, obesity, preceding biliary colic Elevated liver function tests during episode Postcholecystectomy, use of opiates Most common with main duct involvement New onset of RAP, age > 40 years, weight loss Presence of ductal stones/strictures History of Crohn’s disease Dorsal duct dilation or Santorinicele on imaging

Genetic

CFTR SPINK-1 PRSS1

Recurrent sinusitis/bronchitis, male infertility

Infectious

Ascariasis Viral (mumps, coxsackie A)

Autoimmune/Vascular

Type 1 AIP (IgG4-related sclerosing disease)

Type 2 AIP Lupus-associated pancreatitis Medications

Azathioprine, furosemide, valproic acid

Multiple family members in consecutive generations with pancreatitis and/or pancreatic cancer

Typical imaging findings (pancreatic enlargement, capsular enhancement, ductal strictures) Other organ involvement (salivary glands, retroperitoneal fibrosis, renal cortical lesions, etc.) Elevated IgG4 History of IBD Short latency from onset of medication to onset of attack, literature supportive of relationship, positive rechallenge

*Toxic and Metabolic, Idiopathic, Genetic, Autoimmune, Recurrent and Severe Acute Pancreatitis Associated Chronic Pancreatitis, Obstructive. AIP, autoimmune pancreatitis; GI, gastrointestinal; IBD, inflammatory bowel disease; IPMN, intraductal papillary mucinous neoplasm; RAP, recurrent acute pancreatitis.

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CHAPTER 57 Recurrent Acute Pancreatitis

663

Incomplete pancreas divisum

Dorsal duct

Ventral duct

Santorinicele

FIG 57.1 Gallbladder sludge seen on endoscopic ultrasound (EUS) in a 25-year-old woman with recurrent acute pancreatitis (RAP). She had slight alanine transaminase (ALT) elevations during the most recent bout. Transabdominal ultrasound (TAUS) was read as negative for stones. The attacks ceased after cholecystectomy was performed.

with TIRAP and intact gallbladder. Some have even advocated this intervention after a first attack.23 A 2015 interventional trial randomized patients experiencing their first attack of idiopathic AP to empiric cholecystectomy versus watchful waiting.24 Baseline TAUS was negative for stones in all patients. The cholecystectomy group had significantly lower rates of recurrence compared to the observation group (8/39 vs. 23/46, p = 0.016) after a mean of 36 months of follow-up. The number-needed-to-treat with cholecystectomy to prevent one patient from having a recurrence was five. The use of empiric cholecystectomy in IRAP should be considered carefully based on the patient’s clinical presentation and risk factors. For example, in a young, thin patient with IRAP who has normal liver function tests and whose gallbladder appears normal on ultrasonography, it would be prudent to first obtain genetic testing for pancreatitis-causing mutations. The finding of a significant high penetrance mutation (e.g., in PRSS1) may obviate cholecystectomy. Endoscopic biliary sphincterotomy (EBS) is an effective alternative for selected patients. The rationale for performing EBS is that it separates the biliary and pancreatic orifices, allowing crystals and stones to pass into the duodenum with less chance of causing pancreatic duct obstruction or biliary reflux. In observational studies, EBS has been shown to decrease the rate of recurrence of biliary pancreatitis in patients with intact gallbladders to 2% to 6%.25–27 EBS can be considered for very elderly patients, those with comorbidities increasing operative risk, those refusing cholecystectomy, or as a temporizing strategy if cholecystectomy is delayed. The use of EBS has waned since the advent of laparoscopic cholecystectomy, which may be safer than ERCP in this cohort of patients.

FIG 57.2 Endoscopic retrograde cholangiopancreatography (ERCP) performed on a patient with recurrent acute pancreatitis (RAP) shows incomplete pancreas divisum. The ventral duct and dorsal duct are connected by a small branch duct. At the most distal portion of the dorsal duct, a cystic outpunching (called a Santorinicele) is also seen. This patient responded to endoscopic minor papillotomy. (Image courtesy of Adam Slivka and Michael K. Sanders.)

Pancreas Divisum Pancreas divisum (PD) is a relatively common embryological anatomic variant that has been postulated to impair drainage of the pancreatic duct, contributing to obstructive pancreatitis. The pancreas begins as dorsal and ventral buds, each with separate ductal drainage into the foregut. Within the first trimester, the ventral bud rotates axially and fuses with the dorsal part. In most cases, the dorsal and ventral ducts likewise fuse, allowing redundant drainage of the entire pancreas through both minor and major papillae. In cases of PD, the ductal systems do not fuse, leading to separate drainage of the dorsal and ventral ducts, or only partially fuse (incomplete divisum), resulting in the presence of a thread-like connection between the systems (Fig. 57.2). Because the minor papilla is a smaller opening, patients with PD may suffer RAP affecting the dorsal pancreas (superior head, body, and tail of pancreas). Patients with PD are protected from biliary pancreatitis due to lack of continuity between the biliary and pancreatic ducts. As such, the diagnosis of PD may obviate empiric cholecystectomy in patients with IRAP. A rare exception is focal ventral gallstone pancreatitis, which may still occur in PD patients.28 The traditional gold standard for diagnosing PD has been ERCP. Cannulation and injection of the ventral pancreatic duct via the major papilla reveals a short, arborized ventral duct (Fig. 57.3). It is important to recognize that the finding of a short ventral duct may also indicate a benign or malignant pancreatic duct stricture.29 Observance of ventral duct arborization may prompt subsequent endoscopic cannulation and injection of the minor papilla to define the dorsal duct anatomy and allow endoscopic therapy. ERCP is now rarely needed for diagnosis of PD since the advent of MRCP, secretin-enhanced MRCP, and EUS.30 In most cases, endoscopists have a diagnostic MRCP available and undertake ERCP with therapeutic intent.

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SECTION III

Pancreaticobiliary Disorders

The decision to intervene in cases of PD must be considered carefully. PD is common, and its presence does not always indicate that it is a cause of or cofactor in IRAP. A comprehensive analysis of autopsy, ERCP, and MRCP studies suggest that the prevalence of PD in the general Western population is 8%.31 PD is less

FIG 57.3 This 33-year-old female had presumed gallstone pancreatitis, but continued to have recurrent acute pancreatitis (RAP) following cholecystectomy. Endoscopic retrograde cholangiopancreatography (ERCP) with contrast injection of the ventral duct via the major papilla showed an arborized appearance, consistent with pancreas divisum.

common in African Americans (1%–2%)32 and Asians (1.5%).33 Whether this common anomaly is a true cause of IRAP continues to be debated. Favoring causation are ERCP studies that show increased rates of PD among those with IRAP and CP compared to controls.34 However, a 2011 review highlights several biases that may explain these differences.35 Multiple retrospective and prospective studies have suggested that endoscopic therapy consisting of minor papillotomy or transpapillary dilation decreases the frequency of RAP or improves pain (Table 57.2).36–49 However, many of these studies are limited by significant patient heterogeneity, small sample size, limited duration of follow-up, and lack of comparison groups. Recent studies have also found that genetic mutations may confound the relationship of PD and pancreatitis. In a case-control study, patients with idiopathic pancreatitis had the same prevalence of PD as controls (7%), whereas the prevalence of PD was significantly higher in IRAP/CP patients with serine protease inhibitor Kazal type-1 (SPINK-1) (16%) and cystic fibrosis transmembrane conductance regulator (CFTR) mutations (47%). The authors concluded there was an association of PD with these genetic defects in patients with IRAP and CP,50 and that PD was acting as a “partner” in the genesis of pancreatitis. This latter argument (that PD is a cofactor) has been questioned by some who believe that PD does not cause pancreatitis.51 They have argued that PD may be an “innocent bystander” in what is really a genetic problem. In light of these controversies, deciding which patients are most likely to benefit from endoscopic treatment is a frequent clinical conundrum. Signs of impaired dorsal duct drainage (e.g., dorsal duct dilation, the presence of a Santorinicele, which is a saccular dilation of the terminal duodenal portion of the dorsal pancreatic duct [Fig. 57.4], focal inflammation or fibrosis of the dorsal pancreas, and decreased duodenal filling after secretin), may favor causation. Endoscopic therapy for PD involves minor papillotomy to enhance dorsal duct drainage (Fig. 57.5). After minor papillotomy, a temporary pancreatic stent is usually placed to maintain patency

Results of Endoscopic Therapy in Patients With Pancreas Divisum

TABLE 57.2

Mean Follow-Up (mo)

SYMPTOM RELIEF

Author (Year)

Study Design

No.

Russell et al. (1984)36

Retro

5

8

MES

Soehendra et al. (1986)40

Retro

6

3

MES

Liquory et al. (1986)39

Retro

8

24

MES

McCarthy et al. (1988)38

Retro

19

6–36

Stent

Prabhu et al. (1989)37

Retro

18

12–60

Stent

Siegel et al. (1990)42

Retro

31

24

Stent

Lans et al. (1992)

RCT

10 (9 controls)

29

Stent

Sherman et al (1994)43

RCT

16 (17 controls)

25

MES

Lehman et al. (1993)44

Retro

52

20

MES

13/17

Coleman et al. (1994)48

Retro

34

23

Stent

7/9

45

Kozarek et al. (1995)

Retro

39

26

MES and/or stent

11/15

6/19

Boerma et al. (2000)46

Prosp

16

51

Stent

Prosp

25

24

Stent

19/25

Prosp

24

39

MES or Stent

22/24

41

Ertan (2000)

47

Heyries et al. (2002)49

Intervention

NP 1/5

ARP 2/2

CP

CAP

4/4

Restenosis

Chronic Duct Changes

NP

5/8

NP 3/8

17/19

2/19 15/18

NS

26/31

NS 9/10

0/10 7/16

NP

3/11

6/24

10/18

12/20

2/5

NP

1/5

3/26

5/16

NS 10/39 NS 21/25

NS

16/16

ARP, acute recurrent pancreatitis; CAP, chronic abdominal pain; CP, chronic pancreatitis; mo, months; MES, minor papilla endoscopic sphincterotomy; NP, not provided; NS, not significant; Prosp, prospective uncontrolled trial; RCT, randomized controlled trial; Retro, retrospective review.

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CHAPTER 57 Recurrent Acute Pancreatitis

A

665

B

FIG 57.4 Magnetic resonance cholangiopancreatography (MRCP) examples of pancreas divisum with Santorinicele in two patients with recurrent acute pancreatitis (RAP). A, A 15-year-old boy with RAP. There is a normal caliber duct with a Santorinicele. Attacks ceased after endoscopic minor papillotomy. B, A 45-year-old man with RAP and chronic abdominal pain. MRCP shows a Santorinicele and a dilated dorsal duct with dilated side branches, indicating outflow obstruction and possible chronic pancreatitis. This patient had no further acute pancreatitis episodes after minor papillotomy, but continued to suffer with chronic daily pain.

of the orifice during healing and as prophylaxis against post-ERCP pancreatitis. Minor papilla localization and cannulation to achieve dorsal duct access can be challenging. The minor papilla is situated proximally and to the right of the major papilla, and is often best visualized from a long scope position. The minor papilla sometimes appears as a small mound or “mini-papilla,” but in other cases is quite flat with an almost invisible orifice. Localization of the orifice may be aided by intravenous secretin injection, which stimulates pancreatic juice production, causing the orifice to open.52 Methylene blue sprayed over the surrounding mucosa can be a useful adjunct.53 After secretin is administered, the brisk pancreatic flow washes clear the blue dye surrounding the orifice, producing a visible blush for targeted cannulation. Smaller tapered catheters loaded with hydrophilic 0.021-inch wires are best for these cases. It is best to cannulate with the wire because probing with the catheter may cause trauma and bleeding, which can impair localization. After the duct is engaged successfully with a wire and then with the catheter, great care must be taken in passing the wire to the pancreatic tail. If the wire enters a side branch and force is applied, side branch perforation can easily occur, increasing the risk of pancreatitis. As with all pancreatic duct work in the era of MRCP, limited or no contrast injection is needed for guidewire passage. Once the guidewire is positioned, a minor papillotomy can be accomplished with the traction sphincterotome. If the catheter cannot be advanced over the wire because of stenosis, a needle-knife incision can be made over the wire. When wire access fails, precut needle-knife papillotomy may be needed to achieve access. This maneuver should only be performed carefully and incrementally when there is certainty regarding the location of the papillary orifice. Another common technique for minor papillotomy is to place a stent and then perform needle-knife sphincterotomy over the stent. Limited data suggest that the pull-type (traction) and needleknife-over-stent techniques have similar safety and restenosis rates.54 Video 57.1 demonstrates several techniques relative to minor papilla access.

Sphincter of Oddi Disorders Elevated basal sphincter tone or spasm and ampullary stenosis may obstruct the flow of pancreatic secretions or cause bile reflux into the pancreatic duct, triggering episodes of pancreatitis. Sphincter of Oddi disorders (SODs) are sometimes considered as a possible cause of IRAP in postcholecystectomy patients. Pancreatic SOD is included in the well-known Milwaukee classification, with most IRAP patients falling into the type 2 category (pancreatic pain, recurrent elevations in amylase or lipase, and normal pancreatic duct).55 There is ongoing debate over the relationship between SOD and pancreatitis, but evidence is mixed regarding a causative relationship. Multiple studies using manometry have shown elevated sphincter pressures ranging from 15% to 72% in patients with IRAP, although the significance of elevated sphincter pressures remains unclear, and hypertension may not translate to a clinical syndrome that responds to biliary and or pancreatic sphincter ablation.56–64 There are no evidence-based guidelines regarding the role of ERCP in diagnosis and treatment of SOD in IRAP. Relief from recurrent attacks occurs in 52% to 89% of patients with manometrically confirmed pancreatic SOD who undergo endoscopic therapy with sphincterotomy or botulinum toxin.60,61,64–67 In prospective studies, the rates of RAP after endoscopic therapy range from 14% to 48% over a mean follow-up period of 29 to 78 months.60,64,65 The decision to intervene in type 1 pancreatic SOD (i.e., IRAP and a dilated pancreatic duct) is fairly clear-cut. However, most patients fall into the type 2 category, and lack ductal dilation to implicate outflow obstruction. Because of the inherent risk and uncertain effectiveness of endoscopic therapy, it is preferred that the endoscopist meet the patient prior to performing the procedure. This preprocedure consultation allows the establishment of trust and a rapport between the physician and patient, and enables the physician to communicate realistic expectations regarding the risks of the procedure and the likelihood of a response. The risk of post-ERCP pancreatitis is elevated

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SECTION III

Pancreaticobiliary Disorders

A

B

C FIG 57.5 Endoscopic therapy for pancreas divisum. A, Wire cannulation is accomplished using a tapered-tip catheter with a 0.021-inch wire. B, After deep wire access is achieved, a minor papillotomy is performed using a traction sphincterotome and blended current. C, A 5-Fr single pigtail stent is placed to prevent post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis.

in this group compared to other indications (10% vs. 4%),68 and is highest for those with pancreatic sphincter hypertension.69 Many additional patients will require admission for postprocedure abdominal pain, with or without modest enzyme elevations. Endoscopic approaches to SOD have been heterogeneous, and there are few randomized trials to define the optimal technique and the efficacy of the intervention. Furthermore, outcomes in most studies of endoscopic therapy for IRAP have been variably defined, and many studies have suboptimal followup.70 A common practice has been to perform empiric sphincterotomy (without manometry) in RAP, citing the increased time and risk and lack of precision of sphincter of Oddi manometry (SOM) measurements. However, many experts suggest SOM as a guide for sphincterotomy, especially in cases of suspected

pancreatic sphincter hypertension, given the increased risk of pancreatic sphincterotomy. The main argument in favor of SOM is that patients with high pressures have better response rates, whereas those with normal pressures can be spared the additional risk of sphincter ablation because they are unlikely to respond. In addition, it appears that SOM does not add significantly to the risk of the procedure.71 Indirect tests (e.g., secretin-stimulated EUS, nuclear scintigraphy) have not shown sufficient sensitivity to be alternatives to SOM in ruling out SOD.72,73 Another question is what type of sphincterotomy to perform. The sphincter of Oddi is comprised of three components: common, biliary, and pancreatic sphincter fibers. An EBS may suffice to treat patients with type 2 pancreatic SOD, rather than an endoscopic dual sphincterotomy (EDS), as pancreatic sphincter

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CHAPTER 57 Recurrent Acute Pancreatitis hypertension is often primarily due to the common fibers rather than the pancreatic fibers. As such, cutting the common fibers may sufficiently decrease pancreatic sphincter pressure to prevent further attacks. Past observational studies have yielded mixed conclusions regarding the necessity of EDS rather than EBS in type 2 pancreatic SOD.74,75 A 2012 randomized controlled trial compared EBS and EDS in patients with pancreatic sphincter hypertension. Patients with manometrically confirmed pancreatic sphincter hypertension were randomized to EBS (n = 33) or EDS (n = 36) and followed for a mean of 78 months (interquartile range 23–108 months).64 There was no difference in the rate of RAP during follow up (48.5% vs. 47.2%, p = 0.20). The rates of RAP following both EBS/EDS were notably high compared to retrospective studies of pancreatic SOD. This interesting finding suggests that sphincter hypertension may not always be the true pathogenic factor in pancreatic SOD, and that underlying genetic factors or other unknown variables may be at play. The investigators also randomized patients with normal SOM (n = 20) to EBS or sham treatment. There was no difference in the rate of RAP observed during follow-up between these two groups (11% vs. 27%, p = non-significant). The results of this study call into question the role of manometry in directing sphincterotomy, and perhaps even the value of a sphincterotomy in RAP. Although sphincter ablation may still be considered on an individualized basis, we believe a prudent strategy is to selectively cannulate the bile duct and perform EBS without preceding manometry. In patients who recur following EBS, pancreatic manometry with or without EDS can be considered as a “salvage” procedure.

Ampullary and Pancreatic Neoplasms A high suspicion for underlying cancer should be maintained in patients with RAP, especially in those over the age of 40 who have developed RAP in the past several months. Cancers of the duodenum, ampulla,76 and pancreas may obstruct the pancreatic duct, leading to AP episodes (Fig. 57.6). In a consecutive series of 124 patients with pancreatic carcinoma, AP was the presenting symptom in 13.8%.77 Though they do not arise from the pan-

667

creatic duct, neuroendocrine tumors may also occasionally cause AP.78 Intraductal papillary mucinous neoplasm (IPMN) involving the main and branch ducts may be associated with pancreatitis in 7% to 43% of patients, though many of these reports are from surgical series that are enriched with symptomatic patients79–82 (Fig. 57.7). The pathogenesis of pancreatitis is likely related to ductal plugging by mucous secretion. Patients with IPMN presenting with AP tend to be younger, and have greater odds of harboring malignancy compared to those without AP.83 AP is more commonly observed with main-duct and mixed-type variants, but may also be seen in branch-duct IPMN.82 In cases of branch-duct IPMN, it may be difficult to prove that the cyst is causing pancreatitis, as incidental IPMNs are common (Fig. 57.8).

Autoimmune Pancreatitis RAP is rather unusual in type 1 autoimmune pancreatitis (AIP), with obstructive jaundice, diabetes, and weight loss being more common presentations. When AP does occur, the likely explanation is pancreatic duct stricturing. A systematic review of nine studies published in 2008 (140 patients with AIP) reported the occurrence of recurrent pain or pancreatitis.84 The overall rate of recurrent pain or pancreatitis was only 10.1%. RAP appears to be a more common presentation in the type 2 rather than type 1 histological variant. Type 2 AIP is more difficult to diagnose than type 1 because of the lack of a serological marker and the greater difficulty in obtaining diagnostic histology. An international survey reported RAP in 5% of type 1 AIP cases and 34% of type 2 AIP cases.85 The largest US study of type 2 AIP (n = 43) reported an even higher RAP rate of 58.1%.86 In that series, type 2 AIP patients presenting with AP were younger (mean age 28 years vs. 47 years), less apt to have obstructive jaundice (16% vs. 50%), less apt to have a pancreatic mass (12% vs. 67%), and more likely to have inflammatory bowel disease (IBD) (60% vs. 22%). Though still a rare cause of AP, type 2 AIP should be considered in patients with IRAP who fit this clinical profile. Carefully selected patients (especially those with IBD) may warrant core biopsy or empiric corticosteroid trials (Fig. 57.9).

Choledochocele Ampullary cancer

Choledochoceles are cystic dilations of the intraduodenal portion of the common bile duct (CBD). They are classified as type 3 choledochal cysts, the least common subtype.87 RAP is a common clinical presentation among patients with symptomatic choledochoceles, and likely occurs as a result of biliary reflux into the pancreas.88 The incidence of malignancy arising from choledochoceles is thought to be much lower than from other types of choledochal cysts, though rare cases have been reported.89 EBS is the current standard of care for choledochoceles (Fig. 57.10).90 EBS unroofs the cyst and separates the biliary and pancreatic duct drainage. Outcome studies are lacking; however, available evidence suggests that EBS usually resolves pancreatitis.91

EVALUATION AND TREATMENT

FIG 57.6 This 70-year-old patient presented with a single unexplained bout of acute pancreatitis. Subsequent endoscopic examination revealed ampullary cancer. (Image courtesy of Adam Slivka and Michael K. Sanders.)

The evaluation and treatment of RAP can be divided into three phases. In the primary evaluation, simple and obvious causes are sought through a careful history, laboratory testing, ultrasound with or without CT imaging, and careful review of the records from past attacks. In the secondary evaluation, advanced imaging is performed and laboratory testing is obtained to look for “occult” biliary, structural, and genetic causes. In the tertiary evaluation,

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668

SECTION III

Pancreaticobiliary Disorders

Massively dilated main pancreatic duct

A

B FIG 57.7 Example of a patient with recurrent acute pancreatitis (RAP) due to main duct intraductal papillary mucinous neoplasm (IPMN). A, CT scan shows hugely dilated pancreatic duct. B, Sideviewing endoscopy reveals gaping papilla with mucin extrusion. (Images courtesy of Adam Slivka and Michael K. Sanders.)

“Pancreas Centers of Excellence” have been developed throughout the country to provide a comprehensive evaluation of patients with complex pancreatic disorders like IRAP.92 BOP PD

? IPMT

FIG 57.8 This 55-year-old patient had three unexplained bouts of acute pancreatitis. On EUS examination, a cyst was found in the uncinate process that communicated with a side branch suggestive of a branch-type IPMN. BOP, bleeding on probing; EUS, endoscopic ultrasound; IPMN, intraductal papillary mucinous neoplasm; IPMT, intraductal papillary mucinous tumor; PD, pancreas divisum. (Courtesy of Dr. Kevin McGrath, University of Pittsburgh Medical Center.)

endoscopic testing and empiric endoscopic or surgical approaches may be offered to identify causes or prevent attacks. The primary evaluation is often performed during hospitalization for AP, whereas the secondary and tertiary evaluations are often performed in an outpatient setting. A number of multidisciplinary

Primary Evaluation Careful History The evaluation of RAP starts with taking a careful history to ascertain risk factors. Heavy daily or binge alcohol consumption may suggest alcohol as the cause. However, alcohol-related pancreatitis may be overdiagnosed in moderate regular drinkers.93 Alcohol may not be the primary driver in these patients, and other potentially treatable causes should not be missed. Smoking has long been known to be a risk factor for CP and pancreatic cancer, but until recently has been ignored in AP. Several studies now implicate smoking as a cause or cofactor in AP as well.94 Case reports from 2012 implicate cannabis as a trigger.95 Preceding biliary colic may suggest gallstones. New prescription medications started within 1 to 2 months of the index episode or class I or II medications that are known to be associated with pancreatitis may suggest medication-induced pancreatitis.96 The past medical history is also important to review. A personal history of high triglycerides or poorly controlled diabetes may suggest hypertriglyceridemia-mediated AP. A history of cholecystectomy suggests the possibility of SOD. A history of parathyroid issues or renal failure may suggest hypercalcemia-induced AP. A history of recurrent bronchitis or sinusitis, asthma, or male infertility may implicate a CFTR polymorphism. A family history of pancreatitis or cystic fibrosis (CF) may suggest genetic causes. Basic Laboratory Evaluation The primary laboratory evaluation of AP includes serum amylase, lipase, liver function tests, calcium, and triglyceride levels. Serum

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CHAPTER 57 Recurrent Acute Pancreatitis

669

B

A

FIG 57.9 Example of CT findings in autoimmune pancreatitis. A, Pretreatment CT. The pancreatic body and tail are diffusely enlarged, with loss of normal contour. B, Posttreatment with corticosteroids. The previous pancreatic enlargement has resolved. (Images courtesy of Adam Slivka and Michael K. Sanders.)

alcohol levels may also be useful to detect surreptitious alcohol use. In recurrent episodes, it is helpful to obtain and review laboratory data from as many of the past attacks as possible. This serves to confirm whether significant lipase elevations are truly present to confirm the diagnosis of RAP. In addition, the presence of concomitant alkaline phosphatase and/or alanine transaminase (ALT) elevations may implicate gallstones, microlithiasis, or sphincter of Oddi dysfunction.97 The admitting serum triglyceride level may help detect hypertriglyceridemia as a cause. A triglyceride level of more than 1000 mg/dL at the time of presentation strongly supports triglyceride-mediated AP; whereas a level of greater than 500 mg/dL should raise a high degree of suspicion.98 If the triglyceride level was assessed later during the admission (after days of fasting), it may have decreased substantially. In these cases, repeating the serum triglyceride once the patient has returned to his or her usual diet may be warranted. Imaging With TAUS and CT The best initial imaging modality for detecting biliary causes of pancreatitis is TAUS. The results of all previous ultrasounds should be reviewed for findings that may implicate a biliary cause (e.g., sludge or stones in the gallbladder, biliary dilation) and suggest the need for cholecystectomy. CT scans have a limited role during an AP attack, and are performed primarily to detect local complications (necrosis, fluid collections, etc.). To detect necrosis, CT scans are optimally performed 3 days after symptom onset in patients who demonstrate signs of clinical severity.99 If CT scans were performed during past attacks, it is useful to review them to ascertain the presence, severity, and location of inflammation. Most commonly, inflammation is diffused throughout the pancreas. However, inflammation that is focal in one area of the gland may help elucidate a structural cause. For example, inflammation confined to the tail of the pancreas may indicate a pancreatic duct tumor or stricture and indicate the need for further advanced imaging with MRCP or EUS.

Secondary Evaluation In up to 90% of cases of AP, the primary evaluation reveals treatable causes (ongoing alcohol use, gallstones/sludge, liver

function tests or biliary duct abnormalities indicating SOD, high triglycerides, culprit medications, etc.).100 The underlying factors can thus be eliminated or treated, and patients observed for recurrence. However, a subset of cases remains undiagnosed. These cases are properly termed IRAP, and may require “second-line” testing to look for autoimmune, genetic, and structural causes. Autoimmune Testing Serum total IgG and IgG4 levels may be obtained to “screen” for AIP. However, proper diagnosis of AIP is usually more complicated than simply ordering a lab test. Serum IgG4 exhibits only approximately 76% sensitivity for type 1 AIP,101 and levels are normal in patients with type 2 AIP. Additionally, IgG4 may be mildly elevated in the absence of AIP. Several scoring systems have been devised to diagnose AIP, including the HISORt (histology, imaging, serology, other organ involvement and response to therapy) criteria, which include a combination of laboratory, imaging, and histological features.102 It is useful to review pancreatic imaging with an abdominal radiologist to look for features of AIP, such as diffuse pancreatic enlargement, capsular enhancement, or diffuse/multiple pancreatic duct stricturing. If past imaging is not optimal or is confounded by significant acute inflammation, then obtaining a contrastenhanced MRCP may be useful to check for ductal and parenchymal features of AIP. Genetic Testing Testing for genetic causes may be considered in IRAP. There has been an explosion in knowledge regarding the genetics of pancreatitis. Genetic testing for certain pancreatitis-associated mutations is now commercially available, and may be considered in selected patients with IRAP. Important genetic causes include mutations of the cationic trypsinogen (PRSS1), CFTR, SPINK-1, and chymotrypsin C (CTRC) genes. Mutations in PRSS1 cause hereditary pancreatitis (HP). HP is an autosomal dominant disease with high penetrance, so patients will often have multiple family members in consecutive generations affected with pancreatitis. These patients classically

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670

SECTION III

Pancreaticobiliary Disorders

A

B

C

D

E FIG 57.10 Example of choledochocele diagnosis and endoscopic treatment. An 8-year-old boy presented with idiopathic acute recurrent pancreatitis (IRAP). A, Secretin-enhanced magnetic resonance cholangiopancreatography (MRCP) shows a large saccular choledochocele with separate entry of common bile duct and pancreatic duct (outlined in red). B, Endoscopic view showing prominent choledochocele. Endoscopic therapy consisted of C, needle-knife unroofing of the lumen and D, biliary cannulation and extension of the biliary sphincterotomy. E, Methylene blue spray after secretin injection showing exposed pancreatic sphincter (arrows) without injury. Downloaded for Usuario UDEM ([email protected]) at Universidad de Monterrey from ClinicalKey.com by Elsevier on July 25, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved.

CHAPTER 57 Recurrent Acute Pancreatitis develop RAP in childhood and progress to CP in the teen years, and have a 40% lifetime risk of pancreatic cancer.103 CF is a genetic disorder caused by impaired function of the CFTR protein that regulates chloride secretion in the pancreatic duct cells. CF is a heterogeneous disorder, likely because there are over 1200 known mutations that result in a range of problems with CFTR production, transport, and function. When the genetic defects are severe, pancreatic secretions are inspissated and plug the ductules, resulting in rapid and severe fatty replacement and atrophy of the pancreas. Children with severe mutations are often recognized promptly through newborn screening, and their pancreatic, pulmonary, and other problems are quickly and aggressively managed in CF centers. Adults may harbor milder or single allele CFTR defects that do not produce pancreatic insufficiency, but are recognized later in life with atypical manifestations including bronchitis, asthma, and RAP. Mutations in SPINK-1 are unlikely to solely cause RAP, but may promote the development of CP, and sometimes present as a cofactor with other genetic or environmental causes.104,105 Genetic testing may be considered in patients with a family history of pancreatitis and in young patients with IRAP. This testing should be ordered with caution and should be accompanied by appropriate pretest counseling. There are several conceivable benefits of genetic testing, including obtaining insight into the cause and providing further motivation to avoid alcohol use and smoking. Although opponents counter that the results do not meaningfully affect management, this is not always the case. For example, the finding of a PRSS1 mutation may prompt yearly imaging tests because of its associated risk of pancreatic cancer.106 Finding a pancreatitisassociated mutation may also prevent empiric interventions like ERCP with sphincterotomy and cholecystectomy. Genetic mutations in patients with frequent RAP episodes may even prompt consideration of total pancreatectomy.107 A major downside of testing is its high cost, and sometimes the lack of insurance coverage for testing. Second-Line Imaging Tests Some structural causes of RAP may be missed on ultrasound and CT performed at the time of the attack(s), and require more advanced imaging for diagnosis. Occult pancreatic cancer is a major concern, especially in those over age 40 who developed IRAP in the past several months. Pancreatic inflammation or necrosis may mask small cancers on initial imaging. Sometimes, only slight pancreatic duct dilation indicating downstream obstruction is present. In such patients, it is wise to repeat a contrast-enhanced pancreatic protocol CT or magnetic resonance imaging (MRI), or to consider EUS. The findings of these advanced tests often help guide subsequent treatment (see Fig. 57.7). Such testing is best performed 4 to 6 weeks after discharge, once inflammation has improved. Additional obstructive causes include PD, pancreatic duct stricture, IPMN, ampullary neoplasm, and duodenal pathology. In years past, ERCP was frequently employed as a second-line evaluation in patients with RAP. Typically, ERCP would include a cholangiogram to look for biliary stones and a diagnostic pancreatogram to check for ductal pathology. Though ERCP has significant therapeutic potential in RAP, it has since fallen out of favor as a purely diagnostic test because of the advent of MRCP and EUS. Both provide excellent detail of the pancreatic duct and parenchyma, and have been used extensively in the

671

workup of patients with IRAP. However, each has its own advantages and limitations. Magnetic Resonance Cholangiopancreatography MRCP provides complete imaging of the pancreatic parenchyma and duct. MRCP protocols include heavily T2 (fluid)-weighted imaging to generate an “ERCP-like” image of the pancreatic duct. In young patients with IRAP, MRCP is an invaluable tool for screening for PD, and helps stratify its significance based on the presence or absence of dorsal duct dilation and Santorinicele. The addition of secretin administration improves ductal imaging resolution and has higher diagnostic accuracy for PD than standard MRCP (pooled sensitivity 86%; pooled specificity 97%).30,108 The assessment of duct compliance and drainage following secretin administration has been used as a diagnostic test for outflow obstruction from SOD and PD and as a decision point for subsequent ERCP therapy.109 In addition, MRCP detects pancreatic tumors, pancreatic duct strictures, and branch-type and main-duct IPMN. The main limitation of MRCP in the workup for IRAP is the lack of ampullary and luminal visualization. Recent evidence (2015) suggests that secretin MRCP may be quite accurate in detection of underlying CP, which may always be present in patients with RAP.110 In fact, secretin MRCP may be more accurate than EUS in detecting histologically less advanced forms of CP.111 Endoscopic Ultrasound EUS is also frequently used in the secondary evaluation of IRAP and may help guide subsequent evaluation and therapy (Fig. 57.11). It is similar to MRCP in that it provides exquisite imaging of the pancreas. Its advantages over MRCP include luminal visualization, greater detection of biliary sludge and stones, tissue and fluid acquisition, and the ability to detect parenchymal changes indicative of CP. EUS may also be superior to CT for detecting small masses.112 Some observational studies have compared the yield of EUS and MRCP in patients with IRAP.113,114 One included 38 patients with IRAP who underwent both EUS and MRCP. A higher yield was observed for EUS than for MRCP (29% vs. 10.5%). MRCP was superior for detecting ductal abnormalities like PD, whereas EUS was better for biliary causes. The two tests had a combined 50% yield, suggesting that they may be complementary. Linear EUS is most commonly used for pancreaticobiliary examinations, but radial EUS can also suffice, based on physician preference. It is usually best to delay EUS until 3 or 4 weeks after recovery from the last AP episode to maximize the diagnostic yield, as views of the pancreas can be obscured by pancreatic inflammation and peripancreatic fluid. When performing EUS to evaluate RAP, the endoscopist should have the following 7-point “checklist” in mind: 1. Is there duodenal or ampullary pathology? Generally, a screening endoscopy is advisable to look for duodenal inflammation or neoplastic pathology. The ampulla should be examined and photodocumented, with careful inspection for adenomas, masses, mucin extrusion, and diverticulae. Satisfactory ampullary views can often be obtained using the oblique view of the echoendoscope; however, a side-viewing duodenoscope should be passed if necessary. 2. Are biliary stones or sludge present? The bile duct should be carefully traced from the hilum to the ampulla, looking for layering echogenic sludge or echogenic rounded structures

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SECTION III

Pancreaticobiliary Disorders

IRAP

EUS, secretinMRCP

CBD Stones, pancreas divisum, choledochocele, chronic pancreatitis with PD stone or stricture

Gallbladder stones/sludge*

Tumor*

Surgery if appropriate

Normal

Gallbladder in

Endoscopic therapy

?

Cholecystectomy

Gallbladder out ?

ERCP with SO manometry, biliary or dual sphincterotomy if pancreatic SOM abnormal

FIG 57.11 Treatment algorithm for unexplained recurrent pancreatitis. *Indicates conditions for which EUS appears to be superior to MRCP in terms of diagnosis. CBD, common bile duct; ERCP, endoscopic retrograde pancreatography; EUS, endoscopic ultrasound; IRAP, idiopathic acute recurrent pancreatitis; MRCP, magnetic resonance cholangiopancreatography, PD, pancreas divisum; SO, sphincter of Oddi; SOM, sphincter of Oddi manometry.

with shadowing indicating stones. Striving to achieve complete ampullary imaging from both the duodenal bulb (long position) and the second portion (short position) decreases the chance of missing small stones. In patients with their gallbladder in situ, the gallbladder fundus, body, and neck should be carefully scrutinized for stones and layering sludge. 3. Are there pancreatic tumors or strictures affecting the pancreatic duct? The pancreas should be viewed in its entirety, looking for masses or focal hypoechoic regions that indicate possible occult cancer. Fine-needle aspiration (FNA) should be performed of any suspicious lesions. The duct should be carefully traced into the stomach and duodenum to detect obstructing tumors, strictures, or stones, which may result in proximal duct dilation. 4. Is PD present? EUS can have similar or even superior accuracy as MRCP for diagnosing PD,115 but is more operator-dependent. Various EUS findings have been reported as useful in diagnosing pancreas divisum, including a crossed appearance of the bile and pancreatic duct, absence of a “stack sign” (i.e., appearance of portal vein, pancreatic duct, and bile duct in single image), and separate insertion of bile and pancreatic ducts into the duodenal wall. In our experience, the best approach is to trace the pancreatic duct from the point of its insertion with the bile duct at the ampulla into the dorsal pancreas (Video 57.2). A sensitivity of 95% and specificity

of 97% have been reported using this approach; however, this study excluded 22% of patients in whom the ductal anatomy could not be adequately assessed.116 We find EUS to be most useful to rule out PD when the duct can be successfully traced. The inability to trace the duct from ampulla to dorsal pancreas may suggest pancreas divisum, but might also indicate technical limitations preventing continuous visualization of the duct. In those with pancreas divisum, the Santorini duct can sometimes be traced to the minor papilla, and inspection can be made for a Santorinicele indicating functional outflow obstruction. 5. Are the pancreatic and/or bile ducts dilated? It is good practice to measure the CBD and pancreatic ducts to assess for dilation indicating ampullary outflow obstruction. Most experts agree a normal CBD diameter is 6 mm or less in patients with a gallbladder and 9 mm or less in those who are postcholecystectomy. The normal diameter of the pancreatic duct is 3 mm in the head, 2 mm in the body, and 1 mm in the tail.117 Dilation of the ducts may help support a diagnosis of SO dysfunction, ampullary stenosis, or impaired drainage from PD. 6. Is CP present? The EUS diagnosis of CP is discussed in detail elsewhere in the text (see Chapter 59). The presence of CP helps to stage RAP and explains abdominal pain that persists between attacks. The finding of ductal obstruction related to CP (stones and strictures) may also indicate an obstructive

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CHAPTER 57 Recurrent Acute Pancreatitis cause of ongoing RAP that could benefit from endoscopic or surgical management. CP findings are often observed in RAP, with prevalence in early series ranging from 0% to 65%.23 Anecdotally, we find that many patients with IRAP ultimately found to possess genetic mutations have significant CP changes on EUS. 7. Is there evidence of AIP? The EUS appearance of AIP is typically a diffusely enlarged and hypoechoic-appearing gland, sometimes with interspersed hyperechoic lines or foci (Video 57.3).118 Pancreatic duct dilation is typically absent. Focal hypoechoic masses may also be observed. In such cases, FNA is indicated to help rule out malignancy.119 In patients with characteristic EUS features of AIP, FNA might also be considered to make a “tissue diagnosis” of AIP, but obtaining a satisfactory tissue sample that is able to confirm histology may be challenging. Cytological specimens obtained using 22- and 19-gauge needles have shown mixed results for obtaining lymphocytes and plasma cells suitable for IgG4 staining.120,121 It is unusual to detect the more confirmatory finding of obliterative phlebitis using typical EUS needles, suggesting the need for needles that would provide larger tissue specimens with preserved tissue architecture. The use of the Tru-cut biopsy needle has fallen out of favor due to technical difficulties and complications, and is no longer commercially available. However newer, more flexible and easy-to-use fine-needle biopsy (FNB) needles are emerging, which may be able to obtain tissue “cores,” facilitating the endoscopic diagnosis of AIP.

10. 13.

15. 19. 23.

24.

30.

50.

52.

59.

63.

Tertiary Evaluation After these primary and secondary evaluations, endoscopic and surgical approaches may be carefully considered to diagnose or provide targeted or empiric treatment. ERCP is the primary tool in the tertiary evaluation of RAP. As detailed previously, ERCP helps to diagnose and treat SOD, PD, ampullary pathology, and pancreatic duct strictures. Surgical approaches that are selectively employed in the tertiary evaluation of RAP include cholecystectomy; partial pancreatectomy in patients with masses, IPMNs, or strictures; major and minor sphincteroplasty; and total pancreatectomy with autologous islet cell transplant (TP/AIT) for those with genetic or “true” IRAP. In a case series of 49 patients with IRAP without evidence of CP on structural and/ or function testing, improvement in narcotic utilization and quality of life was observed after TP/IAT.9 In addition, 45% of patients were insulin-independent after 1 year of follow-up, with a mean hemoglobin A1C of 6.0%. Further outcome studies are needed to determine if this intervention also decreases hospitalization and health care utilization by eliminating AP attacks.

KEY REFERENCES 1. Tenner S, Baillie J, DeWitt J, Vege SS: American College of Gastroenterology guideline: management of acute pancreatitis, Am J Gastroenterol 108:1400–1415, 2013. 9. Bellin MD, Kerdsirichairat T, Beilman GJ, et al: Total pancreatectomy with islet autotransplantation improves quality of life in patients with

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73. 77. 86.

93.

110.

111.

118.

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A complete reference list can be found online at ExpertConsult .com

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CHAPTER 57 Recurrent Acute Pancreatitis

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Pancreaticobiliary Disorders

49. Heyries L, Barthet M, Delvasto C, et al: Long-term results of endoscopic management of pancreas divisum with recurrent acute pancreatitis, Gastrointest Endosc 55:376–381, 2002. 50. Bertin C, Pelletier A, Vullierme M, et al: Pancreas divisum is not a cause of pancreatitis by itself but acts as a partner of genetic mutation, Am J Gastroenterol 107:311–317, 2012. 51. Dimagno MJ, Dimagno EP: Editorial: Pancreas divisum does not cause pancreatitis, but associates with CFTR mutations, Am J Gastroenterol 107:318–320, 2012. 52. Devereaux BM, Lehman GA, Fein S, et al: Facilitation of pancreatic duct cannulation using a new synthetic porcine secretin, Am J Gastroenterol 97:2279–2281, 2002. 53. Park SH, de Bellis M, McHenry L, et al: Use of methylene blue to identify the minor papilla or its orifice in patients with pancreas divisum, Gastrointest Endosc 57:358–363, 2003. 54. Attwell A, Borak G, Hawes R, et al: Endoscopic pancreatic sphincterotomy for pancreas divisum by using a needle-knife or standard pull-type technique: safety and reintervention rates, Gastrointest Endosc 64:705–711, 2006. 55. Hogan WJ, Geenen JE: Biliary dyskinesia, Endoscopy 20:179–188, 1988. 56. Toouli J, Roberts-Thomson IC, Dent J, et al: Sphincter of Oddi motility disorders in patients with idiopathic recurrent pancreatitis, Br J Surg 72:859–863, 1985. 57. Venu RP, Geenen JE, Hogan W, et al: Idiopathic recurrent pancreatitis: an approach to diagnosis and treatment, Dig Dis Sci 34:56–60, 1989. 58. Eversman D, Fogel EL, Rusche M, et al: Frequency of abnormal pancreatic and biliary sphincter manometry compared with clinical suspicion of sphincter of Oddi dysfunction, Gastrointest Endosc 50: 637–641, 1999. 59. Gregg JA, Carr-Locke DL: Endoscopic pancreatic and biliary manometry in pancreatic, biliary and papillary disease, and after endoscopic sphincterotomy and surgical sphincteroplasty, Gut 25: 1247–1254, 1984. 60. Kaw M, Brodmerkel GJ: ERCP, biliary crystal analysis, and sphincter of Oddi manometry in idiopathic recurrent pancreatitis, Gastrointest Endosc 44:157–162, 2002. 61. Coyle WJ, Pineau BC, Tarnasky PR, et al: Evaluation of unexplained acute and acute recurrent pancreatitis using endoscopic retrograde cholangiopancreatography, sphincter of Oddi manometry, and endoscopic ultrasound, Endoscopy 34:617–623, 2002. 62. Sherman S: Idiopathic acute recurrent pancreatitis: endoscopic approach to diagnosis and therapy, Gastrointest Endosc 38:261A, 1992. 63. Cotton PB, Durkalski V, Romagnuolo J, et al: Effect of endoscopic sphincterotomy for suspected sphincter of Oddi dysfunction on pain-related disability following cholecystectomy: the EPISOD randomized clinical trial, JAMA 311:2101–2109, 2014. 64. Cote G, Imperiale T, Schmidt S, et al: Similar efficacies of biliary, with or without pancreatic sphincterotomy in treatment of idiopathic recurrent acute pancreatitis, Gastroenterology 143:1502–1509, 2012. 65. Wehrmann T, Schmitt T, Arndt A, et al: Endoscopic botulinum toxin injection for treatment of idiopathic recurrent pancreatitis due to sphincter of Oddi dysfunction, Aliment Pharmacol Ther 14:1469–1477, 2000. 66. Testoni PA, Caporuscio S, Bagnolo F, et al: Idiopahtic recurrent pancreatitis: long-term results after ERCP, endoscopic sphincterotomy, or ursodeoxycholic acid treatment, Am J Gastroenterol 95:1702–1707, 2000. 67. Jacob L, Gennen JE, Catalano MF, et al: Prevention of pancreatitis in patients with idiopathic recurrent pancreatitis: a prospective nonblinded randomized study using endoscopic stents, Endoscopy 33:559–562, 2001. 68. Masci E, Mariani A, Curioni S, Testoni PA: Risk factors for pancreatitis following endoscopic retrograde cholangiopancreatography: a meta-analysis, Endoscopy 35:830–834, 2003. 69. Tarnasky P, Cunningham J, Cotton P, et al: Pancreatic sphincter hypertension increases the risk of post-ERCP pancreatitis, Endoscopy 29:252–256, 1997.

70. Romagnuolo J, Guda N, Freeman M, Durkalski V: Preferred designs, outcomes, and analysis strategies for treatment trials in idiopathic recurrent acute pancreatitis, Gastrointest Endosc 68:966–974, 2008. 71. Guda NM, Freeman ML: True culprit of guilt by association? Is sphincter of Oddi manometry the cause of post-ERCP pancreatitis in patients with suspected sphincter of Oddi dysfunction, or is it the patients’ susceptibility? Rev Gastroenterol Disord 4:211–213, 2004. 72. Catalano MF, Lahoti S, Alcocer E, et al: Dynamic imaging of the pancreas using real-time endoscopic ultrasonography with secretin stimulation, Gastrointest Endosc 48:580–587, 1998. 73. Corrazziari E, Cical M, Scopinaro F, et al: Scintigraphic assessment of sphincter of Oddi dysfunction, Gut 52:1655–1656, 2003. 74. Guelrud M, Plaz J, Mendosa S, et al: Endoscopic treatment in type II pancreatic sphincter dysfunction, Gastrointest Endosc 41:A398, 1995. 75. Sherman S, Jamidar P, Reber H, et al: Idiopathic acute pancreatitis (IAP): endoscopic diagnosis and therapy, Am J Gastroenterol 88:1541A, 1993. 76. Petrou A, Bramis K, Williams T, et al: Acute recurrent pancreatitis: a possible clinical manifestation of ampullary cancer, JOP 12:593–597, 2011. 77. Kohler H, Lankisch PG: Acute pancreatitis and hyperamylasemia in pancreatic carcinoma, Pancreas 2:177–179, 1987. 78. Bravo MT, Justo LM, Lasala JP, et al: Acute pancreatitis secondary to neuroendocrine pancreatic tumors. Report of 3 cases and literature review, Pancreas 41:485–489, 2012. 79. Schmidt CM, White PB, Waters JA, et al: Intraductal papillary mucinous neoplasms: predictors of malignant and invasive pathology, Ann Surg 246:644–651, 2007. 80. Pelletier AL, Hammel P, Rebours V, et al: Acute pancreatitis in patients operated on for intraductal papillary mucinous neoplasms of the pancreas: frequency, severity, and clinicopathologic correlations, Pancreas 39:658–661, 2010. 81. Rodriguez JR, Salvia R, Crippa S, et al: Branch-duct intraductal papillary mucinous neoplasms: observations in 145 patients who underwent resection, Gastroenterology 133:72–79, 2007. 82. Jang JW, Kim M, Jeong SU, et al: Clinical characteristics of intraductal papillary mucinous neoplasms manifesting as acute pancreatitis or acute recurrent pancreatitis, J Gastroenterol Hepatol 28:731–738, 2013. 83. Morales-Oyarvide V, Mino-Kenudson M, Ferrone CR, et al: Acute pancreatitis in intraductal papillary mucinous neoplasms: a common predictor of malignant intestinal subtype, Surgery 158:1219–1225, 2015. 84. Pezzilli R: Acute recurrent pancreatitis: an autoimmune disease? World J Gastroenterol 14:999–1006, 2008. 85. Kamisaw T, Chari ST, Giday SA, et al: Clinical profile of autoimmune pancreatitis and its histological subtypes. An international multicenter survey, Pancreas 40:809–814, 2011. 86. Hart PA, Levy MJ, Smyrk TC, et al: Clinical profiles and outcomes in idiopathic duct-centric chronic pancreatitis (type 2 autoimmune pancreatitis): the Mayo Clinic experience, Gut 65:1702–1709, 2016. 87. Todani T, Watanabe Y, Narusue M, et al: Congenital bile duct cysts: classification, operative procedures, and review of thirty-seven cases including cancer arising from choledochal cysts, Am J Surg 134:263– 269, 1977. 88. Sarris GE, Tsang D: Choledochocele: case report, literature review, and a proposed classification, Surgery 105:408–414, 1989. 89. Ladas SD, Ltsogridakis I, Tassios P, et al: Choledochocele, an overlooked diagnosis: report of 15 cases and review of 56 published reports from 1984-1992, Endoscopy 27:233–239, 1995. 90. Law R, Topazian M: Diagnosis and treatment of choledochoceles, Clin Gastroenterol Hepatol 12:196–203, 2014. 91. Antaki F, Tringali A, Deprez P, et al: A case series of symptomatic intraluminal duodenal duplication cysts: presentation, endoscopic therapy, and long-term outcome (with video), Gastrointest Endosc 67:163–168, 2008. 92. Whitcomb DC: What is personalized medicine and what should it replace? Nat Rev Gastroenterol Hepatol 9:418–424, 2012.

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CHAPTER 57 Recurrent Acute Pancreatitis 93. Coté GA, Yadav D, Slivka A, et al: Alcohol and smoking as risk factors in an epidemiology study of patients with chronic pancreatitis, Clin Gastroenterol Hepatol 9:266–273, 2011. 94. Majumder S, Gierisch JM, Bastian LA: The association of smoking and acute pancreatitis: a systematic review and meta-analysis, Pancreas 44:540–546, 2015. 95. Howaizi M, Chahine M, Haydar F, et al: Cannabis-induced recurrent acute pancreatitis, Acta Gastroenterol Belg 75:446–447, 2012. 96. Badalov N, Baradarian R, Iswara K, et al: Drug-induced acute pancreatitis: an evidence-based review, Clin Gastroenterol Hepatol 5:648–661, 2007. 97. Ammori BJ, Boreham B, Lewis P, Roberts SA: The biochemical detection of biliary etiology of acute pancreatitis on admission: a revisit in the modern era of biliary imaging, Pancreas 26:e32–e35, 2003. 98. Scherer J, Singh VP, Pitchumoni CS, Yadav D: Issues in hypertriglyceridemic pancreatitis. An update, J Clin Gastroenterol 48:195–203, 2014. 99. Baker ME, Nelson RC, Rosen MP, et al: ACR Appropriateness Criteria® acute pancreatitis, Ultrasound Q 30:267–273, 2014. 100. Levy MJ, Geenen JE: Idiopathic acute recurrent pancreatitis, Am J Gastroenterol 96:2540–2555, 2001. 101. Ghazale A, Chari ST, Smyrk TC, et al: Value of serum IgG4 in the diagnosis of autoimmune pancreatitis and in distinguishing it from pancreatic cancer, Am J Gastroenterol 102:1646–1653, 2007. 102. Chari ST, Smyrk TC, Levy MJ, et al: Diagnosis of autoimmune pancreatitis: the Mayo Clinic experience, Clin Gastroenterol Hepatol 4:1010–1016, 2006. 103. Lowenfels AB, Maisonneuve P, DiMagno EP, et al: Hereditary pancreatitis and the risk of pancreatic cancer. International Hereditary Pancreatitis Study Group, J Natl Cancer Inst 89:442–446, 1997. 104. Sandhu B, Vitazka P, Ferreira-Gonzalez A, et al: Presence of SPINK-1 variant alters the course of chronic pancreatitis, J Gastroenterol Hepatol 26:965–969, 2011. 105. Teich N, Mössner J: Hereditary pancreatitis, Best Pract Res Clin Gastroenterol 22:115–130, 2008. 106. Brand RE, Lerch MM, Rubinstein WS, et al: Advances in counselling and surveillance of patients at risk for pancreatic cancer, Gut 56:1460– 1469, 2007. 107. Bellin MD, Gelrud A, Arreaza-Rubin G, et al: Total pancreatectomy with islet autotransplantation: summary of a National Institute of Diabetes and Digestive and Kidney diseases workshop, Pancreas 43:1163–1171, 2014. 108. Sherman S, Freeman ML, Tarnasky PR, et al: Secretin (RG1068) administration increases sensitivity of detection of duct abnormalities by magnetic resonance cholangiopancreatography in patients with pancreatitis, Gastroenterology 147:646–654, 2014.

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109. Testoni PA, Mariani A, Curioni S, et al: MRCP-secretin test-guided management of idiopathic recurrent pancreatitis: long-term outcomes, Gastrointest Endosc 67:1028–1034, 2008. 110. Trikudanathan G, Walker SP, Munigala S, et al: Diagnostic performance of contrast-enhanced MRI with secretin-stimulated MRCP for non-calcific chronic pancreatitis: a comparison with histopathology, Am J Gastroenterol 110:1598–1606, 2015. 111. Trikudanathan G, Vega-Peralta J, Malli A, et al: Diagnostic performance of endoscopic ultrasound (EUS) for non-calcific chronic pancreatitis (NCCP) based on histopathology, Am J Gastroenterol 111:568–574, 2016. 112. Dewitt J, Devereaux B, Chriswell M, et al: Comparison of endoscopic ultrasonography and multi-detector computed tomography for detecting and staging pancreatic cancer, Ann Intern Med 141:753–763, 2004. 113. Thevenot A, Bournet B, Otal P, et al: Endoscopic ultrasound and magnetic resonance cholangiopancreatography in patients with idiopathic acute pancreatitis, Dig Dis Sci 58:2361–2368, 2013. 114. Mariani A, Arcidiacono PG, Curioni S, et al: Diagnostic yield of ERCP and secretin-enhanced MRCP and EUS in patients with acute recurrent pancreatitis of unknown aetiology, Dig Liver Dis 41:753–758, 2009. 115. Kushnir VM, Vani SB, Fowler K, et al: Sensitivity of endoscopic ultrasound, multidetector computed tomography, and magnetic resonance cholangiopancreatography in the diagnosis of pancreas divisum: a tertiary care experience, Pancreas 42:436–441, 2013. 116. Lai R, Freeman ML, Cass OW, et al: Accurate diagnosis of pancreas divisum by linear array endoscopic ultrasonography, Endoscopy 46: 705–709, 2004. 117. Wiersema MJ, Hawes RH, Lehman G, et al: Prospective evaluation of endoscopic ultrasonography and endoscopic retrograde cholangiopancreatography, and secretin test in the diagnosis of chronic pancreatitis, Gastrointest Endosc 48:11–17, 1998. 118. Farrell JJ, Garber J, Shahani D, et al: EUS findings in patients with autoimmune pancreatitis, Gastrointest Endosc 60:927–936, 2004. 119. Levy MJ, Wiersema MJ, Chari ST: Chronic pancreatitis: focal pancreatitis or cancer? Is there a role for FNA/biopsy? Autoimmune pancreatitis, Endoscopy 38(Suppl 1):S30–S35, 2006. 120. Iwashita T, Yasuda I, Doi S, et al: Use of samples from endoscopic ultrasound-guided 19-gauge fine-needle aspiration in diagnosis of autoimmune pancreatitis, Clin Gastroenterol Hepatol 10:316–322, 2012. 121. Kanno A, Ishida K, Hamada S, et al: Diagnosis of autoimmune pancreatitis by EUS-FNA by using a 22-gauge needle based on the International Consensus Diagnostic Criteria, Gastrointest Endosc 76:594–602, 2012.

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58 Pancreatic Fluid Collections and Leaks Andrew Nett and Kenneth F. Binmoeller

CHAPTER OUTLINE Introduction, 674 Pancreatic Fluid Collection Classification and Characterization, 674 Pseudocyst Access, 675 Endoscopy-Guided (Without EUS), 675 EUS-Guided, 676 EUS-Guided Versus Endoscopy-Guided, 676 Cyst Drainage, 676 Plastic Stents, 676 Fully Covered Self-Expanding Metal Stents (FCSEMS), 676 Lumen-Apposing Metal Stents (LAMS), 677

Plastic Versus Metal, 678 Surgery Versus Endoscopic Drainage, 679 Endoscopic Versus Percutaneous Drainage, 679 Necrosectomy, 679 Surgical, 679 Percutaneous, 679 Endoscopic, 680 Endoscopic Versus Surgical Necrosectomy, 680 Endoscopic Necrosectomy Versus Percutaneous Drainage, 680 Endoscopic Necrosectomy Technique, 680

INTRODUCTION Pancreatic fluid collections (PFCs) and leaks develop due to main or secondary pancreatic ductal disruption caused by acute or chronic pancreatitis, trauma, or pancreatic surgery. PFCs include acute fluid collections, acute necrotic collections, pseudocysts, and walled-off necrosis.1 Most nonnecrotic PFCs resolve spontaneously without need for drainage. Fluid collections that have become infected, or those that cause persistent symptoms, warrant drainage. Drainage of PFCs has historically been performed by open surgical approaches, but less invasive interventions have replaced open surgery over time. Whereas appropriate management of PFCs entails a multidisciplinary approach involving interventional endoscopy, interventional radiology, and minimally invasive surgery, endoscopic therapy of PFCs and pancreatic leaks has become a predominant initial therapeutic modality. Endoscopic transmural drainage of symptomatic pseudocysts has replaced surgical intervention as first-line therapy due to similar efficacy, less morbidity, shorter recovery, and greater cost-efficacy.2–4

PANCREATIC FLUID COLLECTION CLASSIFICATION AND CHARACTERIZATION Appropriate classification of PFCs helps guide management. The revised Atlanta criteria categorize PFCs as either acute or chronic based upon their presence less than or more than 4 weeks

Metal Stents (FCSEMS or LAMS) for WON, 681 Plastic Versus Metal Stents for WON, 681 Transpapillary Stenting in PFC Management, 682 Pancreatic Duct Leaks, 682 Disconnected Duct Syndrome, 683 Postsurgical Acute Pancreatic Fluid Collections, 683 Conclusion, 684

following an episode of pancreatitis. Categorization further depends on the presence or absence of necrosis.1 Acute collections without significant necrosis are termed acute fluid collections. These may occur in up to 40% of cases of acute pancreatitis. Most of these acute collections remain sterile, are asymptomatic, and spontaneously resolve without intervention. Approximately 30% to 50% of acute fluid collections, however, may persist.5,6 Acute fluid collections that persist longer than 4 weeks may evolve into pancreatic pseudocysts, which have a well-defined wall comprised of fibrous or granulation tissue containing no to minimal necrotic material. Acute collections arising from necrotizing pancreatitis contain necrotic tissue and are termed acute necrotic collections (ANC). Mature, encapsulated collections of pancreatic necrosis may sometimes develop from acute necrotic collections, typically after 4 or more weeks following onset of necrotizing pancreatitis. These collections, called walled-off necrosis (WON), are comprised of a wall of fibrous or granulation tissue separating internal necrotic material from normal pancreatic parenchyma. WON has a well-defined enhancing wall of reactive tissue present on imaging. Approximately 15% of patients with acute pancreatitis will develop pancreatic necrosis, 33% of whom will develop infected necrosis.7 The rate at which ANCs develop into WON is not clear. In general, intervention on PFCs is unnecessary because they typically remain sterile and regress spontaneously. Due to the absence of a mature, noncompliant wall, acute fluid collections

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CHAPTER 58 Pancreatic Fluid Collections and Leaks

Abstract

Keywords

Pancreatic fluid collections (PFCs) and leaks develop due to main or secondary pancreatic ductal disruption caused by acute or chronic pancreatitis, trauma, or pancreatic surgery. PFCs include acute fluid collections, acute necrotic collections, pseudocysts, and walled-off necrosis. Most nonnecrotic PFCs resolve spontaneously without need for drainage. Fluid collections that have become infected, or those that cause persistent symptoms, warrant drainage. Drainage of PFCs has historically been performed by open surgical approaches, but less invasive interventions have displaced open surgery over time. Whereas appropriate management of PFCs entails a multidisciplinary approach involving interventional endoscopy, interventional radiology, and minimally invasive surgery, endoscopic therapy of PFCs and pancreatic leaks has become a predominant initial therapeutic modality.

pancreatic fluid collection pseudocyst walled-off necrosis endoscopic drainage pancreatic duct leak EUS intervention necrosectomy

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CHAPTER 58 Pancreatic Fluid Collections and Leaks rarely cause mass-occupying effects such as gastric outlet or biliary obstruction.6 Conservative observation is thus pursued, monitoring for symptoms or signs of infection. In the absence of infection, most ANCs are also managed conservatively with observation. If sepsis with suspicion of secondary infection of acute fluid and necrotic collections occurs, however, intervention is warranted. Whereas percutaneous drainage through smalldiameter catheters may facilitate clinical improvement in some patients, persistent sepsis necessitates more aggressive débridement using either percutaneous necrosectomy or video-assisted retroperitoneal débridement (VARD).6,8,9 Once maturation of PFCs has occurred, indications for drainage include the presence of infection, gastric outlet or biliary obstruction, radiographic or clinical manifestations of vascular compression, or persistent symptoms such as anorexia, early satiety, weight loss, and refractory pain. In patients with mild symptoms or those with early pseudocysts or WON, medical supportive therapy with observation may still be appropriate to allow time for pseudocyst/WON regression. When indication for drainage is present, the maturity of the collection and differentiation of fluid versus necrotic collections helps to determine the most appropriate approach. Necrotic collections may require more intensive or multistep drainage techniques. Furthermore, the proportion of a WON that is comprised of solid debris may determine the outcome of standard endoscopic drainage, the number of therapeutic sessions required, and the need for direct endoscopic necrosectomy.10 Significant complications may occur if WON is inappropriately managed as a pseudocyst.11 Differentiation of pseudocysts and WON may be performed by noninvasive cross-sectional imaging or by endoscopic ultrasonography (EUS). Although imaging for assessment of organized fluid collections is not standardized, contrast-enhanced computed tomography (CT) is most commonly performed for diagnosis and interventional planning. The sensitivity for detection of solid debris has been reported to be as low as 17% to 25%.12,13 A retrospective review of CT imaging performed in patients with PFCs showed that a radiographic scoring system could improve accuracy in differentiating WON from pseudocysts up to approximately 80%.14 Magnetic resonance imaging (MRI) is more accurate in prediction of solid debris within pancreatic fluid collections, with sensitivity up to 100% reported.12,13 MRI has higher sensitivity for detection of pancreatic duct disruption as well, which may predict the likelihood of spontaneous PFC resolution, as the presence of pancreatic duct disruption is associated with the development of chronic, mature collections.15,16 EUS may also be used to detect the presence of pancreatic necrosis and has been shown to be the most accurate imaging modality for characterizing pancreatic fluid collections (Fig. 58.1).17 Transabdominal ultrasound may also be beneficial. In a prospective comparison of EUS, MRI, or transabdominal ultrasound, transabdominal ultrasound had a sensitivity of 92% (vs. 100% for EUS or MRI) for detection of WON, though it was less sensitive in detection of venous collaterals around the collection compared to EUS.13

PSEUDOCYST ACCESS Endoscopy-Guided (Without EUS) Endoscopic drainage without EUS guidance may be performed when a bulge into the gastrointestinal (GI) lumen is present from extrinsic compression by the pseudocyst (Fig. 58.2). In this instance, use of a duodenoscope permits good visualization of

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FIG 58.1 Endosonographic image of mature walled-off necrosis. (From Siddiqui AA, Adler DG, Nieto J, et al: EUS-guided drainage of peripancreatic fluid collections and necrosis by using a novel lumen-apposing stent: a large retrospective, multicenter US experience [with videos]. Gastrointest Endosc 83[4]:699–707, 2016.)

FIG 58.2 Luminal bulge from an extrinsically compressing pancreatic fluid collection (PFC).

the posterior gastric wall and the posteromedial duodenal wall. A 4.2-mm working channel will enable passage of 10-Fr stents. As described by Ballard and Coté (2012), optimal alignment ensures entrance of the pseudocyst at an area of maximal visible bulging of the gastric or duodenal wall.18 The duodenoscope should be in a stable position with the ideal angle of needle puncture entry at 90 degrees to minimize the length of the GI wall that will be traversed. A cystotome or needle-knife catheter may be used to puncture across the gastric or duodenal wall and establish access into the pseudocyst. Electrocautery can be used to facilitate puncture across the wall and does not seem to affect bleeding complications.19,20 Aspiration of a sample of pseudocyst contents and injection of contrast into the pseudocyst under fluoroscopy may be performed to confirm that access has been

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FIG 58.3 Endosonographic image of a mature pseudocyst.

achieved. A stiff guidewire can then be passed into the pseudocyst and coiled in the cyst under fluoroscopic visualization. The pseudocyst puncture tract is then dilated with a balloon and/or bougie catheter. Plastic or metal stents can then be deployed across the dilated cystgastrostomy or cystduodenostomy tract for drainage.

versus endoscopy-guided transmural access showed higher technical success for EUS-guided access (94% vs. 72%). Furthermore, EUS-guided access was as successful as salvage crossover therapy in all cases where endoscopy-guided access failed because the pseudocysts were nonbulging. No significant difference existed in short-term clinical success rates (defined by cyst resolution) or long-term clinical outcomes.21 Of note, the technical success of both approaches is similar except in cases when a luminal bulge is absent. Thus, the advantage of EUS-guided drainage seems to rest upon enhanced access specifically in cases of nonbulging pseudocysts. A meta-analysis performed by Panamonta et al (2012) examined two randomized-controlled trials and two prospective comparisons involving 229 patients.22 This review confirmed that EUS-guided drainage had significantly higher technical success rates (relative risk [RR] 12.38, 95% confidence interval [CI] 1.39–110.22) and was a successful salvage therapeutic method in all patients with failed endoscopy-guided drainage due to lack of a luminal bulge. In those with technical success, short-term and long-term clinical success rates (defined as symptomatic relief and radiologic resolution of pseudocysts) were comparable (RR 1.03, 95% CI 0.95–1.11 and RR 0.98, 95% CI 0.76–1.25, respectively). Complication rates were also similar (RR 0.98, 95% CI 0.52–1.86), with the most common complications being bleeding and infection.

CYST DRAINAGE

EUS-Guided

Plastic Stents

When EUS-guided pseudocyst drainage is performed, careful characterization of the pseudocyst is important. EUS imaging enables direct assessment of the distance separating the pseudocyst and GI tract wall, confirmation of a mature pseudocyst wall, and exclusion of interceding vessels (Fig. 58.3). As a general rule, the distance separating the pseudocyst and GI tract wall should not exceed 10 mm. Endosonographic visualization allows assessment for the presence of internal debris and/or necrosis that would warrant more aggressive drainage techniques.21 Following endosonographic assessment, the next step in EUS-guided drainage involves puncture into the pseudocyst with a 19-gauge fine-needle aspiration (FNA) needle passed through a therapeutic echoendoscope. A 0.025- or 0.035-inch guidewire is passed through the needle and coiled within the pseudocyst. The needle is then exchanged over the guidewire for either a bougie catheter or dilating balloon, and dilation is performed to a size appropriate for stent delivery. Therapeutic linear echoendoscopes, which have a larger working channel (3.7 to 3.8 mm), enable pseudocyst puncture with a 10-Fr cystotome. The cystotome has an inner needle knife catheter used for initial cyst puncture and an outer 10-Fr sheath with a diathermy ring. After initial puncture, replacement of the inner needle knife catheter with a guidewire is followed by advancement of the 10-Fr outer sheath into the cyst using electrocautery, expanding the puncture site. Multiple guidewires may then be placed through the 10-Fr sheath. Plastic or metal stents may be placed across the tract for pseudocyst drainage.

Multiple studies have reported the use of single and multiple plastic stents ranging from 7- to 10-Fr size for drainage. No randomized controlled trial has compared the benefits of using a single stent versus multiple plastic stents. Retrospective studies have shown that insertion of even a single stent provides high rates of clinical resolution. Secondary infection does seem to be potentially more frequent in cases of single versus multiple-stent drainage, however.23 When using a plastic stent, a double pigtail design is preferentially used to reduce the risk of stent migration. Double pigtail stents also decrease delayed bleeding, as straight stents may erode into the pseudocyst wall with resultant hemorrhage.24 Stents used for cyst drainage are 3 or 4 cm long. Multiple plastic stents are typically placed to enhance drainage by increasing the cumulative diameter of stent lumens, creating channel redundancy in the event one plastic stent occludes, and promoting drainage through the canals between stents. The placement of two stents is best accomplished by initially placing two guide wires. A 10-Fr catheter sheath (e.g., 10-Fr stent pusher tube, cytology brush sheath, multiport ramp catheter) is a helpful tool to accomplish this because the lumen is large enough to pass two 0.035-inch guidewires. Using a 10-Fr cystotome, two guidewires can be immediately inserted after entry into the cyst. Of historic interest is the NAVIX device (NAVIX; Xlumena, Mountain View, CA), which enables exchange-free pseudocyst access, tract dilation, and placement of two guidewires with a single device.25 This device helped streamline the otherwise laborious and time-consuming process of placing multiple plastic stents, and decreased opportunity for technical failure during multiple exchanges.

EUS-Guided Versus Endoscopy-Guided Though direct endoscopic pseudocyst access is possible when the fluid collection causes obvious extrinsic compression of the GI lumen, EUS-guided access has been shown to have higher success rates for pseudocyst drainage with similar adverse events.18 A small, randomized, prospective trial comparing EUS-guided

Fully Covered Self-Expanding Metal Stents (FCSEMS) Compared to plastic stents, the appeal of FCSEMS is their larger lumens with resultant quicker pseudocyst drainage and decreased

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CHAPTER 58 Pancreatic Fluid Collections and Leaks risk of stent occlusion. Procedure time may also be decreased because only a single stent needs deployment. Published studies, however, have not consistently shown an advantage in using FCSEMS. A retrospective comparison has shown improved rates of complete pseudocyst resolution at 1 year follow-up after endoscopic drainage using FCSEMS versus double pigtail plastic stents (98% vs. 89%, p = 0.01). Plastic stent usage also resulted in higher complication rates (odds ratio [OR] 2.9 after multivariate analysis).26 Contrasting results, however, were obtained in a 2014 prospective randomized trial by Lee et al comparing the use of multiple plastic stents versus FCSEMS for PFC drainage. One caveat in this discussion of pseudocyst intervention is that results of this study were not necessarily stratified by fluid collection type. Drainage of WON will be discussed specifically later in this chapter.27 Technical success was achieved for all cases regardless of stent type. Clinical success was achieved in 20 of 23 cases with FCSEMS and 20 of 22 cases with plastic stents (p = 0.97). No statistical difference was present in either adverse event rates or rate of recurrence during follow-up. One point of benefit from use of FCSEMS was shown, however, with achievement of a shorter median procedure time compared to use of plastic stents.

677

FIG 58.4 Fully covered, biflanged, lumen-apposing metal stent (AXIOS, Boston Scientific). (Courtesy Boston Scientific, Marlborough, MA. From Siddiqui AA, Adler DG, Nieto J, et al: EUS-guided drainage of peripancreatic fluid collections and necrosis by using a novel lumen-apposing stent: a large retrospective, multicenter US experience [with videos]. Gastrointest Endosc 83[4]:699–707, 2016.)

Lumen-Apposing Metal Stents (LAMS) Whether plastic or metal, tubular stents have several limitations when applied to transluminal drainage. First, they do not impart lumen-to-lumen anchorage. This may result in leakage of contents if there is physical separation of the lumens. Second, stent migration may occur due to the absence of a stricture to hold it in place. Third, the length of tubular stents exceeds the anatomical requirement of a shorter transluminal anastomosis. The excess exposed stent ends may cause tissue trauma, resulting in bleeding or perforation. Placement of an internal plastic stent within a FCSEMS has been reported in an attempt to reduce migration and mitigate against erosion of the metal stent edge into the collapsed pseudocyst wall, but we have not found this method to prevent migration or tissue injury. Finally, the length of tubular stents predisposes to stent dysfunction. The longer the stent length, the more prone the stent is to clogging from food residue or cyst debris.28 A lumen-apposing metal stent (LAMS) designed for transluminal drainage was developed and first reported by Binmoeller in 2011.5 The AXIOS stent (Boston Scientific, Marlborough, MA) is a nitinol braided FCSEMS with bilateral double walled flanges existing in a dumbbell configuration perpendicular to the lumen for the purpose of anastomosis creation (Fig. 58.4). Fully expanded, the flanges are either 20 mm or 24 mm in diameter, approximately twice that of the stent’s mid-lumen diameter of either 10 mm or 15 mm. The bilateral flanges are designed to reduce stent migration and approximate structures in order to reduce rates of perforation and leak. Furthermore, the flanges are short in length and therefore have limited extension into the GI tract lumen and fluid collection cavity, potentially reducing the risk of stent erosion. The AXIOS stent is deployed through a 10.8-Fr catheter delivery system. The delivery system is attached to the echoendoscope working channel port via a Luer-lock, similar to a standard FNA needle. The catheter is advanced into the fluid collection by manipulation of the distal catheter control hub and then locked into position. Retraction to a halfway point of the proximal stent deployment hub results in unsheathing of the distal stent flange within the collection cavity. The catheter

control hub is then unlocked and retracted until the point at which the distal stent flange starts to compress against the wall of the collection cavity. After relocking the catheter control hub, the stent deployment hub is then completely retracted and the proximal stent flange is unsheathed. To ensure that proximal flange deployment will occur within the GI lumen, catheter retraction until direct endoscopic visualization of the 2 to 3 mm of the black catheter shaft marker is advised prior to proximal flange deployment. Pulling back the echoendoscope to allow direct endoscopic visualization of this marker, however, risks excessive traction on the AXIOS stent, which may result in migration of the distal flange back into the GI lumen. To avoid excessive traction, the proximal flange may also be deployed inside the echoendoscope.29 The unsheathed proximal flange may then be released from the echoendoscope by advancement of the catheter hub, again while pulling back the echoendoscope. Deployment may be performed under endoscopic, endosonographic, and fluoroscopic visualization to help ensure proper placement. With experience, however, deployment completely under endosonographic visualization is possible, and may be preferred as a way to avoid improper deployment due to excess traction on the deployment catheter (Figs. 58.5 and 58.6). An electrocautery-enhanced delivery system (“hot AXIOS”) enables placement of the AXIOS stent in a single step by obviating the need for initial 19-guage needle puncture of the collection cavity, guidewire insertion, and puncture tract dilation. The system has an electrocautery component comprised of two radially distributed diathermic wires that converge around the guidewire lumen at the catheter tip, allowing for direct cavity penetration and transmural advancement of the stent delivery catheter without tract dilation (Fig. 58.7). Thus, delivery can be performed in an exchange-free manner, which may make PFC drainage faster and safer. A pilot study in 2012 using the AXIOS LAMS reported drainage of 15 symptomatic pseudocysts with achievement of a 100% therapeutic success rate and 0% recurrence rate at 11-month follow-up.31 A subsequent multicenter trial reported achieving technical success in 91% of patients with either pseudocysts or

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WON (n = 33) with use of the AXIOS LAMS.32 Table 58.1 summarizes a published series involving LAMS placement for pseudocyst or WON management.

type was performed. No difference was found in treatment success, adverse event rates, or recurrence rates between FCSEMS or plastic stent drainage. It was concluded that available evidence did not support the routine use of metal stents for pseudocyst drainage, particularly given their higher price. Of note, the metal stent studies included in this review consisted of only a small number of patients (maximum n = 22). A retrospective comparison of double pigtail plastic stents versus FCSEMS for pseudocyst drainage involved 230 patients. In this study, stent type was not associated with differences in technical success (92% vs. 98% for double pigtail plastic vs. FCSEMS, p = 0.06).28 Placement of a FCSEMS, however, was associated with a significantly higher rate of complete pseudocyst resolution, which occurred in 98% of pseudocysts drained with a FCSEMS versus 89% drained with double pigtail plastic stents at 12-month follow-up (p = 0.01). FCSEMS placement also was

Plastic Versus Metal A systematic review by Bang et al (2015) of seventeen studies involving 881 total patients compared outcomes of plastic versus metal stent placement for transmural drainage of PFCs.33 Although this review included studies examining drainage of both pseudocysts and WON, subgroup analysis of each fluid collection

FIG 58.5 Lumen-apposing metal stent (LAMS) deployed into a pancreatic fluid collection (PFC). (From Rinninella E, Kunda R, Dollhopf M, et al: EUS-guided drainage of pancreatic fluid collections using a novel lumen-apposing metal stent on an electrocautery-enhanced delivery system: a large retrospective study [with video]. Gastrointest Endosc 82[6]:1039–1046, 2015.)

A

FIG 58.7 Electrocautery-enhanced delivery system (Hot AXIOS). (Courtesy Boston Scientific, Marlborough, MA. From Rinninella E, Kunda R, Dollhopf M, et al: EUS-guided drainage of pancreatic fluid collections using a novel lumen-apposing metal stent on an electrocautery-enhanced delivery system: a large retrospective study [with video]. Gastrointest Endosc 82[6]:1039–1046, 2015.)

B FIG 58.6 Deployed lumen-apposing metal stent (LAMS). A, Radiographic image of deployed LAMS. B, Endoscopic image of deployed LAMS with drainage of pseudocyst contents. (From Siddiqui AA, Adler DG, Nieto J, et al: EUS-guided drainage of peripancreatic fluid collections and necrosis by using a novel lumen-apposing stent: a large retrospective, multicenter US experience [with videos]. Gastrointest Endosc 83[4]:699–707, 2016.)

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CHAPTER 58 Pancreatic Fluid Collections and Leaks

679

Reported Outcomes From Published Series of Lumen-Apposing Metal Stent Placement for Management of Pancreatic Pseudocysts or WON TABLE 58.1

Clinical Success‡‡

Follow-up (mos)

Adverse Event

100%

86.3% 85.7%

4.8%

4

18.5%

0%

8

7.1%

88.2%

1.5%

9

5.9%

98.9%

92.5%

0%

10.7

98%

85%

NR

NR

9%

Year

LAMS

N

Sharaiha et al28

2016

AXIOS

124

Siddiqui et al51

2016

AXIOS

14

PP

Siddiqui et al51

2016

AXIOS

68

WON

Rinninella et al30

2015

Hot AXIOS

93

PP/WON

Walter et al57

2015

AXIOS

61

PP/WON

Shah et al80

2015

AXIOS

33

PP/WON

91%

85%

Gornals et al81

2013

AXIOS

9

PP/WON

88.8%

88.8%

2012

AXIOS

15

31

Itoi, et al

PFC Type

Therapeutic Success

Author

WON

PP

85.7% 199%

100%

Recurrence

100%

5.3%

NR

NR

15.2%

12.5%

12.5

11.1%

0%

11.4

0%

‡‡

Rate calculation incorporates cases of therapeutic failure as well. LAMS, lumen-apposing metal stent; NR, not reported; PFC, pancreatic fluid collection; PP, pseudocyst; WON, walled-off necrosis.

associated with a reduced rate of adverse events at 30 days (31% vs. 16%, p = 0.006). With multivariate analysis, adverse events were 2.9 times more likely with use of double pigtail stents after adjustment for age, sex, number of endoscopy sessions, date of procedure, and original pseudocyst size. No difference occurred in long-term adverse event and recurrence rates.

Surgery Versus Endoscopic Drainage A 2016 Cochrane review performed on management strategies for pancreatic pseudocysts examined four randomized control trials consisting of comparisons among open surgical drainage, EUS-guided drainage, endoscopic drainage, and EUS-guided drainage with nasocystic catheter drainage.3 Short-term, healthrelated quality of life (at 4 weeks to 3 months) was worse following open surgical drainage versus EUS-guided drainage. The cost of surgery was also significantly higher. Statistically significant shorter hospital stays occurred following EUS-guided drainage with nasocystic drainage as opposed to EUS-guided drainage alone, endoscopic drainage, or open surgical drainage. Finally, EUS-guided drainage led to discharge faster than open surgical drainage, though hospital stay was the longest following endoscopic drainage alone. A randomized trial has shown that endoscopic drainage has similar technical success and complication rates, but results in shorter stay, higher physical and mental health component scores, and lower costs compared to surgical cystgastrostomy.2

Endoscopic Versus Percutaneous Drainage Endoscopic drainage has been found on a retrospective review to be favorable to percutaneous drainage with less need for repeat procedures, shorter hospitalization, and decreased need for follow-up imaging while having statistically equivalent rates of technical success, clinical success and adverse events.34

NECROSECTOMY Surgical Open surgical necrosectomy has been the traditional method for management of WON. Open necrosectomy, however, may cause significant morbidity and mortality. Mortality rates are particularly high within 14 days after onset of necrotizing pancreatitis, and early surgery within this time frame is not recommended.35 Besselink et al (2007)36 showed that surgery on

day 30 or later following admission for necrotizing pancreatitis was associated with significantly lower mortality rates than earlier intervention (75% for days 1–14, 45% for days 15–29, 8% for day 30 or later). The mortality benefit that occurs with operative delay persists despite stratification for presence of preoperative organ failure and multiple organ failure.36 A systematic review by the same authors of 11 studies with 1136 patients found a median mortality rate of 25% for open necrosectomy, with a range of 12% to 56%. This review confirmed the association between timing of intervention and mortality. Laparoscopic transperitoneal and retroperitoneal approaches are now preferred methods for surgical drainage.

Percutaneous Percutaneous drainage serves as an alternative option for less invasive débridement of pancreatic necrosis, obviating the need for surgery in 30% to 100% of patients specifically with infected necrosis. In a series of 18 patients, Wronski et al (2013) reported complete resolution of infected necrosis by ultrasound-guided percutaneous catheter drain placement in 33% of patients, though the remaining patients eventually required surgical necrosectomy.37 An overall mortality rate of 17% occurred with this management strategy. Another series of 34 patients with infected necrosis reported use of multiple large-bore percutaneous catheters with aggressive drainage. An average of three catheter sites with four exchanges were used. Surgery was avoided in 47% of patients with an overall mortality rate of 12%.38 Bello and Matthews (2013) reviewed eight studies examining percutaneous drainage, involving a total of 286 patients.39 Percutaneous access was performed via ultrasound or CT guidance, and drains were used with a diameter ranging from 10 to 28 Fr. Saline flush of the drains was typically performed every 8 hours. In this review, 44% of patients had successful therapy with avoidance of surgical necrosectomy. An overall mortality rate of 20% was reported and complications occurred in 28%, including multiple organ failure, colonic perforation, intraabdominal bleeding, and GI and pancreatic fistulae. Though percutaneous drainage is frequently inadequate for definitive management of pancreatic necrosis, a step-up approach, consisting of initial percutaneous drainage of a necrotic collection followed by minimally invasive retroperitoneal necrosectomy, if necessary, is now standard. The PANTER (Minimally Invasive Step Up Approach versus Maximal Necrosectomy in Patients with Acute Necrotizing Pancreatitis)

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trial found a decrease in the primary endpoint of death or composite of major complications with this step-up approach as compared to open necrosectomy (40% vs. 69%, p = 0.0006).8 Even if percutaneous drainage alone is adequate, significant morbidity may occur. Within the literature, a high rate of pancreaticocutaneous and pancreaticoenteric fistula formation occurs with pancreatic drainage approximately 20% of the time.40 Furthermore, percutaneous drainage requires frequent catheter care, repeat procedures with upsizing of catheters, and frequent repeat cross-sectional imaging. WON may alternatively be managed endoscopically by direct endoscopic necrosectomy.

Endoscopic Direct endoscopic necrosectomy was first reported by Seifert et al (2001) in three patients who had failed endoscopic plastic stent drainage of WON.41 A stoma is created between the gastroenteric lumen and the walled-off collection for direct entry into the necrotic cavity with the endoscope. Débridement and removal of necrotic tissue is performed using various endoscopic accessories (Fig. 58.8, Video 58.1). A retrospective comparison by Gardner et al (2009) showed that direct endoscopic necrosectomy was superior to transmural endoscopic drainage, with successful resolution of necrotic cavities in 88% versus 45% of patients.42 Direct endoscopic necrosectomy also resulted in decreased need for subsequent percutaneous drainage, standard surgical drainage, and collection recurrence. Several publications depict endoscopic necrosectomy as a relatively favorable WON intervention. In 2011, Haghshenasskashani et al performed a systematic review of 260 patients in 10 series of patients with a total of 1100 endoscopic necrosectomy procedures.43 Complete resolution of pancreatic necrosis was achieved 76% of the time, and the mortality rate was 5%. A median diagnosis to treatment interval of 6 weeks was present. In 2012, Bello and Matthews systemically reviewed 10 series involving endoscopic necrosectomy that reported success rates ranging from 59% to 100%.39 Subsequent surgical necrosectomy was avoided in 78% of cases overall. Mortality ranged from 0% to 19% and was 5.6% overall. The mean complication rate reported was 28%.

A meta-analysis published in 2014 examined eight studies involving 233 patients with WON with a weighted mean necrotic cavity size of 12.9 cm.44 A weighted mean of 4.1 procedures were necessary for necrotic cavity resolution. Endoscopic transmural necrosectomy had a pooled success rate of 82%. The pooled recurrence rate was 11% and complications occurred in 21%, consisting of bleeding, sepsis, and perforation. Surgery was ultimately required in 13% of patients. Reported adverse event rates of EUS-guided treatment of WON ranges from 5% to 42%. The most significant adverse event rate associated with intervention of WON is infection, with an incidence of 15% to 26%. Additional complications include bleeding between direct endoscopic necrosectomy sessions, perforation/pneumoperitoneum, as well as stent migration, though stents are almost always retrieved successfully. Air and CO2 embolisms are additional complications that may arise from blood vessel rupture with resultant direct insufflation into the bloodstream.45 Air embolism has been reported to occur at a rate of 0.4%.46

Endoscopic Versus Surgical Necrosectomy A 2016 Cochrane review of interventions for necrotizing pancreatitis examined eight randomized controlled trials, concluding that serious adverse events and adverse events were less frequent with an endoscopic-assisted minimally invasive step-up approach versus open necrosectomy. More adverse events occurred with the video-assisted minimally invasive surgery step-up approach group versus the endoscopic-assisted minimally invasive step-up approach group. The number of interventions, however, were less with the video-assisted versus endoscopic-assisted minimally invasive step-up approach.4 The TENSION (transluminal endoscopic step-up approach versus minimally invasive surgical step-up approach in patients with infected necrotizing pancreatitis) trial is currently comparing endoscopic drainage followed by endoscopic necrosectomy, if necessary, versus percutaneous drainage followed by video-assisted necrosectomy, if necessary. Bakker et al (2012) randomized patients with confirmed or suspected infected WON to endoscopic transgastric necrosectomy or surgical necrosectomy with either VARD, when possible, or open laparotomy if necessary.47 The primary endpoint examined was level of interleukin 6 following necrosectomy as a measure of the postprocedure inflammatory response, which was lower following endoscopic necrosectomy (p = 0.004). A secondary endpoint of a composite of major complications or death was significantly lower with endoscopic necrosectomy versus surgery (20% vs. 80%, p = 0.02). Additionally, significantly less pancreatic fistulae occurred with endoscopic necrosectomy (10% vs. 70%).

Endoscopic Necrosectomy Versus Percutaneous Drainage In 2014, a step-up approach with initial percutaneous drainage was compared to direct endoscopic necrosectomy in 24 patients. Resolution occurred in 92% of patients undergoing endoscopic necrosectomy versus 25% who underwent percutaneous drainage. The endoscopic necrosectomy group also had lower rates of antibiotic use, pancreatic insufficiency, and hospitalization.48

Endoscopic Necrosectomy Technique FIG 58.8 Direct endoscopic necrosectomy using a polypectomy snare.

Endoscopic necrosectomy requires the creation of a cystogastrostomy or cystoenterostomy tract that is large enough to allow the passage of an endoscope directly into the cavity. A tract of 15 to 20 mm diameter is usually created by balloon catheter

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CHAPTER 58 Pancreatic Fluid Collections and Leaks dilation, but can also be created with a large diameter metal stent (see following section). Necrosectomy is performed using snares, forceps, baskets, and forceful irrigation. Intersession irrigation of the necrotic cavity with saline and/or hydrogen peroxide may be performed via a nasocystic catheter. Hydrogen peroxide irrigation of the collection cavity during endoscopy may decrease procedure duration, complication rates, and the total number of endoscopic necrosectomy sessions required.40 Repeat necrosectomy sessions are performed until débridement of necrotic material within the cavity is complete.

Metal Stents (FCSEMS or LAMS) for WON FCSEMS may enhance endoscopic drainage of WON. Esophageal FCSEMS have a lumen diameter that will permit endoscope advancement through the deployed, expanded stent. In 2014, two case series were published describing use of esophageal FCSEMS for WON drainage. One study consisted of 17 patients with a complete resolution rate of 88% over an average of five necrosectomy sessions.49 The other involved 10 patients with a resolution rate of 90% after an average of three necrosectomy sessions.50 LAMS have large lumens, which can be immediately dilated following placement to enable direct endoscopic exploration and débridement of the necrotic cavity. The dumbbell structure of these stents allows for more aggressive manipulation without stent dislodgement during the index endoscopic session. The lumen-apposing nature of these stents intends to reduce rates of perforation and leak, particularly in cases where the mature necrotic fluid collection is not entirely adherent to the gastrointestinal wall. In a large, US multicenter, retrospective study of patients who underwent EUS-guided drainage of PFCs using the AXIOS stent,51 68 of 80 patients had WON with a mean PFC size of 11.8 cm. Successful LAMS placement was achieved in 97.5% of patients. Endoscopic débridement was performed through the LAMS in 54 patients requiring a mean of 2.8 +/− 1.3 sessions. Stents remained patent in 98.7% of cases. Overall, endoscopic therapy with use of the LAMS was successful in 88.2% of patients with WON. One patient had PFC recurrence within the 3-month median follow-up. The procedure-related adverse event rate was 9.8%, with complications consisting of self-limiting bleeding, stent maldeployment (n = 2), and gastric perforation following stent maldeployment in one patient requiring surgical repair. A retrospective comparison of LAMS versus FCSEMS has shown LAMS may facilitate complete resolution of WON in fewer procedures (p = 0.04).52 Use of LAMS may cause more early adverse events, however, than either FCSEMS or plastic stents (OR 6.6, p = 0.02). Flared-type biflanged metal stents that are not lumen-apposing have been used for the treatment of WON. In an ex vivo study, biflanged stents were found to have a higher migration rate than LAMS.31 LAMS were also found to have a higher lumen-apposing force than the biflanged stent.53 It is unclear if metal stents should be removed after cavity resolution. Removal is typically pursued, however, given uncertainty regarding long-term adverse effects. Specifically, indefinite stent indwelling could potentially result in migration of food into the collection cavity, bleeding from tissue erosion, or, occasionally, stent burial. In a 2016 ongoing trial comparing LAMS and plastic stents for WON drainage, high rates of delayed complications due to persistent indwelling LAMS have been observed.54 Stent-related bleeding, stent burial, and stent-induced

681

biliary obstruction occurred in 50% of patients receiving LAMS, whereas 0% of plastic stent participants had stent-related adverse events. As LAMS-related events all occurred over 3 weeks after placement, these complications prompted a change in protocol to earlier imaging assessment at 3 weeks followed by LAMS removal if WON resolution was demonstrated. The authors hypothesize that the stiff, immobile nature of LAMS, in contrast to flexible, mobile plastic stents, promotes tissue and vascular erosion and impingement upon WON cavity collapse. Nonetheless, other studies have not observed adverse event rates nearly as high when employing LAMS for WON management.32,55–58

Plastic Versus Metal Stents for WON A two-center, retrospective comparison of EUS-guided drainage of PFCs with double pigtail plastic stents versus a flared-type biflanged FCSEMS (not lumen-apposing) showed that plastic stent use was associated with increased need for repeat drainage procedures (34.2% vs. 6.3% of patients).59 This study is limited by the lack of stratified outcomes based upon the initial collection characteristics (pseudocyst or WON). Stent migration occurred in 18.4% of cases using plastic stents versus 6.3% of cases using the biflanged, but this difference was not statistically significant. Overall, this study did support a benefit to use of FCSEMS over plastic stents. Although technical success occurred in 100% of cases, inadequate drainage occurred in significantly more patients with plastic stents (26.3% vs. 0%). The initial clinical success rate was 92% in those with FCSEMS versus 65% in those with plastic stents (p = 0.074). Furthermore, though the overall cost of plastic stent use was lower in patients with noninfected pseudocysts, the advantage was not seen for infected pseudocysts or WON due to a reduced need for interventions using FCSEMS. A single-center, retrospective series showed no difference between plastic stents and LAMS for treatment of WON in terms of technical success, clinical success, or adverse events, even though the plastic stent group had significantly larger WON.60 Mean procedure times were shorter for the LAMS group for initial EUS-guided drainage and reintervention, however, and no difference in total cost was present between plastic stent and LAMS use. As previously mentioned, a systematic review published by Bang et al in 2015 compared the use of FCSEMS versus plastic stents for PFC drainage.33 No difference was detected in the pooled rate of overall treatment success for PFCs, specifically in patients with WON (78% vs. 70%). No difference occurred in either the rate of adverse events or fluid collection recurrence. No studies in this review were direct comparative studies, however. Siddiqui et al (2017) published a retrospective comparison of 313 patients with WON who underwent endoscopic intervention using either double pigtail plastic stents or 10-mm biliary metal stents (FCSEMS or LAMS).52 Though therapeutic success was comparable regardless of stent type, long-term resolution of WON was more successful using metal stents (95% vs. 81%, p = 0.01). No prospective trials have compared the use of plastic versus metal stents in the management of WON. In some cases, initial placement of a LAMS for facilitation of direct endoscopic necrosectomy may be pursued followed by removal of the LAMS and long-term placement of multiple transmural plastic stents. This approach may be helpful in patients with a disconnected pancreatic tail that are poor surgical candidates. Exchange of the LAMS for plastic stents allows long-term management of the PFC, which may otherwise be expected to recur in the presence

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of duct disruption, and avoids complications of long-term LAMS indwelling, such as tissue erosions and hemorrhage. Several questions exist regarding the role of FCSEMS and LAMS in drainage of WON. Further study is necessary to determine if the theoretical advantages of LAMS are borne out in clinical practice. In prospective trials, does single-step deployment decrease the rate of adverse events by improving the efficiency and simplicity of the procedure? If metal stents are advantageous compared to plastic stents, are LAMS more beneficial compared to FCSEMS? Does LAMS placement decrease the need for necrosectomy entirely? Is the use of LAMS costeffective?29 Other issues to address in the future are the role and duration of antibiotics following transmural endoscopic stent placement as well as the role of nasocystic catheter drainage. No studies have examined the role of nasocystic catheter drainage as adjunct therapy to transmural FCSEMS or LAMS in the management of PFCs. The larger stent lumen of an esophageal FCSEMS or 15-mm LAMS may reduce the need for nasocystic catheter irrigation and drainage. Consideration for nasocystic catheter drain placement should be made, however, particularly when infected necrosis is present.

TRANSPAPILLARY STENTING IN PFC MANAGEMENT Questions have also surrounded the adjunct role of transpapillary pancreatic duct stenting in patients undergoing transmural drainage of PFCs. Pancreatic ductal leaks or disruption are the underlying mechanism of acute and mature PFCs. Spontaneous resolution of PFCs may occur in only 0% to 5% of patients with persistent ductal disruption compared to a normal pancreatic duct.61 Acute pancreatic duct leaks are traditionally treated by transpapillary stent placement. In theory, treatment of persistent pancreatic ductal leaks or disruption may help promote resolution of pancreatic fluid collections, as well when applied as adjunct therapy to endoscopic transmural drainage. Previous retrospective studies have suggested that transpapillary stenting may be an augmenting therapy for patients receiving endoscopic transmural drainage of PFCs.62 Transpapillary drainage alone may be effective in the management of PFCs if the cavity communicates with the pancreatic duct, but there is concern for increased risk of PFC superinfection.63 Transpapillary drainage alone could be considered in cases of small PFCs (< 4 cm) or when transmural drainage is not feasible. It is the practice at the author’s institution to place two stents: one extending into the fluid collection, and the other across the area of pancreatic duct leak. As adjunct therapy, a 2016 multicenter, retrospective comparison of EUS-guided transmural drainage alone versus combined transmural and transpapillary drainage of pancreatic pseudocysts, showed no therapeutic benefit to adjunctive transpapillary drainage. Transpapillary drainage actually negatively affected the rate of long-term resolution of the pancreatic fluid collections (OR 0.11, 95% CI 0.02–0.8, p = 0.03).64 Of note, the pancreatic duct stent traversed the site of ductal disruption in only 36.2% of cases. It is possible that bridging of the defect may have resulted in better outcomes, as bridging across the disruption has been associated with improved outcomes previously.65 Nonetheless, in subgroup analysis of patients in which a pancreatic duct stent did successfully bridge the site of disruption, transpapillary drainage still added no benefit to transmural drainage.66 Thus, at our institution, pancreatogram is only pursued in the setting of fluid collection recurrence to document the

presence of a disconnected duct. These patients would then require either surgical intervention or long-term stent placement with transmural plastic stents and possible transpapillary stent placement.

PANCREATIC DUCT LEAKS Pancreatic leaks may result from trauma either from acute or chronic pancreatitis, direct pancreatic injury from abdominal trauma, or iatrogenic injury during endoscopy or surgery. Apart from manifesting as mature pancreatic fluid collections, pancreatic duct leaks may also result in external or internal fistulae. Magnetic resonance cholangiopancreatography (MRCP) and secretin-MRCP can delineate the ductal anatomy as a noninvasive method of diagnosing pancreatic duct leaks. Fluid aspiration of immature PFCs with amylase analysis can also be performed to diagnose pancreatic duct leaks. Endoscopic retrograde cholangiopancreatography (ERCP) with pancreatogram is the most sensitive method of detecting pancreatic duct leaks and disruption (Fig. 58.9). Internal fistulae result from ductal disruption with the manifestation depending on the location of disruption. Anterior disruption may result in pancreatic ascites, whereas posterior disruption can lead to a mediastinal pseudocyst or pleural fistula.67 Initial noninvasive management of pancreatic duct leaks may be pursued with bowel rest, deep enteral feeding, and use of octreotide. Conservative management is frequently ineffective, however, failing approximately 50% of the time. Failure occurs even more frequently in patients with advanced pancreatitis.68 Given the frequent inefficacy of noninvasive management, endoscopic therapy may be pursued as initial or second-line therapy. Transpapillary pancreatic duct stenting is effective in promoting leak healing by reducing the resistance of transpapillary flow by bypassing potential pancreatic duct strictures and stones and the sphincter of Oddi.69 Tanaka et al (2013) reported on a series of six patients with internal pancreatic fistulae and associated downstream pancreatic duct stenosis.67 Endoscopic therapy

FIG 58.9 Pancreatic duct leak on pancreatogram. Completely disconnected pancreatic duct.

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CHAPTER 58 Pancreatic Fluid Collections and Leaks was performed with placement of a 5-Fr or 7-Fr plastic stent, with intention to perform stent exchange for a total duration of 1 year. Stent placement across the site of stenosis was successful in 100% of patients. Treatment was successful with resolution of leak in 66% of patients (four out of six), though one of these had recurrence refractory to further stenting. Despite endoscopic therapy, however, 50% eventually required surgery for definitive management (due to continuous pain with leak or intracystic bleeding). Bridging of the site of pancreatic duct disruption and long duration of stent therapy may enhance the efficacy of transpapillary stent therapy.70 A more recent (2016) large series of 107 patients with pancreatic duct disruption showed that pancreatic duct stent placement resulted in healing of the leak in 75% of patients. Ninety-six percent had successful pancreatic duct stent placement, but bridging of the point of disruption was successful in only 44% of patients.71 In cases where the disruption point was not bridged, treatment success was only 48%. In both these series, acute pancreatitis as the etiology of pancreatic duct disruption predicted poor response to pancreatic duct stenting. The presence of complete duct disruption was also predictive of failure of therapy. In patients specifically with pleural fistulae, medical and endoscopic therapy is also typically advised prior to surgical intervention due to the latter’s morbidity. Prior to intervention, pancreatic pleural fistulae can be differentiated from reactive pleural effusions that may develop in the setting of acute pancreatitis based upon the presence of a high amylase concentration within the pleural fluid. Imaging may also help diagnose a pancreatic pleural fistula. CT has a 47% sensitivity for detection of the fistulous tract, whereas MRCP and ERCP have roughly 80% sensitivity. For pleural fistulae, ERCP with transpapillary stenting is the standard endoscopic therapy. Following transpapillary stenting, diagnostic ERCP can be performed every 4 to 6 weeks for stent exchange or removal based upon assessment of fistula closure. The majority of patients with pleural fistulae that respond to endotherapeutic stenting have a stent that bridges the site of disruption. Endoscopic management fails in a significant proportion of patients, however.72 Due to high failure rate, preintervention MRCP findings may be useful in guiding management strategies. Those with normal pancreatic ducts without downstream strictures may respond to conservative medical therapy. If a ductal stricture is present or disruption is noted in the head or body of the pancreas, endoscopic therapy may be the most appropriate first-line therapy. If there is complete ductal obstruction or both stricture and leakage from within the pancreatic tail, however, surgical treatment may be most appropriate due to the poor success of endoscopic stenting.73 The treatment of external pancreatic fistulae is similar to that of internal fistulae. In cases of conservative management failure, endoscopic transpapillary stenting may be pursued prior to surgical intervention. In addition, endoscopic fibrin glue injection has been reported for closure of pancreaticocutaneous fistula.74

Disconnected Duct Syndrome Disconnected duct syndrome denotes the presence of a pancreatic leak resulting from complete transection of the pancreatic duct (see Fig. 58.9). Excretions from the upstream proximal pancreas thus drain entirely into the abdominal cavity. Surgical treatment has been the primary management modality for disconnected duct syndrome. Due to the inability to pass a guidewire into the disconnected duct, transpapillary placement of a pancreatic duct stent is typically not effective because bridging of the ductal

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defect cannot be performed.69 Varadarajulu et al (2005) have reported success in only 26% of cases with attempted transpapillary stent placement.65 As an alternative to surgery or endoscopic transpapillary stenting, endoscopic transmural stenting may be performed for creation of a fistula between the fluid collection and the GI tract. Permanent transmural stenting thus produces long-term drainage of the isolated pancreatic segment. Téllez-Ávila et al (2016) reported a series of 21 patients with confirmed disconnected duct syndrome (by MRCP or ERCP) who underwent transmural stent placement with two 7 Fr by 4 cm double pigtail stents.75 Technical success was achieved in 100% of patients and clinical success in 81% after a median follow-up of 28 months. In those with clinical success, 20% had recurrence for which a second endoscopic treatment was successful, consisting of tract dilation with direct endoscopic necrosectomy followed by placement of two double pigtail stents. Reported complications included stent migration (10%), infection after drainage (5%), infection after stent migration (5%), and suspected stent migration with perforation (5%), though perforation was not actually confirmed after surgical exploration.69 As noted previously, if duct disruption results in formation of a mature fluid collection (pseudocyst or WON), transmural drainage is often adequate therapy and transpapillary pancreatic duct stenting does not seem to provide adjunct benefit.64 Larsen and Kozarek (2014) have reported a combined endoscopic and percutaneous approach for patients with WON and disconnected duct syndrome. At their center, frequent development of external pancreaticocutaneous fistulae with solely percutaneous drainage prompted use of combined percutaneous and transmural drainage. In this scenario, plastic transmural stents were left in place indefinitely. This approach prevented development of cutaneous fistulae and successfully avoided need for surgery in more than 95% of patients.69

Postsurgical Acute Pancreatic Fluid Collections Pancreatic duct leaks with resultant acute postoperative PFCs occur in approximately 30% of patients following pancreatic surgeries such as pancreaticoduodenectomy, pancreatic enucleation, and distal pancreatectomy. Spontaneous resolution typically will occur over days to weeks. Symptomatic collections may present with severe pain, gastric outlet obstruction, or intraabdominal infection and sepsis. Classic management consists of bowel rest, TPN, antibiotics, and possible intravenous octreotide. In approximately 20% to 40% of cases, further management may be necessary, at which time percutaneous drainage is traditionally pursued. Percutaneous drainage is effective, but presence of an external drain may decrease patient quality of life, requires monitoring of fluid output, catheter flushing, and possible catheter exchange. In cases of persistent leak, pancreatic duct stenting may also be indicated. Pancreatic duct stenting is not effective, however, if disrupted duct syndrome is present where there is complete transection of the pancreatic duct. Furthermore, large or infected peripancreatic fluid collections may not resolve quickly with a transpapillary stent. The risk of post-ERCP pancreatitis also detracts from the appeal of transpapillary stenting. EUS-guided transmural drainage has been advocated as a possible therapeutic option for acute postoperative PFCs. In 2009, Varadarajulu et al reported a prospective series of 10 patients undergoing EUS-guided plastic stent drainage of PFCs after distal pancreatectomy with 100% technical success, and 90% therapeutic success, though it is unclear if any of these postoperative

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collections were acute.76 A subsequent retrospective comparison of EUS-guided drainage (using one to three double pigtail stents) and percutaneous drainage of 23 patients with symptomatic PFCs following pancreatic enucleation or distal pancreatectomy showed 100% technical success with either method, but a higher rate of clinical success (defined as radiographic resolution of collection, stent, or removal, and symptomatic improvement) with EUS-guided drainage.77 Necrosectomy was required in five patients with EUS-guided drainage, and two patients had concurrent ERCP with pancreatic duct stent placement. Most patients in this study were referred from an outside hospital with the possibility that varying surgical approaches, closure methods, and underlying histology may bias leak rates and subsequent clinical improvement. Furthermore, the maturity of fluid collections within this study were unknown and may not have been comparable between the two treatment groups. In 2014, Tilara et al reported a retrospective analysis of 31 patients who underwent EUS-guided drainage of postoperative fluid collections developing following pancreatic resection.78 A proportion of these patients had acute collections. The indications for PFC drainage were abdominal pain, infection, gastric outlet obstruction, and biliary obstruction. One to three double pigtail stents, 7 Fr or 10 Fr in diameter, were deployed. If symptoms persisted and PFC size did not improve on cross-sectional imaging 4 weeks postdrainage, repeated endoscopy with tract dilation, new stent insertion, and necrosectomy were performed, which was necessary in 19% of patients. Technical success was achieved in 100% of patients. PFC resolution on imaging with clinical improvement occurred in 93% of patients. Among all cases, 55% had successful early drainage within 30 days postoperatively. Forty-two percent of these patients had drainage performed within 2 weeks of surgery. Early drainage was not associated with increased complications. One complication occurred in patients undergoing early drainage: a bleed from a splenic artery stump. Of note, the indication for drainage in patients undergoing early EUS-guided drainage was infection (fever, leukocytosis, or abscess formation) in 70% of cases. In those undergoing drainage within two weeks of surgery, the indication for drainage was infection or sepsis in all cases. Thus, most patients undergoing early EUS-guided drainage of postoperative collections had signs of sepsis necessitating drainage prior to maturation of the PFC. The authors propose that maturity of fluid collection may be less important for drainage of postoperative PFCs versus those that arise from pancreatitis adhesion formation; scarring may effectively compartmentalize the surgical bed and may limit intraperitoneal spillage. Further studies are necessary, however, to prove the safety of endoscopic transmural drainage of acute collections, particularly in the absence of preexisting infection necessitating early intervention.

CONCLUSION Disruption of the main or secondary pancreatic ducts can result in pancreatic leaks and development of PFCs as a complication of pancreatitis, trauma, or iatrogenesis. In general, PFCs are best observed over time to allow for their likely spontaneous regression. When PFC drainage is indicated by persistent symptoms or evidence of infection, however, endoscopic transmural drainage has become a first-line therapy in lieu of surgical intervention. Appropriate management nonetheless rests on a multidisciplinary collaboration involving interventional radiology and surgery.

Overall, endoscopic management is an efficacious treatment modality for pancreatic pseudocysts. Further prospective trials are necessary to establish the benefits of metal stents over plastic stents, particularly given their increased cost. Further study is also required to determine ideal stent length, the need for nasocystic catheter placement, the need for dilation of FCSEMS after placement, the benefit of same-session pseudocyst exploration through the FCSEMS, and the benefit of internal plastic stent placement for metal stent anchoring.79 The use of lumenapposing metal stents over traditional stent design has the theoretical advantages of reducing stent migration and reducing stent erosion. LAMS design may be most useful, however, in cases of walled-off necrosis, in which the large stent diameter facilitates persistent drainage and the lumen-apposing flanges establish a more secure anastomosis that enables immediate direct endoscopic exploration and necrosectomy of the necrotic cavity.

KEY REFERENCES 1. Banks PA, Bollen TL, Dervenis C, et al: Classification of acute pancreatitis–2012: revision of the Atlanta classification and definitions by international consensus, Gut 62(1):102–111, 2013. 2. Varadarajulu S, Bang JY, Sutton BS, et al: Equal efficacy of endoscopic and surgical cystogastrostomy for pancreatic pseudocyst drainage in a randomized trial, Gastroenterology 145(3):583–590, e1, 2013. 3. Gurusamy KS, Pallari E, Hawkins N, et al: Management strategies for pancreatic pseudocysts, Cochrane Database Syst Rev (4):CD011392, 2016. 4. Gurusamy KS, Belgaumkar AP, Haswell A, et al: Interventions for necrotising pancreatitis, Cochrane Database Syst Rev (4):CD011383, 2016. 8. van Santvoort HC, Besselink MG, Cirkel GA, Gooszen HG: A nationwide Dutch study into the optimal treatment of patients with infected necrotising pancreatitis: the PANTER trial, Ned Tijdschr Geneeskd 150(33):1844–1846, 2006. 11. Baron TH, Harewood GC, Morgan DE, Yates MR: Outcome differences after endoscopic drainage of pancreatic necrosis, acute pancreatic pseudocysts, and chronic pancreatic pseudocysts, Gastrointest Endosc 56(1):7–17, 2002. 18. Ballard D, Cote G: Endoscopic (without endoscopic ultrasound guidance drainage of pancreatic fluid collections, Techn Gastrointest Endosc 14: 199–203, 2012. 21. Park DH, Lee SS, Moon SH, et al: Endoscopic ultrasound-guided versus conventional transmural drainage for pancreatic pseudocysts: a prospective randomized trial, Endoscopy 41(10):842–848, 2009. 28. Sharaiha RZ, Tyberg A, Khashab MA, et al: Endoscopic therapy with lumen-apposing metal stents is safe and effective for patients with pancreatic walled-off necrosis, Clin Gastroenterol Hepatol 14(12): 1797–1803, 2016. 31. Itoi T, Binmoeller KF, Shah J, et al: Clinical evaluation of a novel lumen-apposing metal stent for endosonography-guided pancreatic pseudocyst and gallbladder drainage (with videos), Gastrointest Endosc 75(4):870–876, 2012. 32. Shah RJ, Shah JN, Waxman I, et al: Safety and efficacy of endoscopic ultrasound-guided drainage of pancreatic fluid collections with lumen-apposing covered self-expanding metal stents, Clin Gastroenterol Hepatol 13(4):747–752, 2015. 33. Bang JY, Hawes R, Bartolucci A, Varadarajulu S: Efficacy of metal and plastic stents for transmural drainage of pancreatic fluid collections: a systematic review, Dig Endosc 27(4):486–498, 2015. 40. Tyberg A, Karia K, Gabr M, et al: Management of pancreatic fluid collections: a comprehensive review of the literature, World J Gastroenterol 22(7):2256–2270, 2016. 42. Gardner TB, Chahal P, Papachristou GI, et al: A comparison of direct endoscopic necrosectomy with transmural endoscopic drainage for the treatment of walled-off pancreatic necrosis, Gastrointest Endosc 69(6): 1085–1094, 2009.

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CHAPTER 58 Pancreatic Fluid Collections and Leaks 48. Kumar N, Conwell DL, Thompson CC: Direct endoscopic necrosectomy versus step-up approach for walled-off pancreatic necrosis: comparison of clinical outcome and health care utilization, Pancreas 43(8): 1334–1339, 2014. 51. Siddiqui AA, Adler DG, Nieto J, et al: EUS-guided drainage of peripancreatic fluid collections and necrosis by using a novel lumen-apposing stent: a large retrospective, multicenter U.S. experience (with videos), Gastrointest Endosc 83(4):699–707, 2016. 52. Siddiqui AA, Kowalski TE, Loren DE, et al: Fully covered self-expanding metal stents versus lumen-apposing fully covered self-expanding metal stent versus plastic stents for endoscopic drainage of pancreatic walled-off necrosis: clinical outcomes and success, Gastrointest Endosc 85(4):758–765, 2017. 55. Itoi T, Binmoeller KF, Shah J, et al: Clinical evaluation of a novel lumen-apposing metal stent for endosonography-guided pancreatic pseudocyst and gallbladder drainage (with videos), Gastrointest Endosc 75(4):870–876, 2012. 57. Walter D, Will U, Sanchez-Yague A, et al: A novel lumen-apposing metal stent for endoscopic ultrasound-guided drainage of pancreatic fluid collections: a prospective cohort study, Endoscopy 47(1):63–67, 2015.

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59. Ang TL, Kongkam P, Kwek AB, et al: A two-center comparative study of plastic and lumen-apposing large diameter self-expandable metallic stents in endoscopic ultrasound-guided drainage of pancreatic fluid collections, Endosc Ultrasound 5(5):320–327, 2016. 64. Yang D, Amin S, Gonzalez S, et al: Transpapillary drainage has no added benefit on treatment outcomes in patients undergoing EUS-guided transmural drainage of pancreatic pseudocysts: a large multicenter study, Gastrointest Endosc 83(4):720–729, 2016. 69. Larsen M, Kozarek R: Management of pancreatic ductal leaks and fistulae, J Gastroenterol Hepatol 29(7):1360–1370, 2014. 80. Shah RJ, Shah JN, Waxman I, et al: Safety and efficacy of endoscopic ultrasound-guided drainage of pancreatic fluid collections with lumen-apposing covered self-expanding metal stents, Clin Gastroenterol Hepatol 13(4):747–752, 2015. 81. Gornals JB, De la Serna-Higuera C, Sánchez-Yague A, et al: Endosonography-guided drainage of pancreatic fluid collections with a novel lumen-apposing stent, Surg Endosc 27(4):1428–1434, 2013.

A complete reference list can be found online at ExpertConsult .com

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CHAPTER 58 Pancreatic Fluid Collections and Leaks

REFERENCES 1. Banks PA, Bollen TL, Dervenis C, et al: Classification of acute pancreatitis–2012: revision of the Atlanta classification and definitions by international consensus, Gut 62(1):102–111, 2013. 2. Varadarajulu S, Bang JY, Sutton BS, et al: Equal efficacy of endoscopic and surgical cystogastrostomy for pancreatic pseudocyst drainage in a randomized trial, Gastroenterology 145(3):583–590, e1, 2013. 3. Gurusamy KS, Pallari E, Hawkins N, et al: Management strategies for pancreatic pseudocysts, Cochrane Database Syst Rev (4):CD011392, 2016. 4. Gurusamy KS, Belgaumkar AP, Haswell A, et al: Interventions for necrotising pancreatitis, Cochrane Database Syst Rev (4):CD011383, 2016. 5. Cui ML, Kim KH, Kim HG, et al: Incidence, risk factors and clinical course of pancreatic fluid collections in acute pancreatitis, Dig Dis Sci 59(5):1055–1062, 2014. 6. Elkhatib I, Savides T, Fehmi S: Pancretic fluid collections: physiology, natural history, and indications for drainage, Techn Gastrointest Endosc 14:186–194, 2012. 7. Banks PA, Freeman ML: Practice Parameters Committee of the American College of Gastroenterology: practice guidelines in acute pancreatitis, Am J Gastroenterol 101(10):2379–2400, 2006. 8. van Santvoort HC, Besselink MG, Cirkel GA, Gooszen HG: A nationwide Dutch study into the optimal treatment of patients with infected necrotising pancreatitis: the PANTER trial, Ned Tijdschr Geneeskd 150(33):1844–1846, 2006. 9. Logue JA, Carter CR: Minimally invasive necrosectomy techniques in severe acute pancreatitis: role of percutaneous necrosectomy and video-assisted retroperitoneal debridement, Gastroenterol Res Pract 2015:693040, 2015. 10. Rana SS, Bhasin DK, Sharma RK, et al: Do the morphological features of walled off pancreatic necrosis on endoscopic ultrasound determine the outcome of endoscopic transmural drainage?, Endosc Ultrasound 3(2): 118–122, 2014. 11. Baron TH, Harewood GC, Morgan DE, Yates MR: Outcome differences after endoscopic drainage of pancreatic necrosis, acute pancreatic pseudocysts, and chronic pancreatic pseudocysts, Gastrointest Endosc 56(1):7–17, 2002. 12. Morgan DE, Baron TH, Smith JK, et al: Pancreatic fluid collections prior to intervention: evaluation with MR imaging compared with CT and US, Radiology 203(3):773–778, 1997. 13. Rana SS, Chaudhary V, Sharma R, et al: Comparison of abdominal ultrasound, endoscopic ultrasound and magnetic resonance imaging in detection of necrotic debris in walled-off pancreatic necrosis, Gastroenterol Rep (Oxf) 4(1):50–53, 2016. 14. Takahashi N, Papachristou GI, Schmit GD, et al: CT findings of walled-off pancreatic necrosis (WOPN): differentiation from pseudocyst and prediction of outcome after endoscopic therapy, Eur Radiol 18(11): 2522–2529, 2008. 15. Dhaka N, Samanta J, Kochhar S, et al: Pancreatic fluid collections: what is the ideal imaging technique?, World J Gastroenterol 21(48):13403– 13410, 2015. 16. Fischer TD, Gutman DS, Hughes SJ, et al: Disconnected pancreatic duct syndrome: disease classification and management strategies, J Am Coll Surg 219(4):704–712, 2014. 17. Zaheer A, Singh VK, Qureshi RO, Fishman EK: The revised Atlanta classification for acute pancreatitis: updates in imaging terminology and guidelines, Abdom Imaging 38(1):125–136, 2013. 18. Ballard D, Cote G: Endoscopic (without endoscopic ultrasound guidance) drainage of pancreatic fluid collections, Techn Gastrointest Endosc 14:199–203, 2012. 19. Azar RR, Oh YS, Janec EM, et al: Wire-guided pancreatic pseudocyst drainage by using a modified needle knife and therapeutic echoendoscope, Gastrointest Endosc 63(4):688–692, 2006. 20. Kitamura K, Yamamiya A, Ishii Y, et al: Electrocautery vs nonelectrocautery dilation catheters in endoscopic ultrasonography-guided pancreatic fluid collection drainage, World J Gastrointest Endosc 8(13): 458–465, 2016.

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21. Park DH, Lee SS, Moon SH, et al: Endoscopic ultrasound-guided versus conventional transmural drainage for pancreatic pseudocysts: a prospective randomized trial, Endoscopy 41(10):842–848, 2009. 22. Panamonta N, Ngamruengphong S, Kijsirichareanchai K, et al: Endoscopic ultrasound-guided versus conventional transmural techniques have comparable treatment outcomes in draining pancreatic pseudocysts, Eur J Gastroenterol Hepatol 24(12):1355–1362, 2012. 23. Lin H, Zhan XB, Sun SY, et al: Stent selection for endoscopic ultrasoundguided drainage of pancreatic fluid collections: a multicenter study in china, Gastroenterol Res Pract 2014:193562, 2014. 24. Cahen D, Rauws E, Fockens P, et al: Endoscopic drainage of pancreatic pseudocysts: long-term outcome and procedural factors associated with safe and successful treatment, Endoscopy 37(10):977–983, 2005. 25. Binmoeller KF, Smith I, Gaidhane M, Kahaleh M: A kit for EUS-guided access and drainage of pancreatic pseudocysts: efficacy in a porcine model, Endosc Ultrasound 1(3):137–142, 2012. 26. Sharaiha RZ, DeFilippis EM, Kedia P, et al: Metal versus plastic for pancreatic pseudocyst drainage: clinical outcomes and success, Gastrointest Endosc 82(5):822–827, 2015. 27. Lee BU, Song TJ, Lee SS, et al: Newly designed, fully covered metal stents for endoscopic ultrasound (EUS)-guided transmural drainage of peripancreatic fluid collections: a prospective randomized study, Endoscopy 46(12):1078–1084, 2014. 28. Sharaiha RZ, Tyberg A, Khashab MA, et al: Endoscopic therapy with lumen-apposing metal stents is safe and effective for patients with pancreatic walled-off necrosis, Clin Gastroenterol Hepatol 14(12):1797– 1803, 2016. 29. Rodrigues-Pinto E, Baron TH: Evaluation of the AXIOS stent for the treatment of pancreatic fluid collections, Expert Rev Med Devices 13(9): 793–805, 2016. 30. Rinninella E, Kunda R, Dollhopf M, et al: EUS-guided drainage of pancreatic fluid collections using a novel lumen-apposing metal stent on an electrocautery-enhanced delivery system: a large retrospective study (with video), Gastrointest Endosc 82(6):1039–1046, 2015. 31. Itoi T, Binmoeller KF, Shah J, et al: Clinical evaluation of a novel lumen-apposing metal stent for endosonography-guided pancreatic pseudocyst and gallbladder drainage (with videos), Gastrointest Endosc 75(4):870–876, 2012. 32. Shah RJ, Shah JN, Waxman I, et al: Safety and efficacy of endoscopic ultrasound-guided drainage of pancreatic fluid collections with lumen-apposing covered self-expanding metal stents, Clin Gastroenterol Hepatol 13(4):747–752, 2015. 33. Bang JY, Hawes R, Bartolucci A, Varadarajulu S: Efficacy of metal and plastic stents for transmural drainage of pancreatic fluid collections: a systematic review, Dig Endosc 27(4):486–498, 2015. 34. Akshintala VS, Saxena P, Zaheer A, et al: A comparative evaluation of outcomes of endoscopic versus percutaneous drainage for symptomatic pancreatic pseudocysts, Gastrointest Endosc 79(6):921–928, quiz 983.e2, 983.e5, 2014. 35. Uhl W, Warshaw A, Imrie C, et al: IAP guidelines for the surgical management of acute pancreatitis, Pancreatology 2(6):565–573, 2002. 36. Besselink MG, Verwer TJ, Schoenmaeckers EJ, et al: Timing of surgical intervention in necrotizing pancreatitis, Arch Surg 142(12):1194–1201, 2007. 37. Wronski M, Cebulski W, Karkocha D, et al: Ultrasound-guided percutaneous drainage of infected pancreatic necrosis, Surg Endosc 27(8): 2841–2848, 2013. 38. Freeny PC, Hauptmann E, Althaus SJ, et al: Percutaneous CT-guided catheter drainage of infected acute necrotizing pancreatitis: techniques and results, AJR Am J Roentgenol 170(4):969–975, 1998. 39. Bello B, Matthews JB: Minimally invasive treatment of pancreatic necrosis, World J Gastroenterol 18(46):6829–6835, 2012. 40. Tyberg A, Karia K, Gabr M, et al: Management of pancreatic fluid collections: a comprehensive review of the literature, World J Gastroenterol 22(7):2256–2270, 2016. 41. Seifert H, Wehrmann T, Schmitt T, et al: Retroperitoneal endoscopic debridement for infected peripancreatic necrosis, Lancet 356(9230):653– 655, 2000.

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Pancreaticobiliary Disorders

42. Gardner TB, Chahal P, Papachristou GI, et al: A comparison of direct endoscopic necrosectomy with transmural endoscopic drainage for the treatment of walled-off pancreatic necrosis, Gastrointest Endosc 69(6): 1085–1094, 2009. 43. Haghshenasskashani A, Laurence JM, Kwan V, et al: Endoscopic necrosectomy of pancreatic necrosis: a systematic review, Surg Endosc 25(12):3724–3730, 2011. 44. Puli SR, Graumlich JF, Pamulaparthy SR, Kalva N: Endoscopic transmural necrosectomy for walled-off pancreatic necrosis: a systematic review and meta-analysis, Can J Gastroenterol Hepatol 28(1):50–53, 2014. 45. Bonnot B, Nion-Larmurier I, Desaint B, et al: Fatal gas embolism after endoscopic transgastric necrosectomy for infected necrotizing pancreatitis, Am J Gastroenterol 109(4):607, 2014. 46. Luigiano C, Pellicano R, Fusaroli P, et al: Pancreatic necrosectomy: an evidence-based systematic review of the levels of evidence and a comparison of endoscopic versus non-endoscopic techniques, Minerva Chir 71(4):262–269, 2016. 47. Bakker OJ, van Santvoort HC, van Brunschot S, et al: Endoscopic transgastric vs surgical necrosectomy for infected necrotizing pancreatitis: a randomized trial, JAMA 307(10):1053–1061, 2012. 48. Kumar N, Conwell DL, Thompson CC: Direct endoscopic necrosectomy versus step-up approach for walled-off pancreatic necrosis: comparison of clinical outcome and health care utilization, Pancreas 43(8):1334– 1339, 2014. 49. Sarkaria S, Sethi A, Rondon C, et al: Pancreatic necrosectomy using covered esophageal stents: a novel approach, J Clin Gastroenterol 48(2): 145–152, 2014. 50. Attam R, Trikudanathan G, Arain M, et al: Endoscopic transluminal drainage and necrosectomy by using a novel, through-the-scope, fully covered, large-bore esophageal metal stent: preliminary experience in 10 patients, Gastrointest Endosc 80(2):312–318, 2014. 51. Siddiqui AA, Adler DG, Nieto J, et al: EUS-guided drainage of peripancreatic fluid collections and necrosis by using a novel lumenapposing stent: a large retrospective, multicenter U.S. experience (with videos), Gastrointest Endosc 83(4):699–707, 2016. 52. Siddiqui AA, Kowalski TE, Loren DE, et al: Fully covered self-expanding metal stents versus lumen-apposing fully covered self-expanding metal stent versus plastic stents for endoscopic drainage of pancreatic walled-off necrosis: clinical outcomes and success, Gastrointest Endosc 85(4):758–765, 2017. 53. Teoh AY, Ng EK, Chan SM, et al: Ex vivo comparison of the lumenapposing properties of EUS-specific stents (with video), Gastrointest Endosc 84(1):62–68, 2016. 54. Bang JY, Hasan M, Navaneethan U, et al: Lumen-apposing metal stents (LAMS) for pancreatic fluid collection (PFC) drainage: may not be business as usual, Gut 0:1–3, 2016. 55. Itoi T, Binmoeller KF, Shah J, et al: Clinical evaluation of a novel lumen-apposing metal stent for endosonography-guided pancreatic pseudocyst and gallbladder drainage (with videos), Gastrointest Endosc 75(4):870–876, 2012. 56. Leeds JS, Nayar MK, Charnley RM, Oppong KW: Lumen-apposing metal stents for pancreatic fluid collection drainage: may not be business as usual?, Gut 2016. [Epub ahead of print]. 57. Walter D, Will U, Sanchez-Yague A, et al: A novel lumen-apposing metal stent for endoscopic ultrasound-guided drainage of pancreatic fluid collections: a prospective cohort study, Endoscopy 47(1):63–67, 2015. 58. Bang JY, Hasan MK, Navaneethan U, et al: Lumen apposing metal stents (LAMS) for drainage of pancreatic fluid collections: when and for whom?, Dig Endosc 29(1):83–90, 2017. 59. Ang TL, Kongkam P, Kwek AB, et al: A two-center comparative study of plastic and lumen-apposing large diameter self-expandable metallic stents in endoscopic ultrasound-guided drainage of pancreatic fluid collections, Endosc Ultrasound 5(5):320–327, 2016. 60. Mukai S, Itoi T, Baron TH, et al: Endoscopic ultrasound-guided placement of plastic vs. biflanged metal stents for therapy of walled-off necrosis: a retrospective single-center series, Endoscopy 47(1):47–55, 2015.

61. Nealon WH, Bhutani M, Riall TS, et al: A unifying concept: pancreatic ductal anatomy both predicts and determines the major complications resulting from pancreatitis, J Am Coll Surg 208(5):790–799, discussion 799-801, 2009. 62. Trevino JM, Tamhane A, Varadarajulu S: Successful stenting in ductal disruption favorably impacts treatment outcomes in patients undergoing transmural drainage of peripancreatic fluid collections, J Gastroenterol Hepatol 25(3):526–531, 2010. 63. Bhasin DK, Rana SS, Nanda M, et al: Comparative evaluation of transpapillary drainage with nasopancreatic drain and stent in patients with large pseudocysts located near tail of pancreas, J Gastrointest Surg 15(5):772–776, 2011. 64. Yang D, Amin S, Gonzalez S, et al: Transpapillary drainage has no added benefit on treatment outcomes in patients undergoing EUS-guided transmural drainage of pancreatic pseudocysts: a large multicenter study, Gastrointest Endosc 83(4):720–729, 2016. 65. Varadarajulu S, Noone TC, Tutuian R, et al: Predictors of outcome in pancreatic duct disruption managed by endoscopic transpapillary stent placement, Gastrointest Endosc 61(4):568–575, 2005. 66. Hookey LC, Debroux S, Delhaye M, et al: Endoscopic drainage of pancreatic-fluid collections in 116 patients: a comparison of etiologies, drainage techniques, and outcomes, Gastrointest Endosc 63(4):635–643, 2006. 67. Tanaka T, Kuroki T, Kitasato A, et al: Endoscopic transpapillary pancreatic stenting for internal pancreatic fistula with the disruption of the pancreatic ductal system, Pancreatology 13(6):621–624, 2013. 68. Parekh D, Segal I: Pancreatic ascites and effusion. Risk factors for failure of conservative therapy and the role of octreotide, Arch Surg 127(6):707– 712, 1992. 69. Larsen M, Kozarek R: Management of pancreatic ductal leaks and fistulae, J Gastroenterol Hepatol 29(7):1360–1370, 2014. 70. Telford JJ, Farrell JJ, Saltzman JR, et al: Pancreatic stent placement for duct disruption, Gastrointest Endosc 56(1):18–24, 2002. 71. Das R, Papachristou GI, Slivka A, et al: Endotherapy is effective for pancreatic ductal disruption: a dual center experience, Pancreatology 16(2):278–283, 2016. 72. Aswani Y, Hira P: Pancreaticopleural fistula: a review, JOP 16(1):90–94, 2015. 73. Wronski M, Slodkowski M, Cebulski W, et al: Optimizing management of pancreaticopleural fistulas, World J Gastroenterol 17(42):4696–4703, 2011. 74. Choi KM, Kim YD, Ahn JH: Closure of pancreatoduodenal fistula using vascular occluding coil embolization and fibrin glue injection: a case study, Korean J Hepatobiliary Pancreat Surg 17(2):75–78, 2013. 75. Téllez-Ávila FI, Casasola-Sánchez LE, Ramírez-Luna MÁ, et al: Permanent indwelling transmural stents for endoscopic treatment of patients with disconnected pancreatic duct syndrome: long-term results, J Clin Gastroenterol 2016. [Epub ahead of print]. 76. Varadarajulu S, Trevino JM, Christein JD: EUS for the management of peripancreatic fluid collections after distal pancreatectomy, Gastrointest Endosc 70(6):1260–1265, 2009. 77. Kwon YM, Gerdes H, Schattner MA, et al: Management of peripancreatic fluid collections following partial pancreatectomy: a comparison of percutaneous versus EUS-guided drainage, Surg Endosc 27(7):2422–2427, 2013. 78. Tilara A, Gerdes H, Allen P, et al: Endoscopic ultrasound-guided transmural drainage of postoperative pancreatic collections, J Am Coll Surg 218(1):33–40, 2014. 79. Dhir V, Maydeo A: EUS-guided pseudocyst drainage: has the metal proved its mettle?, Gastrointest Endosc 82(5):828–830, 2015. 80. Shah RJ, Shah JN, Waxman I, et al: Safety and efficacy of endoscopic ultrasound-guided drainage of pancreatic fluid collections with lumen-apposing covered self-expanding metal stents, Clin Gastroenterol Hepatol 13(4):747–752, 2015. 81. Gornals JB, De la Serna-Higuera C, Sánchez-Yague A, et al: Endosonography-guided drainage of pancreatic fluid collections with a novel lumen-apposing stent, Surg Endosc 27(4):1428–1434, 2013.

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59 Chronic Pancreatitis Uzma D. Siddiqui and Robert H. Hawes

CHAPTER OUTLINE Introduction, 686 Etiology, 686 Alcohol, 686 Smoking, 686 Genetic Causes, 686 Ductal Obstruction, 687 Idiopathic Chronic Pancreatitis, 687 Clinical features, 687

Abdominal Pain, 687 Pancreatic Insufficiency, 687 Diagnosis, 687 Tests of Pancreatic Function, 687 Tests of Pancreatic Structure, 688 Endoscopic Management, 690 Pain Relief, 690 Pancreatic Duct Strictures, 694 Associated Complications, 695

INTRODUCTION Chronic pancreatitis (CP) is an inflammatory condition that results in fibrosis causing destruction of pancreatic parenchyma and ducts. These permanent structural changes can lead to impairment of exocrine and endocrine function, biliary strictures, and may increase the chances of developing pancreatic cancer.1 This disorder contrasts with acute pancreatitis in that the latter is non-progressive, and the gland returns to histologic and functional normalcy once the acute event subsides. There does exist overlap between the two conditions, and recurrent episodes of acute pancreatitis may lead to more permanent chronic changes. The most common clinical presentation of CP is abdominal pain, which is multifactorial in nature, and if associated with only minimal pancreatic fibrosis, can lead to confusion over the diagnosis. The role of endoscopy has focused on relieving abdominal pain and managing complications, but interpretation of data on this topic remains challenging due to varied presentations, clinical courses, and etiologies. Given the limitations of medical therapy and the invasiveness of surgical options, endoscopic therapy has been widely employed in the treatment of CP, but long-term randomized trials are lacking and therefore its role continues to evolve.

ETIOLOGY Alcohol Alcohol accounts for 70% to 80% of cases of CP (Table 59.1); the mechanism by which this occurs is unclear. The risk seems

Future Trends, 696 Developments in Testing, 696 CFTR Testing in Idiopathic Cases, 696 Micro-RNA for Early Diagnosis, 696 Advances in EUS Techniques, 696

to be related to the duration and amount of alcohol consumed rather than the type of alcohol or the pattern of consumption.2 Only 5% to 10% of alcoholics develop CP, suggesting that other unidentified factors may be important in the pathogenesis of the disease.3

Smoking More recently, smoking has emerged as an independent risk factor for CP, as demonstrated in two studies by the North American Pancreas Study Group.4,5 Similar to alcohol, the effects of smoking on the development of CP appear to be dose dependent, with risk increasing for people smoking more than one pack per day.6 Furthermore, in those with alcohol-induced acute pancreatitis, smoking appears to be the strongest risk factor for progression to CP.7,8

Genetic Causes Several mutations associated with CP have been identified. Mutations in the cationic trypsin gene (PRSS1) that lead to premature trypsinogen activation have been suggested as the cause of hereditary pancreatitis.9–11 PRSS1 inheritance is autosomal dominant with high penetrance. Cystic fibrosis is caused by mutations in the CFTR gene. Most patients with cystic fibrosis develop progressive pancreatic damage as a result of defective ductular and acinar pancreatic secretion.12 In some series, mutations in the CFTR gene have been identified in 13% to 37% of patients with idiopathic CP who have no clinical evidence of cystic fibrosis.13,14 This percentage range could be an underestimation because currently available genetic screening tests identify only 18 to 23 of the most severe CFTR mutations that cause classic childhood cystic fibrosis.

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CHAPTER 59 Chronic Pancreatitis

Abstract

Keywords

Chronic pancreatitis can be described as an inflammatory process characterized by irreversible destruction of pancreatic parenchyma and ductal structures with fibrosis formation. This term describes a wide variety of clinical findings and symptoms that require a multi-disciplinary approach to care. Making an accurate, early diagnosis can be difficult, and therefore it is important to recognize risk factors for chronic pancreatitis development (i.e., alcohol, smoking, genetic factors, etc.) and how to maximize utility from various imaging studies. Goals of treatment include pain management, correction of pancreatic insufficiency, and treating associated complications. Pain control can be the most clinically challenging aspect of care because its etiology is multi-factorial and mechanisms are poorly understood. Chronic pancreatitis management includes a combination of medical, endoscopic, and surgical approaches. This chapter will present current diagnostic and treatment modalities for chronic pancreatitis, along with an overview of the relevant published data that lend credence to their use.

chronic pancreatitis pancreatic duct stones pancreatic duct strictures ERCP EUS

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686.e1

CHAPTER 59 Chronic Pancreatitis TABLE 59.1

Etiology of Chronic

Pancreatitis Alcohol

70%

Idiopathic

10%–30%

Other Pancreatic duct obstruction (trauma, divisum, tumor, fibrosis) Hereditary (CFTR gene mutation, trypsinogen gene mutation) Hyperlipidemia Tropical

10%–15%

CFTR, Cystic fibrosis transmembrane conductance regulator.

SPINK1 is expressed on pancreatic acinar cells during an inflammatory response and codes for a trypsin inhibitor. A mutation in SPINK1 is not an independent risk factor for CP, but has been implicated in the progression of recurrent acute pancreatitis to CP.15 SPINK1 mutations are strongly associated with tropical calcific pancreatitis.16 Co-inheritance of SPINK1 with CFTR mutations can increase the risk of CP.17,18

Ductal Obstruction Obstruction of the pancreatic duct from any cause can lead to CP. The histologic abnormalities that are induced may persist after relief of the obstruction.

Idiopathic Chronic Pancreatitis An etiology for pancreatitis cannot be determined in 10% to 30% of patients with CP despite extensive investigations. Concealed alcohol ingestion, hypersensitivity to small amounts of alcohol, unreported pancreatic trauma, and mutations in the CFTR and trypsinogen genes may be contributing factors in at least a small proportion of patients with idiopathic CP.19,20 Although in the past patients with idiopathic CP were considered as a single group, data from the Mayo Clinic have defined an early- and late-onset form.21 Age distribution at onset of symptoms showed a bimodal distribution of patients with early- and lateonset idiopathic CP with a median age of 19.2 years for early onset and 56.2 years for late onset. No gender differences were observed among patients in either group.

CLINICAL FEATURES Abdominal pain and pancreatic insufficiency are the two cardinal clinical manifestations of CP.

Abdominal Pain Abdominal pain in CP is typically centered in the epigastric area and frequently radiates to the back. The pain is worsened with eating and is sometimes associated with nausea and vomiting. Early in the course of CP, the pain may occur in discrete attacks; as the condition progresses, pain tends to become more continuous. The mechanism for abdominal pain is poorly understood. Causes are likely multifactorial and include inflammation, duct obstruction, high pancreatic tissue pressure, fibrotic encasement of sensory nerves, and neuropathy characterized by both increased numbers and sizes of intrapancreatic sensory nerves, and by inflammatory injury to the nerve sheaths allowing exposure of the neural elements to toxic substances.22,23 The view that chronic

687

pain subsides in a substantial number of patients as the disease progresses to the point of organ failure has been widely accepted, but that process may take an unpredictable number of years or may never occur.24 Furthermore, there has been increasing interest in the central nervous system’s role in mediating pain in CP patients. One small study of 22 patients compared patients with CP versus healthy controls and stimulated pain electrically.25 Electroencephalograms were recorded from 64 surface electrodes, and event-related brain potentials were obtained. The results demonstrated that pain in CP patients leads to changes in cortical projections of the nociceptive system. This has also been demonstrated in other conditions resulting in neuropathic pain, and should be taken into account when considering treatment approaches.

Pancreatic Insufficiency Patients with severe pancreatic exocrine dysfunction cannot properly digest complex foods or absorb digestive breakdown products. Nevertheless, clinically significant protein and fat deficiencies do not occur until more than 90% of pancreatic function is lost.26 In a large natural history study, the median time for development of pancreatic insufficiency was 13.1 years in patients with alcoholic CP, 16.1 years in patients with late-onset idiopathic CP, and 26.3 years in patients with early-onset idiopathic CP.21 Steatorrhea usually occurs before protein deficiencies because lipolytic activity decreases more quickly than proteolysis.27,28 Glucose intolerance occurs frequently in CP, but overt diabetes mellitus usually occurs late in the course of disease. Nearly 40% to 70% of patients with CP develop diabetes on prolonged follow-up. In one study, the median time to develop diabetes was 19.8 years, 11.9 years, and 26.3 years in patients with alcoholic, late-onset idiopathic, and early-onset idiopathic CP.21 The nature of diabetes in this patient population is brittle, and management is more complicated than that of patients with type 1 diabetes.

DIAGNOSIS Advanced CP is more easily diagnosed when compared with early or mild disease, which may require interpretation of clinical symptoms, pancreatic function testing, and expert interpretation of imaging studies such as MRCP and EUS. Tests for CP can be classified into tests that evaluate its exocrine function (Table 59.2) or the structure of the gland (parenchyma, ductal anatomy, or both). Noninvasive pancreatic function tests yield sufficient diagnostic accuracy only in the advanced stages of the disease, and their sensitivity for detection of early or moderate CP is low.29 Tests that evaluate pancreatic structure, although limited by sensitivity, are advantageous in that they are more widely available, and attempts have been made to develop standardized criteria for clinical use.

Tests of Pancreatic Function Invasive or Direct Pancreatic Function Tests (Secretin Stimulation Test) The basis for the secretin simulation test is that secretin (with or without cholecystokinin) causes the secretion of bicarbonaterich fluid from the pancreas. Intravenous secretin is administered, duodenal juice is collected every 10 minutes for 1 hour (either through a duodenal catheter the patient swallows or at endoscopy), and bicarbonate measured. Peak bicarbonate less than 80 mmol/L

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SECTION III

TABLE 59.2

Pancreaticobiliary Disorders

Diagnostic Tests for Chronic

Pancreatitis FUNCTIONAL TESTS

Structural Tests

Indirect

Direct

X-ray

Serum enzymes (trypsinogen)

Secretin stimulation test

Ultrasound

Fecal tests (fat, elastase, chymotrypsin)

CT

Urine tests (bentiromide, pancreolauryl)

MRCP ERCP EUS CT, Computed tomography; ERCP, endoscopic retrograde cholangiopancreatography; EUS, endoscopic ultrasound; MRCP, magnetic resonance cholangiopancreatography.

FIG 59.1 Chronic pancreatitis on digital radiography. Anteroposterior digital radiograph obtained as a scout image during endoscopic retrograde cholangiopancreatography (ERCP) shows multiple calcifications in the expected location of the pancreas with a plastic pancreatic duct stent.

is a widely accepted threshold consistent with pancreatic exocrine insufficiency. Sensitivity ranges from 74% to 97%, and specificity ranges from 80% to 90%.30–35 Limitations of this test (time consuming, expensive, no standardized results) have prevented it from gaining widespread use. Noninvasive or Indirect Pancreatic Function Tests There has been great effort and interest to develop noninvasive tests for evaluating pancreatic function. These tests are designed to measure pancreatic enzymes in blood or stool, or the effect of pancreatic enzymes on an orally administered substrate by collection of metabolites in the blood or urine. Serum enzymes. Because CP is a patchy, focal disease with significant parenchymal fibrosis, pancreatic serum enzyme levels (amylase and lipase) are within normal range or only minimally elevated. Very low levels of serum trypsinogen (< 20 ng/mL) are reasonably specific for CP, but levels as low as this are seen only in very advanced stages of the disease where there is accompanying steatorrhea.26 Fecal tests. Steatorrhea can be diagnosed qualitatively by Sudan staining of feces or quantitatively by determination of fecal fat excretion over 72 hours while the patient is consuming a 100 g/day fat diet for at least 3 days before the test. Excretion of more than 7 g of fat per day is diagnostic of malabsorption, although patients with steatorrhea often have values greater than 20 g/day. Stool fat analysis has limited sensitivity in CP because patients with mild and moderate disease would not be detected by this technique. The low diagnostic value of fat malabsorption in CP led to the discovery of individual pancreatic enzymes in stool specimen that have increased diagnostic sensitivity. The fecal elastase assay exclusively detects the human enzyme form, and so no interference occurs with simultaneous pancreatic enzyme supplementation and is widely used in clinical practice due to ease of testing. Using a cutoff of 200 μg, fecal elastase concentrations greater than this have a sensitivity of 63% for mild, 100% for moderate, and 100% for severe disease. The sensitivity and specificity was 93% for all patients with exocrine pancreatic insufficiency.36 However, this test has lower sensitivity and specificity in early disease and may be falsely abnormal in other diseases causing steatorrhea, such as short-bowel syndrome or small-bowel bacterial overgrowth syndrome.37

FIG 59.2 Chronic pancreatitis on computed tomography (CT). CT image shows diffusely decreased enhancement relative to the renal cortices.

Tests of Pancreatic Structure Plain Abdominal Radiography Calcifications within the pancreas are present on plain films in approximately one-third of patients with CP (Fig. 59.1). Calcifications occur late in the natural history of CP and may take 5 to 25 years to develop.21,24 The finding of calcification is pathognomonic of CP, but the sensitivity of this test is very low. Computed Tomography The sensitivity and specificity of computed tomography (CT) for the diagnosis of CP is 75% to 90% and 85%, respectively.31 The main advantage of CT is that it can be standardized and can visualize the entire pancreas. CT scan is the most sensitive test for detecting calcification, is accurate in detecting main pancreatic duct dilation, and can detect an irregular contour of the gland (Fig. 59.2).31,38,39 These features are seen in advanced CP and CT is excellent in detecting these changes. However, CT is poor at detecting subtle abnormalities in pancreatic parenchyma or changes in side branches of the pancreatic duct, which are commonly seen in milder forms of the disease. CT has good specificity but lacks sensitivity for the diagnosis of CP. The newer multi-detector CT scanners may produce better sensitivity.

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CHAPTER 59 Chronic Pancreatitis

689

FIG 59.3 Chronic pancreatitis on magnetic resonance cholangiopancreatography (MRCP). Coronal two-dimensional MRCP shows diffuse, irregular side branch dilation and dilation of the main pancreatic duct.

Magnetic Resonance Cholangiopancreatography Several small studies have reported on the utility of magnetic resonance cholangiopancreatography (MRCP) in assessing pancreatic duct morphology.40,41 MRCP agrees with endoscopic retrograde cholangiopancreatography (ERCP) in 70% to 80% of findings, with higher rates of agreement in studies using the most advanced image analysis techniques (Fig. 59.3). In studies that compared MRCP findings with ERCP, MRCP visualized the main pancreatic duct in the head, body, and tail in 79%, 64%, and 53% of cases, respectively.41 Correlation with ERCP with respect to main pancreatic duct dilation, narrowing, and filling defects was 83% to 92%, 70% to 92%, and 92% to 100%. The major disadvantage of MRCP compared with conventional cholangiography is that it has a lower spatial resolution, limiting its ability to detect subtle side branch changes, which are the earliest changes of CP. Secretin-enhanced MRCP (SMRCP) involves administering intravenous synthetic secretin (0.2 μg/kg over 1 min) to stimulate pancreatic secretions and obtain heavily weighted T2 images of the pancreatic duct every 30 seconds over 10 minutes. This modality has recently been used to identify early changes of CP by detecting subtle abnormalities in duodenal filling, pancreatic duct compliance, and/or side branch ducts that may not be apparent on conventional MRCP.42 However, due to the additional time, cost, and expertise required for the specialized protocol and interpretation of results, SMRCP is used mainly at specialized centers in select patients. Endoscopic Ultrasound Endoscopic ultrasound (EUS) provides a safe, minimally invasive method of obtaining detailed structural information of the pancreatic parenchyma and ducts. There are two main advantages for EUS that make it a very sensitive test for CP. First, the pancreas lies within a few millimeters of the duodenum and stomach, allowing use of higher frequencies that provide high-resolution images (but less penetration). Second, by positioning the EUS transducer at certain stations in the stomach and duodenum, complete visualization of the pancreas can be achieved. Numerous EUS criteria for pancreatic disease have been described (Fig. 59.4). Lees et al (1986, 1979)43,44 first described EUS findings in patients with clinical and radiologic evidence of CP and characterized EUS criteria that distinguish a normal from an abnormal pancreas. Wiersema et al (1993)45 refined these definitions and found that abnormal EUS changes occurred frequently in patients with abnormal endoscopic pancreatograms

FIG 59.4 Chronic pancreatitis on endoscopic ultrasound (EUS). EUS shows the pancreatic duct (PD) becoming obstructed in the pancreatic head by a calcified intraductal stone causing upstream dilation.

Endoscopic Ultrasound Criteria for Chronic Pancreatitis TABLE 59.3

Parenchymal Changes

Ductal Changes

Inhomogeneity

Ductal dilation

Hyperechoic foci

Hyperechoic main duct margins

Hyperechoic strands

Irregular main duct margins

Lobularity

Visible side branches

Pseudocysts

and were absent in healthy volunteers. Criteria for CP that are specific to EUS can be divided into two groups (Table 59.3): parenchymal and ductal. Parenchymal criteria include inhomogeneity, hyperechoic foci, hyperechoic strands, cysts, and lobularity. Ductal criteria specific to EUS include obvious to more subtle ductal dilation (≥ 3 mm in the head, ≥ 2 mm in the body, ≥ 1 mm in the tail), hyperechoic main duct margins, irregular main duct margins, and visible side branches. A quantitative analysis with nine possible criteria (hyperechoic foci, hyperechoic strands, lobularity, ductal dilation, ductal irregularity, hyperechoic duct margins, visible side branches, calcifications, and cysts) suggested that in a population at lowto-moderate risk of CP, EUS is most reliable only when it is either clearly normal (two or fewer criteria) or clearly abnormal (five or more criteria).46 When the threshold for normal is set at two or fewer criteria and the threshold for abnormal is set at five or more criteria, the predictive values are 85%.47 Some of the controversy regarding the accuracy of EUS may be due to studies that use three or four criteria (i.e., mild abnormalities) as threshold values to distinguish normal from abnormal EUS. It is unclear whether minimal EUS changes reflect early CP disease. In a prospective study that compared EUS findings of the pancreas with surgical histopathology in 42 patients, there was a significant correlation between the number of EUS criteria and fibrosis score at histology (r = 0.85).48 As EUS provides higher resolution imaging than other imaging methods and provides information on both the ducts and the parenchyma, it is logical to assume that it can detect

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SECTION III

Pancreaticobiliary Disorders

earlier changes of CP. Functional testing is said to become abnormal only after greater than 60% to 70% of pancreatic functional reserve is depleted.49 If this is the case, it may also be reasonable to expect that EUS could detect subtle structural changes that predate functional abnormalities. Finally, even severe CP can be asymptomatic. EUS may show pancreatic abnormalities in asymptomatic individuals. It has been shown that alcohol consumption is often associated with asymptomatic abnormalities.50,51 Elastography measures tissue resistance (strain) resulting from compression and different tissue elasticity patterns are demonstrated as different colors in a qualitative analysis (blue = hard tissue and red = soft tissue). Normal pancreatic parenchyma typically has a homogenous yellow and green pattern, whereas CP has a heterogeneous green and blue pattern.52 Quantitative elastography involves calculating the strain ratio between the strain in the region of interest and a reference area in surrounding soft tissue.53 Recently, quantitative elastography has been compared with standard EUS criteria for diagnosing CP. A high correlation was found between the number of EUS criteria and the strain ratio.54,55 Another study has shown a strong correlation between quantitative EUS elastography strain ratio and the probability of suffering from exocrine pancreatic insufficiency.56 To date, the role of contrast-enhanced EUS for the diagnosis of CP has not been not been well studied. Endoscopic Retrograde Cholangiopancreatography In the past, ERCP with use of the “Cambridge criteria” was widely accepted as the most definitive method for interpreting pancreatography (Fig. 59.5). Studies cited a sensitivity of 70% to 90%, and specificity of 80% to 100% for diagnosing CP.30–35 However, there are multiple limitations. CP can involve the pancreatic parenchyma per se and completely spare the radiographically visible portions of the pancreatic ductal system, leading to false-negative studies.57,58 In addition, significant interobserver and intraobserver variability is noted in the interpretation of pancreatography.59 Much of this variability is related to interpretation of mild pancreatographic changes rather than to severe abnormalities. Reliable interpretation of ERCP in the detection of early CP depends on adequate filling of side branches and this increases the risk of post ERCP pancreatitis.

Inadequate opacification of ducts, especially the secondary ducts, occurs in at least 30% of cases.60 ERCP is associated with a 3% to 7% chance of causing acute pancreatitis.61 Therefore, due to the widespread use of EUS, limitations in pancreatography interpretation, and increased risk of pancreatitis, ERCP is no longer used solely for diagnostic purposes in CP.

ENDOSCOPIC MANAGEMENT Major goals of treatment in CP and targets for endoscopic therapy are pain relief and managing associated complications. Pain is thought to result from ductal obstruction and/or nerve damage caused by chronic inflammation and fibrosis. There are three approaches to management: decrease pancreatic exocrine secretion, decompress the pancreatic duct, and, if the first two fail, perform partial or complete resection of the gland. Successful pain management can be clinically challenging and a multidisciplinary approach is warranted. A combination of medical, surgical, and endoscopic modalities are often utilized with varying success rates due to the significant heterogeneity in the clinical presentation and natural history of CP patients. In addition to pain, other associated complications such as pseudocysts, biliary strictures, and duodenal obstruction can occur. For the purposes of this chapter, treatment will focus solely on endoscopic therapies.

Pain Relief EUS-Guided Celiac Plexus Nerve Block Pancreatic pain is predominantly transmitted through the celiac plexus. Celiac plexus neurolysis, via a surgical or transcutaneous approach, has been used for many years to manage abdominal pain resulting from advanced malignancy.62,63 These approaches have had complications such as paralysis, which might be overcome by better visualization of the region. The celiac artery is a landmark structure readily visualized on EUS (Fig. 59.6). Wiersema and Wiersema (1996) performed transgastric EUSguided celiac plexus neurolysis and found that the success rate was similar to surgical or transcutaneous approaches.64 An injection of absolute ethanol that permanently destroys the plexus is referred to as a celiac plexus neurolysis, and an

Celiac artery

Needle injecting into celiac plexus Aorta

FIG 59.5 Chronic pancreatitis on endoscopic retrograde cholangiopancreatography (ERCP). ERCP image shows irregular narrowing and dilation of the main pancreatic duct and irregular side branch dilation, most prominent in the body and tail.

FIG 59.6 Celiac plexus block is being performed with the curvilinear array echoendoscope. The celiac artery is seen emerging from the aorta, and the needle is shown just above this point.

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CHAPTER 59 Chronic Pancreatitis injection of local anesthetic and corticosteroids that temporarily blocks the plexus and reduces inflammation is referred to as a celiac plexus block. EUS-guided celiac plexus block and neurolysis are safe and well-tolerated procedures that can be performed in an outpatient setting with conscious sedation. Mild complications include transient diarrhea (4%–15%), transient orthostasis (1%), and transient increase in pain with neurolysis (9%). Major complications (2.5%) have included retroperitoneal bleeding and peripancreatic abscess.65 In a prospective study, Wiersema et al (1998) evaluated patients with pancreatic malignancy and CP treated by celiac plexus neurolysis, and found that the initial pain scores were similar between the two patient groups.66 However, after 16 weeks of follow-up, the pain score improvement after celiac plexus neurolysis in patients with CP was not found to be significant. The malignant disease group had a mean pain score of less than baseline. Celiac plexus neurolysis is not recommended for the management of CP. Gress et al (1999)67 compared EUS to CTguided injection of triamcinolone in 22 patients with CP. At 8 weeks after the procedure, 50% of EUS patients had significant improvement in pain scores, whereas only 25% achieved this with the CT-guided approach. The corresponding results at 12 weeks were 40% and 12% for EUS and CT, respectively. In a prospective study of 51 patients with CP and pain who underwent celiac plexus block using either 1 or 2 injections, there was no significant difference in short-term pain relief between both cohorts.68 Of patients, 57% who received a single injection had pain relief compared with 54% who received two injections. Based on available data, the technique of performing celiac plexus block does not seem to affect treatment outcomes. Due to the complexity of pain associated with CP and the fact that most patients considered for celiac block have been on narcotics, it makes sense that this procedure is not a panacea for pain control in CP. It can be helpful to treat exacerbations of pain to avoid increasing narcotic dosages and sometimes it can be effective to move patients from an inpatient intravenous narcotic situation to an outpatient oral medical regimen.

A

B

691

ERCP Therapy The goal of ERCP is to evaluate for an obstructive component to the pancreatopathy. Endoscopically treatable causes of obstruction can be at the level of the papilla (papillary stenosis) or along the course of the main pancreatic duct, primarily secondary to stones, strictures, or both. Pancreatic duct stones. Approximately one-third of patients with CP have pancreatic stones. There is no close correlation between the presence of pancreatic duct stones and pain, and many patients with pancreatic duct stones report no pain. It is unclear if pancreatic calculi aggravate the clinical course of CP or are the consequence of ongoing glandular destruction from persistent disease processes. It is postulated that pain in CP is related to increased intrapancreatic pressure arising as a consequence of mechanical duct obstruction by stones with or without strictures.69,70 This notion is supported by studies that show improvement in symptoms after ductal clearance of stones.71–76 Removal of pancreatic duct stones is recommended in patients with symptomatic CP and is most effective when applied to patients with chronic relapsing disease as opposed to those with chronic daily pain. More recently, treatment of obstructive pancreaticolithiasis in asymptomatic CP patients has been suggested to preserve pancreatic function and prevent gland atrophy. Given the limited data and risk of complications with endoscopic therapy, these authors would not currently endorse treatment in completely asymptomatic patients. Pancreatic sphincterotomy, stricture dilation, and stone removal with balloons and baskets. The optimal conditions for successful endoscopic removal of pancreatic stones are a small number of mobile stones in the duct without significant strictures. Initial endoscopic management involves sphincterotomy, stricture dilation, and stone removal by baskets or balloons (Fig. 59.7 and Video 59.1). An impacted stone that impedes injection of contrast material into the pancreatic duct usually requires adjunctive therapy using extracorporeal shock wave lithotripsy (ESWL) or intraductal lithotripsy for clearance. Removal of pancreatic stones requires an adequate opening of the pancreatic orifice. There is often thickening and fibrosis

C

FIG 59.7 Pancreatic stone removal with endoscopic retrograde cholangiopancreatography (ERCP). ERCP images obtained before (A), during (B), and after (C) stone removal by lithotripsy. A, Scout ERCP image reveals a large stone within the main pancreatic duct. B, Second image was obtained during basket capture of the stone. C, Postprocedural ERCP image reveals absence of the stone within the duct and no evidence of residual obstruction.

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SECTION III

Pancreaticobiliary Disorders

or stenosis of the pancreatic orifice in CP. Cholangiography and pancreatography are performed initially, and the termination of both ducts is assessed. A biliary sphincterotomy may be performed first to improve access to the pancreatic orifice and to help expose the landmarks for completing a pancreatic sphincterotomy. Pancreatic sphincterotomy can be performed using either a standard pull-type sphincterotome (with or without a previous biliary sphincterotomy) or a needle-knife (usually over a previously placed pancreatic stent). In patients with pancreas divisum, a minor papilla sphincterotomy is required, which can be completed in the same way using a standard papillotome or a needle knife over a minor papilla stent. The ability to remove a stone by endoscopic methods alone depends on stone size and number, location inside the duct, presence of downstream stricture, and degree of impaction.73 Downstream strictures may require dilation either with catheters or with hydrostatic balloons. The conformation of the main pancreatic duct significantly influences the endoscopic approach to stones. If the duct makes a sigmoid turn or there is an ansa (360-degree turn within the head), it is almost impossible to get baskets or the single-operator cholangioscope around the turns. Negotiating around the genu can also be problematic if the turn is tight or there is a partial ansa. Soft-wire or wire-guided baskets may be necessary to navigate these tortuous areas of the pancreatic duct. Pancreatic stones are usually very hard because of the makeup of their crystalline structure. Careful assessment of the main pancreatic duct downstream of the stone is important prior to grasping stones to avoid basket impaction. In a grossly dilated duct, a “through-the-scope” mechanical lithotripsy device can be used, but this is often restricted to stones in the head of the pancreas with a straight line of approach to the stone. Otherwise, the rigidity of this device and its large diameter are restrictive. This device may also be used through a very dilated dorsal duct if it permits a straight approach. Sherman et al (1991)73 reported that endoscopic therapy was effective in 83% of patients presenting with chronic relapsing pancreatitis compared with 46% of patients presenting with continuous pain alone. Factors favoring successful endoscopic therapy included three or fewer stones, stones confined to the head or body of the pancreas, stone size less than 10 mm, absence of impacted stones, and absence of downstream strictures. After successful stone removal, 25% of patients had regression of ductographic changes of CP, and 42% had a decrease in the main pancreatic duct diameter. The only complication was pancreatitis encountered in 8% of patients. Studies have reported success rates with endoscopic therapy of 45% to 79% and improvement in symptoms of 60% to 90%.71–74 One study reported clinical improvement in steatorrhea in 73% of patients after endoscopic management.75 Advanced Lithotripsy Techniques Electrohydraulic lithotripsy. Electrohydraulic lithotripsy (EHL) may be an effective adjunct to endoscopic treatment of pancreatic stones.76 In this technique, shocks are delivered in a fluid medium under direct visualization because inadvertent firing on tissue can cause perforation or bleeding. This technique requires the use of a small-caliber pancreatoscope (either a “baby” scope or single-operator disposable catheter; SpyDigital, Boston Scientific, Natick, MA) that is passed up the pancreatic duct to the stone. Direct pancreatoscopy is mandatory to assure the EHL probe is against the stone and not the duct, manipulation within the main pancreatic duct remains difficult, and very limited smaller

caliber baby scopes are fragile and have limited one-way tip deflection, which may hinder their utility. Additionally, the operating channel diameter is 0.75 to 1.0 mm and accepts only specialized, ultrathin accessories. The EHL probe is 1.9-Fr in diameter and can be used, but channels of 1.0 mm or less do not allow for much coaxial perfusion of saline necessary for lithotripsy. Saline is essential for transmission of the shock waves at the stone surface and for irrigation to clear debris. Placement of a nasopancreatic tube (5-Fr) beyond the stone before pancreatoscopy is helpful for irrigation purposes, but requires that the main pancreatic duct is very dilated with no downstream strictures. Advancing the pancreatoscope requires an ample pancreatic sphincterotomy for insertion and may require a guidewire to advance through a tortuous pancreatic duct. A 450-cm wire is placed into the duct beforehand, and the proximal stiffer end is back-loaded into the baby scope. The stiff end of the wire should be slightly bent before back-loading to help negotiate the elbow junction of the accessory port and the scope body. Laser lithotripsy. An alternative to EHL is laser lithotripsy. The most common laser used currently is the holmium laser (Lumenis VersaPulse Laser, Boston Scientific, Natick, MA). The holmium laser tends to pulverize stones into smaller particles when compared with EHL, which can be an advantage in the pancreas. The laser fiber is also more durable than the EHL probe. There are limited data available, but a multicenter US study of 28 patients achieved complete duct clearance in 79% (22 patients) and partial clearance in 11% (3 patients).77 Even after treatment, pancreatic stones tend to recur, but this recurrence can be treated again endoscopically, whereas the rate of repeat surgery for recurrent pain is 20%, with a striking increase in morbidity and mortality after repeated surgery.78 Extracorporeal shock wave lithotripsy. ESWL has become almost indispensable to specialized centers treating many patients with advanced CP.79 ESWL is considered a first-line therapy in Europe and Asia for the management of symptomatic chronic calcific pancreatitis. In the United States, it is not widely available, usually performed by urologists who are not experienced with the difference in treatment when compared with kidney stones, and insurance coverage is erratic. As a result, it is used more as a salvage procedure if endoscopic attempts fail. Stones are amendable to ESWL in almost all patients because the biochemical composition of the stones consists of 95% calcium carbonate on a protein matrix. The procedure is contraindicated only in patients who have coagulation disorders or who have calcified aneurysms or lung tissue in the shock wave path. In some patients, a radiologic target is needed that can be provided by the placement of a stent. Fluoroscopic focusing of densely calcified stones can be achieved without pancreatography. In other patients, MRCP with secretin or CT can show pancreatic ductal obstruction related to stones. For very small stones or radiolucent stones, visualization can be improved by instillation of contrast material via a nasopancreatic catheter. Patients require sedation, which can range from conscious sedation to general anesthesia. Routine antibiotic prophylaxis is unnecessary. Shock waves are focused first on the distal-most stone and then on other calculi moving from the head to tail, allowing stone fragments to drain downward through the papilla. In one treatment session, 3000 to 5000 shock waves using the highest possible energy levels are delivered. Pancreatic stones are hard and usually require a higher-powered shock wave (22–24 kV). Each session lasts approximately 45 to 60 minutes.

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693

CHAPTER 59 Chronic Pancreatitis ESWL is an effective adjunct to the nonsurgical endoscopic approach in chronic calcifying pancreatitis with complete or partial relief of symptoms in 80% of patients, which is comparable to the surgical literature.80,81 In one study, stones were successfully fragmented in 99% of patients, resulting in a decrease in duct dilation in 90%.80 The main pancreatic duct was cleared of all stones in 59%. However, one of the challenges in pancreatic duct therapy is evaluating treatment efficacy. Disintegration of a stone can be considered successful when a decrease is seen in the radiographic density of the stone or the stone surface area. In addition, the ability to show relief of ductal obstruction at deep cannulation of the pancreatic duct during ERCP is an indicator of treatment efficacy. Using the aforementioned criteria, the success rate of fragmentation has been approximately 76% to 100% in most series, regardless of the shock wave system used.80–83 Most patients require endoscopic extraction of stone fragments after ESWL for complete clearance from the ductal system. Some authorities recommend that pancreatic sphincterotomy be performed before ESWL to facilitate stone passage.71,84 With the exception of one report73 in which successful treatment was more frequent in patients with solitary stones (74% vs. 43% for multiple stones), successful fragmentation and stone clearance was not correlated with the initial size or the number of main pancreatic duct stones by others.84–86 Repeat ESWL may be required if stones have not been adequately fragmented; this can be the case in patients with large, impacted, or multiple stones. The reported mean number of treatment sessions required to complete lithotripsy has ranged from 1.3 to 4.1 per patient in most reports.71,83,84 The radiographic success of ESWL has been associated with clinical improvement (Table 59.4). Complete or partial pain relief was observed in 62% to 97% of patients in the largest series during a mean follow-up ranging from 7 to 44 months.80,84,86–89 However, complete stone clearance was not required for symptom relief. Many patients gained weight because of a reduction in postprandial pain attacks, improvement in pancreatic function, or both. The number and location of stones, the presence of a stricture, or continued alcohol use did not seem to be associated with recurrent pain.75,84 As a result, ESWL does not have to be restricted to patients without these unfavorable clinical characteristics.

One study79 identified three independent predictors of pain relapse at long-term follow-up after ESWL therapy: (1) a high frequency of pain attacks before treatment (more than or at least two pain attacks during the 2 months before treatment), (2) a long duration of disease before treatment, and (3) the presence of a nonpapillary stenosis of the main pancreatic duct. This study suggests that ESWL in association with endoscopic therapy should be performed as early as possible in the course of CP. In another study, pain relapse was noted to occur more frequently in patients who had incomplete removal of stones than in patients in whom ductal clearance was complete.76 Early ductal decompression of the main pancreatic duct may also help prevent further fibrosis, which can lead to pancreatic insufficiency. In addition, it may improve pancreatic function in patients who have already developed pancreatic insufficiency. Although some studies investigating this issue found that exocrine pancreatic function improved more often after treatment compared with endocrine pancreatic function, others have shown progressive deterioration in both exocrine and endocrine functions at long-term follow-up.78,80,86–88 In a multicenter study, the rate of recurrence of pancreatic duct stones after ESWL was reported to be 20% to 30%.88 Factors predictive of stone recurrence included ongoing alcohol use and the presence of pancreatic duct strictures. Complications in series using ESWL were primarily related to the endoscopic procedure. Endoscopy Versus Surgery Two prospective, randomized studies comparing surgical and endoscopic therapy in chronic calcific pancreatitis have been reported in the literature.89,90 In the first study,89 140 patients with obstructive CP were treated either by endoscopic therapy or by surgical resection or drainage procedures. Although immediate relief of symptoms was identical in both groups (51.6% in the endotherapy group vs. 42.1% in the surgical group), at 5 years of follow-up complete absence of pain was more frequent after surgery (37% vs. 14%), with partial relief of pain being similar (49% vs. 51%). The increase in body weight was also greater by 20% to 25% in the surgical group, whereas new-onset diabetes mellitus developed with similar frequency in both groups (34% in the surgical group vs. 43% in the endotherapy group).

Technical and Clinical Results of Extracorporeal Shock Wave Lithotripsy for Pancreatic Stones TABLE 59.4 Reference Dumonceau et al78 73

No. Patients

Complete or Partial Pain Relief (%)

70

68

Fragmentation (%)

Complete Clearance (%)

58

50

Sherman et al

32

85

99

58

Delhaye et al79

123

85

99

59

Sauerbruch et al80

24

83

87.5

42

Farnbacher et al81

114

93

82

39

Adamek et al82

80

76

54

ND

Schneider et al83

50

62

86

60

Ohara et al84

32

86

100

75

40

80

100

ND

Tadenuma et al

117

97

97

56

Inui et al88

555

91.1

92.4

73

Kozarek et al87 76

ND, Not determined.

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SECTION III

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In the second randomized trial of 39 patients with CP and pain, patients managed surgically had lower pain scores and better quality of life at 2-year follow-up.90 In addition, although only 32% of patients randomly assigned to endoscopy had better or partial pain relief, 75% of patients randomly assigned to surgery had better pain relief. There was no difference in the complications, length of hospital stay, and pancreatic function between both groups; however, patients undergoing endotherapy required more interventions. More recently, these studies have been included in two metaanalyses by the same Dutch group of Ahmed et al, published in 2012 and then updated in 2015, comparing endoscopic versus surgical intervention for painful obstructive CP.91,92 The 2015 study also included an additional study examining surgery versus conservative management (no intervention) for a total of 143 patients.92 This meta-analyses showed that compared with the endoscopic group, the surgical group had a higher proportion of participants with pain relief, both at long-term follow-up (≥5 years; relative risk [RR]: 1.56; 95% confidence interval [CI]: 1.18–2.05). Morbidity and mortality were similar between the two intervention modalities, but the small study sizes may have been underpowered to detect differences. Regarding the comparison of surgical intervention versus conservative treatment, this 2015 study suggested that surgical intervention in an early stage of CP should be considered in terms of managing both pain control and pancreatic function. Obviously, these results will need further validation in larger studies, but the limited available data suggest more durable success in terms of pain management with surgery over endoscopy in patients with obstructive chronic calcific pancreatitis.

Pancreatic Duct Strictures Pancreatic duct strictures (Fig. 59.8) may be a complication of a previously embedded stone or a consequence of acute inflammatory changes around the pancreatic duct. Pancreatic duct strictures may contribute to pain, recurrent acute pancreatitis, and exocrine insufficiency. Strictures may also be associated with stones, pseudocysts, and pancreatic malignancy.93–96 The mechanism of pain in patients with pancreatic strictures is poorly understood, but may be partly attributable to pancreatic duct hypertension. Pancreatic duct strictures may be present in association with biliary strictures, and liver function test abnormalities, jaundice, and cholangitis may be presenting symptoms.

FIG 59.8 Endoscopic retrograde cholangiopancreatography (ERCP) shows changes of chronic pancreatitis with a stricture in the main pancreatic duct.

Endoscopic therapy for pancreatic duct strictures is primarily indicated for patients presenting with refractory abdominal pain, with or without upstream ductal dilation. Stenting and Dilation The technique for placing a stent in the pancreatic duct is similar to the technique used for inserting a biliary stent. A guidewire is first maneuvered beyond the stricture several centimeters. Hydrophilic, flexible-tip wires are generally helpful. Pancreatic stents are similar to biliary stents, except for side holes along their length to allow for flow from side branches. Generally, the diameter of the stent should not exceed the size of a normal downstream duct. In small ducts, 3-, 4-, and 5-Fr stents are used commonly, whereas 7-Fr and 10-Fr stents can be used in advanced CP with dilated pancreatic ducts. Occasionally, in patients with small duct disease who have recurrent strictures, we place multiple 3-Fr stents to dilate the stricture. We believe that stent-induced trauma could be obviated by this method, but data are still forthcoming. In addition, the severity of the stricture, location, and duct size influence the choice of stent. Generally, the best candidates for stent treatment are patients with a distal stricture and upstream dilation. Other therapy, such as pancreatic or biliary sphincterotomy, pancreatic duct stone removal, and dilation of strictures, may be required concomitantly at the time of stent placement. Dilation to widen single or multiple strictures of the main pancreatic duct in CP can be performed successfully. Dilating catheters with graded tips and balloons are generally used. In strictures where only a guidewire can be passed, use of the 7- or 8.5-Fr Soehendra stent-retrieval devices (Cook Endoscopy, Winston-Salem, NC) can be a successful salvage technique. The device is slowly rotated clockwise while pressure is applied with the same technique as advancing a stent through a tight stricture. After dilation, stents of adequate size are left in place to facilitate drainage and to prevent recurrent stricture formation. If stents larger than 7-Fr are to be used, patients often require dual sphincterotomy followed by stricture dilation. For optimal results, therapy must address both the pancreatic duct stricture and duct stones, if any are present. The appropriate duration of pancreatic stent placement is currently unknown. Most stents in diagnostic trials or for shortterm therapy are left in place for 2 to 4 weeks. In contrast, stents for long-term therapy are left in place for several months. If the patient has improvement in symptoms, the stent can be removed and the patient can be followed clinically, stent therapy can be continued for a more prolonged period, or a surgical drainage procedure can be performed. The last option suggests that the results of endoscopic stent treatment would predict the surgical outcome. Two studies support this concept, but more data are warranted.97,98 Quantifying the degree of improvement in pancreatic disorders is often poorly defined. Generally, partial or complete symptom improvement indicates that intraductal hypertension was an etiologic factor. Continued improvement in symptoms after stent removal indicates adequate dilation of the narrowing. The results of stent insertion for dominant pancreatic duct strictures (Table 59.5) have been favorable, with technical success in 72% to 99%, relief of pain in 75% to 94%, and good long-term outcomes in 52% to 81%. Average stent indwelling time ranged between 3 and 12 months.90,99–101 Although long-term symptom resolution has been reported in more than 60% of patients, endoscopic resolution of strictures has been documented in only approximately one-third of patients managed by endoscopic stent placement.99–101 Although these

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CHAPTER 59 Chronic Pancreatitis Stent Therapy for Chronic Pancreatitis With Dominant Strictures TABLE 59.5

Mean Follow-Up Duration (Months)

No. Patients

Technical Success

No. Patients Improved

Cremer et al93

76

75

41

37

Ponchon et al100

28

23

12

26

Smits et al101

51

49

40

34

Binmoeller et al102

93

84

61

39

Costamagna et al103

19

19

16

38

267

231 (94%)

154 (64%)

35

Reference

Total

data suggest that stricture resolution is not a prerequisite for symptom improvement, other concomitant therapies at the time of pancreatic stent placement such as pancreatic sphincterotomy or pancreatic stone removal may account for successful outcomes. It is also likely that pain in CP tends to decrease over time as glandular destruction of the pancreas progresses in an uninhibited manner.24 In a study of 75 patients with pancreatic duct strictures and upstream dilation managed by placement of 10-Fr stents, Cremer et al (1991)93 reported that 71 patients (94%) were improved over a follow-up of 3 years, with 40 patients (53%) symptom free. Improvement in symptoms was associated with a decrease in the pancreatic duct diameter. In addition, in a prospective study of 23 patients, Ponchon et al (1995)100 reported that disappearance of stenosis at stent removal and a reduction in the pancreatic duct diameter by more than 2 mm were predictive of pain relief after pancreatic duct stent placement. Binmoeller et al (1995)102 made a similar observation in their study of 93 patients with CP and dominant pancreatic duct strictures managed by pancreatic duct stent placement. Although 74% of the patients experienced complete or partial symptom relief, most patients were found to have a regression of ductal dilation after successful stent treatment. Multiple Stents Based on data demonstrating that placement of multiple stents results in successful obliteration of benign biliary strictures, the role of multiple stents in pancreatic duct strictures has been evaluated. In a study of 19 patients, 11 patients with a single main pancreatic duct stricture underwent balloon dilation (6–10 mm) followed by placement of multiple stents (8.5–11.5 Fr) across the stricture site.103 All stents were retrieved at a mean follow-up of 7 months. The median number of stents placed per patient was three, and the most common stent diameters used were 10-Fr and 11.5-Fr. During a mean follow-up of 38 months, 84% of patients were asymptomatic, and 10.5% developed symptom recurrence. Self-Expandable Metal Stents Although all the previously described studies used conventional plastic stents, Cremer et al (1990),104 in a pilot study, reported their experience with self-expandable metal stents (SEMSs) in

695

patients with CP. Stent placement through the major duodenal papilla was performed in 22 patients with relapsing dominant strictures of the main pancreatic duct. Successful placement, associated with an immediate decrease of pancreatic duct diameter and disappearance of pain, was noted in 100% of cases. Although no immediate complications were encountered, follow-up of these patients showed a high occlusion rate of these metal stents from mucosal hyperplasia. Another pilot study evaluated the role of covered SEMSs (8-mm) in patients with refractory main pancreatic duct strictures.105 The stents were retrieved by endoscopy 3 months after placement. Although the pain scores improved significantly, three out of six patients developed recurrent strictures warranting subsequent placement of large-caliber (10-mm) metal stents. Although this concept appears novel, more studies with a larger cohort of patients are needed to evaluate the role of covered metal stents in the management of benign pancreatic duct strictures. In addition, modification of these stents, which are designed for the biliary tree, will likely be needed before they are widely applied to the pancreatic duct. Direct comparative studies evaluating the efficacies of surgery and endoscopic therapy are required to identify a subset of patients who would benefit from either treatment modality. Stent-Related Adverse Events Pancreatic stent therapy is not without consequences. Adverse events related directly to stent therapy include acute pancreatitis, pancreatic infection, pseudocyst formation, duct injury, stone formation, and migration.70,106 The rate of pancreatic stent occlusion appears similar to that of biliary stents.99 Most of these occlusions are without adverse clinical events, however, because pancreatic juice may siphon along the sides of the stent. Morphologic changes of the pancreatic duct directly related to stent placement occur in more than 50% of patients.107–110 It is uncertain what the long-term consequences of these stent-induced ductal changes are in most patients, although permanent new strictures are seen in a few patients. EUS identified parenchymal changes in 68% of patients who underwent short-term pancreatic stent treatment.111 Although such changes may have significant longterm consequences in patients with a normal pancreas, the outcomes in patients with advanced CP seem less certain.

Associated Complications CP may be associated with various complications. Splenic vein thrombosis, pseudoaneurysm formation, and common bile duct or duodenal strictures are occasionally encountered. Other complications such as pseudocyst formation and pancreatic ascites or pleural effusion are discussed in Chapter 58. Benign Biliary Strictures Intra-pancreatic common bile duct strictures have been reported in 2.7% to 45.6% of patients with CP.112,113 Common bile duct strictures can have serious sequelae of cholangitis, cholelithiasis, choledocholithiasis, intrahepatic stones, and secondary biliary cirrhosis. Deviere et al (1990)113 evaluated the use of biliary stent placement in patients with biliary strictures secondary to CP. They reported that endoscopic biliary drainage is an effective therapy for resolving cholangitis or jaundice in this patient subset. However, the long-term efficacy of this therapy was unsatisfactory because stricture resolution rarely occurred. Preliminary results using metal stents for this indication suggest they could be an effective alternative to operative biliary diversion.

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SECTION III

Pancreaticobiliary Disorders

More than 90% of patients had no recurrence of strictures at 3 years, but longer follow-up and controlled trials are necessary to confirm these findings.114,115 In a nonrandomized retrospective study that compared surgical drainage procedures with stent insertion, Pitt et al (1989)116 found a significantly higher success rate of 88% in the surgically treated group compared with 55% for patients managed by stent insertion. More recently, Cote et al (2016) published their results comparing plastic stents versus fully covered self-expandable metal stents (FCSEMS) in the treatment of benign biliary strictures, including those encountered in the post-transplant setting (65% of study patients) and with CP (31% of study patients).117 Unfortunately, the study was not adequately powered to conduct subgroup analyses between these two groups and therefore all patients were analyzed together. In this randomized, open-label trial, FCSEMS were shown to be noninferior to multiple plastic stents. However, the mean number of ERCPs to achieve biliary stricture resolution was lower for FCSEMS (2.14) versus plastic (3.24; mean difference: 1.10; 95% CI: 0.74–1.46; p < 0.001). Originally only approved for use in malignant disease, this study led to Food and Drug Administration approval of FCSEMS by Boston Scientific (Natick, MA) for use in benign biliary strictures. In our clinical practice, the FCSEMS is typically left in place for 2 to 3 months before being removed endoscopically using a snare or grasping forceps. Duodenal Obstruction Duodenal stenosis is seen in approximately 5% of patients with CP, particularly patients with alcoholic pancreatitis. Coexistent obstruction of the common bile duct may be seen. The diagnosis is made at upper endoscopy or barium swallow. Attempts to dilate the stricture endoscopically are generally futile. The simplest and safest approach is operative drainage via gastrojejunostomy; this may be combined with drainage of the bile duct or pancreatic duct, or both. Enteral stents that are currently available have been used in malignant obstruction with similarly high success rates (> 90%) compared with surgical gastrojejunostomy. However, more than 50% of enteral stents become occluded after 6 months. In addition, currently available enteral stents are uncovered and thus not removable. For these reasons, they would not be suited for use in benign disease such as CP.118–120

FUTURE TRENDS CP can be a difficult disease both from diagnostic and therapeutic aspects. Improvements in these areas could help prevent and manage long-term complications and perhaps reduce morbidity, mortality, and costs associated with this often debilitating disease.

Developments in Testing The available diagnostic armamentarium for CP focuses exclusively on pancreatic structure and function with inability to diagnose the disease in its early stages.

CFTR Testing in Idiopathic Cases The association between CFTR mutations and idiopathic CP raises the possibility of widespread use of genetic testing to evaluate idiopathic CP. The role of routine CFTR mutation testing is uncertain because no guidelines exist for genetic counseling or altered clinical management based on the results. As further research clarifies whether patients with idiopathic CP with CFTR mutations differ from other patients with idiopathic CP, this

information may lead to wider use of genetic testing during the evaluation of patients with idiopathic CP.

Micro-RNA for Early Diagnosis Micro-RNAs (miRNAs) have been established as modulators that control fibrogenesis and inflammation. One 2017 study demonstrated that there were significant differences of serum miRNA expression in patients with early and late CP and healthy controls.121 This type of testing would enable earlier diagnoses of CP and initiation of management strategies prior to the development of late-stage complications.

Advances in EUS Techniques EUS-Guided Pancreatic Duct Drainage EUS has been advocated more recently as a means to establish pancreatic ductal drainage in patients after failed ERCP.122 EUSguided pancreatic duct drainage (EUS-PDD) can be accomplished either by rendezvous stent placement after passage of a guidewire into the main pancreatic duct and through the ampulla under EUS guidance, or by transmural drainage of the main pancreatic duct via the stomach or duodenum (Fig. 59.9). Itoi et al (2013) published a retrospective review of the published literature on EUS-PDD with varying technical success rates.123 Technical success using the transmural technique was greater than 70% in 75 patients, whereas success rates with the rendezvous technique ranged from 25% to 100% in 52 patients. A more recent 2015 review by Fujii-Lau and Levy included 222 patients.124 Technical success was achieved in 170 out of 222 patients (76.6%) and included both rendezvous and transmural EUS-PDD techniques. Reported technical difficulties include difficulty with dilation, wire passage and stripping, and inability to deploy stents or their migration.123,124 Adverse event rates of nearly 20% have been reported and include pancreatitis, perforation, bleeding, and peripancreatic abscess.124–126 More data are needed on long-term success rates and adverse events related to this technique. EUS-Guided Gastroenterostomy In the past few years, various EUS-guided techniques that utilize lumen-apposing metal stents (LAMS) have been described as an endoscopic treatment of gastric outlet obstruction (off-label indication). The LAMS is placed between the stomach and bypassed small bowel, with different techniques described including direct puncture with cautery-enhanced LAMS or needle puncture of a fluoroscopically placed dilation balloon and then LAMS deployment (both cautery and non-cautery) over a guidewire (Fig. 59.10). Two recent cases series have been published on this technique as a treatment for both malignant and benign etiologies of gastric outlet obstruction. Khashab et al (2015) published the first American series of EUS-guided gastroenterostomy in 10 patients (7 with CP), and demonstrated high technical (90%) and clinical success rates (92%) with no adverse events.127 Meanwhile, an international multicenter experience in 26 patients (9 with CP) reported similarly high technical (92%) and clinical success rates (85%), but did have significant adverse events in 11.5%.128 These adverse events included peritonitis, perforation, and bleeding, with one death. EUS-guided gastroenterostomy is a promising technique that may obviate the need for invasive surgery in select patients. Currently, there are no data on optimal duration of LAMS placement. The goal would be a permanent anastomosis to allow for removal after a few months, but anecdotal reports have noted tract closure once the LAMS is removed. Therefore, some experts have advocated

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CHAPTER 59 Chronic Pancreatitis

A

B

C

D FIG 59.9 Endoscopic ultrasound (EUS)-guided transmural pancreatic ductal drainage (EUS-PDD). A, EUS view of dilated pancreatic duct (PD) of 7 mm. B, Radiographic view of pancreatogram (obtained from direct EUS puncture through the stomach) showing dilated PD with stricture in the head of the pancreas and guidewire placed into the pancreatic tail. C, Single pigtail plastic PD stent on radiographic view. D, PD stent on endoscopic view in the stomach.

A

B FIG 59.10 Endoscopic ultrasound (EUS)-guided gastroenterostomy using lumen-apposing metal stent (LAMS). A, Endoscopic view through LAMS in stomach showing small bowel. B, Radiographic view of LAMS with EUS scope.

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leaving the LAMS in place indefinitely. Limited published data have shown that even in the hands of skilled endoscopists, this procedure can result in significant adverse events and should only be done in select patients at referral centers in collaboration with surgical colleagues. Similar to EUS-PDD, this therapeutic EUS maneuver warrants further study to establish the ideal technique and overall safety profile.

KEY REFERENCES 4. Coté GA, Yadav D, Slivka A, et al; for the North American Pancreatitis Study Group: Alcohol and smoking as risk factors in an epidemiology study of patients with chronic pancreatitis, Clin Gastroenterol Hepatol 9:266–273, 2011. 8. Majumder S, Chari ST: Chronic pancreatitis, Lancet 387:1957–1966, 2016. 13. Cohn JA, Friedman KJ, Noone PG, et al: Relation between mutations of the cystic fibrosis gene and idiopathic pancreatitis, N Engl J Med 339:653–658, 1998. 48. Varadarajulu S, Eltoum I, Tamhane A, et al: Histopathologic correlates of noncalcific chronic pancreatitis by EUS: a prospective tissue characterization study, Gastrointest Endosc 65:501–509, 2007. 52. Janssen J, Schlorer E, Greiner L: EUS elastography of the pancreas: feasibility and pattern description of the normal pancreas, chronic pancreatitis, and focal pancreatic lesions, Gastrointest Endosc 65: 971–978, 2007. 56. Dominguez-Munoz JE, Iglesias-Garcia J, Castineira Alvarino M, et al: EUS elastography to predict pancreatic exocrine insufficiency in patients with chronic pancreatitis, Gastrointest Endosc 81:136–142, 2015. 67. Gress F, Schmitt C, Sherman S, et al: A prospective randomized comparison of endoscopic ultrasound and computed tomography-guided celiac plexus block for managing chronic pancreatitis pain, Am J Gastroenterol 94:900–905, 1999. 76. Tadenuma H, Ishihara T, Yamaguchi T, et al: Long-term results of extracorporeal shockwave lithotripsy and endoscopic therapy for pancreatic stones, Clin Gastroenterol Hepatol 3:1128–1135, 2005. 77. Attwell AR, Patel S, Kahaleh M, et al: ERCP with per-oral pancreatoscopy-guided laser lithotripsy for calcific chronic pancreatitis: a multicenter U.S. experience, Gastrointest Endosc 82(2):311–318, 2015. 89. Dite P, Ruzicka M, Zboril V, et al: A prospective, randomized trial comparing endoscopic and surgical therapy for chronic pancreatitis, Endoscopy 35:553–558, 2003. 90. Cahen DL, Gouma DJ, Nio Y, et al: Endoscopic versus surgical drainage of the pancreatic duct in chronic pancreatitis, N Engl J Med 356: 676–684, 2007.

92. Ahmed AU, Pahlpalatz JM, Nealon WH, et al: Endoscopic or surgical intervention for painful obstructive chronic pancreatitis, Cochrane Database Syst Rev (3):CD007884, 2015. 98. Kwon RS, Young BE, Marsteller WF, et al: Narcotic independence after pancreatic duct stenting predicts narcotic independence after lateral pancreaticojejunostomy for chronic pancreatitis, Pancreas 45:1126–1130, 2016. 111. Sherman S, Hawes RH, Savides TJ, et al: Stent-induced pancreatic ductal and parenchymal changes: correlation of endoscopic ultrasound with ERCP, Gastrointest Endosc 44:276–282, 1996. 113. Deviere J, Devaere S, Baize M, et al: Endoscopic biliary drainage in chronic pancreatitis, Gastrointest Endosc 36:96–100, 1990. 115. Kahl S, Zimmermann S, Glasbrenner B, et al: Treatment of benign biliary strictures in chronic pancreatitis by self-expandable metal stents, Dig Dis Sci 20:199–203, 2002. 117. Cote G, Slivka A, Tarnasky P, et al: Effect of covered metallic stents compared with plastic stents on benign biliary stricture resolution a randomized clinical trial, JAMA 315(12):1250–1257, 2016. 118. Fukami N, Anderson MA, Khan K, et al: ASGE Standards of Practice Guidelines: the role of endoscopy in gastroduodenal obstruction and gastroparesis, Gastrointest Endosc 74(1):13–21, 2011. 119. Jeurnink SM, Steyerberg EW, Hof G, et al: Gastrojejunostomy versus stent placement in patients with malignant gastric outlet obstruction: a comparison in 95 patients, J Surg Oncol 96:389–396, 2007. 122. Gines A, Varadarajulu S, Napoleon B: EUS 2008 Working Group Document. Evaluation of EUS-guided pancreatic-duct drainage, Gastrointest Endosc 69(2 Suppl):S43–S48, 2009. 123. Itoi T, Kasuya K, Sofuni A, et al: Endoscopic ultrasonography-guided pancreatic duct access: techniques and literature review of pancreatography, transmural drainage and rendezvous techniques, Dig Endosc 25(3):241–252, 2013. 125. Fujii LL, Topazian MD, Abu Dayyeh BK, et al: EUS-guided pancreatic duct intervention: outcomes of a single tertiary-care referral center experience, Gastrointest Endosc 78:854–864, 2013. 126. Chapman CG, Waxman I, Siddiqui UD: Endoscopic ultrasound (EUS)-guided pancreatic duct drainage: the basics of when and how to perform EUS-guided pancreatic duct interventions, Clin Endosc 49(2):161–167, 2016. 127. Khashab MA, Kumbhari V, Grimm IS, et al: EUS-guided gastroenterostomy: the first U.S. clinical experience, Gastrointest Endosc 82:932–938, 2015. 128. Tyberg A, Perez-Miranda M, Sanchez-Ocana R, et al: Endoscopic ultrasound-guided gastrojejunostomy with a lumen-apposing metal stent: a multicenter, international experience, Endosc Int Open 4(3): 276–281, 2016.

A complete reference list can be found online at ExpertConsult .com

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CHAPTER 59 Chronic Pancreatitis

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48. Varadarajulu S, Eltoum I, Tamhane A, et al: Histopathologic correlates of noncalcific chronic pancreatitis by EUS: a prospective tissue characterization study, Gastrointest Endosc 65:501–509, 2007. 49. Toskes PP: Diagnosis of chronic pancreatitis and exocrine insufficiency, Hosp Pract 20:97–100, 1985. 50. Sahai AV, Mishra G, Penman I, et al: EUS to detect evidence of pancreatic disease in patients with persistent or nonspecific dyspepsia, Gastrointest Endosc 52:153–159, 2000. 51. Bhutani MS: Endoscopic ultrasonography: changes of chronic pancreatitis in asymptomatic and symptomatic alcoholic patients, J Ultrasound Med 18:455–462, 1999. 52. Janssen J, Schlorer E, Greiner L: EUS elastography of the pancreas: feasibility and pattern description of the normal pancreas, chronic pancreatitis, and focal pancreatic lesions, Gastrointest Endosc 65:971– 978, 2007. 53. Iglesias Garcia J, Lindkvist B, Larino Noia J, et al: Endoscopic ultrasound elastography, Endosc Ultrasound 1:8–16, 2012. 54. Iglesias-Garcia J, Larino-Noia J, Dominguez-Munoz JE: Elastography in the evaluation of chronic pancreatitis, Gastroenterol Hepatol 34:629– 634, 2011. 55. Iglesias-Garcia J, Dominguez-Munoz JE, Castineira-Alvarino M, et al: Quantitative elastography associated with endoscopic ultrasound for the diagnosis of chronic pancreatitis, Endoscopy 45:781–788, 2013. 56. Dominguez-Munoz JE, Iglesias-Garcia J, Castineira Alvarino M, et al: EUS elastography to predict pancreatic exocrine insufficiency in patients with chronic pancreatitis, Gastrointest Endosc 81:136–142, 2015. 57. Walsh TN, Rode J, Theis BA, et al: Minimal change chronic pancreatitis, Gut 33:1566–1571, 1992. 58. Hayakawa T, Kondo T, Shibata T, et al: Relationship between pancreatic exocrine function and histological changes in chronic pancreatitis, Am J Gastroenterol 87:1170–1174, 1992. 59. Schmitz-Moormann P, Himmelmann GW, Brandes JW, et al: Comparative radiological and morphological study of human pancreas: pancreatitis-like changes in postmortem ductograms and their morphological pattern. Possible implication for ERCP, Gut 26:406–414, 1985. 60. Forsmark CE, Toskes PP: What does an abnormal pancreatogram mean? Gastrointest Endosc Clin N Am 5:105–123, 1995. 61. Sherman S, Lehman GA: Endoscopic therapy of pancreatic disease, Gastroenterologist 1:5–17, 1993. 62. Lillemore KD, Cameron JL, Kaufman HS, et al: Chemical splanchniectomy in patients with unresectable pancreatic cancer: a prospective randomized trial, Ann Surg 217:447–455, 1993. 63. Mercadante S: Celiac plexus block versus analgesics in pancreatic cancer pain, Pain 52:187–192, 1993. 64. Wiersema MJ, Wiersema LM: Endosonography-guided celiac plexus neurolysis, Gastrointest Endosc 44:639–662, 1996. 65. Davies DD: Incidence of major complications of neurolytic celiac plexus block, J R Soc Med 86:224–266, 1993. 66. Wiersema MJ, Harada N, Wiersema LM: Endosonography guided celiac plexus neurolysis efficacy in chronic pancreatitis and malignant disease, Acta Endoscopica 28:67–79, 1998. 67. Gress F, Schmitt C, Sherman S, et al: A prospective randomized comparison of endoscopic ultrasound and computed tomographyguided celiac plexus block for managing chronic pancreatitis pain, Am J Gastroenterol 94:900–905, 1999. 68. LeBlan JK, DeWitt J, Johnson C, et al: A prospective randomized trial of 1 versus 2 injections during EUS-guided celiac plexus block for chronic pancreatitis pain, Gastrointest Endosc 69:835–842, 2009. 69. Geenen JE, Rolny P: Endoscopic therapy of acute and chronic pancreatitis, Gastrointest Endosc 37:377–382, 1991. 70. Seigel J, Veerappan A: Endoscopic management of pancreatic disorders: potential risks of pancreatic prosthesis, Endoscopy 23:177–180, 1991. 71. Huibregtse K, Smits ME: Endoscopic management of diseases of the pancreas, Am J Gastroenterol 89:S66–S77, 1994. 72. Neuhaus H: Fragmentation of pancreatic stones by ESWL, Endoscopy 23:161–165, 1991.

73. Sherman S, Lehman GA, Hawes RH, et al: Pancreatic ductal stones: frequency of successful endoscopic removal and improvement in symptoms, Gastrointest Endosc 37:511–517, 1991. 74. Kozarek RA, Ball TJ, Patterson GJ: Endoscopic approach to pancreatic duct calculi and obstructive pancreatitis, Am J Gastroenterol 87:600–603, 1992. 75. Cremer M, Deviere J, Delhaye M, et al: Endoscopic management of chronic pancreatitis, Acta Gastroenterol Belg 56:192–200, 1993. 76. Tadenuma H, Ishihara T, Yamaguchi T, et al: Long-term results of extracorporeal shockwave lithotripsy and endoscopic therapy for pancreatic stones, Clin Gastroenterol Hepatol 3:1128–1135, 2005. 77. Attwell AR, Patel S, Kahaleh M, et al: ERCP with per-oral pancreatoscopy-guided laser lithotripsy for calcific chronic pancreatitis: a multicenter U.S. experience, Gastrointest Endosc 82(2):311–318, 2015. 78. Dumonceau JM, Deviere J, Le Moine O, et al: Endoscopic pancreatic drainage in chronic pancreatitis associated with ductal stones: long-term results, Gastrointest Endosc 43:547–555, 1996. 79. Delhaye M, Vandermeeren A, Baize M, et al: Extracorporeal shock wave lithotripsy of pancreatic calculi, Gastroenterology 102:610–620, 1992. 80. Sauerbruch T, Holl J, Sackmann M, et al: Extracorporeal lithotripsy of pancreatic stones in patients with chronic pancreatitis and pain: a prospective follow-up study, Gut 33:969–972, 1992. 81. Farnbacher MJ, Schoen C, Rabenstein T, et al: Pancreatic duct stones in chronic pancreatitis: criteria for treatment intensity and success, Gastrointest Endosc 56:501–506, 2002. 82. Adamek HE, Jakobs R, Buttmann A, et al: Long term follow up of patients with chronic pancreatitis and pancreatic stones treated with extracorporeal shock wave lithotripsy, Gut 45:402–405, 1999. 83. Schneider HT, May A, Benninger J, et al: Piezoelectric shock wave lithotripsy of pancreatic duct stones, Am J Gastroenterol 89:2042–2048, 1994. 84. Ohara H, Hoshino M, Hayakawa T, et al: Single application extracorporeal shock wave lithotripsy is the first choice for patients with pancreatic duct stones, Am J Gastroenterol 91:1388–1394, 1996. 85. Schreiber F, Gurakuqi GCH, Pristautz H, et al: Sonographically-guided extracorporeal shock wave lithotripsy for pancreatic stones in patients with chronic pancreatitis, J Gastroenterol Hepatol 11:247–251, 1996. 86. Brand B, Kahl M, Sidhu S, et al: Prospective evaluation of morphology, function, and quality of life after extracorporeal shockwave lithotripsy and endoscopic treatment of chronic calcific pancreatitis, Am J Gastroenterol 95:3428–3438, 2000. 87. Kozarek RA, Brandabur JJ, Ball TJ, et al: Clinical outcomes in patients who undergo extracorporeal shock wave lithotripsy for chronic calcific pancreatitis, Gastrointest Endosc 56:496–500, 2002. 88. Inui K, Tazuma S, Yamaguchi T, et al: Treatment of pancreatic stones with extracorporeal shock wave lithotripsy: results of a multicenter study, Pancreas 30:26–30, 2005. 89. Dite P, Ruzicka M, Zboril V, et al: A prospective, randomized trial comparing endoscopic and surgical therapy for chronic pancreatitis, Endoscopy 35:553–558, 2003. 90. Cahen DL, Gouma DJ, Nio Y, et al: Endoscopic versus surgical drainage of the pancreatic duct in chronic pancreatitis, N Engl J Med 356:676– 684, 2007. 91. Ahmed AU, Pahlpalatz JM, Nealon WH, et al: Endoscopic or surgical intervention for painful obstructive chronic pancreatitis, Cochrane Database Syst Rev (1):CD007884, 2012. 92. Ahmed AU, Pahlpalatz JM, Nealon WH, et al: Endoscopic or surgical intervention for painful obstructive chronic pancreatitis, Cochrane Database Syst Rev (3):CD007884, 2015. 93. Cremer M, Deviere J, Delhaye M, et al: Stenting in severe chronic pancreatitis: results of medium-term follow-up in 76 patients, Endoscopy 23:171–176, 1991. 94. Smits ME, Rauws EA, Tytgat GNJ, et al: Endoscopic treatment of pancreatic stones in patients with chronic pancreatitis, Gastrointest Endosc 43:556–560, 1996. 95. Nealon WH, Townsend CJ, Thompson JC: Operative drainage of the pancreatic duct delays functional improvement in patients with chronic pancreatitis: a prospective analysis, Ann Surg 208:321–329, 1988.

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CHAPTER 59 Chronic Pancreatitis 96. Barthet M, Sahel J, Bodiou BC, et al: Endoscopic transpapillary drainage of pancreatic pseudocysts, Gastrointest Endosc 42:208–213, 1995. 97. Catalano MF, Geenen GE, Schmalz MJ, et al: Treatment of pancreatic pseudocysts with ductal communication by transpapillary duct endoprosthesis, Gastrointest Endosc 42:214–218, 1995. 98. Kwon RS, Young BE, Marsteller WF, et al: Narcotic independence after pancreatic duct stenting predicts narcotic independence after lateral pancreaticojejunostomy for chronic pancreatitis, Pancreas 45:1126– 1130, 2016. 99. Morgan DE, Smith JK, Hawkins K, Wilcox CM: Endoscopic stent therapy in advanced chronic pancreatitis: relationships between ductal changes, clinical response, and stent patency, Am J Gastroenterol 98(4):821–826, 2003. 100. Ponchon T, Bory RM, Medeluis F, et al: Endoscopic stenting for pain relief in chronic pancreatitis: results of a standardized protocol, Gastrointest Endosc 42:452–456, 1995. 101. Smits ME, Badiga SM, Rauws AJ, et al: Long-term results of pancreatic stents in chronic pancreatitis, Gastrointest Endosc 42:461– 467, 1995. 102. Binmoeller KF, Jue P, Seifert H, et al: Endoscopic pancreatic stent drainage in chronic pancreatitis and a dominant stricture: long-term results, Endoscopy 27:638–644, 1995. 103. Costamagna G, Bulajic M, Tringali A, et al: Multiple stenting of refractory pancreatic duct strictures in severe chronic pancreatitis: long-term results, Endoscopy 38:254–259, 2006. 104. Cremer M, Suge B, Delhoye M, et al: Expandable pancreatic metal stents (Wallstent) for chronic pancreatitis: first world series [abstract], Gastroenterology 98:215, 1990. 105. Sauer B, Talreja J, Ellen K, et al: Temporary placement of a fully covered self-expandable metals stent in the pancreatic duct for management of symptomatic refractory chronic pancreatitis: preliminary data (with videos), Gastrointest Endosc 68:1173–1178, 2008. 106. Smit MT, Sherman S, Ikenberry SO, et al: Alterations in pancreatic duct morphology following polyethylene pancreatic duct stenting, Gastrointest Endosc 44:268–275, 1996. 107. Kozarek RA: Pancreatic stents can induce ductal changes consistent with chronic pancreatitis, Gastrointest Endosc 36:93–95, 1990. 108. Derfus GA, Geenen JE, Hogan WJ: Effect of endoscopic pancreatic duct stent placement on pancreatic ductal morphology, Gastrointest Endosc 36:206A, 1990. 109. Lehman GA, Sherman S, Nisi R, et al: Pancreas divisum: results of minor papilla sphincterotomy, Gastrointest Endosc 44:268–275, 1996. 110. Eisen G, Coleman S, Troughton A, et al: Morphological changes in the pancreatic duct after stent placement for benign pancreatic disease, Gastrointest Endosc 40:107A, 1994. 111. Sherman S, Hawes RH, Savides TJ, et al: Stent-induced pancreatic ductal and parenchymal changes: correlation of endoscopic ultrasound with ERCP, Gastrointest Endosc 44:276–282, 1996.

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112. Draganov P, Hoffman B, Marsh W, et al: Long-term outcome in patients with benign biliary strictures treated endoscopically with multiple stents, Gastrointest Endosc 55:680–686, 2002. 113. Deviere J, Devaere S, Baize M, et al: Endoscopic biliary drainage in chronic pancreatitis, Gastrointest Endosc 36:96–100, 1990. 114. Deviere J, Cremer M, Love J, et al: Management of common bile duct strictures caused by chronic pancreatitis with metal self-expandable stents, Gut 35:122–126, 1994. 115. Kahl S, Zimmermann S, Glasbrenner B, et al: Treatment of benign biliary strictures in chronic pancreatitis by self-expandable metal stents, Dig Dis Sci 20:199–203, 2002. 116. Pitt HA, Kaufman SL, Coleman J, et al: Benign postoperative biliary strictures: operate or dilate, Ann Surg 210:417–425, 1989. 117. Cote G, Slivka A, Tarnasky P, et al: Effect of covered metallic stents compared with plastic stents on benign biliary stricture resolution a randomized clinical trial, JAMA 315(12):1250–1257, 2016. 118. Fukami N, Anderson MA, Khan K, et al: ASGE Standards of Practice Guidelines: the role of endoscopy in gastroduodenal obstruction and gastroparesis, Gastrointest Endosc 74(1):13–21, 2011. 119. Jeurnink SM, Steyerberg EW, Hof G, et al: Gastrojejunostomy versus stent placement in patients with malignant gastric outlet obstruction: a comparison in 95 patients, J Surg Oncol 96:389–396, 2007. 120. Phillips MS, Gossain S, Bonatti H, et al: Enteral stents for malignancy: a report of 46 consecutive cases over 10 years, with critical review of complications, J Gastrointest Surg 12(11):2045–2050, 2008. 121. Xin L, Gao J, Wang D, et al: Novel blood-based microRNA biomarker for early diagnosis of chronic pancreatitis, Sci Rep 1–9, 2017. 122. Gines A, Varadarajulu S, Napoleon B: EUS 2008 Working Group Document. Evaluation of EUS-guided pancreatic-duct drainage, Gastrointest Endosc 69(2 Suppl):S43–S48, 2009. 123. Itoi T, Kasuya K, Sofuni A, et al: Endoscopic ultrasonography-guided pancreatic duct access: techniques and literature review of pancreatography, transmural drainage and rendezvous techniques, Dig Endosc 25(3):241–252, 2013. 124. Fujii-Lau LL, Levy MJ: Endoscopic ultrasound-guided pancreatic duct drainage, J Hepatobiliary Pancreat Sci 22:51–57, 2015. 125. Fujii LL, Topazian MD, Abu Dayyeh BK, et al: EUS-guided pancreatic duct intervention: outcomes of a single tertiary-care referral center experience, Gastrointest Endosc 78:854–864, 2013. 126. Chapman CG, Waxman I, Siddiqui UD: Endoscopic ultrasound (EUS)-guided pancreatic duct drainage: the basics of when and how to perform EUS-guided pancreatic duct interventions, Clin Endosc 49(2): 161–167, 2016. 127. Khashab MA, Kumbhari V, Grimm IS, et al: EUS-guided gastroenterostomy: the first U.S. clinical experience, Gastrointest Endosc 82:932–938, 2015. 128. Tyberg A, Perez-Miranda M, Sanchez-Ocana R, et al: Endoscopic ultrasound-guided gastrojejunostomy with a lumen-apposing metal stent: a multicenter, international experience, Endosc Int Open 4(3): 276–281, 2016.

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PART FOUR Neoplastic Pancreaticobiliary Disorders

60 The Indeterminate Biliary Stricture Amrita Sethi and Douglas A. Howell

CHAPTER OUTLINE Introduction, 699 Etiologies of Biliary Strictures, 699 Laboratory Evaluation, 700 ERCP, 701 History, 701 Tissue Acquisition During ERCP, 701

Specimen Handling and Analysis, 704 Intraprocedural Techniques at ERCP, 706 FISH, 707 Endoscopic Ultrasound-FNA, 708 Intraductal Ultrasound, 708

INTRODUCTION Indeterminate biliary stricture (IDBS) remains one of the biggest challenges that pancreaticobiliary endoscopists face. While a strict definition of IDBS is frequently not adhered to in the literature, this term refers to biliary strictures with no overt mass on noninvasive imaging such as computed tomography (CT) or magnetic resonance cholangiopancreatography, and that cannot be distinguished as malignant or benign after standard diagnostic procedures such as endoscopic retrograde cholangiopancreatography (ERCP) with tissue sampling (either brushing alone or in combination with biopsies). Surgical series demonstrate that 15% to 24% of patients who undergo resection for suspected malignant strictures based on preoperative imaging or ERCP will ultimately have a benign diagnosis on pathology.1,2 This small but significant cohort of patients with benign strictures highlights the importance of accurate preoperative tissue diagnosis to avoid the morbidity and mortality of hepatobiliary surgery. For example, the two most common causes of malignant strictures are cholangiocarcinoma (CCA) and pancreatic cancer. Diagnosis of these malignancies at an early stage can allow curative surgical resection or even liver transplantation for early stage CCA. Tissue diagnosis of pancreaticobiliary malignancy via endoscopic approaches is well known to be limited due to poor cellular yield and often requires surgical exploration for definite diagnosis. This diagnostic dilemma ultimately serves as the driving force behind advances in biliary imaging, improvements in sampling techniques, and the identification of emerging molecular markers. This section will review the etiologies of biliary strictures, the initial clinical evaluation of IDBSs, the diagnostic yield of

Optical Coherence Tomography, 708 Cholangioscopy, 709 Confocal Laser Endomicroscopy, 711 Evaluation of Strictures in PSC, 711 Conclusion, 712

ERCP-based sampling methods and recommended methods of improving acquisition and analysis, and the role of newer imaging tools in our approach to evaluating strictures.

ETIOLOGIES OF BILIARY STRICTURES The leading causes of malignant biliary obstruction are pancreatic cancer and CCA.3 CCA is a primary malignancy of the bile duct epithelium, and therefore can affect both intra- and extrahepatic ducts. It is the second most common primary liver malignancy after hepatocellular carcinoma.4 When diagnosed in early stages, surgical resection can have an excellent prognosis.5 The challenge, however, is in obtaining a histological diagnosis given the typically inadequate cellular yield from initial sampling methods such as ERCP with brush cytology and/or biopsy. Unfortunately, the differential for CCA includes a host of benign causes of biliary strictures that can radiographically mimic CCA. Biliary strictures due to pancreatic cancer are most often found at the distal common bile duct and are due to extrinsic compression of the extrahepatic duct from a pancreatic head mass with or without biliary invasion. Diagnosis of biliary stricture in the setting of a pancreatic mass does not technically fall into the category of IDBS; however, early tumors may go undetected on cross-sectional imaging, and thorough evaluation of the pancreatic head in such strictures is a necessary part of the evaluation. This is in contrast to CCA, whose desmoplastic nature results in its growing in an infiltrative pattern along the length of the bile duct, making its early detection particularly difficult due to the lack of a visible growth or tumor on imaging. Other less common malignant causes of biliary strictures include intraductal

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CHAPTER 60

The Indeterminate Biliary Stricture

Abstract

Keywords

Indeterminate biliary strictures, defined as biliary strictures with no obvious mass on imaging, that cannot be distinguished as malignant or benign despite initial endoscopic retrograde cholangiopancreatography (ERCP) and standard sampling methods, remain a challenge for pancreaticobiliary endoscopists. Advances in laboratory evaluation such as tumor markers and microRNAs may serve as complementary tools for diagnosing malignancies such as cholangiocarninoma. Advances in imaging such as cholangioscopy, confocal endomicroscopy and optical coherence tomography may also help with optimizing identification of tissue to be targeted for biopsy. And lastly, advances in tissue sampling, such as combination sampling, molecular analysis, specimen presentation, and on-site analysis, may further improve accuracy in the evaluation of indeterminate biliary strictures.

indeterminate biliary strictures ERCP cholangioscopy confocal endomicroscopy tissue sampling FISH

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699.e1

700

SECTION III

TABLE 60.1

Pancreaticobiliary Disorders

Etiologies of Biliary Strictures

Malignant

Benign

Cholangiocarcinoma

Chronic pancreatitis

Pancreatic adenocarcinoma

Primary sclerosing cholangitis

Ampullary adenocarcinoma

Ig4 (autoimmune) sclerosing cholangitis

Gallbladder cancer

Postsurgical, anastomotic stricture

Hepatocellular carcinoma

Mirizzi syndrome

Metastatic disease

Fibrostenotic benign stricture

Lymphoma

Ischemic stricture Radiation-induced stricture Infectious (HIV-associated, parasitic cholangiopathy, tuberculosis) Vasculitis

hepatocellular carcinoma, metastatic lesion, and extrinsic compression of the biliary tree from an associated visible mass or lymphadenopathy (Table 60.1). The varying forms of malignant biliary obstruction are pathologically distinct and represent special problems when attempting tissue sampling. The first major pathologic factor influencing biopsy or cytologic yield is tumor cellularity. Pancreatic carcinoma, in particular, often stimulates an intense desmoplastic and fibrotic reaction, making the tumor very dense and of low cellularity. Sampling often produces acellular or false-negative specimens.6,7 Maximizing yield requires repeated, deep, or large specimen sampling. Occasionally, an immune response or relative ischemia produces ulceration, bleeding, exudate, or debris that can obscure the rare malignant cell recovered in an endoscopic specimen. CCA of the primary type begins in the mucosa of the primary or secondary bile ducts. It is a relatively cellular cancer, and cells are more often shed in bile and can be more readily collected by sampling the superficial epithelium. However, the intrahepatic location of these tumors poses difficult access issues, making endoscopic ultrasound fine-needle aspiration (EUS FNA) yields lower, although the procedure is technically possible in select patients.6,8–10 Hepatocellular carcinoma can often invade and extend intraductally. Superficial sampling generally obtains diagnostic cells in this setting as well. As with pancreatic cancer, gallbladder cancer and, especially, metastatic cancer, encase or compress the biliary tree, often while preserving intact benign biliary epithelium. Establishing a tissue diagnosis often requires sampling deeper than the surface epithelium.6,8–10 Very well-differentiated tumors represent a significant minority of malignant pancreaticobiliary tumors and prove very difficult to diagnose by cytologic criteria. Large specimens are often necessary to permit the pathologist to examine and compare these tumors to differentiate them from normal tissue. This fact likely explains why no biopsy technique, even open surgical wedge biopsy, has a 100% yield. These pathogenetic factors demand refined techniques and devices if adequate specimens are to be obtained to permit a positive cytologic or histologic diagnosis to be made in most cases. Causes of benign biliary strictures include a variety of diseases ranging from recurrent cholangitis, postsurgical causes (most commonly after cholecystectomy or liver transplantation) to cholangiopathy from autoimmune disease, HIV, and primary sclerosing cholangitis (PSC). A long-standing yet poorly understood impersonator of a malignant stricture is autoimmune or

Ig4-associated sclerosing cholangitis (IgG4-SC). The prevalence and pathogenesis of this disease remains largely unknown, but more than 80% of patients will have elevations of serum IgG4 above the upper limit of normal, and a similar percentage of patients will have an associated autoimmune pancreatitis.11,12 On cholangiogram, hilar IgG4-SC strictures can be indistinguishable from CCA. Histologic sampling, which can be diagnostic, may demonstrate diffuse infiltration of IgG4-positive plasma cells with fibroinflammatory involvement of the submucosa of the bile duct wall.11

LABORATORY EVALUATION The most common laboratory abnormality seen in patients with malignant biliary stricture is obstructive cholestasis. Direct hyperbilirubinemia is seen more commonly in patients with malignant obstruction than those with a benign etiology such as choledocholithiasis.13 Hyperbilirubinemia also has a higher likelihood of being associated with malignancy than elevations in alkaline phosphatase.13,14 The most frequently used serologic markers for CCA are CA19-9 and possibly carcinoembryonic antigen (CEA). CEA has sensitivities and specificities that range from 33% to 84% and 50% to 87.8%, respectively.15–17 Unfortunately, CA19-9 also has a wide range of sensitivity and specificity: 38% to 93% and 67% to 98%.15–19 Furthermore, it can be undetectable in 7% of the general population due to absence of the Lewis antigen.20 The variable diagnostic accuracies of CA19-9, therefore, limit its role in screening, and its greatest value may be in the surveillance of patients with PSC. In response to this poor reliability of CA19-9, other serum tumor markers have been recently evaluated. For example, cytokeratin-19 fragments (CYFRA 21-1) get released into the bloodstream by malignant epithelial cells.20 Several studies have demonstrated elevated CYFRA 21-1 expression in CCA, albeit with variable sensitivities depending on the cut-off value.17,20,21 Specificities also vary given that elevation of CYFRA 21-1 expression has been reported in multiple other gastrointestinal (GI) and non-GI epithelial malignancies such as gastric, breast, and cervical. Similarly, high matrix metalloproteinase-7 (MMP-7) expression has been found to be associated with cancer invasion in esophageal,22 colon,23 and pancreatic24 cancers. Given the lack of specificity for these individual markers, use of combinations of the markers may be the most useful, such as in multimarker panels. For example, a panel with the combination of these markers with CEA and CA19-9 demonstrated the highest diagnostic accuracy of 93.9%.20 Another serum marker, interleukin-6 (IL-6), which has been shown to be a biliary epithelial growth factor,25 has demonstrated sensitivity as high as 100% in diagnosing CCA.26 Like the other markers mentioned earlier, however, the specificities are limited due to its elevation in patients with hepatocellular carcinoma, benign biliary disease, and metastatic lesions.27 Sperm-specific protein 411 (SSP411) is a protein that shows some promise in serving as a single serum-based biomarker given its elevation in the bile of CCA patients and use in distinguishing CCA from choledocholithiasis.28 Recent work has been performed evaluating the utility of measuring microRNAs (miRNAs) that are shed into the circulation in a free form when dysregulated in the setting of malignancies, compared to their stable protein-bound form.29 The value of miRNAs lies in their tissue-specific patterns of expression.

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CHAPTER 60 MicroRNAs that are commonly upregulated in other epithelial cancers such as miR-192, 194, and 215 in colon, liver, pancreas, and stomach cancers,30 are not altered in CCA. Conversely, CCA-specific miRNA expression profiles do exist, such as downregulation of miR-125a, -31,31,32 or, alternatively, upregulation of some miRNA’s such as miR-21.33–35 The specificity is limited, however, given its upregulation in other cancers (gastric,36 breast,37 and colon38). As with tumor markers discussed earlier, perhaps the evaluation for miRNAs are best performed as part of a multimarker panels specific for CCA.

The Indeterminate Biliary Stricture

701

A

B

C

ERCP History While noninvasive imaging modalities such as magnetic resonance imaging/magnetic resonance cholangiopancreatography and computed tomography (CT) are an essential part of the baseline evaluation of biliary strictures, they carry low diagnostic accuracy in distinguishing benign from malignant causes of obstruction.10 Furthermore, they provide no means by which to obtain tissue diagnosis and thus, when discussing IDBS, the gold standard remains ERCP. ERCP was developed in the late 1960s as a diagnostic technique to provide detailed radiography of the biliary tree and pancreatic ducts. ERCP remained primarily a diagnostic tool until 1973, when endoscopic sphincterotomy was performed in Japan and Germany, specifically to allow for additional diagnostic and therapeutic maneuvers, such as performing forceps biopsies of proximal strictures.

Tissue Acquisition During ERCP The goals of ERCP for a suspected malignant biliary stricture are to first obtain definite tissue diagnosis to obviate the need for exploratory surgery, and second, to provide palliation of biliary obstruction with stent placement. In fact, the constant quest for improved methods of tissue acquisition remains the focus of innovation in biliary technology. Initial efforts were limited to simple aspiration of bile and occasionally pancreatic juice when deep cannulation was achieved. While specificity in early reports was uniformly 100%, low sensitivities of only 6% to 32% in six published studies39–44 have caused this technique to fall from practice. Aspirating bile after brush cytology has occasionally been reported to increase yield using standard cell block preparation.45 Combined methods of tissue sampling will be presented later in this chapter. Finally, advanced molecular diagnostics in bile, including proteomic, lipidomic, and volatile organic compound analysis, may reopen bile aspiration as an accepted modality to determine a malignant diagnosis with sufficient specificity. Brush Cytology Sampling Methods Inadequate tissue acquisition at ERCP remains the most common reason for failing to establish an accurate pathologic diagnosis. Technical difficulty, time consideration, patient restlessness, and the need to proceed with the primary goal of biliary drainage all contribute to limit the time and thoroughness of tissue collection for many endoscopists. Because of these factors, brush cytology has been the universally adopted technique in clinical practice. Initially, standard nonwire guided endoscopic brushes were inserted, usually after sphincterotomy; however, negotiation through the stricture was often problematic. This factor and the

D FIG 60.1 Brushes for endoscopic retrograde cholangiopancreatography (ERCP) brush cytology. From top to bottom: A, Standard metal-tipped brush, B, Geenen spring-nosed brush in a diagnostic catheter, C, Cytomax 8-Fr brush catheter over a 0.035-inch guidewire, D, large HBIB brush for use in the Howell biliary introducer (HBI).

very superficial nature of this technique of sampling produced disappointing yields, and it never became popular. Thus, a variety of cytology brushes, some of which could be inserted over a guidewire placed through the malignant-appearing stricture before attempted sampling, were developed and are the devices we currently use today. These brushes are housed in catheters with a variety of diameters and stiffnesses, and the brushes themselves range in configuration as well as bristle length (Fig. 60.1). Techniques for performing brushing have subtle varieties but are centered around the idea of advancing the brush and catheter over the guidewire through the stricture, followed by manipulation of the exposed brush through the stricture multiple times. Protection of the acquired cells is paramount and best achieved by withdrawing the brush back into the catheter before leaving the area of the stricture (Fig. 60.2). Some also advocate for simultaneous aspiration of bile immediately after brushing, thereby collecting loose cells in the milieu of the brushing into the catheter before removing the entire device from the duct. Published yields of ERCP brush cytology devices vary widely for reasons that can only be speculated. Generally, series that have a higher proportion of pancreatic adenocarcinomas and, perhaps, earlier smaller tumors, have a much lower yield of positive results compared with series with more cholangiocarcinomas. Published overall sensitivities using these devices range from 8% to 57%.43,46–51 A 2013 review of ERCP brush cytology covered 16 studies over 10 years from 2002 to 2012, which included a total of 1586 patients.52 The combined yield of brush cytology ranged from 6% to 64% with an overall sensitivity of only 41.6% +/− 3.2%, and did not appear to vary across new devices and techniques. As discussed subsequently, many of these series are also flawed by including patients with “suspicious for malignancy” reports as positive results. A single center study of 142 patients with pancreatic or biliary cancer undergoing ERCP brushing reported in 2016 is such an example. The overall sensitivity was 58%, but actually only 50% in distal and presumably pancreatic cancer strictures. Adding “atypia” as a positive result increased yield to 65.5% but decreased specificity from 100% to 68.6%, clearly an unacceptable result.53

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702

SECTION III

Pancreaticobiliary Disorders

Common duct

Malignant stricture

Long-nosed brush Catheter

0.035" Guidewire

A

20 GA hole punched 1–2 cm from tip

B FIG 60.2 A, Monorail brush: a long-nosed brush is preloaded into a diagnostic catheter and passed with the catheter over a guidewire in a monorail fashion through the stricture. B, The monorail catheter has been passed over the end of the guidewire well above the stricture. Once off the guidewire, the long-nosed brush can be advanced to brush the stricture. The long nose maintains access. The guidewire remains in place.

A probable pathologic explanation for these varied yields relates to the observation that the interiors of malignant strictures are composed of benign epithelium compressed by surrounding neoplastic tissue, with the exception of CCA of the major bile ducts. This fact explains the low yield of simple bile aspiration for cytology because few, if any, malignant cells are in contact with the bile flow as previously discussed. When the stricture is traumatized by dilation, removing the benign epithelium, the yield of aspirating bile increases.51 The yield of brushing is lower with deeper and more remote encasing tumors. One would predict the lowest yield is in metastatic malignancy, followed by pancreatic cancer, with a much higher yield with primary CCA. Generally, this prediction has been confirmed in clinical practice. The type of brush bristles, the overall brush length, and the amount of time spent brushing all affect yield. Rabinovitz et al (1990)54 used three separate brushes at each ERCP and repeated the procedure with three new brushes when suspicious strictures

were initially negative. Positive yield continued to increase until diagnoses were eventually made by brushing alone in 62% of their patients. Two additional ERCP brushing studies have been performed in an attempt to increase yield. In a large number of patients, a newer long cytology brush with stiff angulated bristles was compared with the standard-length brushes described previously. The true-positive yields were uniformly disappointing—only 27% and 30%—and no advantage was observed with the new brush.55 The second study compared brushing with a more traumatic technique of inserting a grasping basket through the suspicious stricture. Of 50 malignant strictures, the basket technique had a near doubling of yield to 80% compared with a brush yield of 48% (p = 0.018). The unexpected high yield of the brushing suggests some selection bias, and this technique requires additional study.56 Building on this concept of traumatizing the surface epithelium, a new scraping device was developed and trialed in Japan.57 In 123 indeterminate stricture cases, 119 were eventually proven

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CHAPTER 60

The Indeterminate Biliary Stricture

703

FIG 60.3 The Howell biliary aspiration needle (HBAN-22) is a 22-gauge Chiba-type needle mounted in a 7-Fr ball-tipped catheter, precurved for placement into the common bile duct (CBD) after sphincterotomy.

to be malignant. This device involves a three-leaf clover–type design of three nitinol loops, rather than bristles, that are compressed in guidewire-compatible catheters. The structure is roughly scraped and bile is aspirated using the device’s side angled port. The yield was compared to a transpapillary forceps biopsy, and the device was also used in combination. The yields of forceps biopsy, the new scraping device, and both were 51%, 65%, and 75%, respectively. It is important to consider that 67% of their 119 cases had CCA and only 32% had pancreatic cancer. Furthermore, experience with this device is needed. ERCP Needle Biopsy Intraductal FNA during ERCP required the development of a specifically designed endoscopic accessory device. Howell et al (1992)46 reported on such a device after developing a ball-tipped catheter with a retractable 22-gauge Chiba-type biopsy needle (HBAN-22; Wilson-Cook Medical, Bloomington, IN). The needle extends 7 mm beyond the ball tip when the catheter is placed within the duct, and permits deeper sampling than afforded by brushing (Fig. 60.3). Unlike transmural EUS-FNA, intraductal FNA cytology during ERCP traverses only tissue to be resected en bloc, and therefore there can be no contamination of the peritoneal cavity, including the lesser sac behind the stomach. The technique requires sphincterotomy, however, and proves to be technically challenging. The initial relatively high yield of 62% (positive and suspicious samples) has not been reproduced in more recent series. The true-positive sensitivity has been reported to be 27% to 30% of cases in three series.47,58,59 This technique has been used in combination with cytology and forceps biopsy, known as triple sampling, and is described later in the chapter. Forceps Biopsy Initially, there was only one method of performing intraductal forceps biopsies, known as fluoroscopically guided biopsies. Subsequently, with the development of cholangioscopy systems and accessories, directly visualized mini-biopsy forceps can be used as well. This method and its performance will be reviewed during the discussion of the role of cholangioscopy in indeterminate strictures. Initial efforts to perform fluoroscopically guided biopsies used gastroscopic forceps until special flexible-tipped duodenoscopic forceps (Olympus Medical, Center Valley, PA) were developed and proved to work better over the elevator. A large sphincterotomy was still required to pass these forceps retrograde up the duct. The technique of forceps biopsy involves insertion of the device to the lower edge of the stricture. Using fluoroscopy, an accurate biopsy specimen can be obtained from the lower edge of the apparent tumor. Several passes of the forceps are required to produce an optimal yield. Reporting on their experience, Ponchon et al (1995)9 suggested a minimum of three forceps bites. For the technique to be practical, specialized forceps were developed. Several devices have been marketed to permit easier

FIG 60.4 Howell biliary introducer (HBI; Wilson-Cook) with three tissue sampling devices advanced to biopsy or cytology position. Each device is placed sequentially to attempt to maximize yield at a single endoscopic retrograde cholangiopancreatography (ERCP) procedure. The HBI is placed over a prepositioned 0.035inch guidewire.

insertion, including two devices that are purported not to need sphincterotomy. Easier to insert but still unguided, pediatric forceps of 5-Fr to 6-Fr work reasonably well but provide small specimens. Disposable 6-Fr pediatric forceps are now available, although they are relatively expensive. A device has been marketed to enable forceps placement over a guidewire. As previously discussed, the guidewire is generally placed early in therapeutic ERCP to ensure that the major goal of biliary stent placement is successful. It is logical to use the in-place guidewire for subsequent tissue sampling. The guidewire-based device currently in use, developed by the author, is the Howell biliary introducer (HBI; Cook Medical). The 10-Fr device goes over a 0.035-inch or smaller guidewire while permitting the passage of a specially designed reusable 5-Fr long forceps (Fig. 60.4). Multiple passes of the forceps and other sampling devices can be quickly accomplished once the introducer is in position. In a review published in two consecutive issues of Gastrointestinal Endoscopy, the journal of the American Society of Gastrointestinal Endoscopy (ASGE), de Bellis et al (2002)60 tabulated all reports in the literature for the three major techniques, including forceps biopsy and ERCP tissue sampling, since 1989 (see Table 60.1). Complications of forceps biopsy have been reported but seem to be rare. Among the 502 patients tabulated in Table 60.1, major bleeding requiring transfusion in one cancer patient was reported,61 and a significant perforation of a benign stricture required surgery in one additional patient.50 The perforation may have been caused by the use of a large cup forceps and repeated biopsy sampling of the same location. Pediatric forceps produce a smaller specimen, but no complications were encountered in more than 200 cases. A review of the devices for endoscopic tissue sampling has been published by the ASGE Technology Assessment Committee.62 Combining Multiple Sampling Techniques With the disappointing yields of single technique sampling as presented previously, endoscopists began to report their experience of combining techniques during the same ERCP procedure. Although this approach takes more time than a single technique, improved yields have made the combined approach the preferred

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704

SECTION III

Pancreaticobiliary Disorders

sequence in many, particularly academic, centers. Using standard brushes and nonguidewire forceps, Ponchon et al (1995)9 reported improved combined yields for diagnosing cancer at ERCP. Although brushing had a sensitivity of 43% and forceps biopsy had a sensitivity of 30%, their combined yield was increased to 63% (a 20% overall gain). A more comprehensive approach was studied by the Indiana University group. Researchers attempted to perform all three techniques of brush, FNA, and forceps sampling and submitted withdrawn indwelling stents for cytology when present. This demanding approach resulted in a positive diagnosis in 82% of patients at a single ERCP.49 When the investigators analyzed their results, each technique contributed to making the diagnosis in at least some patients. In other words, many patients had only one of the techniques positive, and the other two or three techniques were negative or equivocal. Despite this report and the logic of this approach, the technique of triple sampling has not become a standard practice during ERCP. Several explanations can be advanced. The first and probably most important reason was previously discussed: triple sampling is technically difficult, time-consuming, and ancillary to the main goal of the therapeutic procedure. The second may be the delay in tissue diagnosis when specimens are submitted for processing. Most important has been the wider availability of EUS-guided FNA cytology with its high sensitivity and safety.63 EUS procedures are often done before ERCP, or during the same setting, especially when anesthesia is being used. This approach can shorten the ERCP, have a higher yield with multiple needle passes, and permit immediate cytologic diagnosis when a cytologist is in-suite. However, in many patients, a role remains for ERCP tissue sampling, especially when advanced disease makes EUS less valuable for staging and a cytologist is not available. Finally, newer techniques for intraprocedural tissue diagnosis during initial ERCP have been developed and will be discussed later in this chapter. As introduced earlier, the HBI 10-Fr device introducer was developed to enhance the ability of the average endoscopist to perform triple sampling with a minimum of time, expense, and risk. The goal was to permit maximum sampling at various depths to increase the chance of detecting all three types of malignancy and to do so without requiring a sphincterotomy if so desired. The details of the device and our initial procedural sequence, techniques, and yields were reported in 1996.64 An overall sensitivity of 69%, despite a large proportion of small early pancreatic cancers, suggested the potential of the device. The HBI introducer is a double-lumen 10-Fr tapered dilator that contains a 0.035-inch channel for a standard ERCP guidewire and a 6-Fr large channel for the introduction of endoscopic accessories. The device includes a biliary introducer needle, which is a 5-Fr ball-tip catheter with a 22-gauge needle (HBIN, Cook Medical), 5-Fr reusable forceps (HBI forceps, Cook Medical). and a spring-tipped, through-the-channel brush (HBIB, Cook Medical). This brush has extra-long, extra-stiff bristles and is mounted on a stiff braided-wire shaft resulting in an aggressive device (see Fig. 60.1D). Its use is illustrated in Fig. 60.5. A comparative trial of the HBI device against standard brushing was reported.65 For the purpose of their study, the authors considered any “positive,” “suspicious,” or “atypical or suggestive of malignancy” to be true-positive samples. The authors used only the HBIN 22-gauge needle and HBI brush and reported an 85% yield compared with a sensitivity of 57% for brushing alone. Presumably, if the HBI forceps had also been used, yield would have been greater.

Other Methods of Endoscopic Retrograde Cholangiopancreatography Tissue Sampling Numerous, less productive or controversial techniques of tissue acquisition have been reported and warrant review. Leung et al (1989)67 originally reported that examining indwelling plastic biliary stents on their removal may produce a positive cytologic specimen when the diagnosis had not been established at the initial ERCP placement. Since 1989, only one series60 has approached the initial 70% yield of Leung and coworkers. Most centers report only 11% to 44% positive specimens.43,68,69 The most recent report (1997) of stent cytology included withdrawn pancreatic stents and stents from biliary strictures.70 The truepositive yield from pancreatic stents was 25% compared with only 11% from biliary stents. In addition, the investigators agreed with other authors that the technique had limited clinical value because of the long delay in diagnosis when positive results were obtained. Another approach to tissue acquisition at ERCP has been to attempt to collect specimens from the adjacent stricture of the pancreatic duct. Collection of pancreatic juice has been advocated by a few authors.71,72 The technique involves deep insertion of a standard ERCP catheter and aspiration of juice below a malignant-appearing stricture. Yields may increase to greater than 50% with the infusion of secretin. This approach has not become popular, perhaps because of its complexity and concern for inducing pancreatitis. Pugliese et al (1995)50 concluded that pancreatic juice collection did not add to positive diagnosis when pancreatic duct strictures were directly sampled by brushing. Brushing in the pancreatic duct has been reported since 1979.73 More recent reports (1994–96) emphasize that yields increase very little when a biliary stricture is also present and can be sampled.74–76 Most concerning has been the report of postprocedural pancreatitis after pancreatic ductal stricture brushing. Vandervoort et al (1999)77 noted a 21.5% pancreatitis rate after such procedures in both benign and malignant cases, but noted a marked decrease in risk if pancreatic temporary plastic stents were placed. Other authors have also advocated stent placement after pancreatic brushing, but all studies do not outline the eventual management and outcome of these temporary stents. The utility of stents is likely outweighed by subsequent procedures for pancreatic stent removal and delayed stent obstruction with resulting pancreatitis or sepsis, and other approaches to tissue sampling are favored. At the present time, we sample from the pancreatic duct only when a pancreatic stent is clinically warranted to manage obstructing pancreatitis, fistula, or upstream pseudocyst. We prefer to use the over-the-guidewire technique for brushing as outlined previously, so that the guidewire, which was placed before tissue sampling, can remain in position.

Specimen Handling and Analysis When intraprocedural diagnosis is not a goal or not available, specimens need optimal care. Improper handling of collected specimens remains a problem in many endoscopy units. A major cause of uninterpretable smears is an air-drying artifact that can occur rapidly after creation of appropriate thin smear.6 Thick smears and specimens with excessive blood are other significant problems.78 Slide preparation requires the time and attention of ERCP team members during a busy and often complex procedure. Preference should be given to depositing all collected specimens into transport media rather than preparing any smears or slides in the ERCP suite, unless an in-suite cytologist is present. Available transport media include 95% ethanol or commercially prepared

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CHAPTER 60

The Indeterminate Biliary Stricture

A

B

C

D

705

FIG 60.5 Howell biliary introducer (HBI) triple device tissue sampling. A, The guidewire is first negotiated through a malignant-appearing stricture. Sphincterotomy is optional. B, HBI preloaded with the 5-Fr, 22-gauge needle for fine-needle aspiration (FNA) is placed over the guidewire and positioned just beneath the lower edge of the stricture. The needle has been thrust into the tumor at 30 degrees from the axis of the guidewire. C, The 5-Fr reusable HBIN forceps is passed for repeat biopsies of the lower edge of the stricture. D, To perform brush cytology with the HBI, the introducer is advanced so that the metal port lies above the stricture. The special brush (HBIB) is advanced into the proximal duct. The introducer is pulled down into the stricture to permit vigorous brushing with adequate side pressure to maximize cellular collection.

solutions such as CytoLyt (Cytyc Corporation, Marlborough, MA) or CytoRich (UtoCyte, Burlington, NC). Papanicolaoustained spun smears and, when applicable, hematoxylin and eosin-stained cell block sections are prepared for cytologic evaluation. In our institution, we prefer CytoLyt solution, which lyses red blood cells and minimizes obscuring debris, with smears prepared via the Thin Prep method (Cytyc Corporation). Interpretation of specimens should follow accepted cytologic criteria to be clinically useful. Several such schemes exist with each accepting frankly positive (Fig. 60.6A) and negative (see Fig. 60.6B) features. Intermediate cytologic abnormalities present

on the slides may lead to interpretations such as “atypical,” in which mild cellular abnormalities are usually associated with inflammation and reparative changes, and “suspicious,” in which there are rare cells exhibiting cytologic features of malignancy, but they are present in insufficient numbers to render a definitive diagnosis of malignancy. In patients with PSC or postbiliary irradiation, be aware that cytologic changes can result in occasional false-positive samples. A larger series noted only 80% specificity in this setting.79 The findings of “cellular atypia” should include criteria that make the diagnosis of malignancy unlikely and demand further

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B

A

FIG 60.6 A, Benign biliary sample collected at endoscopic retrograde cholangiopancreatography (ERCP) by fine-needle aspiration (FNA). The specimen shows normal monolayer architecture with cells of high cytoplasm-to-nuclear ratio. The nuclei are smooth with fine chromatin and without obvious nucleoli. B, ERCP-collected specimen reveals malignant features diagnostic of adenocarcinomas. Note the clusters of cells with nuclear crowding. The nuclei have irregular membranes, coarse chromatin, and prominent nucleoli. Finally, the nuclei are large, producing high nuclei-tocytoplasmic ratio.

attempts at confirmation. We interpret all atypia findings as negative, understanding that many will turn out to be falsely negative. Finally, because of the inherent difficulties in ERCP tissue sampling, negative results can never be accepted as definitive.7,11 Sampling problems are often due to the relative hardness of pancreaticobiliary adenocarcinomas that may greatly resist needle puncture and forceps sampling. These desmoplastic tumors can be relatively hypocellular, resulting in inadequate numbers of cells for interpretation. A small fraction of adenocarcinomas are so well differentiated they can be diagnosed histologically only in the setting of an excisional biopsy to permit the recognition of invasion; this is also true of lymphoma, which does occasionally produce biliary obstruction. As previously discussed, metastatic lesions obstructing the biliary tree are relatively deep and cannot be readily accessed at ERCP from within the ductal stricture, except occasionally by intraductal FNA. These lesions are best approached with EUS FNA or the new core-type needles. All these factors result in a low negative predictive value in all series reporting techniques of tissue sampling. This low negative predictive value should not discourage endoscopists from developing a preferred sequence of tissue sampling at ERCP because specificity in most reports is generally 100% for true-positive samples except as noted previously. A false-negative result leads to additional invasive tests, procedures, or surgery,80 the same result as when no effort is made. Using the outlined techniques of endobiliary sampling during ERCP, patients receive benefit at a minimum of expense and risk.

Intraprocedural Techniques at ERCP A major development in indeterminate biliary stricture sampling has been the development of intraprocedural analysis of specimens obtained by EUS FNA, and ERCP specimens as well. We have experimented with triple sampling as previously outlined and on occasion had ERCP FNA or brushings slides made and sent for immediate Papanicolaou staining and interpretation. With additional experience, we noted increasing yield

with increased numbers of forceps biopsy without an increase in complications, but needed techniques for immediate processing and interpretation. ERCP-guided FNA has the disadvantages of technical difficulty, more shallow depth of puncture, and limited number of passes before needing to employ a new needle. A new technique developed in our unit using a new cytologic preparation of forceps specimens at ERCP can permit direct intraprocedural diagnosis similar to the sequence used at EUS.81 In neurosurgery, intraoperative samples of margins during brain tumor resection have been sampled by preparing quick fixed smears of brain tissue on dry slides. Termed squash prep, this technique evolved because frozen sections cannot be done on fat-rich brain tissue. Paralleling this established technique, our group prepared small 5-Fr or 6-Fr forceps biopsy specimens by vigorously smashing them between two dry glass slides to attempt to create a monolayer. These specimens are immediately stained by rapid Papanicolaou and read in suite. This new technique is termed SMASH protocol (Video 60.1).81 At our center, experience with this approach added only an additional 10 to 20 minutes to the ERCP procedure and produced a definitive positive diagnosis in 49/66 (74%) of pancreaticobiliary cancers.82 This high yield is in part produced by the cytopathologist who can request additional specimens similar to EUS. We generally halt at 10 specimens, in favor of collecting additional biopsy specimens for histology and a final one or two ERCP-guided FNA passes. This new approach at tissue sampling adds little time and little cost and avoids delay in tissue diagnosis in most patients. Immediate tissue diagnosis avoids additional efforts at biopsy, such as EUS-guided FNA or CT-guided FNA, and often shortens hospital stay.81 When in-suite cytopathology is not available and time permits, we have reported a further method of intraprocedural diagnosis. Forceps biopsies can be sent to most hospital pathology labs for frozen section analysis, often on short notice and at odd hours. Our initial technique was to send five rapidly obtained specimens from the lower edge of an indeterminate stricture using only

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CHAPTER 60

A

The Indeterminate Biliary Stricture

707

B FIG 60.7 A, Trisomy of chromosomes 3,7,17 (3 copies of red, green, and aqua probes). B, Homozygous deletion of 9p21 (absence of gold probes in all but one normal cell). (Images courtesy of Dr. Tamas Gonda.)

fluoroscopic guidewire during ERCP. If negative, an additional five specimens could be sent. Noting no complications in greater than 50 cases using only 5-Fr or 6-Fr pediatric forceps, we now send 10 specimens and complete our sampling with two forceps specimens for H&E staining and do a single ERCP FNA sample. Our experience suggests that the yield of the frozen section protocol is somewhat lower than SMASH protocol, likely due to the absence of the cytopathologist, but provides prompt, simple, and widely available interpretation with a true positive yield of 80+%.83 In the specific setting of CCA of the common bile duct, common hepatic duct, or bifurcation, these techniques of forceps tissue sampling by SMASH, frozen, or standard triple sampling established an overall true positive diagnosis in 87% of consecutive cases at our institution.82,84 The intraprocedural diagnosis by SMASH or frozen was 79% and the addition of H&E and ERCP FNA added 8% to achieve the final total. Advanced Specimen Analysis Despite these advances in tissue sampling of indeterminate biliary strictures, false negative specimens still plague the goal of 100% diagnostic accuracy. After collection, specimens can undergo additional techniques of analysis in an attempt at increasing positive results, only their current status demands an update.

FISH While improved methods of acquisition of tissue remains a challenge, developments in the methods of analysis of available tissue has made significant advancement. One promising tissuebased diagnostic tool that gained a prominent role in the diagnostic armamentarium for IDBS is the use of fluorescent in-situ hybridization (FISH) to detect chromosomal aneuploidy or polysomy. Positive findings are found in an estimated 80% of pancreaticobiliary malignancies.85 FISH uses fluorescently

labeled chromosome-specific DNA probes to identify cells with an abnormal number of chromosomes or mutations. The four commercially available FISH probes target chromosomes 3 (CEP3), 7 (CEP7), 17 (CEP17), and the 9p21 locus of chromosome 9 (Fig. 60.7). While this method of molecular analysis is markedly different from the cytological methods used conventionally, its use adds no additional burden of sampling as these tests can be performed on cells obtained from routine brush cytology samples during ERCP. In fact, the same brush can even be used to provide both FISH results and cytology results with the use of a multipart brush, such as a brush with 3 separate clusters of bristles (Infinity Brush, US Endoscopy, Mentor, OH). The relative disadvantage is that centers that analyze FISH samples are limited and may require samples to be sent out. Another disadvantage is that FISH analysis typically can take up to 3 weeks to return, depending on the practices of the individual center, as many samples are run in batches and the evaluation for aneuploidy or polysomy is not an automated process. Data regarding diagnostic yield has been variable and is dependent on the specific panel of probes included in individual studies. Early prospective data on the diagnostic yield of FISH in indeterminate strictures by Levy et al (2008), using CEP3, CEP7, and CEP 17 probes found that, in previously cytologynegative strictures, the sensitivity of FISH was 62%, with specificity of 79% for malignancy.85 When a fourth probe to the 9p21 loci of chromosome 9 (associated with mutation of the p16 tumor suppressor gene) is added to the repertoire, the sensitivity of FISH can be improved significantly from 47% to 84%, with preserved specificity of 97%.86 As discussed earlier with respect to combined sampling, Nanda et al (2007) demonstrated that triple modality sampling with brush cytology, fluoroscopically guided biopsies, and FISH resulted in significantly higher sensitivity of 82% versus 42% for brush cytology alone.87 Individual modality results for cytology, biopsies, and FISH were 27%, 50%,

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and 59% respectively. Cost analysis in a study population, in which the respective sensitivity of cytology and FISH was 42% and 70% respectively, suggested that FISH testing be used as a second-line evaluation if cytology samples were negative given the significant additional cost for FISH analysis.88 The main limitation of FISH is its reduced specificity in the setting of chronic inflammatory conditions such as PSC where polysomy can occur in the absence of CCA.89 By adding trisomy-7 as a marker of malignancy in the combined cohort of both PSC and non-PSC patients, the overall sensitivity for diagnosing malignancy was 64%, specificity 82%, and diagnostic accuracy 72%. However, trisomy 7 in particular can be found in benign strictures of PSC patients and decreases the specificity of FISH for malignancy in that challenging cohort. This elevated rate of false positive results in the setting of PSC has resulted in recommendations suggesting FISH results be followed in surveillance sampling of PSC patients and that a positive FISH result alone not be considered positive. Other molecular-based techniques that have been examined to improve the diagnostic yield include bile aspirate analysis for p53 and KRAS mutations, but these are not currently considered part of the routine workup and are still in the early phases of investigation.90 One study has evaluated the value of combination testing of FISH and genetic analysis (KRAS mutation, LOH, tumor suppressor genes at 10 loci)91 and found that adding both FISH and molecular profiling to cytology can increase sensitivity from 32% to 73% (p < 0.001). This supports that sampling methods and analysis should be performed in tandem to optimize diagnostic accuracies. Nevertheless, the proven performance of FISH in the evaluation of biliary strictures has earned the recommendation by cytologic societies that it be considered the only ancillary technique to biliary brushing with sufficient efficacy.92

Endoscopic Ultrasound-FNA EUS FNA is another modality that has entered the algorithm of evaluation of IDBS as a complementary tool to ERCP. A discussion regarding its role and results in tissue sampling is discussed elsewhere. It is worthy to note, however, that the exact role of FNA in the setting of suspected proximal CCA remains controversial. This is mostly due to the theoretical potential for malignant peritoneal seeding via the needle access pathway. Data from a small number of case series of patients who underwent percutaneous biliary biopsies for CCA who developed carcinomatosis with rates as high as 83%93,94 have driven most transplant centers to adopt protocols in which tissue sampling with EUS FNA of the primary lesion is a contraindication to liver transplantation of hilar CCA.95 For those patients who are not going to be considered for transplant or who have extrahepatic disease and are being considered for resection only, the reported overall sensitivity of EUS FNA is 43% to 86% for the diagnosis of all malignant strictures.96–98 EUS FNA is generally less reliable in the evaluation of proximal CCA, as its sensitivity decreases to 59% compared to 81% in distal CCA.98 The presence of a previously placed biliary stent can also decrease its sensitivity for malignancy detection due to a combination of stent-related acoustic shadowing, image degradation, and difficult needle access.

Intraductal Ultrasound If the infiltrative nature of CCA and other biliary strictures serves as an obstacle to adequate tissue acquisition, then having a method of investigating wall layers to identify and characterize

that invasion might be helpful in providing a predictive diagnosis, as well as targeting tissue. One such intraductal imaging modality is intraductal ultrasound (IDUS), which enhances endobiliary imaging by the wire-guided placement of a high-frequency probe directly into the bile ducts. Technically, this is a simple maneuver to perform as the probe is a small-caliber catheter that is passed over a wire during ERCP, does not require a sphincterotomy, and is radiopaque, and thus the probe’s exact location can be determined. The probe provides high-quality imaging of the periductal tissue along with limited tumor staging, such as mass size and periportal vascular invasion (full lymph node staging still requires EUS).99 IDUS criteria for differentiating benign from malignant strictures have been established and include disruption of the normal triple layer wall architecture, eccentric wall thickening, presence of a hypoechoic mass with irregular margins or invasion of adjacent structures, papillary surface, and malignant-appearing periductal lymph nodes.100 These criteria have been validated in multiple studies demonstrating diagnostic sensitivities of IDUS to be 80% to 90%, specificity 83%, and improvement in the accuracy of ERCP from 58% to 83%.101,102 The disadvantage to IDUS is that it is solely an adjunctive imaging tool that helps direct evaluation of IDBSs but does not provide histopathology. This may explain the relatively rare use of this modality in the algorithm of evaluation. Furthermore, the probe itself is relatively fragile, and not disposable, and requires a separate processor, and therefore, it falls into the capital inventory of most endoscopy suites and limitations this incurs.

Optical Coherence Tomography Another technology that allows for greater evaluation of the bile duct wall layers is optical coherence tomography (OCT), which was introduced over 20 years ago103 and allows for high-resolution, cross-sectional, tomographic imaging of tissue. An earlier catheter version worked by measuring the interference of low-power infrared light (750–1300 nm) reflected from the tissue and light reflected from reference mirrors. In-vitro and in-vivo studies have demonstrated the feasibility of using this catheter to visualize multiple wall layers of the gut and pancreaticobiliary ducts, as well as visualizing microscopic structures, such as blood vessels, lymphoid aggregates, crypts, and glands.104–108 Early animal and human studies of the pancreaticobiliary epithelium and sphincter of Oddi helped to demonstrate OCT findings that correlated to the three ductal wall layers, single layer epithelium, deeper fibromuscular layer, and an outer smooth muscle layer. The corresponding OCT images were an inner hyporeflective layer, a homogenous hyperreflective layer, and a less defined hyporeflective layer, respectively.109 In addition, neoplastic and nonplastic tissue could be differentiated.109–111 Using two OCT criteria to diagnose malignancy, including unrecognizable layer architecture, and the presence of large, nonreflective areas compatible with tumor vessels, Arvanitakis et al (2009)112 evaluated the feasibility of OCT in detecting malignant biliary strictures in 35 patients. Using the mid-focus OCT probe (PENTAX Corporation Tokyo, Japan/Lightlab Imaging Ltd, Boston, MA; outer diameter 0.75 mm, depth of penetration 1 mm, resolution 10 um) malignant strictures were diagnosed in 19/25 (54%) of patients compared to tissue as gold standard. The sensitivity of at least one or both OCT was 79% and 53%, respectively, and accuracy was 70% for both categories. When combining brushings and biopsies to at least one criteria, sensitivity increased to 84%.112

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CHAPTER 60

A

B

The Indeterminate Biliary Stricture

709

C

FIG 60.8 A, VLE cross-sectional image of biliary stricture with hyperreflective surface (white arrow), and periductal vessel (asterisk). B, Spy image of corresponding biliary stricture to (A). C, Longitudinal image of biliary stricture with features of subepithelial glands (black arrow) and hyperreflective surface (white arrow). (Images courtesy of Dr. Doug Pleskow.)

A newer probe has just become commercially available in the United States that uses volumetric laser electromicrography to provide very similar images to the prior OCT catheter (NinePoint Medical, Cambridge, MA). Similar to its predecessor, the probe fits through the working channel of the ERCP scope, is not currently wire-guided, and requires a dedicated processor for imaging. Circumferential radial and 6-cm longitudinal images are provided with depth of 3 mm, lateral resolution of 40 microns, and axial resolution of 7 microns. Similar to prior OCT work, the principles of image interpretation come from data using the technology in setting of Barrett’s epithelium, where features such as loss of wall definition, increased reflectivity, and glandular structures are indicative of dysplastic areas (Fig. 60.8). Data regarding the use of this low-profile catheter is currently being collected from select centers. Similar to its predecessor, it holds promise as an additional tool to increase the predictive value of imaging and targeting for further sampling of pancreaticobiliary strictures.

Cholangioscopy Logically, the most direct way to diagnose a malignancy in the practice of any endoscopy is to directly visualize the epithelium to allow for a diagnostic impression and for precise targeted sampling. This technique, cholangioscopy, was first made possible in the 1970s with the use of the first generation “mother-baby” cholangioscopes. While newer versions of the video cholangioscopy systems provided outstanding imaging, widespread adoption was limited due to the need for two operators, scope fragility, limited tip maneuverability, and prolonged procedures.113 The development of single-operator cholangioscopy (SOC), and the release of the Spyglass Direct Visualization System (Boston Scientific, Marlborough, MA) in 2005 have measurably changed the practice of cholangioscopy worldwide. The Spyglass system (Boston Scientific, Marlborough, MA) consists of a 10-Fr access catheter (SpyScope) that can be inserted through the standard 4.2-mm working channel of a therapeutic duodenoscope, a reusable optical probe (SpyGlass) that fits through the SpyScope catheter, and disposable 3-Fr biliary biopsy forceps to allow visually-directed biopsies (SpyBite). The optical catheter provides 6000 pixel images and has tip maneuverability to allow 30-degree views in four directions.114 A second-generation

FIG 60.9 Spy DS scope and spybite forceps (insert). (Courtesy of Boston Scientific, Marlborough, MA.)

Spyglass system, known as Spyglass DS, has a digital chip embedded at the end of the SpyScope and thus eliminates the need for the optic fiber and the necessary preprocedural calibration required, while providing a wider field of view (Fig. 60.9). The accessory channel size is also slightly larger and thus facilitates passage of accessories such as forceps and lithotripsy probes. Last, there are dedicated individual irrigation and aspiration

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C

B

FIG 60.10 A, Spy image of benign biliary stricture. B, Spy image of malignant biliary stricture. C, Spy image of directly visualized biopsy. (Images courtesy of Dr. Amrita Sethi.)

channels that improve duct clearance of debris and visualization significantly. At this stage, data regarding outcomes of the use of SOC in the evaluation of IDBSs reflect use of the first-generation system. The largest prospective, multicentered, observational study of the operating characteristics of the SOC system by Chen et al (2011) 115 included 226 patients with biliary strictures (not all were cytology negative) with a sensitivity, specificity, positive predictive value, and negative predictive value for malignancy of 78%, 82%, 80%, and 80%, respectively, based on the visual impression criteria.115,116 Visual impression had a higher sensitivity compared to visually targeted biopsies, which was only 47%, although biopsy specificity was much higher at 98%, with a positive predictive value of 100%. A smaller prospective series from Ramchandani et al (2011)117 involving 36 patients with indeterminate strictures also found the sensitivity of the SOC visual impression to be 95%, and specificity of 79%, while sensitivity and specificity for SpyBite biopsies were lower at 82%. A comparison study of directly visualized (DV) biopsies versus both brush cytology and fluoroscopically guided biopsies in 26 patients demonstrated that despite adequate tissue quantity with all three modalities, the accuracy of the DV biopsies was 84.6%, which was significantly higher than brush cytology (38.5%) and standard forceps (53.8%).118 By analysis in a systematic review, the sensitivity and specificity of cholangioscopy-directed biopsies’ ability to detect malignancy in IDBS with prior negative findings in a total of four studies was 74.7% (95% confidence interval [CI], 63.3%–84.0%) and 93.3% (95% CI, 85.1%–97.8%).119 Another systematic review found that the sensitivity and specificity of visual impression were 90% (95%CI, 73%–97%), and 87% (95% CI, 76%–94%), respectively.120 In a more recent study evaluating the role of performing rapid on-site evaluation of touch imprints of DV biopsy specimens (ROSE-TIC), Varadarajulu et al (2016) studied 31 patients and with a mean of 3.3 biopsies, were able to achieve a sensitivity of 100% and accuracy of 93.5% in diagnosing malignancy in IDBS.121 The issue of visual impression remains an unanswered topic given the lack of validated criteria by which to diagnose malignancy. Early imaging with video cholangioscopy led to considerations for imaging criteria that have been proposed for the diagnosis of malignancy including dilated, tortuous blood vessels (also termed tumor vessels), intraductal nodules or masses,

Malignant Stricture Criteria for SOC Cholangioscopy BOX 60.1

Dilated, tortuous blood vessels Intraductal nodules or mass Infiltrative or ulcerated stricture Papillary or villous mucosal projections

SOC, single-operator digital cholangioscopy. Data from Seo DW, Lee SK, Yoo KS, et al: Cholangioscopic findings in bile duct tumors. Gastrointest Endosc 52(5):630–634, 2000.

infiltrative or ulcerated strictures, and papillary or villous mucosal projections122 (Fig. 60.10; Video 60.2). The strongest feature suggestive of malignancy has been the presence of dilated and tortuous vessels with a reported specificity and positive predictive value of 100%123–125 (Box 60.1), as this was felt to represent underlying neovascularization of the malignant tumor. However, when viewed by first fiber optic and now digital cholangioscopy, and when removed from clinical context, it is not clear that these findings are validated. In two consecutive studies, interobserver agreement of SOC visual findings, using the fiber optic system, and final diagnosis, were only slight to fair and the accuracy was less than 50% on diagnosing malignancy.126,127 Further attempts are being made by multiple groups to create a new classification system using the digital cholangioscopy system, with the hopes that clearer imaging and new tissue-correlated definitions may lead to a validated system. Ultimately, however, in this tissue-based era, it is unclear what role visual impression alone will play and whether the true benefit will be in the ability to target sampling and additional diagnostic methods. A few considerations need to be made when performing cholangioscopy, namely, the need for biliary sphincterotomy to advance the system into the biliary tree and higher rates of complications due to sphincterotomy and cholangitis. Chen et al (2011)115 reported serious procedural complication rates of 7.5%; a later study by Sethi et al (2011)128 confirmed a complication rate of 7.0% versus the routine ERCP rate of 2.9%, with the difference attributed to higher incidence of cholangitis in the cholangioscopy group. Such findings have led to routine use of antibiotics when performing cholangioscopy in otherwise low-risk patients during ERCP.

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CHAPTER 60

Confocal Laser Endomicroscopy Another method of direct evaluation of the biliary epithelium is probe-based confocal laser endomicroscopy (pCLE), which uses an optical probe during ERCP to allow real-time, microscopic level examination of the bile ducts.129 The CholangioFlex probe (Maunakea Tech, Paris, France) fits into multiple ERCP accessory devices or the 1.2 mm-diameter working channel of the SpyGlass (Boston Scientific) cholangioscope. This probe provides images to a depth 40 to 70 μm below the tissue surface. An intravenous contrast agent, usually fluorescein, is used to delineate cellular features that have been determined to represent criteria of malignancy versus benign disease and inflammation. Identification of these criteria have been performed in a series of steps, the first iteration known as the “Miami Classification,” which helped to distinguish malignant from benign features. This was prospectively studied in a multicentered, larger cohort of 89 patients with indeterminate pancreaticobiliary strictures by eight investigators (Table 60.2).130,131 The sensitivity, specificity, positive predictive value, and negative predictive value of pCLE using the Miami criteria were 98%, 67%, 71%, and 97%; the accuracy of combination ERCP with pCLE was significantly higher than ERCP with tissue sampling alone (90% vs. 73%).130 In attempts to improve the specificity of these criteria, refinement with the Paris classification was conducted that allowed for identification of features that would predict inflammation from benign and malignant disease (Fig. 60.11). Addition of these

Miami and Paris Classification of pCLE for Predicting Malignant Biliary Stricture TABLE 60.2

Criteria Suggestive of Inflammation

Criteria Suggestive of Benign Disease

Thick, dark bands (> 40 μm)

Thick reticular network

Thin, dark bands

Thick, white bands (> 20 μm)

Increased intraglandular space

Thin, white bands

Dark clumps

Vascular congestion

Criteria Suggestive of Malignancy

Villous glands Fluorescein leakage pCLE, probe-based confocal laser endomicroscopy.

A

B

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criteria did in fact improve specificity from 61% to 81.2% in lesions previously scored by the Miami classification system.132 Prospective validation of the Paris criteria was performed by Slivka et al (2015)133 in the FOCUS trial in which confocal diagnosis was added to ERCP imaging and sampling, as well as clinical history, and scored by two physicians. The results of this prospective study demonstrated that the additive value of all three diagnosis (pCLE, ERCP, and sampling) could provide an accuracy of 88% in the diagnosis of malignancy in indeterminate strictures.133 Practically, the low specificity of pCLE and the dedicated operator training needed (as has been demonstrated in interobserver agreement studies)134 for accurate interpretation of confocal images remain the major limiting factors of its widespread use as a routine tool in the evaluation of indeterminate strictures. However, in expert centers with pCLE experience, it has become a valuable tool in the multimodality approach to the management of difficult cases of biliary stricture.

EVALUATION OF STRICTURES IN PSC The caveat to the preceding discussion regarding IDBSs is the ever-elusive diagnosis of CCA in PSC. PSC is a chronic, progressive inflammatory condition of the intrahepatic and extrahepatic bile ducts, characterized by diffuse stricturing that can lead to biliary cirrhosis and increases patients’ risk for CCA threefold.135,136 Liver transplantation is the only curative treatment for both end-stage biliary cirrhosis and early-stage hilar CCA, with a posttransplant, 5-year survival of 65% to 88% when performed in expert centers under rigorous protocols.137,138 However, due to the chronic stricturing nature of the disease, differentiating between benign and malignant strictures in this population is particularly difficult. Per guidelines, the presence of a dominant stricture prompts an endoscopic evaluation that often includes many of the modalities discussed earlier in this chapter. However, the diagnostic performance of these modalities from molecular analysis to advanced imaging appear to be even more challenged in PSC patients. A recent meta-analysis showed that FISH sensitivity for CCA in PSC is only 51%, although specificity is preserved at 93%.139 Similarly, confocal endomicroscopy’s reduced reliability in distinguishing chronic inflammatory benign changes from malignant transformation suggests that further refinement is needed for evaluation of PSC strictures by this modality. Cholangioscopy may be the most promising method, with some prospective studies suggesting sensitivity for CCA in PSC patients of 92%, specificity 93%, and overall accuracy

C

FIG 60.11 A, Miami criteria of epithelial structure. B, Paris criteria of increased intraglandular space or scales. C, Paris criteria of thickened reticulum. (Images courtesy of Dr. Amrita Sethi.)

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of 93%, but in half of the patients a second cholangioscopy was needed for tissue diagnosis.113 Furthermore, there is the theoretical increased risk of cholangitis when performing these advanced imaging modalities in patients with PSC. Thus, the literature suggests a multimodality approach in any PSC patient in whom there is a high clinical suspicion for malignancy, such as a persistently, markedly elevated CA19-9 despite biliary decompression, or new or symptomatic dominant stricture, is likely to offer the greatest diagnostic value.

CONCLUSION IDBSs remain a challenge despite developments in imaging, tissue acquisition, development of additional tissue analysis methods, and even serum markers. There is no question, however, that a multimodality approach must be employed to optimize diagnostic results. The components of this combined approach will depend on local expertise and resources. First-line approach should include routine ERCP with brushings and FISH, and if nondiagnostic despite high clinical concern, consider an adjunct endobiliary imaging study, to either confirm clinical suspicions or to use for continued close surveillance. Proximal biliary strictures may be best imaged by IDUS, whereas EUS can evaluate for suspicious periductal lymph nodes. Practices in the use of cholangioscopy and confocal endomicroscopy will vary more widely depending on its availability, operator experience, and further definition and validation of diagnostic criteria. Ultimately, the future for endoscopic evaluation of biliary strictures will need to move toward developing a diagnostic algorithm that reconciles the cost-effectiveness of extensive and repeated evaluations for stable-appearing strictures with the potential for a missed malignancy and/or unnecessary surgical exploration. Ultimately, the inherent problem may not lie within the methods used, but rather the nature of the disease. And in this era of tissue-specific diagnoses, future efforts will likely focus on identifying the highest yield area for sampling and maximizing acquisition from this area. Indeed, the evaluation of IDBS remains a rich area for research and eventual change in practice as new tools are developed and their respective roles established.

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A complete reference list can be found online at ExpertConsult .com

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CHAPTER 60

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CHAPTER 60 89. Bangarulingam SY, Bjornsson E, Enders F, et al: Long-term outcomes of positive fluorescence in situ hybridization tests in primary sclerosing cholangitis, Hepatology 51(1):174–180, 2010. 90. Nault JC, Zucman-Rossi J: Genetics of hepatobiliary carcinogenesis, Semin Liver Dis 31(2):173–187, 2011. 91. Gonda TA, Viterbo D, Gausman V, et al: Mutation profile and fluorescence in situ hybridization analyses increase detection of malignancies in biliary strictures, Clin Gastroenterol Hepatol 2016. [Epub ahead of print]. 92. Layfield LJ, Ehya H, Filie AC, et al: Utilization of ancillary studies in the cytologic diagnosis of biliary and pancreatic lesions: the Papanicolaou Society of Cytopathology Guidelines, Cytojournal 11(Suppl 1):4, 2014. 93. Heimbach JK, Sanchez W, Rosen CB, Gores GJ: Trans-peritoneal fine needle aspiration biopsy of hilar cholangiocarcinoma is associated with disease dissemination, HPB (Oxford) 13(5):356–360, 2011. 94. Nakamuta M, Tanabe Y, Ohashi M, et al: Transabdominal seeding of hepatocellular carcinoma after fine-needle aspiration biopsy, J Clin Ultrasound 21(8):551–556, 1993. 95. Rosen CB, Heimbach JK, Gores GJ: Liver transplantation for cholangiocarcinoma, Transpl Int 23(7):692–697, 2010. 96. Eloubeidi MA, Chen VK, Jhala NC, et al: Endoscopic ultrasound-guided fine needle aspiration biopsy of suspected cholangiocarcinoma, Clin Gastroenterol Hepatol 2(3):209–213, 2004. 97. Fritscher-Ravens A, Broering DC, Sriram PV, et al: EUS-guided fine-needle aspiration cytodiagnosis of hilar cholangiocarcinoma: a case series, Gastrointest Endosc 52(4):534–540, 2000. 98. Mohamadnejad M, DeWitt JM, Sherman S, et al: Role of EUS for preoperative evaluation of cholangiocarcinoma: a large single-center experience, Gastrointest Endosc 73(1):71–78, 2011. 99. Tamada K, Ueno N, Tomiyama T, et al: Characterization of biliary strictures using intraductal ultrasonography: comparison with percutaneous cholangioscopic biopsy, Gastrointest Endosc 47(5):341– 349, 1998. 100. Farrell RJ, Agarwal B, Brandwein SL, et al: Intraductal US is a useful adjunct to ERCP for distinguishing malignant from benign biliary strictures, Gastrointest Endosc 56(5):681–687, 2002. 101. Stavropoulos S, Larghi A, Verna E, et al: Intraductal ultrasound for the evaluation of patients with biliary strictures and no abdominal mass on computed tomography, Endoscopy 37(8):715–721, 2005. 102. Vazquez-Sequeiros E, Baron TH, Clain JE, et al: Evaluation of indeterminate bile duct strictures by intraductal US, Gastrointest Endosc 56(3):372–379, 2002. 103. Huang D, Swanson EA, Lin CP, et al: Optical coherence tomography, Science 254(5035):1178–1181, 1991. 104. Cilesiz I, Fockens P, Kerindongo R, et al: Comparative optical coherence tomography imaging of human esophagus: how accurate is localization of the muscularis mucosae? Gastrointest Endosc 56(6):852–857, 2002. 105. Kobayashi K, Izatt JA, Kulkarni MD, et al: High-resolution cross-sectional imaging of the gastrointestinal tract using optical coherence tomography: preliminary results, Gastrointest Endosc 47(6):515–523, 1998. 106. Tearney GJ, Brezinski ME, Bouma BE, et al: In vivo endoscopic optical biopsy with optical coherence tomography, Science 276(5321):2037– 2039, 1997. 107. Tearney GJ, Brezinski ME, Southern JF, et al: Optical biopsy in human gastrointestinal tissue using optical coherence tomography, Am J Gastroenterol 92(10):1800–1804, 1997. 108. Testoni PA, Mariani A, Mangiavillano B, et al: Main pancreatic duct, common bile duct and sphincter of Oddi structure visualized by optical coherence tomography: an ex vivo study compared with histology, Dig Liver Dis 38(6):409–414, 2006. 109. Testoni PA, Mangiavillano B, Albarello L, et al: Optical coherence tomography compared with histology of the main pancreatic duct structure in normal and pathological conditions: an ‘ex vivo study’, Dig Liver Dis 38(9):688–695, 2006. 110. Pitris C, Jesser C, Boppart SA, et al: Feasibility of optical coherence tomography for high-resolution imaging of human gastrointestinal tract malignancies, J Gastroenterol 35(2):87–92, 2000.

The Indeterminate Biliary Stricture

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111. Sergeev A, Gelikonov V, Gelikonov G, et al: In vivo endoscopic OCT imaging of precancer and cancer states of human mucosa, Opt Express 1(13):432–440, 1997. 112. Arvanitakis M, Hookey L, Tessier G, et al: Intraductal optical coherence tomography during endoscopic retrograde cholangiopancreatography for investigation of biliary strictures, Endoscopy 41(8):696–701, 2009. 113. Tischendorf JJ, Kruger M, Trautwein C, et al: Cholangioscopic characterization of dominant bile duct stenoses in patients with primary sclerosing cholangitis, Endoscopy 38(7):665–669, 2006. 114. Chen YK, Pleskow DK: SpyGlass single-operator peroral cholangiopancreatoscopy system for the diagnosis and therapy of bile-duct disorders: a clinical feasibility study (with video), Gastrointest Endosc 65(6):832–841, 2007. 115. Chen YK, Parsi MA, Binmoeller KF, et al: Single-operator cholangioscopy in patients requiring evaluation of bile duct disease or therapy of biliary stones (with videos), Gastrointest Endosc 74(4):805– 814, 2011. 116. Nishikawa T, Tsuyuguchi T, Sakai Y, et al: Comparison of the diagnostic accuracy of peroral video-cholangioscopic visual findings and cholangioscopy-guided forceps biopsy findings for indeterminate biliary lesions: a prospective study, Gastrointest Endosc 77(2):219–226, 2013. 117. Ramchandani M, Reddy DN, Gupta R, et al: Role of single-operator peroral cholangioscopy in the diagnosis of indeterminate biliary lesions: a single-center, prospective study, Gastrointest Endosc 74(3):511–519, 2011. 118. Draganov PV, Chauhan S, Wagh MS, et al: Diagnostic accuracy of conventional and cholangioscopy-guided sampling of indeterminate biliary lesions at the time of ERCP: a prospective, long-term follow-up study, Gastrointest Endosc 75(2):347–353, 2012. 119. Navaneethan U, Hasan MK, Lourdusamy V, et al: Single-operator cholangioscopy and targeted biopsies in the diagnosis of indeterminate biliary strictures: a systematic review, Gastrointest Endosc 82(4):608– 614.e2, 2015. 120. Sun X, Zhou Z, Tian J, et al: Is single-operator peroral cholangioscopy a useful tool for the diagnosis of indeterminate biliary lesion? A systematic review and meta-analysis, Gastrointest Endosc 82(1):79–87, 2015. 121. Varadarajulu S, Bang JY, Hasan MK, et al: Improving the diagnostic yield of single-operator cholangioscopy-guided biopsy of indeterminate biliary strictures: ROSE to the rescue? (with video), Gastrointest Endosc 84(4):681–687, 2016. 122. Seo DW, Lee SK, Yoo KS, et al: Cholangioscopic findings in bile duct tumors, Gastrointest Endosc 52(5):630–634, 2000. 123. Itoi T, Neuhaus H, Chen YK: Diagnostic value of image-enhanced video cholangiopancreatoscopy, Gastrointest Endosc Clin N Am 19(4):557–566, 2009. 124. Kim HJ, Kim MH, Lee SK, et al: Tumor vessel: a valuable cholangioscopic clue of malignant biliary stricture, Gastrointest Endosc 52(5):635–638, 2000. 125. Nimura Y, Kamiya J: Cholangioscopy, Endoscopy 30(2):182–188, 1998. 126. Sethi A, Doukides T, Sejpal DV, et al: Interobserver agreement for single operator choledochoscopy imaging: can we do better? Diagn Ther Endosc 2014:730731, 2014. 127. Sethi A, Widmer J, Shah NL, et al: Interobserver agreement for evaluation of imaging with single operator choledochoscopy: what are we looking at?, Dig Liver Dis 46(6):518–522, 2014. 128. Sethi A, Chen YK, Austin GL, et al: ERCP with cholangiopancreatoscopy may be associated with higher rates of complications than ERCP alone: a single-center experience, Gastrointest Endosc 73(2):251–256, 2011. 129. 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 5(11):1261–1267, 2007. 130. Meining A, Chen YK, Pleskow D, et al: Direct visualization of indeterminate pancreaticobiliary strictures with probe-based confocal laser endomicroscopy: a multicenter experience, Gastrointest Endosc 74(5):961–968, 2011.

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131. Meining A, Shah RJ, Slivka A, et al: Classification of probe-based confocal laser endomicroscopy findings in pancreaticobiliary strictures, Endoscopy 44(3):251–257, 2012. 132. Caillol F, Filoche B, Gaidhane M, Kahaleh M: Refined probe-based confocal laser endomicroscopy classification for biliary strictures: the Paris Classification, Dig Dis Sci 58(6):1784–1789, 2013. 133. Slivka A, Gan I, Jamidar P, et al: Validation of the diagnostic accuracy of probe-based confocal laser endomicroscopy for the characterization of indeterminate biliary strictures: results of a prospective multicenter international study, Gastrointest Endosc 81(2):282–290, 2015. 134. Talreja JP, Turner BG, Gress FG, et al: Pre- and post-training session evaluation for interobserver agreement and diagnostic accuracy of probe-based confocal laser endomicroscopy for biliary strictures, Dig Endosc 26(4):577–580, 2014. 135. Farrant JM, Hayllar KM, Wilkinson ML, et al: Natural history and prognostic variables in primary sclerosing cholangitis, Gastroenterology 100(6):1710–1717, 1991.

136. LaRusso NF, Wiesner RH, Ludwig J, MacCarty RL: Current concepts. Primary sclerosing cholangitis, N Engl J Med 310(14):899–903, 1984. 137. Darwish Murad S, Kim WR, Harnois DM, et al: Efficacy of neoadjuvant chemoradiation, followed by liver transplantation, for perihilar cholangiocarcinoma at 12 US centers, Gastroenterology 143(1):88–98.e3, quiz e14, 2012. 138. Heimbach JK, Gores GJ, Haddock MG, et al: Liver transplantation for unresectable perihilar cholangiocarcinoma, Semin Liver Dis 24(2):201– 207, 2004. 139. Navaneethan U, Njei B, Venkatesh PG, et al: Fluorescence in situ hybridization for diagnosis of cholangiocarcinoma in primary sclerosing cholangitis: a systematic review and meta-analysis, Gastrointest Endosc 79(6):943–950.e3, 2014.

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61 Pancreatic Cystic Lesions Anne Marie Lennon, Omer Basar, and William R. Brugge

CHAPTER OUTLINE Nonneoplastic Cysts, 713 Pancreatic Pseudocysts, 713 Neoplastic Cysts, 713 Mucinous Cystic Neoplasm, 714

Intraductal Papillary Mucinous Neoplasm, 715 Serous Cystic Neoplasm, 717 Solid-Pseudopapillary Neoplasm, 718

Pancreatic cysts are relatively rare lesions, and their diagnosis has increased with the widespread availability and use of crosssectional imaging. In many cases pancreatic cysts are detected on imaging performed for another indication; however, they can also be seen in patients with symptoms such as abdominal pain or jaundice. Pancreatic cysts are reported to be found in 3% of computed tomography (CT) scans and 20% of magnetic resonance imaging (MRI) scans, and an increased prevalence is reported with advancing age. Patients with intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs) are at higher risk of pancreatic malignancy compared to the general population. The majority of pancreatic cystic lesions are nonneoplastic cysts, which are predominantly pancreatic pseudocysts (PPs) and are mostly seen as a local complication of pancreatitis.1 Neoplastic cysts of the pancreas are broadly categorized as mucinous and nonmucinous lesions, and the type of epithelial lining determines the risk of malignancy. Once a PP has been eliminated as a possibility, the next step is to determine the type of cyst based on cross-sectional imaging, aspiration cytology, and cyst fluid analysis (Box 61.1).

NONNEOPLASTIC CYSTS Pancreatic Pseudocysts PPs may occur secondary to acute or chronic pancreatitis or pancreatic trauma. They are inflammatory fluid collections and 10% to 20% of patients with acute pancreatitis develop a PP.2 A pseudocyst is often diagnosed when cross-sectional imaging demonstrates an enhancing capsule surrounding a peripancreatic fluid collection 4 weeks from the onset of acute nonnecrotizing pancreatitis. The capsule does not contain an “epithelial lining,”3 and a PP usually contains an opaque, dark, low-viscosity fluid free of epithelial cells. PPs are usually sterile collections, but may become infected or hemorrhagic. The majority of PPs are solitary, unilocular cysts ranging from 2 to 20 cm in diameter.1,3,4 Abdominal pain, early satiety, and weight loss are common symptoms, and a PP is suspected when abdominal pain continues and serum amylase is consistently elevated after clinical resolution

Pancreatic Neuroendocrine Tumors, 719 Approach for a Patient With a Pancreatic Cyst, 720

of pancreatitis.5 PPs may be complicated by intracystic hemorrhage, infection or rupture, which leads to pancreatic ascites. Symptoms of abdominal pain, fever, and chills suggest an infection in a patient with known PP. Large PPs are well-circumscribed, oval or round, thick-walled fluid collections on abdominal ultrasound (US) and CT1 (Fig. 61.1). CT imaging may also reveal signs of inflammation of the pancreatic tissue in the course of acute or chronic pancreatitis. MRI, magnetic resonance cholangiopancreatography (MRCP), and endoscopic retrograde cholangiopancreatography (ERCP) do not contribute much to the diagnosis. Currently, endoscopic ultrasound (EUS) is the most used modality for the differential diagnosis, and they appear as hypoechoic fluid collections surrounded by a thick rim (Fig. 61.2). Cysts can be aspirated by EUS-guided fine-needle aspiration (FNA) (EUS-FNA), and the cyst fluid is high in amylase and low in carcinoembryonic antigen (CEA)6; cytologic analysis shows histiocytes and inflammatory cells. The majority of PPs resolve spontaneously.7–9 Symptomatic and large PPs can be drained endoscopically or via a percutaneous route. With a high degree of success and low recurrence rate, EUS-guided transgastric or transduodenal endoscopic drainage is the current choice of treatment.6 Furthermore, cystogastrostomy or cystoduodenostomy allows removal of debris and necrotic material in some patients. Surgical drainage is not preferred currently, except in the face of endoscopic drainage failure.10

NEOPLASTIC CYSTS Neoplastic cysts of the pancreas can be broadly categorized as mucinous cystic lesions and nonmucinous cystic lesions. MCNs and IPMNs both produce mucin and are often combined and called either mucin-producing neoplasms or mucinous neoplasms. MCNs and IPMNs share similar cyst fluid features, and have the potential for transformation into pancreatic adenocarcinoma.11,12 Nonmucinous neoplastic cystic lesions include serous cystic neoplasms, solid pseudopapillary neoplasms (SPNs), and cystic pancreatic neuroendocrine tumors (PNETs). The common

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CHAPTER 61

Pancreatic Cystic Lesions

Abstract

Keywords

Pancreatic cysts are relatively rare lesions, and their diagnosis has increased with the widespread availability and use of crosssectional imaging. In many cases pancreatic cysts are detected on imaging performed for another indication; however, they can also be seen in patients with symptoms such as abdominal pain or jaundice. The majority of pancreatic cystic lesions are nonneoplastic cysts, which are predominantly pancreatic pseudocysts (PPs) and are mostly seen as a local complication of pancreatitis. Neoplastic cysts of the pancreas are broadly categorized as mucinous and nonmucinous lesions, and the type of epithelial lining determines the risk of malignancy. Once a PP has been eliminated as a possibility, the next step is to determine the type of cyst based on cross-sectional imaging, aspiration cytology, and cyst fluid analysis.

pancreatic cystic lesions pancreatic pseudocysts intraductal papillary mucinous neoplasms mucinous cystic neoplasms solid pseudopapillary neoplasms cystic pancreatic neuroendocrine tumors

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713.e1

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features of pancreatic cystic neoplasms (PCNs) are summarized in Table 61.1.

Mucinous Cystic Neoplasm MCNs are relatively rare, and account for 16% of surgically resected pancreatic cysts.13 They occur almost exclusively in women, with men accounting for less than 5% of MCNs in large

Common Types of Pancreatic Cysts

BOX 61.1

Neoplastic Pancreatic Cysts Mucinous cystic lesions Intraductal papillary mucinous neoplasm Mucinous cystic neoplasm Nonmucinous cystic lesions Serous cystic neoplasm Solid-pseudopapillary neoplasm Pancreatic neuroendocrine tumors

Nonneoplastic Pancreatic Cysts Pancreatic pseudocysts Retention cysts Squamoid cysts of the pancreatic duct Lymphoepithelial cysts

FIG 61.1 CT showing a pseudocyst measuring 5.7 × 7.6 × 5.0 cm.

series.14,15 Although over 70% of patients are symptomatic, most of the symptoms are nonspecific abdominal pain and unrelated to the cyst, with only 13% of patients who undergo surgical resection for MCNs presenting with symptoms related to their cyst. The most common of these is acute pancreatitis, which occurs in approximately 9%.14,15 MCNs have some features that are very helpful in differentiating them from other types of pancreatic cysts; they are single, occur almost exclusively in women, and are located in the body and tail of the pancreas in over 97% of cases.14,15 They can be uni- or multilocular and are classically well defined with a thin wall. Approximately 15% of MCNs have calcification, which is located at the edge of the cyst, in contrast to serous cystadenomas (SCAs) in which the calcification occurs in the center of the cyst (Fig. 61.3). The key-imaging feature used to differentiate IPMNs from MCNs, is that in MCNs, the main pancreatic duct is of normal diameter with no communication between it and the MCN. Both MCNs and IPMNs are mucin-producing cysts and have very similar cyst fluid analysis features, namely, a high cyst fluid CEA and the presence of mucin on cytology. There is debate about the optimum CEA level to differentiate mucin from nonmucin-producing cysts, with all major studies defining

FIG 61.2 Endoscopic ultrasound (EUS) showing a 4.8 cm unilocular pseudocyst in the pancreatic body. The cyst is adjacent to the gastric wall and contains some debris.

TABLE 61.1

General Features of Pancreatic Cystic Neoplasms

Cysts Type

Sex

Median Age

IPMN

ᄝ/ᄛ

65

Pancreatic Localization Head

Morphology Unilocular, septated, associated dilated main pancreatic duct

Communication with PD

Epithelium Type

Malignancy Risk

Yes

Papillary mucinous

High

MCN

ᄛ

40

Body & tail

Unilocular

No

Mucinous

High

SCN

ᄛ

60

Entire pancreas

Microcystic

No

Serous (PAS-positive for glycogen)

Low

SPN

ᄛ

30

Body & tail

Mixed solid and cystic

No

Endocrine-like

Low

PNET

ᄝ/ᄛ

50

Entire pancreas

Associated mass

No

Endocrine

Low

IPMN, Intraductal papillary neoplasm; MCN, mucinous cystic neoplasm; SCN, serous cystic neoplasm; SPN, solid-pseudopapillary neoplasm; PD, pancreatic duct; PNET, pancreatic neuroendocrine tumor.

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CHAPTER 61

A

Pancreatic Cystic Lesions

715

B FIG 61.3 A and B, Cross-sectional CT scan demonstrating a mucinous cystic neoplasm (MCN) (arrows) in the body with a calcification in the wall.

mucin-producing cysts as those with a CEA greater than 192 ng/ mL, which was derived from the 2004 prospective, multicenter cooperative cyst study by Brugge et al.12 However, cyst fluid CEA alone is imperfect; a recent meta-analysis of 18 studies with 1438 patients found that cyst fluid CEA had 63% sensitivity and 88% specificity for identifying mucin-producing cysts.16 Cyst fluid amylase levels are high in both MCNs and IPMNs, and cannot be used to differentiate MCNs from IPMNs.17 In both IPMNs and MCNs, columnar or cuboidal epithelial cells, as well as mucin, can be found. In addition, cytology can detect marked atypia (the cytological equivalent of high-grade dysplasia) or invasive adenocarcinoma. Although cytology has a high specificity of over 90%, it suffers from a low sensitivity of only 50% in the diagnosis of a mucinous cyst. In addition, over 60% of cases are found to have inadequate cellularity. On the other hand, the cyst fluid cytology rarely provides a definitive diagnosis. A needle-guided tissue micro forceps was approved recently for epithelial tissue acquisition in pancreatic cysts. In a study, the micro forceps provided a tissue sample that was sufficient for histological evaluation in 90% of patients. It also provided better information about the subgroup of PCN and the grade of dysplasia.18 In surgically resected cysts, MCNs are differentiated from IPMNs by the presence of ovarian-like stroma. There are no long-term studies examining the natural history of MCNs; thus the estimate of the risk of malignant transformation into pancreatic adenocarcinoma is based on retrospective surgical series in which the risk of invasive adenocarcinoma in modern series is between 4% to 13% at the time of resection.14,19 There is debate about whether MCNs can be watched or if all should undergo surgical resection.20–23 There is an agreement that MCNs that are clearly causing symptoms, such as acute pancreatitis, have imaging features concerning for malignant transformation, such as a solid component or cytology showing marked atypia (the cytological equivalent of high-grade dysplasia), or invasive adenocarcinoma should undergo surgical resection. However authors, guidelines, and surgeons differ as to the management of presumed MCNs that measure less than 3 cm and have no concerning features. Some authors argue that all MCNs should be resected.20 This is because (1) they occur in young women, who would otherwise require 30 to 40 years of

surveillance, (2) they are single cysts which, in contrast to IPMNs, do not recur, and (3) they are located in the body or tail of the pancreas, which is technically easier to surgically resect than performing a Whipple. However, others argue that it is not always possible to differentiate MCNs from IPMNs preoperatively, that more recent data suggest that the risk of malignant transformation of MCNs is less than that of branch-duct IPMNs, and that although associated with a low mortality, a distal pancreatectomy has an approximate 25% morbidity rate, which includes a 15% to 20% risk of diabetes.21,22 When caring for a patient with a presumed MCN, it is important to discuss these two differing views, the pros and cons of each approach, and ensure that the patient is reviewed by a multidisciplinary pancreatic cyst group.24 Once patients undergo surgical resection for an MCN, in the absence of invasive adenocarcinoma, no further follow-up is required.

Intraductal Papillary Mucinous Neoplasm IPMNs are the most common type of neoplastic pancreatic cyst encountered, and account for over 50% of surgically resected pancreatic cysts in modern series.13 They can occur at any age, but usually present in patients in their late 60s or early 70s, with an equal distribution between men and women. IPMNs can cause symptoms including jaundice and acute pancreatitis; however, the vast majority of patients with IPMNs do not have pancreatic symptoms. IPMNs can present with dilation of the main pancreatic duct alone (≥ 5 mm) which is called main-duct IPMN (Fig. 61.4A).20 IPMNs can also present with a pancreatic cyst(s) termed branchduct or side-branch IPMNs (see Fig. 61.4B). Finally, a small number of patients present with both a dilated main pancreatic duct and pancreatic cysts, which is referred to as a mixed IPMN. Up to 40% of IPMNs have multiple pancreatic cysts. This finding is useful; with the exception of pseudocysts, the majority of other types of cysts are single. Although they have a slight preponderance for the head and uncinate process, they can also occur in the body and tail. Thus, unlike MCNs, the location of IPMNs is not helpful. Branch-duct IPMNs can be uni- or multilocular, are typically well defined with thin walls, and have no calcification. The classic feature of a branch-duct IPMN is the presence of

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A

B FIG 61.4 A, CT image of main-duct intraductal papillary mucinous neoplasm (IPMN) (arrow highlights a dilated main pancreatic duct in the head of the pancreas). B, Endoscopic ultrasound (EUS) image of main-duct IPMN.

A

B FIG 61.5 A, A branch-duct intraductal papillary mucinous neoplasm (IPMN) showing a mucin ball (arrow). B, Endoscopic ultrasound fine-needle aspiration (EUS-FNA) of the lesion in Fig. 5A showing that the lesion (arrow) is not attached to the wall and is indeed mucin and not a mural nodule.

communication, or a connection, between the main pancreatic duct and the cyst. This feature of communication between the cyst and the main pancreatic duct is used to differentiate IPMNs from MCNs. This is best assessed with EUS or MRI/MRCP, which have a reported sensitivity of between 89% to 100%.25 IPMNs are neoplastic cysts and have the potential for progression to invasive adenocarcinoma. Imaging features that raise concern that an IPMN may have high-grade dysplasia or an associated invasive adenocarcinoma are the presence of a mural nodule (particularly if it is shown to enhance on CT or MRI), a dilated main pancreatic duct (especially if it is over 9 mm in diameter), and thick or enhancing cyst walls or an abrupt change in the diameter of the main pancreatic duct, particularly if there is evidence of upstream ductal obstruction. On EUS it can sometimes be difficult to differentiate a mural nodule from a mucin ball within the cyst (Figs. 61.5 and 61.6). Three features can be used to separate these two entities: (1) mucin will have a smooth edge whereas a mural nodule has an irregular edge, (2) mucin is hypoechoic compared with adjacent tissue, whereas a mural nodule is iso- or hyperechoic compared with surrounding

FIG 61.6 Mural nodule (arrow) within a branch duct intraductal papillary mucinous neoplasm (IPMN). The patient underwent surgery, and high-grade dysplasia was detected.

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CHAPTER 61 tissue, (3) mucin has a hyperechoic (bright) rim whereas a mural nodule has none. The presence of all three of these features can differentiate mucin from a mural nodule with 90% accuracy.26 The second issue that endoscopists encounter is whether a slight protuberance of the wall of a cyst is significant or not. The first question is whether this area is enhancing on CT or MRI. The presence of an enhancing mural nodule is highly concerning for the presence of high-grade dysplasia or an associated invasive adenocarcinoma. It is important to remember that the main pancreatic duct can be dilated for a number of reasons, such as a small pancreatic adenocarcinoma, ampullary adenoma, papillary stenosis, chronic pancreatitis, or main-duct IPMN, and can also increase with age. When referring a patient with a dilated main pancreatic duct, it is important to try to exclude these other entities. The presence of a “fish mouth” in which mucin is seen extruding from the ampulla, is highly suggestive of main-duct IPMN. On EUS the presence of mucin within the main pancreatic duct, or a thickened or irregular wall, are suggestive of main-duct IPMN. In cases where the diagnosis remains unclear, pancreatoscopy has been used to identify papillary projections and to determine the extent of involvement of the main pancreatic duct. The cyst fluid analysis for IPMNs is identical to that of MCNs described previously. The presence of an elevated cyst fluid CEA or mucin is used to make the diagnosis of a mucin-producing cyst. The presence of marked atypia or invasive adenocarcinoma on cytology raises the concern for the presence of high-grade dysplasia or an associated invasive adenocarcinoma. Patients with these cytology findings should be seen by a multidisciplinary group and considered for surgical resection. Several studies have focused on the underlying genetic mutations in pancreatic cysts, and have found that cysts have a unique molecular profile (Table 61.2).27 MCNs and IPMNs share mutations in KRAS, RNF43, and TP53, whereas IPMNs have a unique mutation in GNAS, which is present in 58% of IPMNs and can be used to differentiate IPMNs from other types of cysts.27 Preliminary studies examining the use of a combination of molecular markers in cyst fluid to identify different types of pancreatic cysts appears very promising, identifying SCAs with 100% sensitivity and 91% specificity, MCNs with 100% sensitivity and 75% specificity, and IPMNs with 76% sensitivity and 97% specificity.28 The presence of a mutation in GNAS or KRAS is particularly helpful in identifying mucin-producing cysts, and is found in over 90% of IPMNs.28,29 Recent studies (2016) have shown that the use of molecular markers is cost effective and alters patient management.30,31 The final results of large, multicenter studies are expected to be published in 2017. If these studies confirm the findings of the smaller studies, it is likely that the use of molecular markers will be incorporated into clinical practice in cases in which the diagnosis is unclear. It is TABLE 61.2 Genetic Profile of Pancreatic Cysts Mutation

SCA

SPN

KRAS

MCN

IPMN

+

+

GNAS

+

RNF43

+

CTNNB1 VHL

+ +

+ +

Pancreatic Cystic Lesions

717

important to note that not all techniques for identifying molecular markers are the same, with significant variations in the sensitivity for identifying a mutation. The results reported previously were performed using SafeSeq sequencing, which can detect a mutation that is present in 0.01% of alleles. IPMNs are neoplastic pancreatic cysts with the potential to progress from low-, to intermediate-, to high-grade dysplasia, and ultimately invasive pancreatic adenocarcinoma.11 It is currently impossible to know the exact grade of dysplasia present in an IPMN without sending the patient for surgical resection; however, certain imaging features are associated with a higher prevalence of high-grade dysplasia or invasive adenocarcinoma. The presence of a mural nodule or solid component within the cyst is associated with an odds ratio (OR) of 7.73, the presence of a dilated main pancreatic has an OR of 2.38, and cyst size greater than 3 cm is associated with an OR of 2.97 for high-grade dysplasia or invasive cancer. In contrast, there is accumulating evidence that the risk for developing invasive malignancy from suspected branch duct (BD)-IPMN without concerning features is low, about 0.72% per year, or 2% to 4% (average 2.8%, 95% confidence interval 1.8%–4%) over a period of 10 years.32 Several different groups have developed guidelines for the management of IPMNs.20–22 The most commonly used guidelines are the International Consensus Criteria (ICC), which will be reviewed here.20 These guidelines recommend consideration of surgical resection in the presence of “high risk features,” which are jaundice caused by an IPMN, an enhancing mural nodule, or main-duct IPMN measuring greater than 9 mm. “Worrisome features” are the presence of dilation of the main pancreatic duct between 5 to 9 mm, abrupt change in caliber in the main pancreatic duct, a nonenhancing mural nodule, thickened or enhancing wall, cyst size of 3 cm or more, or a recent history of acute pancreatitis. In the case of worrisome features, EUS should be performed; where there is clear evidence of main-duct IPMN, a definite mural nodule on EUS, or cytology showing marked atypia or invasive adenocarcinoma, surgical resection should be considered. In all other cases surveillance can be undertaken with the interval determined by the size of the cyst. The positive predictive value of worrisome, high-risk, or worrisome or high-risk features is 29%, 66%, and 36%, respectively, for the presence of high-grade dysplasia or invasive cancer.33 The absence of any of these features has a negative predictive value of 90%.33 IPMNs affect the entire pancreas and can develop in the residual pancreas following resection. In addition, patients with IPMNs are also at risk of developing pancreatic adenocarcinoma in an area unrelated to a pancreatic cyst.34 The remnant pancreas should therefore undergo surveillance following a Whipple or distal pancreatectomy.20,21 In cases that cannot tolerate or refuse surgery, or in asymptomatic BD-IPMN patients without risk factors, EUS-guided cyst ablation has emerged as a promising approach. The first well-demonstrated study showed a 33% rate of complete cyst ablation following EUS-guided cyst lavage with ethanol.35 Infusing and leaving paclitaxel in the cyst after ethanol lavage raised the complete ablation rates to 60% to 79% in further studies.35–37 EUS-guided radiofrequency ablation is another alternative treatment. In a preliminary study, the response ranged from complete resolution to a 50% reduction in size.38

Serous Cystic Neoplasm SCNs are predominantly benign neoplasms that can arise anywhere in the pancreas, and malignant SCNs are extremely

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FIG 61.7 Macroscopic view of a serous cystic neoplasm. Note the stellate-shaped central scar and numerous small cysts.

rare39 (Fig. 61.7). The degree of dysplasia categorizes these cysts into serous cystadenomas and serous cystadenocarcinomas. The typical clinical presentation of a SCN occurs mostly in women over the age of 60 years. SCNs are slow-growing tumors40 and are usually incidentally detected on abdominal imaging for other unrelated conditions.41,42 The VHL gene mutation plays an important role in the pathogenesis of SCNs43,44 and, in contrast with mucinous cysts, KRAS mutations are not seen in SCN.43 Glycogen-rich cells that are stained periodic acid–Schiff (PAS)-positive arise from centroacinar cells of the pancreas and line SCNs. The SCN wall is thin and surrounds a thin nonviscous and bloody cyst fluid. SCNs contain a prominent fibrous stroma, glycogen-rich epithelial cells, and endothelial, as well as smooth, muscle cells.44 Ultrastructurally, the fibrocollagenous stroma is composed of myofibroblasts and endothelial cells embedded in thick collagen bundles. Estrogen and progesterone receptors are not present.45 Histologic variants include macrocystic serous cystadenomas, solid serous adenomas, VHL-associated SCNs, and mixed serous neuroendocrine neoplasms.39 The majority of SCNs are microcystic, and the classical appearance of a microcystic SCN is a cluster of numerous tiny cysts separated by a delicate fibrous septa, which resembles a “honeycomb-like appearance” on crosssectional abdominal imaging or EUS. Microcystic lesions grow slowly; however, they may reach large diameters. Frequently the large lesions have a stellate-shaped central scar. Macrocystic (oligocystic) serous cystadenomas are composed of fewer and larger cysts46–49 and can be difficult to distinguish from an MCN, BD-IPMN, and a pseudocyst. VHL-associated SCN consists of multiple SCNs that affect patients with the VHL syndrome. The mixed serous neuroendocrine neoplasms are rare and highly suggestive of VHL syndrome.39 Although most SCN patients present with abdominal pain and discomfort historically, many patients may present with a palpable mass when the cyst attains a large size. Currently, SCNs are mostly detected in asymptomatic patients during evaluation for another indication. On CT and MRI, the diagnostic classical appearance is a solitary lesion composed of a central scar surrounded by multiple tiny cysts. Alternatively, the macrocystic serous cystadenomas

on cross-sectional imaging are usually indistinguishable from BD-IPMNs and MCNs.49,50 As discussed previously, MCNs are solitary, thinly septated cysts and may have “eggshell” peripheral calcification, which is in contrast with central scar and calcification in SCNs. Pseudocysts are unilocular lesions with pancreatic parenchymal changes (calcification and atrophy). The presence of multiple, small, thin-walled cysts is suggestive of VHL syndrome.51 Additionally, SCNs generally do not communicate with the pancreatic duct, which is best seen on MRCP. The typical appearance of SCNs on EUS is numerous anechoic small cysts with thin septations. EUS with Doppler may demonstrate the characteristic hypervascular central region. The cyst fluid is nonviscous and may be bloody (because of this hypervascular nature) during EUS-FNA. The cytology is negative for malignancy, but PAS-positive small cuboidal cells are diagnostic for SCNs.52 However, diagnostic cytology for SCN is rare. A CEA level of less than 5 ng/mL is also highly suggestive of an SCN,53 and SCNs are negative for both KRAS and GNAS mutations but positive for VHL mutations.54–56 Currently, with the available diagnostic studies, the differentiation of pancreatic cysts is sometimes challenging. Needle-based confocal endomicroscopy is a novel endoscopic technique that enables real-time optical biopsies and provides in vivo histopathological assessment during EUS-FNA. On confocal endomicroscopy, SCNs demonstrate a typical superficial vascular network, whereas IPMNs show papillary projections with an epithelial border and vascular core.57,58 The prognosis for SCNs is excellent.39 Generally, SCNs should be followed by surveillance imaging. Previously large SCA size or rapid growth had been considered indications for surgical resection; however, a large, multicenter study in over 2500 patients with SCA found that the risk of serous cystadenocarcinoma was 0.1%.59 Surgery should only be considered for symptomatic SCAs or when there is an uncertainty about the diagnosis and a concern for malignancy.60

Solid-Pseudopapillary Neoplasm SPNs are rare neoplasms of the pancreas that typically affect women in their 30s. Microscopically, a mixture of solid (solid pseudopapillary) and cystic (hemorrhagic-necrotic pseudocystic) components is observed. SPNs are usually well-circumcised, single, round, and fluctuant masses and are most commonly found in the body and tail of pancreas.61,62 The majority of SPNs were symptomatic in the past; however, currently incidental detection on cross-sectional imaging is becoming more common. The most common symptoms are abdominal pain, vomiting, nausea, and patients may have a palpable mass.63 Although the majority of SPNs demonstrate a benign behavior, they are generally considered as low-grade malignant neoplasms. Criteria for solid pseudopapillary carcinoma are defined as vascular invasion, perineural invasion, invasion of adjacent tissues, or metastases.64 The most common site of metastases is the liver. On CT and MRI, SPNs may appear as well-demarcated encapsulated pancreatic masses mixed with solid components without septa (Fig. 61.8). MRI reveals lower signal intensity on T1-weighted images and higher signal intensity on T2-weighted images. The capsule is usually thick, and sometimes internal calcifications may be observed.65 The typical appearance of SPN on EUS is a well-demarcated, hypoechoic, solid-appearing mass, which can also sometimes appear as a mixed cystic and solid lesion or purely cystic lesion.66 The aspirated fluid is typically bloody, highly cellular, and CEA level is low, consistent with nonmucinous epithelium.67

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CHAPTER 61 SPNs are slow-growing neoplasms, and complete resection is the treatment of choice. Surgery is curative in most cases, and recurrence rates after resection are very low.41,68 Prolonged survival is reported even in patients with recurrence and metastases.64,69,70

Pancreatic Cystic Lesions

Pancreatic Neuroendocrine Tumors PNETs are rare neoplasms that account for less than 10% of all pancreatic neoplasms.46,71 They are indolent tumors, which arise from both endocrine and nervous system cells with a variable malignant potential. 1% to 2% of pancreatic neoplasms are PNETs,72 both sexes are equally affected, and the incidence of PNETs increases with age. The majority of PNETs are hormonally nonfunctional and are frequently sporadic; however, an association with von Hippel-Lindau syndrome (vHL), multiple endocrine neoplasia type 1, and neurofibromatosis type 1 may be seen.73–76 PNETs are well-circumscribed lesions, surrounded by a thick, fibrous capsule and may be unilocular or multilocular. Generally, they do not communicate with the pancreatic duct, and their size varies from small to large. The aspirated fluid is usually hemorrhagic, and the lesion appears like a hypoechoic mass after aspiration. A large hypervascular pancreatic mass on CT/ MRI in a patient without producing hormonal symptoms is highly suspicious for nonfunctional PNETs.77,78 To differentiate from malignant tumors of pancreas, EUS-FNA and scintigraphy are the most valuable tools (Fig. 61.9). Surgery with complete resection is the only curative therapy for PNETs. Somatostatin analogs for functional tumors are recommended. Locoregional treatment is suggested for liver metastasis and chemotherapy is suggested for residual disease.79 The prognosis is better than for pancreatic adenocarcinoma.80

FIG 61.8 CT showing a solid-pseudopapillary neoplasm. Note the mixture of solid and cystic components.

A

B

719

C FIG 61.9 A, CT showing a thick-walled cystic lesion consistent with a cystic pancreatic neuroendocrine neoplasm. B, Macroscopic view of the same lesion. C, Histologic view of the same lesion. Downloaded for Usuario UDEM ([email protected]) at Universidad de Monterrey from ClinicalKey.com by Elsevier on July 25, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved.

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APPROACH FOR A PATIENT WITH A PANCREATIC CYST When a patient with a pancreatic cyst is seen, we review their cross-sectional imaging to determine the type of cyst, and to evaluate whether there are any features concerning for the presence of high-grade dysplasia or invasive carcinoma. In cases in which the diagnosis is unclear, or there are concerning features, then EUS +/− FNA is performed with cyst fluid sent for CEA, amylase (if there is concern for a pseudocyst), KRAS, GNAS, and cytology. For patients with BD-IPMNs, there are several different guidelines available, including those developed by the American College of Gastroenterology23 (ACG), the ICC,20 the European Consensus Criteria (ECC),21 and the American Gastroenterology Association (AGA).22 Updated guidelines are expected from the ACG and ECC in 2017, as concerns have been raised about several aspects of the AGA guidelines.81–86 We therefore currently follow the revised ICC with presumed BD-IPMNs measuring under 1 cm followed every 2 years, 1 to 2 cm BD-IPMNs followed yearly, and BD-IPMNs over 2 cm, or IPMNs with main duct involvement, followed every 6 months. Surveillance intervals can be increased if the cysts are stable in size and have no concerning features.

KEY REFERENCES 3. Brun A, Agarwal N, Pitchumoni CS: Fluid collections in and around the pancreas in acute pancreatitis, J Clin Gastroenterol 45:614–625, 2011. 5. Cannon JW, Callery MP, Vollmer CM, Jr: Diagnosis and management of pancreatic pseudocysts: what is the evidence? J Am Coll Surg 209: 385–393, 2009. 6. Brugge WR: Approaches to the drainage of pancreatic pseudocysts, Curr Opin Gastroenterol 20:488–492, 2004. 8. Brugge WR: The use of EUS to diagnose cystic neoplasms of the pancreas, Gastrointest Endosc 69:S203–S209, 2009. 11. Lennon AM, Wolfgang CL, Canto MI, et al: The early detection of pancreatic cancer: what will it take to diagnose and treat curable pancreatic neoplasia? Cancer Res 74:3381–3389, 2014. 12. Brugge WR, Lewandrowski K, Lee-Lewandrowski E, et al: Diagnosis of pancreatic cystic neoplasms: a report of the cooperative pancreatic cyst study, Gastroenterology 126:1330–1336, 2004. 13. Valsangkar NP, Morales-Oyarvide V, Thayer SP, et al: 851 resected cystic tumors of the pancreas: a 33-year experience at the Massachusetts General Hospital, Surgery 152:S4–S12, 2012. 16. Anand N, Sampath K, Wu BU: Cyst features and risk of malignancy in intraductal papillary mucinous neoplasms of the pancreas: a meta-analysis, Clin Gastroenterol Hepatol 11:913–921, quiz e59–e60, 2013. 17. Thornton GD, McPhail MJ, Nayagam S, et al: Endoscopic ultrasound guided fine needle aspiration for the diagnosis of pancreatic cystic neoplasms: a meta-analysis, Pancreatology 13:48–57, 2013.

20. Tanaka M, Fernandez-Del Castillo C, Adsay V, et al: International consensus guidelines 2012 for the management of IPMN and MCN of the pancreas, Pancreatology 12:183–197, 2012. 22. Vege SS, Ziring B, Jain R, et al: American gastroenterological association institute guideline on the diagnosis and management of asymptomatic neoplastic pancreatic cysts, Gastroenterology 148:819–822, 2015. 23. Khalid A, Brugge W: ACG practice guidelines for the diagnosis and management of neoplastic pancreatic cysts, Am J Gastroenterol 102: 2339–2349, 2007. 24. Lennon AM, Manos LL, Hruban RH, et al: Role of a multidisciplinary clinic in the management of patients with pancreatic cysts: a single-center cohort study, Ann Surg Oncol 21(11):3668–3674, 2014. 28. Springer S, Wang Y, Dal Molin M, et al: A combination of molecular markers and clinical features improve the classification of pancreatic cysts, Gastroenterology 149:1501–1510, 2015. 30. Singhi AD, Zeh HJ, Brand RE, et al: American Gastroenterological Association guidelines are inaccurate in detecting pancreatic cysts with advanced neoplasia: a clinicopathologic study of 225 patients with supporting molecular data, Gastrointest Endosc 83(6):1107–1117.e2, 2016. 32. Scheiman JM, Hwang JH, Moayyedi P: American Gastroenterological Association technical review on the diagnosis and management of asymptomatic neoplastic pancreatic cysts, Gastroenterology 148: 824–848 e22, 2015. 33. Goh BK, Tan DM, Ho MM, et al: Utility of the sendai consensus guidelines for branch-duct intraductal papillary mucinous neoplasms: a systematic review, J Gastrointest Surg 18:1350–1357, 2014. 36. Oh HC, Brugge WR: EUS-guided pancreatic cyst ablation: a critical review (with video), Gastrointest Endosc 77:526–533, 2013. 41. Yoon WJ, Brugge WR: Pancreatic cystic neoplasms: diagnosis and management, Gastroenterol Clin North Am 41:103–118, 2012. 46. Brugge WR, Lauwers GY, Sahani D, et al: Cystic neoplasms of the pancreas, N Engl J Med 351:1218–1226, 2004. 56. Kadayifci A, Brugge WR: Endoscopic ultrasound-guided fine-needle aspiration for the differential diagnosis of intraductal papillary mucinous neoplasms and size stratification for surveillance, Endoscopy 46:357, 2014. 67. Jani N, Dewitt J, Eloubeidi M, et al: Endoscopic ultrasound-guided fine-needle aspiration for diagnosis of solid pseudopapillary tumors of the pancreas: a multicenter experience, Endoscopy 40:200–203, 2008. 72. Halfdanarson TR, Rabe KG, Rubin J, et al: Pancreatic neuroendocrine tumors (PNETs): incidence, prognosis and recent trend toward improved survival, Ann Oncol 19:1727–1733, 2008. 74. Boninsegna L, Partelli S, D’Innocenzio MM, et al: Pancreatic cystic endocrine tumors: a different morphological entity associated with a less aggressive behavior, Neuroendocrinology 92:246–251, 2010. 79. Dimou AT, Syrigos KN, Saif MW: Neuroendocrine tumors of the pancreas: what’s new. Highlights from the “2010 ASCO Gastrointestinal Cancers Symposium”. Orlando, FL, USA. January 22-24, 2010, J Pancreas 11:135–138, 2010.

A complete reference list can be found online at ExpertConsult .com

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CHAPTER 61

REFERENCES 1. Habashi S, Draganov PV: Pancreatic pseudocyst, World J Gastroenterol 15:38–47, 2009. 2. Memis A, Parildar M: Interventional radiological treatment in complications of pancreatitis, Eur J Radiol 43:219–228, 2002. 3. Brun A, Agarwal N, Pitchumoni CS: Fluid collections in and around the pancreas in acute pancreatitis, J Clin Gastroenterol 45:614–625, 2011. 4. Aghdassi A, Mayerle J, Kraft M, et al: Diagnosis and treatment of pancreatic pseudocysts in chronic pancreatitis, Pancreas 36:105–112, 2008. 5. Cannon JW, Callery MP, Vollmer CM, Jr: Diagnosis and management of pancreatic pseudocysts: what is the evidence? J Am Coll Surg 209:385– 393, 2009. 6. Brugge WR: Approaches to the drainage of pancreatic pseudocysts, Curr Opin Gastroenterol 20:488–492, 2004. 7. Balthazar EJ, Freeny PC, van Sonnenberg E: Imaging and intervention in acute pancreatitis, Radiology 193:297–306, 1994. 8. Brugge WR: The use of EUS to diagnose cystic neoplasms of the pancreas, Gastrointest Endosc 69:S203–S209, 2009. 9. Johnson MD, Walsh RM, Henderson JM, et al: Surgical versus nonsurgical management of pancreatic pseudocysts, J Clin Gastroenterol 43:586–590, 2009. 10. Lerch MM, Stier A, Wahnschaffe U, Mayerle J: Pancreatic pseudocysts: observation, endoscopic drainage, or resection? Dtsch Arztebl Int 106: 614–621, 2009. 11. Lennon AM, Wolfgang CL, Canto MI, et al: The early detection of pancreatic cancer: what will it take to diagnose and treat curable pancreatic neoplasia? Cancer Res 74:3381–3389, 2014. 12. Brugge WR, Lewandrowski K, Lee-Lewandrowski E, et al: Diagnosis of pancreatic cystic neoplasms: a report of the cooperative pancreatic cyst study, Gastroenterology 126:1330–1336, 2004. 13. Valsangkar NP, Morales-Oyarvide V, Thayer SP, et al: 851 resected cystic tumors of the pancreas: a 33-year experience at the Massachusetts General Hospital, Surgery 152:S4–S12, 2012. 14. Yamao K, Yanagisawa A, Takahashi K, et al: Clinicopathological features and prognosis of mucinous cystic neoplasm with ovarian-type stroma: a multi-institutional study of the Japan Pancreas Society, Pancreas 40: 67–71, 2011. 15. Crippa S, Salvia R, Warshaw AL, et al: Mucinous cystic neoplasm of the pancreas is not an aggressive entity: lessons from 163 resected patients, Ann Surg 247:571–579, 2008. 16. Anand N, Sampath K, Wu BU: Cyst features and risk of malignancy in intraductal papillary mucinous neoplasms of the pancreas: a metaanalysis, Clin Gastroenterol Hepatol 11:913–921, quiz e59-e60, 2013. 17. Thornton GD, McPhail MJ, Nayagam S, et al: Endoscopic ultrasound guided fine needle aspiration for the diagnosis of pancreatic cystic neoplasms: a meta-analysis, Pancreatology 13:48–57, 2013. 18. Basar O, Yuksel O, Yang D, et al: The micro-forceps for pancreatic cysts: a game changer? Pancreas 45:1497, 2016. 19. Baker ML, Seeley ES, Pai R, et al: Invasive mucinous cystic neoplasms of the pancreas, Exp Mol Pathol 93:345–349, 2012. 20. Tanaka M, Fernandez-Del Castillo C, Adsay V, et al: International consensus guidelines 2012 for the management of IPMN and MCN of the pancreas, Pancreatology 12:183–197, 2012. 21. Del Chiaro M, Verbeke C, Salvia R, et al: European experts consensus statement on cystic tumours of the pancreas, Dig Liver Dis 45:703–711, 2013. 22. Vege SS, Ziring B, Jain R, et al: American gastroenterological association institute guideline on the diagnosis and management of asymptomatic neoplastic pancreatic cysts, Gastroenterology 148:819–822, 2015. 23. Khalid A, Brugge W: ACG practice guidelines for the diagnosis and management of neoplastic pancreatic cysts, Am J Gastroenterol 102: 2339–2349, 2007. 24. Lennon AM, Manos LL, Hruban RH, et al: Role of a multidisciplinary clinic in the management of patients with pancreatic cysts: a singlecenter cohort study, Ann Surg Oncol 21(11):3668–3674, 2014.

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25. Kim YC, Choi JY, Chung YE, et al: Comparison of MRI and endoscopic ultrasound in the characterization of pancreatic cystic lesions, Am J Roentgenol 195:947–952, 2010. 26. Zhong N, Zhang L, Takahashi N, et al: Histologic and imaging features of mural nodules in mucinous pancreatic cysts, Clin Gastroenterol Hepatol 10:192–198, 8 e1-e2, 2012. 27. Wu J, Jiao Y, Dal Molin M, et al: Whole-exome sequencing of neoplastic cysts of the pancreas reveals recurrent mutations in components of ubiquitin-dependent pathways, Proc Natl Acad Sci USA 108:21188–21193, 2011. 28. Springer S, Wang Y, Dal Molin M, et al: A combination of molecular markers and clinical features improve the classification of pancreatic cysts, Gastroenterology 149:1501–1510, 2015. 29. Singhi AD, Nikiforova MN, Fasanella KE, et al: Preoperative GNAS and KRAS testing in the diagnosis of pancreatic mucinous cysts, Clin Cancer Res 20(16):4381–4389, 2014. 30. Singhi AD, Zeh HJ, Brand RE, et al: American Gastroenterological Association guidelines are inaccurate in detecting pancreatic cysts with advanced neoplasia: a clinicopathologic study of 225 patients with supporting molecular data, Gastrointest Endosc 83(6):1107–1117.e2, 2016. 31. Jones M, Zheng Z, Wang J, et al: Impact of next-generation sequencing on the clinical diagnosis of pancreatic cysts, Gastrointest Endosc 83: 140–148, 2016. 32. Scheiman JM, Hwang JH, Moayyedi P: American Gastroenterological Association technical review on the diagnosis and management of asymptomatic neoplastic pancreatic cysts, Gastroenterology 148: 824–848 e22, 2015. 33. Goh BK, Tan DM, Ho MM, et al: Utility of the sendai consensus guidelines for branch-duct intraductal papillary mucinous neoplasms: a systematic review, J Gastrointest Surg 18:1350–1357, 2014. 34. Law JK, Wolfgang CL, Weiss MJ, Lennon AM: Concomitant pancreatic adenocarcinoma in a patient with branch-duct intraductal papillary mucinous neoplasm, World J Gastroenterol 20:9200–9204, 2014. 35. DeWitt J, McGreevy K, Schmidt CM, et al: EUS-guided ethanol versus saline solution lavage for pancreatic cysts: a randomized, double-blind study, Gastrointest Endosc 70:710–723, 2009. 36. Oh HC, Brugge WR: EUS-guided pancreatic cyst ablation: a critical review (with video), Gastrointest Endosc 77:526–533, 2013. 37. Oh HC, Seo DW, Lee TY, et al: New treatment for cystic tumors of the pancreas: EUS-guided ethanol lavage with paclitaxel injection, Gastrointest Endosc 67:636–642, 2008. 38. Pai M, Habib N, Senturk H, et al: Endoscopic ultrasound guided radiofrequency ablation, for pancreatic cystic neoplasms and neuroendocrine tumors, World J Gastrointest Surg 7:52–59, 2015. 39. Terris B, Fukushima N, Hruban RH: Serous neoplasms of the pancreas. In Bosman FT, Carneiro F, Hruban RH, et al, editors: WHO classification of tumours of the digestive system, ed 4, Lyon, France, 2010, International Agency for Research on Cancer. 40. Sakorafas GH, Smyrniotis V, Reid-Lombardo KM, et al: Part I: serous cystic neoplasms, Surg Oncol 20:84–92, 2011. 41. Yoon WJ, Brugge WR: Pancreatic cystic neoplasms: diagnosis and management, Gastroenterol Clin North Am 41:103–118, 2012. 42. Bassi C, Salvia R, Molinari E, et al: Management of 100 consecutive cases of pancreatic serous cystadenoma: wait for symptoms and see at imaging or vice versa? World J Surg 27:319–323, 2003. 43. Moore PS, Zamboni G, Brighenti A, et al: Molecular characterization of pancreatic serous microcystic adenomas: evidence for a tumor suppressor gene on chromosome 10q, Am J Pathol 158:317–321, 2001. 44. Mohr VH, Vortmeyer AO, Zhuang Z, et al: Histopathology and molecular genetics of multiple cysts and microcystic (serous) adenomas of the pancreas in von Hippel–Lindau patients, Am J Pathol 157:1615–1621, 2000. 45. Yasuhara Y, Sakaida N, Uemura Y, et al: Serous microcystic adenoma (glycogen-rich cystadenoma) of the pancreas: study of 11 cases showing clinicopathological and immunohistochemical correlations, Pathol Int 52:307–312, 2002. 46. Brugge WR, Lauwers GY, Sahani D, et al: Cystic neoplasms of the pancreas, N Engl J Med 351:1218–1226, 2004.

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47. Gouhiri M, Soyer P, Barbagelatta M, et al: Macrocystic serous cystadenoma of the pancreas: CT and endosonographic features, Abdom Imaging 24:72–74, 1999. 48. Lewandrowski K, Warshaw A, Compton C: Macrocystic serous cystadenoma of the pancreas: a morphologic variant differing from microcystic adenoma, Hum Pathol 23:871–875, 1992. 49. Khurana B, Mortele KJ, Glickman J, et al: Macrocystic serous adenoma of the pancreas: radiologic-pathologic correlation, AJR Am J Roentgenol 181:119–123, 2003. 50. Chatelain D, Hammel P, O’Toole D, et al: Macrocystic form of serous pancreatic cystadenoma, Am J Gastroenterol 97:2566–2571, 2002. 51. Cheng TY, Su CH, Shyr YM, et al: Management of pancreatic lesions in von Hippel–Lindau disease, World J Surg 21:307–312, 1997. 52. Belsley NA, Pitman MB, Lauwers GY, et al: Serous cystadenoma of the pancreas: limitations and pitfalls of endoscopic ultrasound-guided fine-needle aspiration biopsy, Cancer 114:102–110, 2008. 53. Hammel P, Voitot H, Vilgrain V, et al: Diagnostic value of CA 72-4 and carcinoembryonic antigen determination in the fluid of pancreatic cystic lesions, Eur J Gastroenterol Hepatol 10:345–348, 1998. 54. Jimenez RE, Warshaw AL, Z’Graggen K, et al: Sequential accumulation of K-ras mutations and p53 overexpression in the progression of pancreatic mucinous cystic neoplasms to malignancy, Ann Surg 230: 501–509, 1999. 55. Iacobuzio-Donahue CA, Wilentz RE, Argani P, et al: Dpc4 protein in mucinous cystic neoplasms of the pancreas: frequent loss of expression in invasive carcinomas suggests a role in genetic progression, Am J Surg Pathol 24:1544–1548, 2000. 56. Kadayifci A, Brugge WR: Endoscopic ultrasound-guided fine-needle aspiration for the differential diagnosis of intraductal papillary mucinous neoplasms and size stratification for surveillance, Endoscopy 46:357, 2014. 57. Napoléon B, Lemaistre AI, Pujol B, et al: A novel approach to the diagnosis of pancreatic serous cystadenoma: needle-based confocal laser endomicroscopy, Endoscopy 47:26–32, 2015. 58. Karia K, Waxman I, Konda VJ, et al: Needle-based confocal endomicroscopy for pancreatic cysts: the current agreement in interpretation, Gastrointest Endosc 83:924–927, 2016. 59. Jais B, Rebours V, Malleo G, et al: Serous cystic neoplasm of the pancreas: a multinational study of 2622 patients under the auspices of the International Association of Pancreatology and European Pancreatic Club (European Study Group on Cystic Tumors of the Pancreas), Gut 65:305–312, 2016. 60. Le Borgne J, de Calan L, Partensky C: Cystadenomas and cystadenocarcinomas of the pancreas: a multiinstitutional retrospective study of 398 cases. French Surgical Association, Ann Surg 230:152–161, 1999. 61. Master SS, Savides TJ: Diagnosis of solid-pseudopapillary neoplasm of the pancreas by EUS-guided FNA, Gastrointest Endosc 57:965–968, 2003. 62. Mergener K, Detweiler SE, Traverso LW: Solid pseudopapillary tumor of the pancreas: diagnosis by EUS-guided fine-needle aspiration, Endoscopy 35:1083–1084, 2003. 63. Romics L, Jr, Oláh A, Belágyi T, et al: Solid pseudopapillary neoplasm of the pancreas-proposed algorithms for diagnosis and surgical treatment, Langenbecks Arch Surg 395:747–755, 2010. 64. Law JK, Ahmed A, Singh VK, et al: A systematic review of solidpseudopapillary neoplasms: are these rare lesions? Pancreas 43:331–337, 2014. 65. Yu MH, Lee JY, Kim MA, et al: MR imaging features of small solid pseudopapillary tumors: retrospective differentiation from other small solid pancreatic tumors, AJR Am J Roentgenol 195:1324–1332, 2010.

66. Fasanella KE, McGrath K: Cystic lesions and intraductal neoplasms of the pancreas, Best Pract Res Clin Gastroenterol 23:35–48, 2009. 67. Jani N, Dewitt J, Eloubeidi M, et al: Endoscopic ultrasound-guided fine-needle aspiration for diagnosis of solid pseudopapillary tumors of the pancreas: a multicenter experience, Endoscopy 40:200–203, 2008. 68. Matos JM, Grützmann R, Agaram NP, et al: Solid pseudopapillary neoplasms of the pancreas: a multi-institutional study of 21 patients, J Surg Res 157:e137–e142, 2009. 69. Lee SE, Jang JY, Hwang DW, et al: Clinical features and outcome of solid pseudopapillary neoplasm: differences between adults and children, Arch Surg 143:1218–1221, 2008. 70. Butte JM, Brennan MF, Gönen M, et al: Solid pseudopapillary tumors of the pancreas. Clinical features, surgical outcomes, and long-term survival in 45 consecutive patients from a single center, J Gastrointest Surg 15: 350–357, 2011. 71. Yoon WJ, Yoon YB, Lee KH, et al: The cystic neoplasms of the pancreas in Korea, Korean J Med 70:261–267, 2006. 72. Halfdanarson TR, Rabe KG, Rubin J, et al: Pancreatic neuroendocrine tumors (PNETs): incidence, prognosis and recent trend toward improved survival, Ann Oncol 19:1727–1733, 2008. 73. Bordeianou L, Vagefi PA, Sahani D, et al: Cystic pancreatic endocrine neoplasms: a distinct tumor type? J Am Coll Surg 206:1154–1158, 2008. 74. Boninsegna L, Partelli S, D’Innocenzio MM, et al: Pancreatic cystic endocrine tumors: a different morphological entity associated with a less aggressive behavior, Neuroendocrinology 92:246–251, 2010. 75. Ahrendt SA, Komorowski RA, Demeure MJ, et al: Cystic pancreatic neuroendocrine tumors: is preoperative diagnosis possible? J Gastrointest Surg 6:66–74, 2002. 76. Marcos HB, Libutti SK, Alexander HR, et al: Neuroendocrine tumors of the pancreas in von Hippel–Lindau disease: spectrum of appearances at CT and MR imaging with histopathologic comparison, Radiology 225: 751–758, 2002. 77. Falconi M, Plockinger U, Kwekkeboom DJ, et al: Well-differentiated pancreatic nonfunctioning tumors/carcinoma, Neuroendocrinology 84:196–211, 2006. 78. Plockinger U, Wiedenmann B: Diagnosis of non-functioning neuroendocrine gastro-enteropancreatic tumours, Neuroendocrinology 80(Suppl 1):35–38, 2004. 79. Dimou AT, Syrigos KN, Saif MW: Neuroendocrine tumors of the pancreas: what’s new. Highlights from the “2010 ASCO Gastrointestinal Cancers Symposium”. Orlando, FL, USA. January 22-24, 2010, J Pancreas 11:135–138, 2010. 80. Ehehalt F, Saeger HD, Schmidt CM: Grutzmann R: Neuroendocrine tumors of the pancreas, Oncologist 14:456–467, 2009. 81. Singhi AD, Zeh HJ, Brand RE, et al: American Gastroenterological Association guidelines are inaccurate in detecting pancreatic cysts with advanced neoplasia: a clinicopathologic study of 225 patients with supporting molecular data, Gastrointest Endosc 8:1107–1117.e2, 2016. 82. Basar O, Brugge WR: Which guidelines should be used for branch-duct intraductal papillary mucinous neoplasms? Gastrointest Endosc 84: 446–449, 2016. 83. Lennon AM, Ahuja N, Wolfgang CL: AGA guidelines for the management of pancreatic cysts, Gastroenterology 149:825, 2015. 84. Brugge WR: Pancreatic cyst surveillance: threat or opportunity? Gastrointest Endosc 83:1118–1120, 2016. 85. Canto MI, Hruban RH: Managing pancreatic cysts: less is more? Gastroenterology 148:688–691, 2015. 86. Fernández-Del Castillo C, Tanaka M: Management of pancreatic cysts: the evidence is not here yet, Gastroenterology 148(4):685–687, 2015.

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62 Evaluation and Staging of Pancreaticobiliary Malignancy Michael Levy and Mohammad Al-Haddad

CHAPTER OUTLINE EUS for the Evaluation and Staging of Pancreatic Tumors, 721 Introduction, 721 EUS Detection of Pancreatic Tumors, 721 Assessment of Vascular Invasion, 724 Resectability of Pancreatic Tumors, 724 EUS-FNA of Pancreatic Cancer, 724

Pancreatic Neuroendocrine Tumors, 726 Other Pancreatic Tumors, 726 Conclusion, 727 Evaluation and Staging of Cholangiocarcinoma, 727 Introduction, 727 EUS Stricture/Tumor Detection, 728 EUS-FNA Diagnostic Accuracy, 729

EUS FOR THE EVALUATION AND STAGING OF PANCREATIC TUMORS Introduction Examination of the pancreas and biliary structures by endoscopic ultrasound (EUS) can be technically challenging to master due to the need to recognize patterns of normal, benign, and pathologic anatomy. However, once these skills are learned, EUS permits the most detailed nonoperative view of the pancreas and the bile ducts. This chapter summarizes the role of EUS for the evaluation of solid malignant pancreatic and biliary neoplasms.

EUS Detection of Pancreatic Tumors EUS is the most sensitive imaging test for the detection of all pancreatic and periampullary lesions (Table 62.1).1-8 In studies that compared EUS and computed tomography (CT), the sensitivity of EUS for mass detection was superior to CT.1–8 EUS is clearly superior to conventional CT1–3,6 and transabdominal ultrasound (US).1–3,5 A few comparative studies between EUS and multidetector-row CT (MDCT) for pancreatic tumors have demonstrated the superiority of EUS for tumor detection. There are relatively sparse comparative data between EUS and magnetic resonance imaging (MRI) for tumor detection, with at least one study showing the superiority of EUS.4 EUS is particularly useful for identification of small tumors that can go undetected by other imaging modalities.1,4,7,8 For tumors of 30 mm or less in diameter (Fig. 62.1), EUS was found in early literature to have a sensitivity of 93% compared to 53% for CT and 67% for MRI.4 Nowadays, with thinner slice imaging and precisely timed contrast administration coupled with multiplanar reconstruction, CT (often referred to as pancreas protocol) may now be able to identify

Tumor Seeding, 730 Staging and Resectability, 730 EUS Nodal Staging and Features of Malignant and Benign Lymph Nodes, 731 Potentially Confounding Variables and Complications, 732 Conclusion, 732

small pancreatic masses that previously may have been undetected by conventional or even single-detector dual-phase imaging.8 EUS remains the test of choice in all patients with obstructive jaundice or dual pancreatic and bile duct dilations in whom CT or MRI do not identify a lesion. EUS has a few limitations including the potential failure to identify true pancreatic masses in patients with chronic pancreatitis, a diffusely infiltrating carcinoma, a prominent ventral/ dorsal split, or after a recent episode (< 4 weeks) of acute pancreatitis. Therefore, a normal pancreas by EUS examination essentially rules out pancreatic cancer, although follow-up EUS or other studies should be undertaken in the setting of chronic pancreatitis due to impaired visualization. It is also important to remember that acoustic shadowing caused by an indwelling biliary or pancreatic stent may also impede visualization of a small pancreatic mass. Due to the ability of EUS to provide high-resolution images, there has been increasing interest in using this technique to screen asymptomatic high-risk cohorts for early cancer detection. A consensus statement by the International Cancer of the Pancreas Screening Consortium recommended screening with EUS and/ or MRI for the following groups: first-degree relatives (FDRs) of patients with pancreatic cancer from a familial pancreatic cancer kindred with at least two affected FDRs; Peutz-Jeghers syndrome; p16 or BRCA2 mutations; and hereditary nonpolyposis colorectal cancer mutation carriers with 1 or more affected FDRs.9 A 2016 comparative analysis highlighted the complementary roles EUS and MRI play in screening these high-risk individuals.10 MRI was found to be more sensitive for the detection of cystic lesions of any size; EUS, however, detected more solid lesions then MRI. The optimal screening modality, interval, need for

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CHAPTER 62 Evaluation and Staging of Pancreaticobiliary Malignancy

Abstract

Keywords

Endoscopic ultrasound (EUS) permits the most detailed nonoperative view of the pancreas and extrahepatic biliary system that is available. This facilitates the detection of malignant pancreaticobiliary lesions at an early stage before such lesions become detectable by conventional cross-sectional imaging like computed tomography (CT) or magnetic resonance (MR). The tissue acquisition (TA) capabilities of EUS add a substantial depth to its clinical applications, providing a safe and accurate method to confirm various types of pancreaticobiliary pathologies prior to initiation of therapy. EUS continues to play an important role in the care of pancreaticobiliary malignancies by triaging patients to operative or non-operative care largely due to its ability to detect early metastasis and vascular invasion. Recently, EUS provided a solid platform for a variety of novel tissue and imaging-based technologies that can help render better-quality care to this group of patients. This chapter summarizes the role of EUS for the evaluation of solid malignant pancreatic and biliary neoplasms.

endoscopic ultrasound pancreatic cancer bile duct cancer fine-needle aspiration cancer staging

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721.e1

722

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Sensitivity (%) of EUS Compared to Other Imaging Tests for Detection of Pancreatic Masses TABLE 62.1

Author (yr)

EUS

CT

Rosch et al. (1991)1

No. Patients 102

99

77

67

Rosch et al. (1992)2

60

98

85

78

Palazzo et al. (1993)

49

91

66

Muller et al. (1994)4

33

94

69

Sugiyama et al. (1997)5

73

96

86

Gress et al. (1999)6

81

100

74

Agarwal et al. (2004)7

71

100

86

DeWitt et al. (2004)8

80

98

86

3

MRI

US

64 83 81

CT, computed tomography; EUS, endoscopic ultrasound; MRI, magnetic resonance imaging; US, ultrasound.

FIG 62.2 Endoscopic ultrasound images of autoimmune pancreatitis presenting as a hypoechoic mass in the head of the pancreas with dilation of the common bile duct. CONF, Portovenous confluence; HOP, head of pancreas.

meta-analysis of 12 studies involving 1139 patients reported a pooled sensitivity, specificity, and receiver operating characteristic (ROC) of 94%, 89%, and 0.9732, respectively.14 EUS elastography is another emerging technique based on the different stiffness of benign and malignant tissue. In a meta-analysis of 13 studies involving 1044 patients, the pooled sensitivity, specificity, and ROC was 95%, 67%, and 0.90.15 However, several limitations to their routine use exist and include costs and the lack of both agent availability and expertise with the technique. FIG 62.1 Endoscopic ultrasound images of a 2.9-cm hypoechoic, irregular pancreatic body mass encasing the splenic vessels. SA, Splenic artery; TU, tumor.

fine-needle aspiration (FNA), and screening abnormalities of sufficient concern for surgery remain unknown, and further studies are required to answer these questions. Autoimmune pancreatitis (AIP) may mimic pancreatic adenocarcinoma, and accurate preoperative detection may avoid unnecessary surgery. The EUS morphology of AIP may include diffuse pancreatic enlargement, a focal mass, focal hypoechoic areas, bile duct wall thickening, or peripancreatic lymphadenopathy (Fig. 62.2).11 EUS-guided fine-needle aspiration (EUS-FNA) may demonstrate a nonspecific plasmacytic predominant chronic inflammatory infiltrate, but this finding has variable sensitivity and poor specificity. Diagnosis may be confirmed by EUS-guided core biopsies with staining for IgG4 plasma cells.12,13 Imaging-based technologies such as contrast-enhanced ultrasonography (CE-EUS) may be able to differentiate pancreatic adenocarcinoma from pancreatic neuroendocrine tumors (PNETs) and inflammatory pseudotumors, which can all present as a hypoechoic mass. Whereas ductal adenocarcinomas typically demonstrate hypoenhancement, PNET and inflammatory pseudotumors are hyperenhancing or isoenhancing. A recent

Staging of Pancreatic Adenocarcinoma Staging of pancreatic malignancy is done according to the American Joint Committee for Cancer (AJCC) Staging TNM classification, which describes the tumor extension (T), lymph node (N), and distant metastases (M) of tumors, respectively. Reported accuracies of T-staging by EUS range from 62% to 94% (Table 62.2).2–4,6,8,16–21 This wide variation may be due to improved detection of distant metastasis or vascular invasion by MDCT, resulting in less operative management for suspected locally advanced or metastatic disease. The exclusion of such patients may have resulted in the decreased T-staging accuracy of some recent studies compared to earlier ones. For the last decade, some tertiary referral centers will attempt to achieve negative surgical margins by surgical resection with or without reconstruction of the portal and/or superior mesenteric vein in patients with venous invasion without thrombosis or occlusion. Currently, only vascular invasion of the celiac or superior mesenteric arteries is classified as T4 cancer (Box 62.1). Nodal (N) metastases have uniformly been classified as absent (N0) or present (N1) across all AJCC editions. The accuracy of EUS for N-staging of pancreatic tumors ranges from 50% to 86%.2–4,6,8,17–19 Various criteria have been proposed for endosonographic features of metastatic lymph nodes including: size greater than 1 cm, hypoechoic echogenicity, distinct margins, and round shape. When all four features are present within a lymph node, there is an 80% to 100% chance of malignant invasion.22 However,

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CHAPTER 62 Evaluation and Staging of Pancreaticobiliary Malignancy

723

TABLE 62.2 Accuracy of EUS for Tumor (T) and Nodal (N) Staging of Pancreatic Cancer No. Patients to Surgery With No. N T Enrolled Pancreatic Stage Stage Patients Cancer

Author (year) Rosch et al. (1992)2

60

40

NR

72

Rosch et al. (1992)18

46

35

94

80 64

Palazzo (1993)

3

64

49

82

Muller (1994)4

49

16

82

50

Midwinter et al. (1999)17

48

23

NR

74

151

75

85

72

Gress et al. (1999)6 16

Ahmad (2000)

NA

89

69

54

Soriano et al. (2004)19

127

62

62

65

DeWitt et al. (2004)8

104

53

67

41

Shami et al. (2011)21

50

50

80

NR

127

48

71*

NR

Tellez-Avila et al. (2012)20

FIG 62.3 A 9-mm oval hypoechoic hepatic nodule in a patient with a pancreatic mass. Fine-needle aspiration of the liver nodule demonstrated metastatic adenocarcinoma of pancreatic origin. LVH, Left hepatic vein.

*Reported as accuracy for overall stage. EUS, endoscopic ultrasound; NA, not applicable; NR, not reported.

American Joint Committee on Cancer (AJCC) 2010 TNM Staging Classification for Pancreatic Cancer

BOX 62.1

Primary tumor (T) TX: Primary tumor cannot be assessed T0: No evidence of primary tumor Tis: Carcinoma in situ T1: Tumor limited to the pancreas, 2 cm or less in greatest dimension T2: Tumor limited to the pancreas, more than 2 cm in greatest dimension T3: Tumor extends beyond the pancreas but without involvement of the celiac axis or the superior mesenteric artery T4: Tumor involves the celiac axis or the superior mesenteric artery (unresectable primary tumor)

Regional lymph nodes (N) NX: Regional lymph nodes cannot be assessed N0: No regional lymph node metastasis N1: Regional lymph node metastasis

Distant metastasis (M) MX: Distant metastasis cannot be assessed M0: No distant metastasis M1: Distant metastasis

AJCC Stage Groupings Stage Stage Stage Stage Stage Stage Stage

0: Tis, N0, M0 IA: T1, N0, M0 IB: T2, N0, M0 IIA: T3, N0, M0 IIB: T1, N1, M0 or T2, N1, M0 or T3, N1, M0 III: T4, any N, M0 IV: Any T, any N, M1

From Edge SB, Byrd DR, Compton CC, et al (editors): American Joint Committee on Cancer: AJCC Cancer Staging Manual, 7th ed. New York, Springer, 2010, pp 241–250.

sensitivity of EUS for malignant lymphadenopathy is often lower, presumably for two reasons. First, most metastatic lymph nodes do not have all four endosonographic features described previously. Second, peritumoral inflammation and large tumor size may obscure visualization of adenopathy. The specificity of EUS alone for the diagnosis of metastatic adenopathy in pancreatic cancer is 26% to 100%,3,4,17,19 with most reported specificities being above 70%. It is presumed that the addition of EUS-FNA of suspicious lymph nodes may increase specificity, although little data support this. For tumors involving the head of the pancreas, malignant lymph nodes are removed en bloc, with the surgical specimen and accurate detection of these lymph nodes not essential. However, as preoperative identification and EUS-FNA of celiac nodes may preclude surgery, meticulous survey of this region is critical during staging of all pancreatic tumors. Mediastinal lymph node metastases occur in a minority of patients and thus, a brief survey of this region may be helpful during staging of pancreatic lesions. Although early studies found EUS to be superior to conventional CT for tumor3,4 and nodal2–4 staging of pancreatic cancer, more recent studies have found that the two are equivalent for both tumor17,19 and nodal staging.8,17,19 Similarly, early experience reporting on the superiority of EUS over MRI3,4 have been replaced by more recent data that have found little to no difference.19,21,23 Clearly, the initial advantage demonstrated by EUS over other imaging modalities for the staging of pancreatic tumors has narrowed considerably due to the rapid advancement in imaging technologies. For detection of non-nodal metastatic cancer, CT and MRI are superior to EUS due to both the anatomic limitations of normal upper gastrointestinal anatomy and the limited range of EUS imaging. However, EUS still has an important role in the evaluation of hepatic metastasis in the left or caudate lobe and malignant ascites, both of which may be accessible by EUS-FNA (Fig. 62.3). Identification of liver metastases or malignant ascites by EUS-FNA may preclude surgical resection and is associated with poor survival following diagnosis.24

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724

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Pancreaticobiliary Disorders

Assessment of Vascular Invasion Interpretation of data regarding the accuracy of EUS for vascular invasion is difficult for several reasons. First, there is little histologic correlation with intraoperative findings regarding vascular invasion in most studies. Second, there is no established consensus among endosonographers for the optimal criteria to utilize for determination of vascular invasion. Consequently, multiple criteria have been proposed by various authors for this indication. For overall vascular invasion, the accuracy of EUS ranges from 68% to 93%.6,19,23,25 Sensitivity and specificity of EUS for malignant vascular invasion range from 42% to 91% and 89% to 100%, respectively.6,19,23,25 Although some have reported EUS as more accurate6 than CT for vascular invasion, others report the opposite.19,23 Overall accuracy of MRI is reportedly equivalent19 or superior23 to EUS. The sensitivity of EUS for tumor invasion of the portal vein (PV) or PV confluence is 60% to 100%2,5,17,18,26 with most studies demonstrating sensitivities over 80% (Fig. 62.4). The sensitivity of EUS for PV invasion is consistently superior to that of CT.2,5,17,18 For the superior mesenteric vein, superior mesenteric artery (SMA), and celiac artery, the sensitivity of EUS is only 17% to 83%,25 17%,27 and approximately 50%,2,18 respectively. The sensitivity of CT for staging of the SMA17,27 and celiac artery2,18 appear to be better than EUS. EUS staging of the superior mesenteric vessels may be difficult due to either the inability to visualize the entire course of the vessel or the obscuring of these vessels by a large tumor in the uncinate or inferior portion of the pancreatic head.26 This is in contrast to the splenic artery and vein, which are generally easily seen and staged well by EUS.18,26 Until further conclusive data become available, assessment of tumor resectability should be done by both EUS and CT (or MRI) rather than by EUS alone. Several studies have attempted to describe the accuracy of various endosonographic features to assess vascular invasion by malignant pancreatic tumors. Using the criteria of abnormal contour, loss of hyperechoic interface, and close contact, Rosch et al (1992)2 found a sensitivity, specificity, and accuracy of 91%, 96%, and 94%, respectively, for invasion of the PV. The same

authors later found that no single criterion was able to predict venous invasion with a sensitivity and specificity exceeding 80%.26 However, they found that both complete vascular obstruction and the presence of collaterals demonstrated a specificity of 94% for vascular invasion. There exists a tradeoff between various criteria for sensitivity and specificity for vascular invasion. However, criteria with the highest specificity are needed to optimize selection of those most likely to benefit from surgical exploration. Therefore, the findings of an irregular vascular wall, venous collaterals and visible tumor within the vessel are the preferred criteria for assessment of vascular invasion.

Resectability of Pancreatic Tumors Complete surgical resection of pancreatic cancer with negative histopathologic margins (R0 resection) is the only potentially curative treatment and is an independent predictor of postoperative survival.28,29 Therefore, the main role of preoperative evaluation is to accurately identify patients with resectable disease who may benefit from surgery while avoiding surgery in patients with suspected unresectable disease (Fig. 62.5). In a pooled analysis of 9 studies involving 377 patients, the sensitivity and specificity of EUS for resectability of pancreatic cancer was 69% and 82%, respectively.6,8,16,19,23,25,30–32 Ranges of reported sensitivities and specificities were 23% to 91% and 63% to 100%, respectively. Overall EUS accuracy for tumor resectability was 77%. Because most studies have reported that EUS is similar to both CT and MRI for assessment of resectability, some authors have proposed that optimal preoperative imaging of pancreatic cancer requires the use of multiple modalities. Using a decision analysis, Soriano et al (2004)19 found that accuracy for tumor resectability was maximized and costs were minimized when CT or EUS was performed initially, followed by the other test in those with potentially resectable neoplasms. Ahmad et al (2000)16 proposed that although EUS and MRI individually are not sensitive for tumor resectability, their use together may increase positive predictive value of resectability compared to either test alone. When surgery is performed only when MDCT and EUS agree on tumor resectability, DeWitt et al (2004)8 reported a nonsignificant trend toward improved accuracy of resectability compared to either study alone. However, a study by Bao et al (2008)33 found that MDCT was a better predictor of resectability than EUS, although the performance of EUS improved in patients without biliary stents. From a practical standpoint, the actual role of EUS in staging of pancreatic cancer will depend on its availability, referral patterns, and local expertise.

EUS-FNA of Pancreatic Cancer

FIG 62.4 A pancreatic head mass with direct invasion into the portal vein (PV) and superior mesenteric artery (SMA). CON, Portovenous confluence.

EUS-FNA remains the preferred method to sample pancreatic mass lesions due to its high accuracy, well demonstrated by two meta-analyses that reported sensitivity and specificity in the range of 85% to 89% and 96% to 98%, respectively.34,35 However, the diagnostic accuracy of EUS-FNA may be impaired in the setting of chronic pancreatitis. Fritscher-Ravens et al (2002)36 found that in a series of 207 consecutive patients with focal pancreatic lesions, the sensitivity of EUS-FNA for the diagnosis of malignancy in patients with normal parenchyma (89%) was superior to those with parenchymal evidence of chronic pancreatitis (54%). On-site cytopathology review is available currently at most referral centers to provide immediate feedback to the endosonographer about the quality of EUS-FNA specimens obtained. On-site

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CHAPTER 62 Evaluation and Staging of Pancreaticobiliary Malignancy

725

Suspected pancreatic cancer

Multidetector CT scan

Pancreatic mass Clearly unresectable

ERCP if needed, EUS-FNA

Equivocally resectable

No pancreatic mass or equivocal

Clearly resectable Unfit for surgery fit for ERCP if ERCP if surgery needed needed

Surgery

fit for surgery

Systemic therapy for palliation, celiac block, Surgery

EUS-FNA

EUS unresectable EUS resectable Palliation

FIG 62.5 Endoscopic ultrasound based management algorithm for suspected pancreatic cancer. CT, computed tomography; ERCP, endoscopic retrograde cholangiopancreatography; EUS, endoscopic ultrasound; FNA, fine-needle aspiration.

review was found to correlate highly with the final diagnosis and can improve diagnostic certainty.37 Occasionally, on-site cytology review of a suspected pancreatic cancer demonstrates insufficient tissue to confirm malignancy. This may be due to tumor necrosis, fibrosis, or hypervascularity. Yield may be increased by “fanning the lesion” using different angles of scope deflection in order to sample the peripheral parts of the lesion with a more viable tumor.38 Increasing the number of passes may also overcome this problem, but the additional yield typically plateaus at 7 passes, and the amount of blood in the aspirate may increase with additional passes.39 In this situation, avoiding suction and switching to a smaller-gauge needle could help limit the amount of blood in the specimen. Improving the yield of EUS-FNA by modifying the current sampling techniques has been the focus of several recent studies. Among the factors found to not increase the diagnostic yield include replacing the stylet after every pass.40 Use of suction during FNA is generally recommended for pancreatic solid lesions but not for associated adenopathy due to increase in bloodiness of the sample.40 Other novel techniques involving wet suction instead of vacuum, and the capillary stylet withdrawal technique showed superior diagnostic yield and cellularity and is discussed elsewhere in this book.41,42 The most commonly used commercially available EUS-FNA needles are 19-, 22- and 25-gauge needles. The impact of needle size on the diagnostic accuracy of EUS-FNA has been an area of uncertainty until recently. In a meta-analysis of 8 studies involving 1292 patients who underwent EUS-FNA with either a 22- or 25-gauge needle and had surgical histology or at least 6 months follow-up as the reference standard, Madhoun et al (2013)43 reported that the sensitivity of the 25-gauge needle was superior to the 22-gauge (93% vs. 85%, p = 0.0003), although they have comparable specificity (97% and 100%, respectively).

Major complications following EUS-FNA of solid pancreatic masses occur in 0.5% to 2.5% of patients, including a 1.2% risk of pancreatitis and a 1% risk of severe bleeding.44–46 In another prospective study, no delayed complications following EUS-FNA were reported in 127 patients with solid pancreatic masses followed for 30 days.46 The risk of peritoneal seeding of tumor cells following EUS-FNA (2.2%) appears to be less than CT-guided FNA (16.3%) but requires further study.47 Despite excellent accuracy and a low incidence of major complications, EUS-FNA of pancreatic masses has several limitations. First, an on-site cytopathologist during EUS-FNA is recommended for assessment of specimen adequacy but is not available at some centers. Second, primary pancreatic lymphomas and well-differentiated ductal adenocarcinomas are often difficult to diagnose by use of cytology alone. Finally, the low negative predictive value of EUS-FNA does not permit exclusion of malignancy in negative specimens. To address these limitations, core biopsy devices have been developed to obtain histological tissue samples using a standard linear array echoendoscope. Two such devices include the Quick-Core and ProCore biopsy needles (Cook Medical, Bloomington, IN). In a multi-center cohort study of 109 patients with intestinal and extra-intestinal lesions (including 47 pancreatic tumors), the ProCore needle provided adequate histology and a correct diagnosis in 96% and 89% of cases, respectively.49 However, a recent meta-analysis comparing the performance of the ProCore needle with standard FNA needles, including nine studies of 576 patients, demonstrated no difference in diagnostic adequacy (75% vs. 89%), diagnostic accuracy (86% vs. 86%) or rate of histological core specimen acquisition (78% vs. 77%) between the ProCore and standard FNA needles, respectively. The mean number of passes required for diagnosis, however, was significantly lower when using the ProCore needle

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SECTION III

Pancreaticobiliary Disorders

(standardized mean difference 1.2, p < 0.001).49 Nevertheless, ProCore biopsy needles will continue to have niche applications including autoimmune pancreatitis12 and lymphoma,50 where its superiority has been demonstrated. In addition, core biopsy needles could be used as a rescue technique when on-site FNA results are inconclusive or if this service is not available. Some investigators have evaluated whether analysis of abnormal genes may increase the diagnostic yield of EUS-FNA of pancreatic masses. A meta-analysis of 8 prospective studies, involving 931 patients who had k-ras mutation, reported a pooled sensitivity and specificity of 77% and 93%, respectively.51 When combined with EUS-FNA alone, the addition of k-ras mutation testing increased sensitivity from 81% to 89% but reduced specificity from 97% to 92%. Fluorescence in situ hybridization is another assay that was found to augment the sensitivity of cytology alone by 11%, according to Levy et al (2012).52 Due to the high diagnostic accuracy of standard EUS-FNA, as well as the cost and limited availability of these genetic tests, it appears that use of genetic testing of EUS-FNA samples should be limited to inconclusive specimens and research protocols. Additional assays (like microRNAs and proteomics) are being evaluated on an experimental basis,53 but clinical studies are needed to define its role in the diagnostic work-up of pancreatic tumors.

Pancreatic Neuroendocrine Tumors PNETs are rare solid, cystic or mixed neoplasms that represent less than 10% of pancreatic tumors (Fig. 62.6). Approximately one-third of these tumors are classified as functional PNETs (FPNETs) in which excessive hormone secretion produces a distinct clinical syndrome. The two most clinically important FPNETs are gastrinomas and insulinomas. When PNETs do not produce a clinical syndrome, they are classified as nonfunctional (NFPNETs). Due to a lack of characteristic symptoms related to hormone excess, NFPNETs are usually recognized later, with larger tumors and nonspecific symptoms such as jaundice, weight loss, abdominal pain, or pancreatitis. Similar to primary ductal adenocarcinoma, surgical resection is the only cure for these tumors. Therefore, a high index of suspicion coupled with a stepwise preoperative evaluation for localization may optimize patient selection for potentially curative surgery.

In a series of studies that compared EUS to other imaging modalities, the sensitivity of EUS for detection of PNETs was 77% to 94%.54–58 EUS appears especially useful for detection of small PNETs (< 2.5 cm) missed by other imaging studies. The sensitivity of transabdominal ultrasound for detection of PNETs is poor and only between 7% and 29%.54,55,57 Similarly, early studies with CT demonstrated poor sensitivity that was generally less than 30%.54,55,57 However, with ongoing improvements in CT scanners and the development of MDCT, the sensitivity of CT for PNETs has improved. In their study of 217 patients with 231 PNETs, Khashab et al (2011)59 reported an overall sensitivity for MDCT of 84%. Factors associated with reduced sensitivity include small lesions less than 2 cm in diameter and insulinomas, which had a sensitivity of 54%. Among the 56 patients who had both CT and EUS, the sensitivity of EUS was far greater than CT (91.7% vs. 63.3%, p = 0.0002). Whereas MDCT is a suitable initial imaging modality for PNET, EUS provides cytologic confirmation and the detection of suspected CT negative PNET. In addition, EUS is the preferred initial imaging modality for insulinomas due to the low sensitivity of MDCT. In addition to their known role in assessing cystic lesions, MRI is an excellent imaging modality for PNET with sensitivity of 85% to 100%.60,61 The use of EUS-FNA permits tissue confirmation of a suspected PNET. In a retrospective study of 30 patients, Ardengh et al (2004)62 reported a sensitivity, specificity, positive and negative predictive values, and accuracy of EUS-guided FNA of 82.6%, 85.7%, 95%, 60%, and 83.3%, respectively for tumor diagnosis. In a larger 2012 study of 81 patients, EUS-FNA correctly diagnosed a PNET in 73 out of 81 patients, with a diagnostic accuracy of 90.1%.63 For cystic PNETs, the use of FNA was studied by Ridtitid et al (2015) in a case-controlled study comprising 50 patients with cystic PNETS compared to a cohort of 50 patients with solid PNETS over a 14-year period.64 EUS-FNA accuracies for malignancy of cystic and solid PNETs were 89% and 90%, respectively; cystic PNETs were less associated with metastatic adenopathy (22% vs. 42%, p = 0.03) and liver metastasis (0% vs. 26%, p < 0.001). Cyst fluid analysis showed that benign cystic PNETs had low carcinoembryonic antigen, Ki-67 (< 2%). Immunocytochemistry staining for synaptophysin was seen in all 100 cases included in the study, whereas chromogranin A was positive in 90% and 88% of the cystic and solid PNETs, respectively. Preoperative EUS-guided tattooing has been demonstrated to aid in intraoperative localization of an insulinoma,65 and more recently demonstrated to be of utility for all small pancreatic lesions.66 This information may confirm clinically suspected tumors and aid in appropriate planning of medical or surgical management.

Other Pancreatic Tumors

FIG 62.6 Thick-walled cystic tumor in the head of the pancreas diagnosed on fine-needle aspiration (FNA) as a neuroendocrine tumor.

Primary pancreatic lymphoma (PPL) is rare and accounts for less than 0.5% of pancreatic tumors.67 They are localized to the pancreas and peripancreatic lymph nodes and, by definition, do not involve other lymphoid tissue. PPL may present as a hypoechoic mass with poorly defined borders indistinguishable from pancreatic adenocarcinoma (Fig. 62.7). Whereas EUS and radiographic imaging alone may not confirm the diagnosis, EUS-FNA with flow cytometry is very accurate for PPL. In a case series of 16 patients with PPL, Khashab et al (2010)68 reported a sensitivity and specificity of EUS-FNA with cytology and flow cytometry of 85% and 100%, respectively. This is in contrast to EUS-FNA with cytology alone, which had a sensitivity and

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CHAPTER 62 Evaluation and Staging of Pancreaticobiliary Malignancy

727

Conclusion We can confidently state that EUS has passed the test of time as the modality of choice for the detection of pancreatic tumors, mainly small solid lesions. Although the competitive edge of EUS in the staging of pancreatic tumors appears to be eroding due to the rapid improvement in imaging technologies, the role that EUS plays in predicting their resectability remains obvious due to its ability to detect occult metastasis missed by other preoperative imaging studies. EUS-guided tissue acquisition is essential in the management of pancreatic tumors, mainly due to its high accuracy and low overall morbidity and mortality. Tissue confirmation is of particular importance in pancreatic cancer where the majority of patients are unresectable and tissue is needed prior to initiation of any systemic palliative therapies or neoadjuvant therapy in some potentially resectable patients. Finally, EUS-guided tissue helps triage the patients to the appropriate care in some conditions presenting as pancreatic cancer, such as pancreatic lymphoma and autoimmune pancreatitis. FIG 62.7 A well-delineated hypoechoic mass in the pancreatic tail adjacent to a cyst, diagnosed on FNA as a primary pancreatic lymphoma.

EVALUATION AND STAGING OF CHOLANGIOCARCINOMA Introduction

specificity of less than 30%. This diagnosis should be suspected based on clinical appearance, lack of definite malignancy, and abundance of abnormal lymphocytes on rapid cytological review. Isolated pancreatic masses are usually due to focal chronic pancreatitis, benign neoplasms, or primary pancreatic malignancies. Rarely, metastasis to the pancreas from another primary malignancy occurs and has been reported in 2% to 3% of pancreatic resections.69 Accurate identification of isolated pancreatic metastases is clinically important because aggressive surgical resection in selected patients may permit long-term survival. In other patients, however, proper diagnosis may avoid unnecessary surgery and permit triage to more appropriate nonoperative therapy. EUS features of pancreatic metastases appear to be different from those observed in cases of primary pancreatic cancer. In 7 patients with metastatic pancreatic lesions, Palazzo et al (1996)70 described homogeneous, round, well-circumscribed lesions in 15 out of 16 masses observed. Compared to patients with primary cancer (n = 80), DeWitt et al (2005)71 found that pancreatic metastases (n = 24) were more likely to have well-defined borders compared to irregular margins. In another report of 11 patients with metastatic renal cell carcinoma (RCC),72 ten had well-defined borders (Video 62.1). Therefore, it appears that EUS visualization of a well-defined pancreatic mass in a patient with a history of malignancy should raise suspicion for a metastatic lesion. EUS-FNA permits an accurate cytologic diagnosis of metastatic lesions to the pancreas. In the largest series to date of 72 masses in 49 patients, El Hajj et al (2013)73 reported metastatic lesions from the kidney (n = 21), lung (n = 8), skin (n = 6), colon (n = 4), breast (n = 3), small bowel (n = 2), stomach (n = 2), liver (n = 1), ovary (n = 1), and bladder (n = 1). Metastasis to the pancreas may occur many years (especially for RCC) after diagnosis of the primary tumor. In patients with a remote history of malignancy, obtaining additional cytological material for cell block and the use of immunocytochemistry may be helpful to confirm the diagnosis of pancreatic metastases and recurrent malignancy.

Cholangiocarcinoma (CCA) is rare tumor that is occurring with increasing frequency and develops from bile duct epithelium found within the intrahepatic and extrahepatic biliary tree, excluding the ampulla or gallbladder.74 CCA is associated with a poor prognosis largely due to the tumor biology, late presentation, and difficulty in diagnosis. For hilar CCA, the 5-year survival after resection is 20% to 40%, largely dependent on tumor stage.75–78 Liver transplantation of unresectable hilar CCA has a 5-year survival that approaches 75%.79–81 Diagnostic and staging procedures must be improved to help identify patients most apt to benefit from these aggressive medical and surgical therapies, especially in regard to liver transplantation. This information helps direct resource utilization and allocation of scarcely available organs. The limitations of diagnostic and staging modalities largely encouraged the new technology development. One such technology, EUS has seen a growing use for CCA due to its unprecedented imaging and tissue acquisition capabilities. However, there is some controversy regarding the role of EUS in CCA, especially as it pertains to the use of primary tumor FNA. Although FNA enhances diagnosis, it does so at the risk of tumor seeding. Whereas EUS findings help guide patient care and improve outcomes, misdirected use may result in iatrogenic upstaging and compromise patient care. An aim of this section is to suggest a role for EUS in patients with suspected or known extrahepatic CCA based on published data. These data must be carefully considered because some investigators preselected patients with a suspected or confirmed CCA, versus others who evaluated a broader cohort having a “biliary stricture,” “jaundice,” or “pancreatic head mass”82–87 (Table 62.3). Enrollment from a diverse patient cohort does help determine the role of EUS among patients with a given symptom or presentation. However, such studies often lack the ideal target enrollment population and often provide insufficient detail to establish the role of EUS in this setting (see Tables 62.3 and 62.4).82–87 Another potential limitation when drawing any conclusion from existing studies of patients with CCA is the lack of clarity regarding the tumor location within the biliary tree. The

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SECTION III

TABLE 62.3

Pancreaticobiliary Disorders

Study Design, Inclusion Criteria, Enrollment, and Tumor Site for EUS Literature Study Total Enrollment Population

PRIMARY STRICTURE/TUMOR SITE AND NUMBER PER SITE

Study

Design

Inclusion Criteria

Mohamadnejad (2011)87

Retrospective

Known cholangiocarcinoma

81

81

Proximal Distal

Rosch et al. (2004)86

Prospective

Indeterminate biliary stricture or pancreatic head mass

50

50

Hilar CBD

Eloubeidi et al. (2004)85

Prospective

Bile duct stricture Suspected cholangiocarcinoma1

28

253

Proximal Distal

15 13

Lee et al. (2004)84

Retrospective

Known or suspected bile duct stricture Prior intraductal tissue sampling, if any, negative Prior CT and/or MRI failed to demonstrate the cause

42

404

CHD CBD

1 39

Byrne et al. (2004)83

Retrospective

Bile duct mass or stricture with biliary EUS FNA

35

315

CHD CBD

3 32

Fritscher-Ravens et al. (2003)81

Prospective

Clinical suspicion of hilar cholangiocarcinoma ERC2 with nondiagnostic tissue sampling Fit for hepatic resection

44

44

Hilar

44

280

271

“Perihilar”6 “Distal”7

30 51 4 8

97 (40%) 143 (60%)

1

Patients ultimately found to have pancreatic cancer or nodal metastasis were excluded. Endoscopic retrograde cholangiography. 3 patients were excluded because the tumor could not be visualized with linear imaging. 4 2 patients were excluded because of inadequate follow-up. 5 4 patients were excluded because of the absence of a diagnostic gold standard. 6 We employ the term perihilar to represent tumors designated as hilar, common hepatic duct, or proximal. 7 We employ the term distal to represent tumors designated as distal or common bile duct. CBD, common bile duct; CHD, common hepatic duct; CT, computed tomography; EUS, endoscopic ultrasound; FNA, fine-needle aspiration; MRI, magnetic resonance imaging. 2 3

TABLE 62.4

Tumor Type and EUS Stricture/Tumor Detection

Details Regarding Malignancy

Primary Stricture/Tumor Detection With EUS (Grouped Data)

Primary Stricture/Tumor Detection With EUS (CCA Patients Alone)

Study

Benign Versus Malignant

Mohamadnejad et al. (2011)87

Malignant Benign

81 0

Cholangiocarcinoma (n = 81)

N/A

76 of 81 (94%)3

Rosch et al. (2004)86

Malignant Benign

28 22

Cholangiocarcinoma (n = 12) Pancreatic (n = 16)

47 of 50 (94%)

11 of 12 (92%)

Eloubeidi et al. (2004)85

Malignant Benign

21 4

Cholangiocarcinoma (n = 21)

25 of 28 (89%)

~

Lee et al. (2004)84

Malignant Benign

24 16

Cholangiocarcinoma/Pancreatic (n = 23)1 Metastatic (n = 1)

40 of 40 (100%)

~

Byrne et al. (2004)83

Malignant Benign

14 17

Cholangiocarcinoma/Pancreatic (n = 11)1 Metastatic (n = 3)

(Preselected)2

~

Fritscher-Ravens et al. (2003)82

Malignant Benign

36 8

Cholangiocarcinoma (n = 30)1 Metastatic (n = 6)

44 of 44 (100%)

~

Summary

Malignant Benign

Cholangiocarcinoma (n = 144-178)1

156 of 162 (96%) (excluding preselected)

87 of 93 (94%)

204 (73%) 76 (27%)

1 Patients with cholangiocarcinoma cannot be reliably distinguished because the studies combine data from patients with other pathologies (e.g., pancreatic carcinoma, metastatic biliary lesions). Therefore, some of the following analyses are based on grouped data. 2 The cited study included preselected patients whose enrollment necessitated endoscopic ultrasound (EUS) visualization and fine-needle aspiration (FNA). Therefore, the findings do not apply in terms of stricture/tumor detection. 3 Tumor detection varied by site: Proximal 25/30 (83%) versus distal 51/51 (100%). CCA, cholangiocarcinoma.

clinical presentation, diagnostic approach, and management vary for tumors within the proximal versus distal extrahepatic duct. Therefore, uncertainty regarding the tumor location leaves uncertainty as to how best to interpret and apply the data. Likewise, there are no published data to guide the use of EUS for intrahepatic CCA. To facilitate our discussion, we use the term perihilar to indicate tumors that studies designated as hilar,

common hepatic duct, or proximal,88 and use the term distal to represent tumors designated as distal or common bile duct (Video 62.2).

EUS Stricture/Tumor Detection Studies indicate that EUS imaging (not necessarily with FNA confirmation), identified 156 of 162 (96%) biliary strictures or

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729

CHAPTER 62 Evaluation and Staging of Pancreaticobiliary Malignancy TABLE 62.5

Details Regarding Performance of EUS FNA

Study

Onsite Review Available

Number of FNA Performed 87

Cytological Interpretations Indicative of a Positive FNA Test Result

Mohamadnejad et al. (2011)

Median 5 Passes (range 1–12)

Yes

Positive or Suspicious

Rosch et al. (2004)86

≥ 2 passes with material sufficient for assessment3 Mean 2.8 passes (range 2–4)

No

Only Positive

Eloubeidi et al. (2004)85

≥ 5 passes unless onsite review confirmed malignant cells Median 3 passes (range 1–7)

Yes

Dual Analyses2

Lee et al. (2004)84

Until adequate cellularity or ≥ 5 passes Mean 2.8 passes

Yes

Dual Analyses2

Range 2–7 passes

Yes1

Dual Analyses2

2 or 3 passes

No

Dual Analyses2

Byrne et al. (2004)83 82

Fritscher-Ravens et al. (2003) 1

On-site cytopathology review available in 32 of 35 patients. Data provided when considering “Positive” for malignancy as the only indicator of a positive test result. Authors also provided data when considering either a “Positive” or “Suspicious” interpretation as indicative of a positive test result. 3 Based on gross inspection by the endosonographer who deemed the material sufficient when visible material was identified. EUS, endoscopic ultrasound; FNA, fine-needle aspiration. 2

TABLE 62.6

Diagnostic Sensitivity

of EUS FNA “Positive” or “Suspicious” Interpretation Equates to Positive for Malignancy

Study Mohamadnejad et al. (2011)87 86

Rosch et al. (2004)

54/74 (73%)1 ~

Only “Positive” Interpretation Equates to Positive for Malignancy ~ 3/11 (27%)

Eloubeidi et al. (2004)85

18/21 (86%)

17/21 (75%)

Lee et al. (2004)84

11/24 (47%)

7/24 (29%)

83

Byrne et al. (2004)

Fritscher-Ravens et al. (2003)82

9/14 (64%)

6/14 (43%)

32/36 (89%) 124/169 (73%)

30/36 (83%) 63/106 (59%)

FIG 62.8 Endoscopic ultrasound guided fine-needle aspiration for sampling of a common hepatic duct cholangiocarcinoma.

~ Indicates that data were not provided. 1 The diagnostic sensitivity was significantly greater when sampling distal versus proximal CCA; 38 of 47 (81%) versus 16 of 27 (59%), p = 0.04. EUS, endoscopic ultrasound; FNA, fine-needle aspiration.

tumors.82,84–86 In the two studies that clearly and specifically reported their data for CCA patients, EUS imaging detected 87 of 93 (94%) primary tumors.86,87 One study provided separate data for proximal versus distal tumors and noted that proximal CCA was identified less often than distal CCA; 25 of 30 (83%) versus 51 of 51 (100%), respectively.87

10% to 30%, but in combination with standard cytology and biopsy still offer a composite sensitivity of only 60% to 70% in most series.92–94 Published reports show a diagnostic sensitivity for primary tumor EUS FNA between 29% and 89%, depending on the means by which cytological specimens were analyzed82–87 (Tables 62.5 and 62.6). For studies that deemed a “positive” or “suspicious” cytological interpretation as indicative of malignancy, the diagnostic sensitivity was 124 of 169 (73%).82–85,87 However, studies requiring a “positive” cytological interpretation reported a diagnostic sensitivity of only 63/106 (59%).82–86 The diagnostic sensitivity of EUS FNA may be greater for distal versus proximal CCA; 38 of 47 (81%) versus 16 of 27 (59%), p = 0.04.87 In contrast, one study reported a sensitivity of 32/36 (89%) for hilar strictures or tumors.82 The diagnostic capabilities of EUS FNA are further demonstrated in studies employing FNA after either a negative or unsuccessful endoscopic retrograde cholangiography (ERC) sampling, yielding sensitivities of 77% and 89% for EUS FNA in these respective settings.82,87

EUS-FNA Diagnostic Accuracy One of the most beneficial yet potentially harmful applications of EUS in CCA patients is the use of FNA for primary tumor diagnosis (Fig. 62.8). The desmoplasia and tendency for longitudinal rather than radial growth associated with CCA can compromise efforts at a tissue diagnosis and result in a delayed or failed diagnosis. Endoscopic retrograde cholangiography and brush cytology with intraductal biopsy are the standard diagnostic approaches yielding a high specificity, but low diagnostic sensitivity of 20% to 60%.89–91 The poor performance characteristics have led to the use of molecular markers, such as fluorescence in situ hybridization which increases diagnostic sensitivity by

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SECTION III

Pancreaticobiliary Disorders

Tumor Seeding The perceived risk and implications of tumor seeding following EUS FNA for CCA is debated. There are insufficient data to meaningfully guide this discussion, but our views are largely based on those of transplant centers, for which the impact of any perceived risk of tumor seeding most substantially impacts patient management. Tumor seeding is often referred to as needle track seeding or implantation metastasis and has been reported following EUS-,95–97 percutaneous ultrasound– or CT-guided FNA of various sites including the brain, eye, thyroid, breast, lung, tongue, liver, gallbladder, pancreas, colon, kidney, ureter, bladder, stromal tumor, bone and bone marrow, and bile duct among others.98–103 Tumor seeding has also been associated with preoperative percutaneous drainage and ERC with stent placement.104,105 Limited data suggest that the risk of clinically apparent tumor seeding following FNA is 1/10,000–40,000.106,107 However, there are a number of limitations in determining the incidence of tumor seeding and the cited rates likely significantly underestimate the occurrence. The high mortality, short survival, and obviated need for subsequent abdominal imaging in patients with unresectable cancer prohibit accurate determination of the tumor seeding rate. Even for patients who undergo potentially curative resection, tumor seeding may result in minute foci of occult cells undetected in the surgical specimen or result in deposition outside the field of resection. These occult reservoirs of tumor cells may ultimately result in apparent clinical disease that is falsely considered to represent tumor recurrence rather than disease progression of occult tumor cells deposited during needle track seeding. There is also controversy as to the implications of tumor seeding, with some finding a correlation with clinical outcomes including tumor stage, prognosis, resectability, surgical margin status, recurrence, and survival.108–118 Other investigators have failed to discover a correlation with clinical outcomes.119–122 The potential of tumor cells to be displaced during FNA was been demonstrated.123 In 140 prospectively enrolled patients who underwent EUS, luminal fluid that is typically aspirated via the accessory channel was instead submitted for cytological analysis. The cytology specimens from the aspirated luminal fluid were positive for malignancy in 48% of patients, who had a luminal cancer, which may be accounted for by cells shed from the luminal cancer. More concerning was the post-FNA luminal fluid cytology that was positive for malignancy in 3/26 patients with pancreatic adenocarcinoma. Among patients with extraluminal cancers one would not anticipate recovering malignant cells from the gastrointestinal luminal fluid. These findings may indicate that the process of FNA displaces some malignant cells from the original primary site to the needle track and even more distant locations, and may help explain the process of needle track seeding. This hypothesis is supported in a study that evaluated the rates of peritoneal carcinomatosis in matched pancreatic adenocarcinoma cohorts diagnosed by either EUS versus percutaneously guided FNA.124 Peritoneal carcinomatosis developed in 1 in 7 patients (2.2% vs. 16.3%; p < 0.025) in the EUS FNA versus percutaneous FNA group, respectively. The findings indicate a potential difference in tumor seeding risk between biopsy approaches and potentially greater frequency of tumor seeding than historically appreciated. Similarly, a meta-analysis of 8 studies identified tumor seeding in 2.7% of patients following hepatocellular carcinoma biopsy.125

Another study evaluated the tumor seeding risk among 191 patients with hilar CCA who underwent primary tumor transperitoneal FNA as part of liver transplant evaluation for locally unresectable disease.126 Among all 16 patients who underwent transperitoneal FNA (13 percutaneous, 3 EUS), the initial cytological specimens were interpreted as positive for malignancy (n = 6), negative for nine (n = 9), and one equivocal test result (n = 1). During intraoperative staging, peritoneal metastases were identified in 5/6 (83%) versus 0/9 (0%) patients who had an FNA interpretation of positive versus negative, respectively. In addition, peritoneal metastases were discovered in only 14/175 (8%) patients who did not undergo FNA versus 5/6 (83%), p = 0.0097, with a positive preoperative FNA. However, the study findings must be carefully considered. For instance, based on their data it is not possible to determine whether clinical or tumor-related features indicated more advanced disease, which might have removed concern for tumor seeding, thereby leading to FNA. In addition, whereas both study groups had similar CA 19-9 levels, frequency of mass detection, tumor size, and histology, precise staging information was not provided. A discrepancy in staging may itself explain the greater occurrence of peritoneal metastasis rather than performing FNA. Based on our communications, most liver transplant centers consider primary tumor FNA of suspected CCA an absolute contraindication, which must not only be considered by colleagues within such centers, but also by referring clinicians given the medical implications. This philosophy places additional burden and exhaustive efforts to firmly establish a CCA. Caution is needed if proceeding to surgery without a tissue diagnosis because 10% to 20% of patients resected for presumed CCA are ultimately diagnosed with benign disease or alternate tumor type.127–130 The challenges of CCA diagnosis leads some to advocate less stringent surrogate markers (e.g., CA 19-9 levels and imaging criteria alone) as means of a presumptive diagnosis setting. Whereas this practice may be questioned even for highly experienced clinicians, there is particular concern for false diagnosis that may result in inappropriate and often risky surgery. Proper patient counseling is required to convey the potential for extensive operative intervention (even transplantation) for benign disease. Patients often accept this approach once understanding the diagnostic challenges and the importance of avoiding delayed oncologic care, as well as the risks and implications of tumor seeding.

Staging and Resectability Accurate tumor staging is needed to optimize clinical decision making. Several staging systems are utilized for CCA,77,131,132 which differ in intended application and accuracy for determining prognosis and resectability, and when guiding the extent of resection. Common features employed by each staging system including the longitudinal tumor margins (proximal and distal), presence of nodal disease, vascular infiltration, parenchymal lobar atrophy, and distant metastasis. Improved preoperative staging reduces the need for isolated staging laparoscopy and rate of tumor upstaging at laparoscopy (Fig. 62.9). Published data are limited and prohibit any meaningful effort to establish the utility of EUS for CCA staging. Existing studies provide few EUS staging details and the underlying aims and methodologies were insufficient to determine of EUS staging accuracy. One study did provide some useful staging data for the cohort of 81 patients, 75 of whom underwent evaluation for surgical candidacy.87 Among the 15 patients ultimately designated as unresectable, EUS discovered the evidence of unresectable

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CHAPTER 62 Evaluation and Staging of Pancreaticobiliary Malignancy EUS Features for Malignant and Benign Lymph Nodes TABLE 62.7 Mean

Malignant LN

Benign LN

1.61 +/− 0.61

1.47 +/− 0.78

0.68

Roundness Score

2.5 +/− 1.55

2.9 +/− 0.81

0.32

Echogenicity Score

4.0 +/− 0.63

3.78 +/− 0.71

0.48

Homogeneity Score

3.0 +/− 1.1

3.32 +/− 0.84

0.41

Long Axis (mm)

P Value

EUS, endoscopic ultrasound.

FIG 62.9 A cholangiocarcinoma infiltrating the portal vein on linear endoscopic ultrasound (EUS) exam. The X’s delineate the interface between the bile duct and the portal vein.

disease in a greater number than CT; 8/15 (53%) versus 5/15 (33%), respectively. EUS identified six disease sites that were not discovered by CT/MRI including tumor infiltration of the PV (n = 2), hepatic artery, celiac lymph node, liver metastasis, and peritoneum. In contrast, the sites discovered by CT/MRI that were not identified by EUS included PV invasion (n = 2) and celiac lymphadenopathy (n = 1). Finally, 4 disease sites were confirmed only at surgery and failed prior EUS or CT/MRI detection including malignant infiltration of the hepatic artery, PV, celiac node, and longitudinal bile duct extension. Other key data were excluded from this report, thereby limiting firm calculation of EUS staging and resectability accuracy.

FIG 62.10 Endoscopic ultrasound image of a biopsy proven malignant lymph node.

EUS Nodal Staging and Features of Malignant and Benign Lymph Nodes Most published data do not thoroughly indicate the accuracy of EUS nodal staging.87,133 Other studies only indicated if any nodes had been identified82,84 or often ignored this issue.83,85,86 For CCA, lymph node metastasis is a poor prognostic indicator,134,135 and distant malignant nodal involvement precludes curative resection. However, the significance of locoregional lymph node metastasis is debated. Transplant centers uniformly view any nodal involvement as an absolute contraindication to liver transplant and for many centers even precludes attempted curative resection. The accuracy of EUS FNA nodal staging was studied among 47 patients with locally unresectable hilar CCA undergoing liver transplantation evaluation.133 Lymph nodes were seen at EUS in each patient, resulting in FNA of 70 lymph nodes with metastatic adenopathy diagnosed in 8 patients. Only 2/8 patients’ malignant nodes were detected by CT and/or MRI. For the 22 patients who had benign lymph nodes at FNA cytology, 20 (91%) were confirmed benign at exploratory laparotomy. However, EUS failed to detect malignant lymph nodes in 2 patients. Data were also obtained to help determine EUS features to distinguish benign from malignant nodes in patients with CCA. Conventional EUS features that include long-axis length, roundness, echogenicity, and homogeneity both individually and collectively provided poor predictive value (Table 62.7; Figs. 62.10 and 62.11). Therefore, in our practice, in patients with CCA we biopsy all

FIG 62.11 Endoscopic ultrasound image of an established benign lymph node.

locoregional visualized lymph nodes regardless of the EUS appearance. A separate study compared EUS and surgical nodal staging in 45 patients and reported an EUS diagnostic sensitivity of only 2/23 (9%). In this study, locoregional lymph nodes were not routinely sampled, which may have contributed to the low sensitivity.87

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Potentially Confounding Variables and Complications TABLE 62.8

PSC1 Present

Stent Present at time of EUS

Complications Related to EUS

Mohamadnejad et al. (2011)87

2 of 81 (2%)

64/74 (86%)4

1 (Hemobilia)

Rosch et al. (2004)85

~

~

0

Eloubeidi et al. (2004)85

1 of 28 (4%)

27/28 (96%)

0

Study

Lee et al. (2004)84 3 of 40 (8%)2 40/42 (95%)5

0

Byrne et al. (2004)83

0 of 35 (0%)

~

Fritscher-Ravens et al. (2003)82

4 of 44 (9%)3 44 of 44 (Implied) 0

Summary

10/228 (4%)

~

131/146 (90%)

~ Indicates that data were not provided. 1 Primary sclerosing cholangitis. 2 There was no evidence of PSC at the time of EUS. Cholangiographic features of PSC subsequently developed in 3 patients. 3 EUS FNA was falsely negative in the 4 patients with PSC. 4 The diagnostic sensitivity of EUS FNA was 45 of 64 (70%) versus 9 of 10 (90%) for patients with and without a stent, respectively. 5 Stent data were given for the initial 42 patients evaluated, but not specifically for the 40 patients ultimately included in the overall analyses. EUS, endoscopic ultrasound; FNA, fine-needle aspiration.

Potentially Confounding Variables and Complications Primary sclerosing cholangitis (PSC) is a prime risk factor for developing CCA. Although details pertaining to PSC were typically limited or omitted among the 5 studies documenting this information, only 10/228 (4%) patients had PSC (Table 62.8).82–87 This is important, as PSC is routinely associated with multiple and diffuse bile duct strictures, increased desmoplasia, and benign lymphadenopathy. Each of these features can negatively impact EUS imaging and FNA performance. Therefore, the low rate of PSC in the study cohort is likely to have artificially improved EUS imaging and FNA results from most practice settings. Among the cited studies, a biliary stent was in place at the time of EUS in 131/146 (90%) patients (see Table 62.8). The presence of an indwelling biliary stent can impair EUS imaging due to stent-induced artifacts and stent-induced sludge. However, any impaired imaging is seldom of consequence except for diminutive biliary or pancreatic lesions. Imaging can be optimized by examination various locations, by limiting the amount of air insufflated that may pass through the stent into the duct, or by removing the stent prior to EUS. The presence of a stent can facilitate detection of a biliary mass, as the stent often courses through the lesion, aiding detection.

Conclusion The proper management of patients with suspected CCA requires a definitive tissue diagnosis. EUS is increasingly being used to both diagnose and stage CCA largely due to the limitations of endoscopic bile duct sampling. Whereas studies indicate the utility of EUS in patients with CCA, there remains debate as to the accuracy and role in this setting. Although some perform bile duct EUS FNA for primary tumor diagnosis, we strongly discourage doing so because of the potential for tumor seeding and impact on transplant candidacy or standard resection.

One should also consider the high false-negative of primary tumor FNA. We consider CCA data to most strongly support EUS FNA to evaluate lymphadenopathy when considering liver transplantation. Confirmation of malignant lymphadenopathy avoids unnecessary neoadjuvant therapy and staging laparotomy, and resulting quality of life and cost. We believe EUS is indicated irrespective of the CT and/or MRI findings due to their insufficient sensitivity for lymph node detection and poor discrimination of benign from malignant nodes. Likewise, extensive sampling is indicated regardless of the nodal appearance due to the poor predictive value of EUS imaging features. Patients with negative FNA cytology subsequently undergo staging laparotomy to verify N0 status. Additional data are needed to clarify the role of EUS regarding other staging criteria in patients being considered for liver transplantation. More research is also needed to determine the impact of EUS staging among patients considered for non-transplant forms of operative intervention. Finally, existing reports provide no information pertaining to the use of EUS for intrahepatic CCA.

KEY REFERENCES 8. DeWitt J, Devereaux B, Chriswell M, et al: Comparison of endoscopic ultrasonography and multidetector computed tomography for detecting and staging pancreatic cancer, Ann Intern Med 141(10):753–763, 2004. 9. Canto MI, Harinck F, Hruban RH, et al: International Cancer of the Pancreas Screening (CAPS) Consortium summit on the management of patients with increased risk for familial pancreatic cancer, Gut 62(3): 339–347, 2013. 11. Farrell JJ, Garber J, Sahani D, Brugge WR: EUS findings in patients with autoimmune pancreatitis, Gastrointest Endosc 60(6):927–936, 2004. 13. Iwashita T, Yasuda I, Doi S, et al: Use of samples from endoscopic ultrasound-guided 19-gauge fine-needle aspiration in diagnosis of autoimmune pancreatitis, Clin Gastroenterol 10(3):316–322, 2012. 19. Soriano A, Castells A, Ayuso C, et al: Preoperative staging and tumor resectability assessment of pancreatic cancer: prospective study comparing endoscopic ultrasonography, helical computed tomography, magnetic resonance imaging, and angiography, Am J Gastroenterol 99(3):492–501, 2004. 22. Catalano MF, Sivak MV, Jr, Rice T, et al: Endosonographic features predictive of lymph node metastasis, Gastrointest Endosc 40(4):442–446, 1994. 34. Hewitt MJ, McPhail MJ, Possamai L, et al: EUS-guided FNA for diagnosis of solid pancreatic neoplasms: a meta-analysis, Gastrointest Endosc 75(2):319–331, 2012. 42. Wani S, Muthusamy VR, Komanduri S: EUS-guided tissue acquisition: an evidence-based approach (with videos), Gastrointest Endosc 80(6): 939–959.e7, 2014. 51. Fuccio L, Hassan C, Laterza L, et al: The role of K-ras gene mutation analysis in EUS-guided FNA cytology specimens for the differential diagnosis of pancreatic solid masses: a meta-analysis of prospective studies, Gastrointest Endosc 78(4):596–608, 2013. 53. Frampton AE, Krell J, Jamieson NB, et al: microRNAs with prognostic significance in pancreatic ductal adenocarcinoma: a meta-analysis, Eur J Cancer 51(11):1389–1404, 2015. 58. van Asselt SJ, Brouwers AH, van Dullemen HM, et al: EUS is superior for detection of pancreatic lesions compared with standard imaging in patients with multiple endocrine neoplasia type 1, Gastrointest Endosc 81(1):159–167.e2, 2015. 59. Khashab MA, Yong E, Lennon AM, et al: EUS is still superior to multidetector computerized tomography for detection of pancreatic neuroendocrine tumors, Gastrointest Endosc 73(4):691–696, 2011. 64. Ridtitid W, Halawi H, DeWitt JM, et al: Cystic pancreatic neuroendocrine tumors: outcomes of preoperative

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CHAPTER 62 Evaluation and Staging of Pancreaticobiliary Malignancy

78.

81.

86.

87.

92.

93.

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A complete reference list can be found online at ExpertConsult .com

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CHAPTER 62 Evaluation and Staging of Pancreaticobiliary Malignancy

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42.

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60.

61.

62.

SECTION III

Pancreaticobiliary Disorders

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63. Atiq M, Bhutani MS, Bektas M, et al: EUS-FNA for pancreatic neuroendocrine tumors: a tertiary cancer center experience, Dig Dis Sci 57(3):791–800, 2012. 64. Ridtitid W, Halawi H, DeWitt JM, et al: Cystic pancreatic neuroendocrine tumors: outcomes of preoperative endosonographyguided fine needle aspiration, and recurrence during long-term follow-up, Endoscopy 47(7):617–625, 2015. 65. Zografos GN, Stathopoulou A, Mitropapas G, et al: Preoperative imaging and localization of small sized insulinoma with EUS-guided fine needle tattoing: a case report, Hormones (Athens) 4(2):111–116, 2005. 66. Lennon AM, Newman N, Makary MA, et al: EUS-guided tattooing before laparoscopic distal pancreatic resection (with video), Gastrointest Endosc 72(5):1089–1094, 2010. 67. Nayer H, Weir EG, Sheth S, Ali SZ: Primary pancreatic lymphomas: a cytopathologic analysis of a rare malignancy, Cancer 102(5):315–321, 2004. 68. Khashab M, Mokadem M, DeWitt J, et al: Endoscopic ultrasoundguided fine-needle aspiration with or without flow cytometry for the diagnosis of primary pancreatic lymphoma - a case series, Endoscopy 42(3):228–231, 2010. 69. Roland CF, van Heerden JA: Nonpancreatic primary tumors with metastasis to the pancreas, Surg Gynecol Obstet 168(4):345–347, 1989. 70. Palazzo L, Borotto E, Cellier C, et al: Endosonographic features of pancreatic metastases, Gastrointest Endosc 44(4):433–436, 1996. 71. DeWitt J, Jowell P, Leblanc J, et al: EUS-guided FNA of pancreatic metastases: a multicenter experience, Gastrointest Endosc 61(6):689–696, 2005. 72. Bechade D, Palazzo L, Fabre M, Algayres JP: EUS-guided FNA of pancreatic metastasis from renal cell carcinoma, Gastrointest Endosc 58(5):784–788, 2003. 73. El Hajj II, LeBlanc JK, Sherman S, et al: Endoscopic ultrasound-guided biopsy of pancreatic metastases: a large single-center experience, Pancreas 42(3):524–530, 2013. 74. Maggs JR, Chapman RW: An update on primary sclerosing cholangitis, Curr Opin Gastroenterol 24(3):377–383, 2008. 75. Pichlmayr R, Weimann A, Klempnauer J, et al: Surgical treatment in proximal bile duct cancer. A single-center experience, Ann Surg 224(5): 628–638, 1996. 76. Kosuge T, Yamamoto J, Shimada K, et al: Improved surgical results for hilar cholangiocarcinoma with procedures including major hepatic resection, Ann Surg 230(5):663–671, 1999. 77. Jarnagin WR, Fong Y, DeMatteo RP, et al: Staging, resectability, and outcome in 225 patients with hilar cholangiocarcinoma, Ann Surg 234(4):507–517, discussion 517-519, 2001. 78. DeOliveira ML, Cunningham SC, Cameron JL, et al: Cholangiocarcinoma: thirty-one-year experience with 564 patients at a single institution, Ann Surg 245(5):755–762, 2007. 79. Heimbach JK, Gores GJ, Haddock MG, et al: Liver transplantation for unresectable perihilar cholangiocarcinoma, Semin Liver Dis 24(2):201– 207, 2004. 80. Heimbach JK, Gores GJ, Haddock MG, et al: Predictors of disease recurrence following neoadjuvant chemoradiotherapy and liver transplantation for unresectable perihilar cholangiocarcinoma, Transplantation 82(12):1703–1707, 2006. 81. Rea DJ, Heimbach JK, Rosen CB, et al: Liver transplantation with neoadjuvant chemoradiation is more effective than resection for hilar cholangiocarcinoma, Ann Surg 242(3):451–458, discussion 458-461, 2005. 82. Fritscher-Ravens A, Broering DC, Knoefel WT, et al: EUS-guided fine-needle aspiration of suspected hilar cholangiocarcinoma in potentially operable patients with negative brush cytology, Am J Gastroenterol 99(1):45–51, 2003. 83. Byrne MF, Gerke H, Mitchell RM, et al: Yield of endoscopic ultrasoundguided fine-needle aspiration of bile duct lesions, Endoscopy 36(8):715– 719, 2004. 84. Lee JH, Salem R, Aslanian H, et al: Endoscopic ultrasound and fine-needle aspiration of unexplained bile duct strictures, Am J Gastroenterol 99(6):1069–1073, 2004.

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CHAPTER 62 Evaluation and Staging of Pancreaticobiliary Malignancy 85. Eloubeidi MA, Chen VK, Jhala NC, et al: Endoscopic ultrasound-guided fine needle aspiration biopsy of suspected cholangiocarcinoma, Clin Gastroenterol Hepatol 2(3):209–213, 2004. 86. Rosch T, Hofrichter K, Frimberger E, et al: ERCP or EUS for tissue diagnosis of biliary strictures? A prospective comparative study, Gastrointest Endosc 60(3):390–396, 2004. 87. Mohamadnejad M, DeWitt JM, Sherman S, et al: Role of EUS for preoperative evaluation of cholangiocarcinoma: a large single-center experience, Gastrointest Endosc 73(1):71–78, 2011. 88. Blechacz B, Komuta M, Roskams T, Gores GJ: Clinical diagnosis and staging of cholangiocarcinoma, Nat Rev Gastroenterol Hepatol 8(9): 512–522, 2011. 89. Ponchon T, Gagnon P, Berger F, et al: Value of endobiliary brush cytology and biopsies for the diagnosis of malignant bile duct stenosis: results of a prospective study, Gastrointest Endosc 42(6):565–572, 1995. 90. Khan SA, Davidson BR, Goldin R, et al: Guidelines for the diagnosis and treatment of cholangiocarcinoma: consensus document, Gut 51(Suppl 6):VI1–VI9, 2002. 91. Gores GJ, Nagorney DM, Rosen CB: Cholangiocarcinoma: is transplantation an option? For whom? J Hepatol 47(4):455–459, 2007. 92. Moreno Luna LE, Kipp B, Halling KC, et al: Advanced cytologic techniques for the detection of malignant pancreatobiliary strictures, Gastroenterology 131(4):1064–1072, 2006. 93. Levy MJ, Baron TH, Clayton AC, et al: Prospective evaluation of advanced molecular markers and imaging techniques in patients with indeterminate bile duct strictures, Am J Gastroenterol 103(5):1263–1273, 2008. 94. Fritcher EGB, Kipp BR, Halling KC, et al: A multivariable model using advanced cytologic methods for the evaluation of indeterminate pancreatobiliary strictures, Gastroenterology 136(7):2180–2186, 2009. 95. Paquin SC, Gariepy G, Lepanto L, et al: A first report of tumor seeding because of EUS-guided FNA of a pancreatic adenocarcinoma, Gastrointest Endosc 61(4):610–611, 2005. 96. Shah JN, Fraker D, Guerry D, et al: Melanoma seeding of an EUSguided fine needle track, Gastrointest Endosc 59(7):923–924, 2004. 97. Doi S, Yasuda I, Iwashita T, et al: Needle tract implantation on the esophageal wall after EUS-guided FNA of metastatic mediastinal lymphadenopathy, Gastrointest Endosc 67(6):988–990, 2008. 98. Ito Y, Asahi S, Matsuzuka F, et al: Needle tract implantation of follicular neoplasm after fine-needle aspiration biopsy: report of a case, Thyroid 16(10):1059–1062, 2006. 99. Suzuki K, Takamochi K, Funai K, Kazui T: Needle tract implantation clearly visualized by computed tomography following needle biopsy of malignant mesothelioma, Eur J Cardiothorac Surg 29(6):1051, 2006. 100. Fowler N, Asatiani E, Cheson B: Needle tract seeding after bone marrow biopsy in non-Hodgkin lymphoma, Leuk Lymphoma 49(1):156–158, 2008. 101. Chang S, Kim SH, Lim HK, et al: Needle tract implantation after percutaneous interventional procedures in hepatocellular carcinomas: lessons learned from a 10-year experience, Korean J Radiol 9(3):268– 274, 2008. 102. Rowe LR, Mulvihill SJ, Emerson L, Gopez EV: Subcutaneous tumor seeding following needle core biopsy of hepatocellular carcinoma, Diagn Cytopathol 35(11):717–721, 2007. 103. Liu Y-W, Chen C-L, Chen Y-S, et al: Needle tract implantation of hepatocellular carcinoma after fine needle biopsy, Dig Dis Sci 52(1): 228–231, 2007. 104. Sakata J, Shirai Y, Wakai T, et al: Catheter tract implantation metastases associated with percutaneous biliary drainage for extrahepatic cholangiocarcinoma, World J Gastroenterol 11(44):7024–7027, 2005. 105. Gerhards MF, Gonzalez DG, ten Hoopen-Neumann H, et al: Prevention of implantation metastases after resection of proximal bile duct tumours with pre-operative low dose radiation therapy, Eur J Surg Oncol 26(5):480–485, 2000. 106. Lundstedt C, Stridbeck H, Andersson R, et al: Tumor seeding occurring after fine-needle biopsy of abdominal malignancies, Acta Radiol 32(6): 518–520, 1991.

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107. Smith EH: Complications of percutaneous abdominal fine-needle biopsy, Radiology 178(1):253–258, 1991. 108. Castells A, Boix L, Bessa X, et al: Detection of colonic cells in peripheral blood of colorectal cancer patients by means of reverse transcriptase and polymerase chain reaction, Br J Cancer 78(10):1368–1372, 1998. 109. Wyld DK, Selby P, Perren TJ, et al: Detection of colorectal cancer cells in peripheral blood by reverse-transcriptase polymerase chain reaction for cytokeratin 20, Int J Cancer 79(3):288–293, 1998. 110. Gunn J, McCall JL, Yun K, Wright PA: Detection of micrometastases in colorectal cancer patients by K19 and K20 reverse-transcription polymerase chain reaction, Lab Invest 75(4):611–616, 1996. 111. Soeth E, Roder C, Juhl H, et al: The detection of disseminated tumor cells in bone marrow from colorectal-cancer patients by a cytokeratin20-specific nested reverse-transcriptase-polymerase-chain reaction is related to the stage of disease, Int J Cancer 69(4):278–282, 1996. 112. Nakamura T, Yasumura T, Hayashi K, et al: Immunocytochemical detection of circulating esophageal carcinoma cells by immunomagnetic separation, Anticancer Res 20(6C):4739–4744, 2000. 113. Mori M, Mimori K, Ueo H, et al: Clinical significance of molecular detection of carcinoma cells in lymph nodes and peripheral blood by reverse transcription-polymerase chain reaction in patients with gastrointestinal or breast carcinomas, J Clin Oncol 16(1):128–132, 1998. 114. Miyazono F, Natsugoe S, Takao S, et al: Surgical maneuvers enhance molecular detection of circulating tumor cells during gastric cancer surgery, Ann Surg 233(2):189–194, 2001. 115. Z’Graggen K, Centeno BA, Fernandez-del Castillo C, et al: Biological implications of tumor cells in blood and bone marrow of pancreatic cancer patients, Surgery 129(5):537–546, 2001. 116. Hardingham JE, Kotasek D, Sage RE, et al: Detection of circulating tumor cells in colorectal cancer by immunobead-PCR is a sensitive prognostic marker for relapse of disease, Mol Med 1(7):789–794, 1995. 117. Funaki NO, Tanaka J, Imamura M: Quantitative analysis of alphafetoprotein mRNA in circulating peripheral blood of patients with hepatocellular and alpha-fetoprotein-producing gastric carcinomas, Life Sci 62(21):1973–1984, 1998. 118. Uchikura K, Takao S, Nakajo A, et al: Intraoperative molecular detection of circulating tumor cells by reverse transcription-polymerase chain reaction in patients with biliary-pancreatic cancer is associated with hematogenous metastasis, Ann Surg Oncol 9(4):364–370, 2002. 119. Koike M, Hibi K, Kasai Y, et al: Molecular detection of circulating esophageal squamous cell cancer cells in the peripheral blood, Clin Cancer Res 8(9):2879–2882, 2002. 120. Piva MG, Navaglia F, Basso D, et al: CEA mRNA identification in peripheral blood is feasible for colorectal, but not for gastric or pancreatic cancer staging, Oncology 59(4):323–328, 2000. 121. Yeh KH, Chen YC, Yeh SH, et al: Detection of circulating cancer cells by nested reverse transcription-polymerase chain reaction of cytokeratin-19 (K19)–possible clinical significance in advanced gastric cancer, Anticancer Res 18(2B):1283–1286, 1998. 122. Bessa X, Elizalde JI, Boix L, et al: Lack of prognostic influence of circulating tumor cells in peripheral blood of patients with colorectal cancer, Gastroenterology 120(5):1084–1092, 2001. 123. Levy MJ, Gleeson FC, Campion MB, et al: Prospective cytological assessment of gastrointestinal luminal fluid acquired during EUS: a potential source of false-positive FNA and needle tract seeding, Am J Gastroenterol 105(6):1311–1318, 2010. 124. Micames C, Jowell PS, White R, et al: Lower frequency of peritoneal carcinomatosis in patients with pancreatic cancer diagnosed by EUS-guided FNA vs. percutaneous FNA, Gastrointest Endosc 58(5):690– 695, 2003. 125. Silva MA, Hegab B, Hyde C, et al: Needle track seeding following biopsy of liver lesions in the diagnosis of hepatocellular cancer: a systematic review and meta-analysis, Gut 57(11):1592–1596, 2008. 126. Heimbach JK, Sanchez W, Rosen CB, Gores GJ: Trans-peritoneal fine needle aspiration biopsy of hilar cholangiocarcinoma is associated with disease dissemination, HPB (Oxford) 13(5):356–360, 2011.

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127. Wetter LA, Ring EJ, Pellegrini CA, Way LW: Differential diagnosis of sclerosing cholangiocarcinomas of the common hepatic duct (Klatskin tumors), Am J Surg 161(1):57–62, discussion 63, 1991. 128. Verbeek PC, van Leeuwen DJ, de Wit LT, et al: Benign fibrosing disease at the hepatic confluence mimicking Klatskin tumors, Surgery 112(5): 866–871, 1992. 129. Vauthey JN, Blumgart LH: Recent advances in the management of cholangiocarcinomas, Semin Liver Dis 14(2):109–114, 1994. 130. Gerhards MF, Vos P, van Gulik TM, et al: Incidence of benign lesions in patients resected for suspicious hilar obstruction, Br J Surg 88(1):48–51, 2001. 131. Bismuth H, Nakache R, Diamond T: Management strategies in resection for hilar cholangiocarcinoma, Ann Surg 215(1):31–38, 1992.

132. Nathan H, Aloia TA, Vauthey J-N, et al: A proposed staging system for intrahepatic cholangiocarcinoma, Ann Surg Oncol 16(1):14–22, 2009. 133. Gleeson FC, Rajan E, Levy MJ, et al: EUS-guided FNA of regional lymph nodes in patients with unresectable hilar cholangiocarcinoma, Gastrointest Endosc 67(3):438–443, 2008. 134. Puhalla H, Gruenberger T, Pokorny H, et al: Resection of hilar cholangiocarcinomas: pivotal prognostic factors and impact of tumor sclerosis, World J Surg 27(6):680–684, 2003. 135. Nakagawa T, Kamiyama T, Kurauchi N, et al: Number of lymph node metastases is a significant prognostic factor in intrahepatic cholangiocarcinoma, World J Surg 29(6):728–733, 2005.

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63 Palliation of Malignant Pancreaticobiliary Obstruction Marco J. Bruno and Fauze Maluf-Filho

CHAPTER OUTLINE Introduction, 734 Epidemiology, 734 Clinical Features, 735 Pathology, 735 Differential Diagnosis, 735

Endoscopic Stenting of Malignant Biliary Obstruction, 736 Indications and Contraindications, 736 Plastic Stents, 737 Self-Expanding Metal Stents, 738

INTRODUCTION Pancreaticobiliary malignancies comprise a mixed bag of cancers including pancreatic cancer, carcinoma of the ampulla of Vater, duodenal carcinoma, gallbladder carcinoma, and cholangiocarcinomas. When they are located at the level of the liver hilum, cholangiocarcinomas are referred to as Klatskin’s tumors. Although there are marked differences in biologic behavior and clinical outcome, the overall prognosis of these tumors is dismal. At the time of presentation, more than 80% to 90% of patients have locally unresectable disease or distant metastases, leaving only a few patients suitable for curative resection. Other treatment modalities such as chemotherapy and radiotherapy have little to no effect on survival, although various multimodality schemes in a (neo)adjuvant setting to surgery are currently being explored. Hence many patients, sooner or later in their disease course, are in need of optimal palliative treatment directed toward relief of jaundice, pain, and gastric outlet obstruction. More than 85% of patients with pancreaticobiliary malignancies develop obstructive jaundice, and often it is a presenting symptom. Endoscopic retrograde cholangiopancreatography (ERCP) with placement of plastic or metallic self-expandable biliary stents has become the standard of care to relieve jaundice and has largely replaced surgical treatment. In case of failure of ERCP, percutaneous transhepatic cholangiographic drainage (PTCD) or endosonographic guided (EUS) biliary drainage are alternative treatment options.

EPIDEMIOLOGY Of all pancreaticobiliary malignancies, pancreatic adenocarcinoma has the highest incidence. It is the fourth leading cause of cancer death in the United States, and it is estimated that in 2016 approximately 53,070 people will be diagnosed with pancreatic cancer, and 41,780 will die as a result of the disease.1 It is predicted to become the second leading cause of cancer death in the United

Technique of Biliary Stent Placement, 739 Duodenal Stenosis, 744 Postprocedural Care, 744 Complications, 744 Future Trends, 746

States by 2030.2 Only a minority of patients (10% to 20%) are suitable candidates for curative resection, although this number is increasing with the advent of (neo)adjuvant chemo(radiation) therapy. The overall 5-year survival rate is still less than 4%. For patients having undergone a surgical resection it is less than 20%. Tobacco smoking doubles the risk of pancreatic cancer.3 Patients with chronic pancreatitis have an increased risk for developing pancreatic cancer that is estimated at 4% per 20 years.4 The risk of developing pancreatic cancer in patients with hereditary pancreatitis is 20% to 40%, with smoking as an important risk modifier.5 The incidence of gallbladder carcinomas averages 1 per 100,000 person-years, but is considerably higher among Native Americans. Patients most likely to survive are those in whom early cancer is detected in a postcholecystectomy specimen, with a 5-year survival of 80% to 100% for early T1–T2 cancers.6 For locally advanced T3/4 tumors, survival drops to 10% to 30%. Gallstone disease is the most important risk factor for gallbladder cancer.7 Hilar cholangiocarcinoma originates from the biliary epithelium at the hepatic confluence. Radical surgical resection of the tumor offers the only chance for long-term survival, with 5-year survival rates reported between 25% and 40%.8,9 The median survival of patients with unresectable disease is only 12 to 15 months.10 Neoadjuvant chemoradiation followed by orthotopic liver transplantation has been employed for the treatment of patients with unresectable, nonmetastatic, perihilar cholangiocarcinoma with encouraging results.11 Established risk factors for cholangiocarcinoma include parasitic infection of the biliary tract, primary sclerosing cholangitis (PSC), bile duct cysts, hepatolithiasis, and toxins (e.g., Thorotrast).12 Duodenal cancer is a rare condition that may occur sporadically, but patients with multiple duodenal adenomas, such as those that occur in familial adenomatous polyposis (FAP) and Gardner syndrome, are at particularly high risk.13,14 Ampullary carcinoma is a rare condition with an incidence of 0.49 per 100,000 persons.15 Biliary obstruction usually develops

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CHAPTER 63 Palliation of Malignant Pancreaticobiliary Obstruction

Abstract

Keywords

Pancreaticobiliary malignancies include, but are not limited to, pancreatic cancer, carcinoma of the ampulla of Vater, duodenal carcinoma, gallbladder carcinoma, and cholangiocarcinomas. The overall prognosis of these tumors is dismal. At the time of presentation, more than 80% of patients have local unresectable disease or distant metastases. Chemotherapy and radiotherapy have limited effect on survival, although various multimodality schemes in a (neo)adjuvant setting to surgery are currently being explored. It is recognized that more than 85% of patients with pancreaticobiliary malignancies develop obstructive jaundice, and often it is a presenting symptom. Many of them will need optimal palliative treatment directed toward relief of jaundice, pain, and gastric outlet obstruction. Endoscopic retrograde cholangiopancreatography (ERCP) with placement of plastic or metal biliary stents has become the standard of care to relieve jaundice. Plastic stents insertion is usually reserved for patients with expected survival time limited to 3–4 months. Another indication for the use of plastic stents is the uncertainty of the malignant diagnosis, although the use of fully covered metal stents has been increasingly advocated for this situation. There is robust evidence on the superiority of metal stents over plastic ones with regard to long-term patency rate. There is a trend to give preference to fully and partially covered metal stents over uncovered ones, even considering a possible discrete increase in some adverse event rates such as migration and acute cholecystitis. Endoscopic biliary drainage of malignant hilar obstruction should aim for draining greater than 50% of liver parenchyma and every manipulated liver segment. Finally, in case of ERCP failure, endoscopic ultrasound (EUS)–guided biliary drainage has emerged as a valid option to percutaneous drainage. Local expertise, logistics, and cost issues should be taken into consideration in the planning of the therapeutic algorithm in case of ERCP failure.

pancreatic cancer palliation biliary stenting duodenal stenting jaundice

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CHAPTER 63 Palliation of Malignant Pancreaticobiliary Obstruction early in the course of the disease. As a result, tumors are often relatively small, and radical resection is possible in a large proportion of cases with an overall 5-year survival rate of 50%.16

735

forceps biopsies is higher compared to brush cytology and approaches 50% to 60%.17,18 Sampling of ductal fluid is a simple method that is not widely used, but may offer an additional way of obtaining a tissue diagnosis.19 Several studies have shown that sensitivity can be increased by combining various techniques of tissue sampling. Endoscopic ultrasound (EUS)–guided fine-needle aspiration (FNA) or biopsy (FNB) has an excellent sensitivity of 85% to 90% and specificity that approaches 100%.20 Although FNB provides the opportunity to obtain tissue cores with preservation of cellular architecture, thereby potentially increasing sensitivity and accuracy (including a better opportunity for advanced tissue processing, such as immunohistochemical analyses), that verdict is still out. Percutaneous computed tomography (CT)guided FNA biopsy is another method for confirmation of malignancy, with a reported sensitivity of 60% to 90%. Some have argued that, because of the risk of needle tract seeding, this technique should only be used in cases of unresectable disease. Single-operator digital cholangioscopy (SOC) and probe-based confocal laser endomicroscopy (pCLE) are recent additions for determining the nature of indeterminate biliary strictures. In a multicenter, observational study, SOC was performed in 44 patients with indeterminate biliary strictures.21 The sensitivity and specificity of SOC visual impression for diagnosis of malignancy was 90% and 95.8%, respectively. All 44 patients underwent SOC-guided biopsies of which specimens were adequate for histologic evaluation in 43 patients (97.7%). The sensitivity and specificity of SOC-guided biopsies for diagnosis of malignancy was 85% and 100%. In a prospective, international, multicenter study, pCLE was investigated in 112 patients with indeterminate biliary strictures, of which 71 finally proved to be malignant. ERCP and pCLE had an 89% sensitivity, 71% specificity, and 82% accuracy rate for the correct diagnosis of the nature of the biliary stricture.22

CLINICAL FEATURES The most common presenting symptoms of pancreaticobiliary malignancies are painless jaundice, anorexia, and weight loss. If pain occurs, it is most often located in the epigastric region or right upper quadrant and may radiate to the back. Back pain usually indicates retroperitoneal tumor infiltration and unresectability. Other symptoms related to obstructive jaundice include dark urine, pale stools, and pruritus. At the time of presentation, approximately 80% of patients with pancreatic cancer have impaired glucose tolerance or diabetes mellitus. Carcinoma of the body and tail of the pancreas manifests with similar features, although jaundice is usually absent or develops very late in the course of the disease.

PATHOLOGY Approximately 90% of pancreaticobiliary malignancies are ductal adenocarcinomas (Fig. 63.1). Most tumors arise from the pancreatic head. Other exocrine malignancies are mucinous cystic adenocarcinoma and acinar cell carcinomas. Endocrine tumors include gastrinoma and insulinoma. Metastases of a primary tumor (mammary, lung, and melanoma) and lymphoma are rare but must be considered because of important treatment implications (e.g., chemotherapy) that influence prognosis. Mesenchymal tumors are extremely rare. The definitive diagnosis of malignancy is dependent on acquiring a tissue diagnosis. Currently, with various means of tissue acquisition that all have proven to be safe procedures, it is advisable to always attempt to obtain a tissue diagnosis for diagnostic confirmation regardless of management consequences. Evidently it is a prerequisite when (neo)adjuvant or palliative chemo(radio) therapy is considered. If an ERCP is indicated for biliary drainage, one can attempt to obtain a tissue diagnosis by means of brush cytology, intraductal biopsies, or fluid collection from the bile duct or pancreas or both. Cytologic brushings are easy to obtain. Specificity approaches 100%, but sensitivity is relatively low, ranging from 30% to 45%.17 The yield of intraductal

DIFFERENTIAL DIAGNOSIS Adequate discrimination between a benign or malignant nature of a pancreatic head lesion is pivotal, as management differs substantially. In the case of the former, surgery may not be indicated and even harmful to the patient. In the latter case, surgery is the treatment of choice, if a lesion proves to be resectable. An enlarged pancreatic head may be caused either by

Obstructive jaundice and suspicion pancreaticobiliary malignancy

Helical CT (± MRCP) Mass (± FNA)

Not resectable: ERCP and stent

No mass

Endoscopic ultrasound

Resectable: surgery

Mass (± FNA)

Not resectable: ERCP and stent

Resectable: surgery

No mass

ERCP (brush) and intraductal ultrasound

FIG 63.1 Algorithm for diagnosis of pancreaticobiliary cancer. CT, computed tomography; ERCP, endoscopic retrograde cholangiopancreatography; FNA, fine-needle aspiration; MRCP, magnetic resonance cholangiopancreatography.

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736

SECTION III

Pancreaticobiliary Disorders

A

B FIG 63.2 A, Stenosis of both the common bile duct and the pancreatic duct, also called a doubleduct sign, caused by pancreatic adenocarcinoma. B, A 10-Fr, 9-cm plastic endoprosthesis inserted through a distal bile duct stricture.

pancreatitis or by carcinoma. Autoimmune pancreatitis is a condition that is increasingly recognized and may mimic a malignant tumor. Differential diagnosis is based on a distinct clinical picture with a diffusely enlarged pancreas with a nondilated pancreatic duct, elevated IgG4 levels, and a prompt response to corticosteroid therapy with improvement of clinical symptoms, including jaundice, and resolution of morphologic abnormalities on cross-sectional imaging.23 Paraduodenal pancreatitis, also known as groove pancreatitis, may also mimic pancreatic adenocarcinoma.24 This condition is associated with chronic pancreatitis, male gender, and alcohol abuse.25 Cross-sectional imaging typically demonstrates an enhancing mass in the paraduodenal space, with medial duodenal wall thickening and multiple cysts.26 Cystic lesions of the pancreas may be benign (pancreatic pseudocyst or serous cystadenoma), premalignant (intrapancreatic mucinous neoplasm [IPMN] mucinous cystadenoma), or malignant (cystadenocarcinoma, malignant degenerated IPMN). Radiologic imaging is used to characterize these lesions, although differential diagnosis, as well as assessing the degree of neoplastic progression, is notoriously difficult and challenging. EUS in combination with FNA, fluid analysis, intracystic biopsy, and probe-assisted CLE may increase diagnostic accuracy.27 Whenever there is a suspicious stricture in the mid–bile duct or proximal bile duct, a gallbladder carcinoma should be considered. It is also important to exclude benign causes of strictures, such as Mirizzi’s syndrome, primary and secondary sclerosing cholangitis, and postoperative conditions. An algorithm for the diagnosis of pancreaticobiliary cancer is presented in Fig. 63.2.

ENDOSCOPIC STENTING OF MALIGNANT BILIARY OBSTRUCTION Since the introduction of endoscopic biliary stent therapy in 1980, the management of biliary obstruction due to pancreati-

FIG 63.3 Different types of plastic endoprosthesis (from top downward): double-pigtail stent, Amsterdam-type stent (one side hole and one side flap at each end), and Tannenbaum-type stent (without side holes and multiple side flaps at each end).

cobiliary malignancies has changed considerably. Nowadays, endoscopic stent placement is the preferred treatment to relieve jaundice (Fig. 63.3). Compared with percutaneous and surgical drainage, endoscopic biliary stent therapy is associated with lower morbidity and mortality rates.28,29 A potential complication of endoscopic biliary drainage is late stent occlusion causing recurrent jaundice, or cholangitis, which necessitates stent exchange. The technical success rate of endoscopic biliary drainage is between 70% to 90% and is higher for distal tumors compared with proximal malignancies involving the bifurcation. The complication rate of therapeutic ERCP is 5% to 10%.30

Indications and Contraindications Nowadays ERCP is almost exclusively a therapeutic procedure. Magnetic resonance imaging (MRI) and EUS have largely replaced

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CHAPTER 63 Palliation of Malignant Pancreaticobiliary Obstruction it for diagnostic purposes. Clinical symptoms that prompt biliary drainage via ERCP include jaundice, fever, and pruritus. Biliary stent placement has been shown to improve symptoms of anorexia and quality of life.31,32 It has also been suggested that preoperative biliary drainage may improve surgical outcome after pancreaticoduodenectomy, but this has not been substantiated in clinical trials.33–35 In a randomized study comprising 202 patients with pancreatic head carcinoma comparing direct surgery with delayed surgery after biliary drainage, surgical outcome and complication rates were not affected by preoperative stent placement.36 The overall complication rate in the delayed surgery group with preoperative stent placement was significantly increased, mainly owing to stent-related complications. The outcome of this study strongly argues against standard preoperative drainage in patients with pancreatic head cancer in whom immediate surgery is planned. Preoperative drainage is indicated, however, when operative resection is not imminent; for example, because serum bilirubin exceeds 14 mg/dL, or when patients need to undergo neoadjuvant chemotherapy. In such cases, biliary drainage should be accomplished by inserting a metal biliary stent, as stent-related complications (occlusion and exchange) are significantly lower (6% versus 31%) compared to plastic stenting.37 There are few absolute contraindications to perform ERCP. Coagulation disorders are a relative contraindication and should be corrected before ERCP.

Plastic Stents The median patency of a conventional 10-Fr plastic stent is 3 to 6 months. The incidence of stent occlusion is 20% to 50%.38–40 The initial event in stent blockage is adherence of proteins and bacteria to the inner wall of the stent and subsequent formation of a biofilm. Bacteria are introduced into the biliary system during transpapillary placement of the stent. Sludge forms from the accumulation of bacteria, which produce β-glucuronidase and

A

737

form calcium bilirubinate and calcium palmitate.40 Many efforts have been made to prolong stent patency, some of which are discussed in the following paragraphs. Stent Diameter The first biliary stents that were placed were only 7-Fr or 8-Fr in diameter because of limitations of the diameter of the working channel of the endoscope (2.8 mm). When side-viewing endoscopes with large-diameter working channels (4.2 mm) were introduced in 1980, it became possible to insert large-bore plastic stents. Larger stents (10-Fr) perform better than smaller stents (7- or 8-Fr) because of the higher flow rate, as predicted by Poiseuille’s law, and because there is less stasis with larger diameter stents.41 Theoretically, bile flow rate is proportional to the internal diameter raised to the fourth power; even a small increase in diameter results in a substantial increase in flow capacity. Contrary to this hypothesis, the use of even larger diameter plastic stents of 11.5-Fr or 12-Fr did not result in further improvements in stent patency.42–44 Stent Design The first biliary stents had a pigtail configuration at the proximal end to provide better anchorage. Straight stents were developed because of their improved bile flow characteristics compared with pigtail stents (Fig. 63.4).45–47 Huibregtse and Tytgat developed the Amsterdam-type stent—a straight design with two side holes to facilitate biliary drainage and two side flaps to prevent dislocation—which has been the standard type of stent since 1980.48 Sludge in plastic stents mainly accumulates around side holes.39,49 This accumulation seems to be the result of higher intraluminal flow turbulence and decreased flow rates.45 Soehendra and others postulated that elimination of side holes might improve patency rates and designed the so-called Teflon Tannenbaum stent (a straight stent without side holes and with multiple

B FIG 63.4 A, Mid–common bile duct stricture caused by gallbladder carcinoma. B, An 11-cm, 10-Fr plastic endoprosthesis has been inserted.

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Pancreaticobiliary Disorders

proximal and distal side flaps to prevent dislocation).50,51 At first, uncontrolled results were encouraging, with patency rates comparable to metal stents, but randomized trials could not confirm these initial results.52–54 Omitting side holes in a standarddesign polyethylene stent also did not improve stent patency.55 Stent Material and Coating Different materials have been used for stent construction, including polyethylene, polyurethane, and polytef (Teflon). In vitro studies have shown a direct relationship between the coefficient of friction and the amount of encrusted material. Teflon has the lowest friction coefficient and the best potential for preventing stent clogging. Initially, Teflon Tannenbaum stents showed a favorable patency rate.50,51 A randomized study comparing Amsterdam-type stents made from polyethylene versus Teflon did not show a difference in stent patency.56 Other controlled clinical trials also could not confirm the superiority of Teflon material in a Tannenbaum-design stent.52–54 Scanning electron microscopy of out-of-package biliary stents has shown that the inner surface smoothness of plastic stents is highly variable. This variability is possibly a result of the manufacturing process of plastic stents by extrusion. Only the polyurethane stent was found to have an extremely smooth surface.57 Two new polymers were introduced with an ultra-smooth surface, Vivathane and Hydromer. Both materials have been shown to reduce bacterial adherence in vitro. In addition, the Hydromer stent not only has a smooth texture but also a coating that absorbs water and provides a hydrophilic sheath. Because bacteria initially attach by hydrophobic interactions, this coating could potentially lower bacterial adhesion and increase stent patency. However, the encouraging results of in vitro studies could not be confirmed in prospective clinical trials.58,59 Priming the inner surface of a stent with a coating that comprises some form of antiadhesive property may reduce biofilm formation and stent clogging. Antibiotics, antithrombotics, silver, and hydrophilic coating all were effective in reducing bacterial colonization in vitro.60–62 However, clinical studies using antibioticcoated or hydrophilic-coated stents did not show any benefit. Supra- Versus Transpapillary Plastic Stent Placement Placing a plastic stent entirely within the common bile duct has the theoretical advantage of preserving the barrier function of the sphincter of Oddi; this prevents duodenal reflux of food and bacteria into the stent and biliary tree. This so-called inside stent approach can be performed only when a free margin of 1 to 2 cm is maintained between the distal end of the stricture and the papilla. With this parameter in mind, approximately one-third of patients with malignant obstructive jaundice are potential candidates for such treatment.63 However, for plastic stents no difference was found in stent performance in a randomized trial. In the inside stent group, stent migration occurred significantly more often.64 Oral Antibiotics Bacteria can enter the bile duct through the portal circulation, but more easily directly from the duodenum. When an endoprosthesis is placed, the barrier function of the sphincter of Oddi is lost, and bacteria enter the biliary tract freely. Sludge may form because these bacteria produce β-glucuronidase and form calcium bilirubinate and calcium palmitate. To prolong stent patency, prophylactic treatment with antibiotics seemed a logical step. In vitro studies showed that antibiotic treatment reduced

bacterial adherence to plastic stents.65 In a prospective randomized study with ciprofloxacin, no difference in stent patency was found.66 In another study, rotating antibiotics (cycles of 2 weeks of ampicillin, metronidazole, and ciprofloxacin) were combined with ursodeoxycholic acid, and no difference in stent patency was shown.67 Only one small pilot study showed a reduced rate of stent blockage with norfloxacin plus ursodeoxycholic acid.68 Other studies combining antibiotics and bile salts (ofloxacin and ursodeoxycholic acid, ciprofloxacin, and rowachol) did not show a longer duration of stent patency.69,70 There is no compelling evidence that stent patency benefits from antibiotic prophylaxis. Bile Salts Bile salts have a potent antibacterial effect and may stimulate bile flow. Because bacteria attach by hydrophobic interactions, hydrophobic bile salts (deoxycholate, taurodeoxycholate) inhibit initial bacterial attachment, as was shown in experimental studies.71 However, hydrophobic bile salts are not well tolerated. Hydrophilic bile salts such as ursodeoxycholate, which are better tolerated, have a minimal effect on bacterial adhesion. Except for one small pilot study, different prospective clinical studies using ursodeoxycholic acid alone or combining ursodeoxycholic acid with antibiotics could not show an improvement in stent patency.67–70 Aspirin Animal studies in prairie dogs showed that aspirin inhibits mucous glycoprotein secretion by blocking prostaglandin synthesis.72 In a clinical study, the use of aspirin reduced the content of all sludge components, although no effect was shown on stent patency.73 No further studies using aspirin to prevent early stent clogging have been performed. Elective Stent Exchange Some endoscopists prefer to schedule patients for elective stent exchanges, usually every 3 to 4 months. The optimal time interval however, is unknown.74,75 Prophylactic stent exchanges require multiple elective endoscopies over time. The risk and burden of such policy must be weighed against a policy of watchful waiting with a risk of (severe) cholangitis developing. Because many patients do not experience stent occlusion before dying of the underlying disease, some endoscopists favor an expectant management strategy.

Self-Expanding Metal Stents The diameter of biliary stents was restricted by the size of the instrumentation channel of the endoscope until the development of self-expanding metal stents (SEMSs). All currently available expandable stents are made of metal. They differ in the way they are braided, the size of the mesh, the metal used, and their rigidity. One of the first available metal stents was the self-expanding Wallstent (Boston Scientific, Marlborough, MA). This stent is delivered in a collapsed configuration on an 8-Fr delivery system. When deployed, it expands to a final diameter of 30 Fr (approximately 10 mm) and foreshortens approximately 30% in length. The final diameter is achieved after 2 days to 1 week, when equilibrium is achieved between the dilating force of the stent and the resistance of the bile duct wall and tumor. These largecaliber SEMSs of 30 Fr remain patent for longer than plastic stents but do not prevent blockage indefinitely. Metal stents with a 6-mm diameter occlude significantly more frequently than 10-mm (30-Fr) metal stents, again showing that size is the most

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CHAPTER 63 Palliation of Malignant Pancreaticobiliary Obstruction TABLE 63.1

Results of Randomized-Controlled Trials Comparing Self-Expandable Stents With

Plastic Stents NO. PATIENTS

DRAINAGE (%)

OCCLUSION RATE (%)

MEDIAN STENT PATENCY (DAYS)

Reference

PE

SEMS

PE

SEMS

PE

SEMS

PE

SEMS

Davids et al77

49

56

95

96

54

33

126

273

78

86

95

98

13

13

62

111

31

31

100

100

43

22

140*

189*

Carr-Locke et al Knyrim et al78

79

*Mean. PE, polyethylene stent; SEMS, self-expanding metal stent.

important determining factor for stent patency.76 Because of their design, SEMSs have much less surface to which bacteria can adhere. The mechanism of stent blockage differs from that seen in plastic stents and includes tumor ingrowth through the interstices of the stent or overgrowth of the end of the stent and intima hyperplasia. Several studies have shown a median stent patency of approximately 6 to 9 months of uncovered metal stents (Table 63.1).75,77–79 Various types of SEMSs are available to date. The wire construction is made of Nitinol or platinol-cored Nitinol Platinol (Boston Sci, Natick, MA). Stents are available in uncovered, partially covered, and fully covered versions. The covering is intended to resist tumor ingrowth. Partially covered stents have noncovered parts at both stent ends. It was thought that the covering would reduce stent obstruction while fixation of the proximal stent end due to intimal hyperplasia would prevent stent migration. This, however, was not substantiated in a 2015 trial.80 Nowadays, depending on the manufacturer, metallic expandable stents are available in 3 diameters (6, 8, and 10 mm) and various stent lengths ranging from 40 up to 120 mm. Most expandable metal stents foreshorten, and this should be taken into account when they are deployed. Stents with a slotted tube design like the Zilver biliary self-expandable stent (Wilson-Cook Medical, Winston-Salem, NC) have a particular advantage in that they do not foreshorten on expansion. Specially designed metal uncovered stents with a Y-type and T-type design are available for the treatment of hilar obstruction (see later section on Intrahepatic Biliary Obstruction). Covered Metal Stents Tissue ingrowth through the mesh of the stent is responsible for stent occlusion in approximately 22% to 33% of patients.77,78 To overcome this problem, SEMSs have been covered with a polyurethane or silicone membrane. At first, many prospective cohort studies could not confirm a lower rate of tumor ingrowth while using covered metal stents.81,82 However, in a prospective comparative study, stent obstruction owing to tumor ingrowth occurred significantly less frequently with covered stents compared with uncovered stents.83 Data with regard to the risk of complications are limited, but stent migration, cholecystitis, and pancreatitis seem to occur at a slightly higher rate.82–84 There seems to be no benefit from endoscopic papillotomy before deployment of covered metal stents with regard to the prevention of pancreatitis, whereas migration rates may increase.85 Covered stents should not be used intrahepatically because of occlusion of hepatic side branches by the covering membrane. Taking into consideration the previously mentioned points, many endoscopists have more often used fully covered SEMS as the first-line stent to palliate malignant obstruction.

Supra- Versus Transpapillary Metal Stent Placement No studies have compared endoscopic supra- versus transpapillary metal stent placement without a preceding sphincterotomy to reduce metal stent clogging. After percutaneous transhepatic SEMS placement, however, stent occlusions by tumor growth was more frequently observed after suprapapillary stent placement (p = 0.007), whereas stent occlusion by sludge incrustation was more frequently found after transpapillary stent placement.86 Overall there was no significant difference in cumulative stent patency (p = 0.401). For more proximal strictures, our routine practice is to place metal stents not crossing the papilla (after sphincterotomy), ensuring that the distal stent ends aligns horizontally with the duct for easy recannulation in case of obstruction. However there is no evidence to preferentially support either approach (having stent(s) cross the papilla after sphincterotomy or not). Plastic Versus Metal Stent SEMSs have a longer duration of patency than plastic stents and ideally should be placed in all patients. The high initial costs have limited their use in different health care settings worldwide. In a cost-effective approach, the choice between a plastic and metal stent depends mainly on an estimate of patient survival. Tumor size seems to be a reliable predictor of survival. Prat et al (1998) claimed that in the case of a tumor greater than 30 mm, a polyethylene stent should be placed because of shorter expected survival.87 The presence and number of liver metastases have also been shown to be independently related to prognosis.88,89 Comparative studies did not show any benefit of SEMSs compared with polyethylene stents in the first 3 months after insertion.75,77 Therefore, it seems reasonable to insert a polyethylene stent in patients with a life expectancy of less than 3 months (Fig. 63.5). If expected survival is 3 to 6 months, a SEMS should be considered (Fig. 63.6), as various authors have shown this strategy to be cost-effective.77,90–93 Patients scheduled to undergo neoadjuvant chemo(radio) therapy in preparation of a surgical resection are immunocompromised and at particular risk of severe cholangitis and cholangiosepsis due to stent clogging. In these patients, a metal expandable stent should be inserted to minimize this risk.37

Technique of Biliary Stent Placement A large-channel (4.2-mm) side-viewing therapeutic endoscope is introduced into the second portion of the duodenum. Standard cannulation of the papilla of Vater is performed by a ball-tip, cone-tip catheter or sphincterotome with or without a guidewire. Use of the latter device may aid in achieving an optimal angle for bile duct cannulation. If a sphincterotome is unsuccessful, a precut sphincterotomy is performed to obtain biliary access.

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Pancreaticobiliary Disorders

B

A

FIG 63.5 A, Distal common bile duct stricture caused by pancreatic adenocarcinoma. B, Selfexpanding metal stent has been inserted.

With the use of all these different techniques, deep cannulation is achieved in up to 95% of patients. After the bile duct is selectively cannulated, a contrast agent is injected. It is important to define the exact anatomy, location, and nature of the stenosis. To avoid postprocedural cholangitis in patients with complex hilar strictures, contrast filling of segments that are not to be drained should be avoided as much as possible. A guidewire is used to pass strictures and to facilitate introduction of devices. Various guidewires are available with different flexibility, diameter, and tip shape. On the one hand, rigid guidewires facilitate the introduction of devices (e.g., an intraductal ultrasound probe) and small-diameter stents. On the other hand, very slippery guidewires with a hydropolymer coating are used to pass asymmetric strictures. After the guidewire is passed through the stricture, a catheter can be advanced, and selective contrast filling can be achieved. If only one biliary stent is inserted, a sphincterotomy is not routinely required. Plastic Stents Preferably, a guiding catheter is introduced over the guidewire through the stricture to ensure a more rigid introductory system to facilitate stent placement. This can be achieved by the conventional method using a long wire and a standard guiding catheter, as well as with the so-called short wire exchange technique in which the guidewire follows the devices only at its distal tip, making it possible to use a short guidewire which, during device manipulation, can be safely locked at the scope handle using a locking device. The endoprosthesis is positioned over the guiding catheter and inserted into the instrumentation

channel. With a pusher tube, the stent is advanced farther toward the tip of the endoscope with the elevator bridge closed. When the prosthesis has reached the distal end of the instrumentation channel, the elevator bridge is opened, and the stent is pushed out of the endoscope under endoscopic and fluoroscopic control. During advancement of the stent, it is important to keep the endoscope tip close to the papilla. The stent should be pushed out the scope and into the common bile duct one step at a time to avoid looping and dislocation into the duodenal lumen. After the stent has been pushed out a little, the elevator bridge is closed, which raises and fixates the stent. The tip of the endoscope is moved closer to the papilla using the up-and-down knob, thus pushing the stent into the common bile duct. These steps are repeated until the distal side flap has reached the papilla. Finally, the assistant pulls out the guiding catheter and guidewire while the endoscopist keeps the endoprosthesis in position with the pusher tube. In most distal common bile duct and mid– common bile duct strictures, it is usually possible to insert a 10-Fr endoprosthesis without prior dilation. In proximal strictures, however, the stricture may need to be dilated to allow stent passage; this can be achieved with the use of dilating catheters that are introduced over a rigid guidewire or, more easily, with a dilation balloon. If it is still impossible to insert a 10-Fr stent, a smaller-caliber prosthesis (7-Fr) should be inserted that can be exchanged for a 10-Fr prosthesis at a later stage. When both right and left liver lobes have to be drained, it is usually more convenient to drain the left side first, followed by the right side, which is typically straighter and thus presents less challenge to stent insertion.

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CHAPTER 63 Palliation of Malignant Pancreaticobiliary Obstruction

A

C

741

B

D

FIG 63.6 A, Klatskin type II tumor (unresectable because of vascular involvement). B, Guidewires inserted to both the left and the right biliary system. C, Self-expanding metal stent has been inserted into the left system and deployed. D, Bilateral self-expanding metal stent drainage.

The required length of the endoprosthesis can be determined by checking the predefined markers on the guidewire or by using the guidewire as a ruler. For this, the proximal tip of the guidewire is positioned under fluoroscopic control at the level at which the proximal tip of the endoprosthesis is intended. The guidewire is then fixed between index finger and thumb at the level where it exits the working channel. Subsequently, under fluoroscopic control, the guidewire is withdrawn from the catheter until the proximal tip reaches the duodenum. When using a short wire system, the distance between finger and thumb and the exit hole of the working channel is the required length of the endoprosthesis. When using a long wire system, the technician can obtain the same measurement at the end of the catheter. Biliary plastic stents are available in various diameters (range 5-Fr to 12-Fr) and lengths (range 5 to 20 cm). Management of plastic stent occlusion. A clogged plastic stent can be removed with the use of a snare or basket. When a snare is used, the stent is caught in the snare and removed either by pulling out the scope or by pulling the stent through the instrumentation channel of the endoscope. When a basket is used, the stent is pulled close to the endoscope and, while the catheter of the basket is kept fixed at the scope handle, both the endoscope

and the stent are withdrawn. When massive tumor invasion is present in the duodenum, and difficult stent exchange is anticipated because of a nonoptimal scope position, it can be helpful to leave the occluded stent in place and use it as a guide for common bile duct cannulation and introduction of a second stent. Soehendra et al (1990) described a technique that enables the removal of a clogged stent while maintaining the original pathway into the bile duct.94 A ball-tip catheter is positioned at the distal end of the stent, after which the stent is cannulated with the guidewire. A Soehendra retriever is introduced over the guidewire, and its tip is screwed into the distal end of the stent. The retriever is pulled out the scope along with the stent, leaving the guidewire in place to facilitate the placement of a new stent. Self-Expanding Metal Stents (Video 63.1) For introduction of a SEMS, a stiff guidewire is positioned through the stricture using standard techniques. The insertion device containing the constrained metal stent is inserted through the instrumentation channel over the guidewire. When the insertion device has been properly positioned across the stricture with the help of the radiopaque markers, the prosthesis can be released

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SECTION III

Pancreaticobiliary Disorders

by removing the outer catheter while keeping the inner catheter in place. Deployment occurs gradually as the outer catheter is withdrawn and can be followed fluoroscopically. If deployment is not proceeding according to plan and repositioning is required, the stent may be constrained again by pushing the outer catheter inward, provided that the point of no return has not yet been passed. This point may vary with stent type but may extend up to 83% of total stent deployment and is indicated by a fluoroscopic marker and a marker on the handle of the insertion device. Deployment reduces the length of certain SEMSs up to approximately 30%. It is therefore important to constantly adjust the position of the expanding stent under fluoroscopic or endoscopic control, meaning that the endoscopist has to pull on the insertion device while deploying the stent. When the expanding metal stent needs to bridge the ampulla, for example in the case of a distal common bile duct stricture, the endoscopic image is used to keep a fixed distance of approximately 1 cm between the papillary orifice and the distal margin of the stent. The distal end of the stent can be checked either fluoroscopically (represented by the most distal radiopaque distal marker) or endoscopically (represented by a color indicator on the insertion catheter). Stent diameter ranges from 6 to 10 mm, and stent lengths are available from 40 mm to 120 mm. There are two techniques for inserting dual metal stents in the intrahepatic biliary tree. The conventional technique consists of inserting stents side-by-side (SBS technique; Fig. 63.7).95 The potential limitation of the SBS technique is failure to advance the second metal stent alongside the first metal stent that is already expanded. A 6-Fr delivery system made possible simultaneous introduction and positioning of two insertion devices with subsequent simultaneous deployment of metal stents in 85% to 100% of patients. Another technique is referred to as the “stentin-stent” (SIS) technique. This technique makes use of a specially designed “Y” stent consisting of two uncovered Niti-S Y-type biliary stents (TaeWoong Medical Co. Ltd., Goyang, South Korea). The first SEMS has a radiologically marked segment with wider mesh holes in its middle part, through which the second stent is advanced into the contralateral liver lobe.96 A more challenging approach for introducing a second stent through the wire mesh of a conventional metal stent using balloon dilation has also been described.97 The slim 6-Fr delivery system seems particularly suited to pass the dilated metal mesh.98,99 There are only retrospective reports comparing SBS and SIS techniques for the management of intrahepatic malignant obstruction. In one study, no

I

II

IIIA

differences in stent patency or adverse event rates were observed.100 In another study a higher adverse event rate (44% vs. 13%) but longer stent patency were reported in the SBS group (469 vs. 181 days, respectively).101 To facilitate reintervention in case of stent obstruction, it is important to either ensure that the ends of both metal stents cross the ampulla or to confirm that when located within the common bile duct, both distal metal stent ends are positioned at the same level. Management of self-expanding metal stent occlusion. Covered metal stents can be removed by grasping the distal stent end with a snare or with a forceps in case a retrieval loop is present. An uncovered SEMS can only be removed early after its deployment. These stents quickly become embedded due to tumor ingrowth and formation of hyperplastic tissue through the stent mesh after which stent extraction becomes extremely difficult or impossible. Mechanical cleaning using a balloon and water flushing is effective only in cases of sludge formation. Placement of a polyethylene stent or a second SEMS through the occluded SEMS may resolve the obstruction but may not provide optimal drainage because the new stent may not expand to its intended size, leaving the patient at higher risk for reobstruction. A novel technique for removal of metal stents entails the so-called SIS technique.102,103 With this technique, a fully covered stent is deployed through the obstructed stent (either an uncovered or a partially covered stent), making sure that both stent ends are covered. Tissue that has grown through the interstices or over the stent ends is entrapped by the newly placed fully covered stent and becomes necrotic. Two to four weeks after placement of the fully covered stent in the obstructed stent, it is pulled out, after which the original stent can usually be removed without much difficulty. This strategy proves particularly useful when an uncovered metal stent is inadvertently placed into an apparently malignant biliary stricture that ultimately proves to be benign. Intrahepatic Biliary Obstruction Strictures at the level of the hepatic confluence account for approximately 20% of malignant bile duct obstructions and mainly involve primary cholangiocarcinoma, gallbladder neoplasms, and metastatic spread to hilar nodes. Cholangiocarcinomas arising at the hilar level are also referred to as Klatskin tumors and are classified according to the degree of involvement of the intrahepatic bile ducts (Fig. 63.8).104 Stent placement in case of a proximal stricture in the biliary tree is more challenging and

IIIB

IV

FIG 63.7 Bismuth classification. I: Stricture involving the common hepatic duct. II: Stricture involving both the right and the left hepatic duct. IIIA: Stricture extending proximally to the right secondary intrahepatic ducts. IIIB: Stricture extending proximally to the left secondary intrahepatic ducts. IV: Stricture involving secondary intrahepatic ducts bilaterally.

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CHAPTER 63 Palliation of Malignant Pancreaticobiliary Obstruction

FIG 63.8 Pancreatic adenocarcinoma growing into the duodenum with a self-expanding metal stent (not yet fully deployed) in the biliary tract and a self-expanding metal stent in the duodenum.

associated with lower success rates than stent placement for distal common bile duct stenosis. Drainage can be achieved either endoscopically (retrograde) or percutaneously (antegrade). Procedure-induced cholangitis caused by contrast agent injection into undrained biliary branches is the main complication and occurs in 30% of cases.105–107 The current management strategy (depending on local services available) is first to attempt endoscopic drainage. When this is unsuccessful, percutaneous drainage is attempted.108–110 When internal drainage fails, an external drain can be left in situ, thus minimizing the risk of cholangitis. Based on consensus statements, some societies have suggested that the percutaneous route is the preferred option to drain patients with a Bismuth III and IV hilar strictures. As long as scientific data are not available, local expertise should guide individual patient management.111 Unilateral versus bilateral drainage. There is controversy regarding whether to drain one or both liver lobes in patients with a proximal cholangiocarcinoma (Klatskin tumor) with a Bismuth type II, III, and IV stricture. In Bismuth type I, one stent suffices because the left and right ducts communicate. An early study suggested that at least 25% of the liver volume should be drained to achieve biochemical improvement and relief of symptoms.112 More recently, it has been suggested that drainage of more than 50% of liver volume of patients with malignant hilar strictures is predictive for lower cholangitis and higher survival rates.110,113 Drainage of a dilated duct of an atrophic hepatic segment does not contribute to relief of jaundice and therefore should only be attempted in case of segmental cholangitis. For patients with Bismuth III and IV strictures, this concept has important implications, as drainage of either the right or left lobe is usually not enough to achieve this goal. What seems undisputed based on the literature is that the worst treatment results are achieved in patients with cholangiographic opacification of both lobes, but drainage of only one.114 Obviously, such practice promotes bacterial contamination with ensuing cholangitis in the undrained lobe. Indeed, in a prospective randomized trial comparing unilateral with bilateral hepatic duct drainage,

743

the latter procedure was associated with a significantly higher rate of complications because of early cholangitis.115 Magnetic resonance cholangiopancreatography (MRCP)–guided endoscopic stent placement in Bismuth III and IV malignancies has been shown to be associated with lower morbidity and mortality rates in an uncontrolled study.116 The intention was to place a unilateral stent in one lobe guided by MRCP findings, and to avoid guidewire entry and contrast agent injection in the contralateral lobe. In patients in whom, by accident, guidewire entry (50%) or contrast agent injection (20%) occurred in the contralateral liver lobe, stents were placed bilaterally. This treatment strategy resulted in a very low cholangitis rate of only 6%. In a 2003 study in which selective unilateral MRCP-targeted or CT-targeted drainage was evaluated, no episodes of cholangitis were observed.117 The message seems to emerge that unilateral drainage is appropriate when unilateral cannulation and opacification has been achieved. If the contralateral lobe is (unintentionally) opacified or probed, it should also be drained to avoid cholangitis. On the other hand, a 2015 meta-analysis suggests that bilateral stenting for malignant hilar strictures is not recommended because it does not reduce obstruction or 30-day mortality rates. A point of criticism is that most studies pooled in this meta-analysis included patients with Bismuth I hilar strictures for whom bilateral stents are not useful.118 It seems that clinical decision-making and future studies should focus on the following three factors: (1) Complete versus incomplete drainage based on MRCP findings with the aim to drain at least 50% of liver parenchyma; (2) Drainage of all endoscopically manipulated liver segments during ERCP (unintentional contrast injection, guidewire entry or cannulation); and (3) Avoiding drainage of massively dilated but atrophic intrahepatic segments. Plastic versus self-expanding metal stents in hilar malignant strictures. By design, expandable stents may be more suitable than plastic stents for draining hilar tumors. The stent lumen is much wider, and, more importantly, intrahepatic side branches can drain through the metal mesh. SEMSs that were inserted via the percutaneous route showed a higher rate of treatment efficacy than plastic stents.108,119 No randomized studies comparing endoscopic and percutaneous insertion of SEMSs in hilar strictures are available. Additional proof of the superiority of SEMSs over plastic stents is suggested by a retrospective series of patients with unresectable hilar cholangiocarcinoma in whom plastic stents were replaced by metal expandable stents during stent treatment.120 Successful palliation without the need for further biliary reintervention was achieved in most patients (69%). In a prospective multicenter observational cohort study in patients with a malignant hilar biliary obstruction, metal stents were superior to plastic stent in terms of short-term outcomes (30 days), independent of disease severity, Bismuth class, or drainage quality.121 A 2015 meta-analysis on the use of plastic versus metal stents for hilar strictures showed that for the latter, 30-day and long-term occlusion rates were lower with no impact on survival.118 Antibiotics before stent placement to avoid postprocedure cholangitis. The mainstay of therapy for patients presenting with a biliary obstruction caused by a malignancy with or without cholangitis is endoscopic drainage. There is controversy about the routine use of preprocedure antibiotic prophylaxis.122–124 Preoperative administration of antibiotics should definitely be started in a patient with fever. Because failure to drain the entire biliary tree is the most important risk factor associated with

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SECTION III

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occurrence of cholangitis after ERCP, in particular when contrast has been injected into segments that cannot be drained, antibiotic prophylaxis should also be administered in patients in whom incomplete drainage is anticipated, such as patients with a hilar malignancy or patients with PSC.125,126 Prophylaxis can be commenced by a single intravenous dose shortly before the procedure and is usually continued orally for 3 to 5 days. Gram-negative bacteria are consistently the most common organisms in bile (Escherichia coli and to a lesser extent Klebsiella species and gram-positive Enterococcus species). Antibiotics in these cases should be bactericidal and aimed at gram-negative bacteria with good penetration in liver tissue and bile. Ciprofloxacin is currently the first choice of antibiotic in our unit, with the caveat that it does not cover enterococci. In cases of fever despite ciprofloxacin, the addition of amoxicillin or a switch to piperacillin/tazobactam is advisable.

Duodenal Stenosis Duodenal stenosis resulting from pancreaticobiliary malignancies occurs in 10% to 20% of patients.127 Symptoms include nausea and vomiting resulting from gastric outlet obstruction. Duodenal stenosis is usually a late event in patients in poor general condition who have already undergone biliary drainage. Surgical bypass has a significant procedure-related mortality of 10% and related morbidity and prolonged hospital stay.29,128,129 Placement of a duodenal stent has a high technical success rate without major procedure-related complications.130–132 In a systematic review comprising 1281 patients from 19 studies early (< 30 days) and late (> 30 days), perforations occur in 0.7% and in 0.5% of patients, respectively.133 Massive bleeding requiring urgent intervention was observed in 0.8% of cases. Duodenal stent placement is performed under simultaneous endoscopic and fluoroscopic control. Immediately after stent placement patients are usually able to tolerate a liquid diet. Full stent expansion may take a few days, during which time soft foods are allowed. Uncovered duodenal stents seem to be associated with a higher occlusion rate, whereas partially covered duodenal stents seem to have a higher migration rate.133 A retrospective study in 95 patients suggested that duodenal stent placement is associated with better short-term outcomes, whereas surgical gastrojejunostomy is associated with better long-term outcomes.134 The choice of treatment modality may depend on the life expectancy of the patient. On the other hand, in patients with longer survival, duodenal stenting may still be considered a valid treatment modality, as endoscopic reintervention for stent dysfunction, albeit common (30%–40% of the cases), is clinically successful in most cases. Some recent small case series (2015–16) have reported promising results of EUS-guided gastrojejunostomy thanks to the advent of lumen apposing metal stents.135–137 Similar success rates have been reported for simultaneous endoscopic decompression of biliary and duodenal obstruction compared with duodenal stent placement alone.138 In the former case, because of the difficulty accessing the biliary tree after duodenal stent placement, an expandable metal biliary stent should be placed first (Fig. 63.9). In case a plastic biliary stent is already in situ, it should be exchanged for a metal expandable stent. In expert hands, it may be feasible to drain the biliary tree endoscopically through the mesh of a metal duodenal stent, but this is a technically challenging procedure.139 More recently, EUS-guided biliary drainage has been employed in the setting of a failed biliary drainage by means of ERCP in patients with

a duodenal stent in situ. In a small case series, this approach was successful in most of the patients using various strategies, including transmural hepaticogastrostomy or choledochoduodenostomy or even antegrade or “rendez-vous” transpapillary drainage.140 If endoscopic treatment of biliary obstruction after duodenal stent placement fails, remaining treatment options include percutaneous stent placement, combined percutaneous and endoscopic management, and surgical bypass.

Postprocedural Care General measures after conscious sedation include observation in a day care unit for several hours monitoring blood pressure and oxygen saturation. When a patient develops fever after ERCP, blood samples should be obtained for culture, and antibiotics should be administered. If fever does not subside, the accuracy of biliary drainage should be reassessed, and migration and early stent occlusion should be excluded. In the case of a complex malignant hilar stricture, it is important to check for undrained dilated intrahepatic segments and to rule out abscesses by transabdominal ultrasound or CT. Depending on the findings, ERCP should be reattempted or percutaneous drainage performed.

Complications Early Complications Early complications are defined as complications that occur less than 1 week after the conclusion of the procedure. The rate of complications is 5% to 10% for therapeutic ERCP with a mortality rate of up to 1%.30,141,142 Cotton et al (1991) introduced a classification system in which complications are graded as mild, moderate, and severe, and these guidelines are still widely used.141 The most frequent early complication is cholangitis, probably resulting from introduction of bacteria into the biliary tract during the procedure. Cholangitis is reported in approximately 10% to 15% of patients in most series. It occurs more often after endoscopic procedures for complex hilar strictures when incomplete drainage is achieved. The same holds true for patients with PSC. In these high-risk procedures, antibiotics should be administered prophylactically and continued for a few days after the procedure. Pancreatitis develops after ERCP in approximately 5% to 7% of patients. It is defined as new-onset or increased abdominal pain lasting at least 24 hours after ERCP, with associated elevation in serum amylase or lipase to at least three times normal, and a minimum of 2 days of hospital admission.30,141 Most cases are mild and self-limiting, requiring only intravenous fluids and gut rest. Selected cases may evolve into (infected) necrotizing pancreatitis with multi-organ failure. The rate of postsphincterotomy bleeding is approximately 0.2% to 5%, with an associated mortality rate less than 1%.143 Bleeding usually occurs immediately after sphincterotomy but can be delayed for hours or several days. In our experience, most episodes of delayed bleeding are managed successfully by conservative measures and blood transfusions. Postsphincterotomy bleeding usually occurs at the apex of the sphincterotomy site and can be managed endoscopically with injection of epinephrine. When clipping or thermal coagulation are used to stop the bleeding, one should be cautious to avoid the pancreatic orifice for obvious reasons. When in doubt, or the site of hemostatic therapy is close to the pancreatic orifice, a protective pancreatic stent should be placed first. In some situations, the apex of the sphincterotomy can be clipped away from the pancreatic orifice with minimal risk of pancreatitis. In such cases, the risk of further

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CHAPTER 63 Palliation of Malignant Pancreaticobiliary Obstruction

A

C

E

B

D

F FIG 63.9 EUS-guided choledochoduodenal anastomosis with concomitant duodenal stenting in a patient with a malignant biliary and duodenal stricture due to advanced adenocarcinoma of the pancreas. A, Duodenal stenosis caused by advanced pancreatic adenocarcinoma, B, EUS-guided puncture of the dilated common bile duct with a 19-gauge needle, C, EUS-guided cholangiography revealing a long and tortuous malignant stricture of the distal common bile duct stricture, D, bulbo-choledochal fistula created with a cystotome with a guidewire positioned well into the biliary tree, E, Endoscopic image of the expanded biliary and duodenal stent, F, Radiologic image of the expanded biliary and duodenal stent. Downloaded for Usuario UDEM ([email protected]) at Universidad de Monterrey from ClinicalKey.com by Elsevier on July 25, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved.

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manipulation of the pancreatic duct for prophylactic pancreatic stent insertion may not be justified. Retroperitoneal perforation occurs in less than 1% of cases.144 It may be caused by standard sphincterotomy, precut sphincterotomy, or guidewire manipulation. Most cases are diagnosed or suspected during ERCP. These retroperitoneal perforations mostly heal with conservative measures consisting of nil per mouth, intravenous antibiotics, and nasogastric suction. In cases of peritoneal perforation caused by the duodenoscope, prompt exploratory laparotomy, with repair or oversewing of the defect in the duodenal wall, has traditionally been deemed mandatory.145 Recently, the use of large over-the-scope clips has been reported to successfully close duodenal perforations caused by side viewing endoscopes.146 Late Complications The most common late complication of stent placement is occlusion of the endoprosthesis, which occurs in approximately 50% of cases.77,78 These patients clinically present with recurrent jaundice, a flulike syndrome with cholestasis or frank cholangitis. Treatment consists of exchange of the occluded stent or, in the case of an occluded uncovered SEMS, of insertion of a polyethylene stent or second SEMS through the obstructed expanding stent. See also the earlier sections on Management of Plastic Stent Occlusion and Management of Self-Expanding Metal Stent Occlusion.

Future Trends Photodynamic Therapy Photodynamic therapy (PDT) involves the intravenous administration of a photosensitizer that is activated with a laser light, causing necrosis of the exposed tissue. Preliminary results suggest prolonged survival and stent patency for PDT in cholangiocarcinoma at the hilum.147–149 There are, however, no prospective randomized controlled studies available. Previously, it was thought that metal stents and PDT were incompatible.150 However, this does not seem to be a major issue as long as the light dose is adjusted to counteract the reduction of light transmittance caused by the metal.151 PDT has also been used successfully to recanalize metal stents that were blocked by tumor ingrowth.152 Radiofrequency Ablation Radiofrequency ablation (RFA) is a relatively simple low-cost procedure that is increasingly being studied for local treatment of biliary obstructive malignancies.153 RFA can be performed via an antegrade route by means of PTC or a retrograde route using ERCP. With the use of a bipolar probe that is mounted on a catheter, coagulative necrosis of the intraductal tumor mass is achieved after which biliary stents are placed; generally plastic when multiple RFA sessions are planned. A retrospective study comparing 16 patients treated with RFA and 32 patients treated with PDT did not show a difference in median survival (9.6 vs. 7.5 months).154 Some studies have successfully explored the use of RFA to de-obstruct metal expandable stents after they had become clogged with tumorous or hyperplastic tissue ingrowth.155,156 Drug-Coated Biliary Stents Covering biliary stents with a chemotherapeutic agent, thereby delivering the drug directly into the tumor, may provide protection against tumor ingrowth and overgrowth. For an optimal therapeutic effect, these drugs should be released over a longer period with good penetration into the tumorous tissue and without

causing systemic toxicity. Carboplatin and paclitaxel have been shown to inhibit cell proliferation in vitro.157,158 Carboplatincoated plastic stents have been used with promising preliminary results in a few patients.158 In a small pilot study, placement of a metal stent covered with a paclitaxel-incorporated membrane in patients with malignant biliary obstruction proved feasible, safe, and effective.159 Median patency was 270 days (range 68 to 810 days), and cumulative patency rates at 3 months, 6 months, and 12 months were 100%, 71%, and 36%. However, whether drug-eluting stents represent an advancement in the treatment of patients with malignant biliary strictures remains to be proven in prospective comparative trials. Endoscopic Ultrasound–Guided Biliary Drainage EUS-guided biliary drainage is being explored as an alternative to ERCP. The successful outcome of EUS-guided drainage of pancreatic pseudocysts and infected pancreatic necrosis, and the development of specially designed fully covered metal lumen apposing stents has accelerated its introduction for this novel indication. EUS-guided biliary drainage encompasses EUS-guided antegrade rendezvous drainage, EUS-guided choledochoduodenostomy, and EUS-guided hepaticogastrostomy. In a retrospective study including 208 patients from multiple tertiary referral centers, a single session of EUS-guided biliary drainage (EUS-BD) after 1 or more failed ERCP attempts, either EUS-guided choledochoduodenostomy or EUS-guided antegrade rendezvous drainage, was compared to ERCP in patients with a distal common bile duct obstruction requiring placement of a SEMS.160 SEMS was equally successful after both procedures (93.26% vs. 94.23%, p = 1.00). The frequency of adverse events in the ERCP and EUS-BD groups was comparable (8.65%), but postprocedure pancreatitis rates were higher in the ERCP group (4.8% vs 0%, p = 0.059). EUS-guided hepaticogastrostomy has been reported by several groups as an alternative treatment to percutaneous biliary drainage or surgical bypass in the case of failed ERCP, in particular in the case of a bulboduodenal obstruction or a proximal stricture at the level of the hepatic hilum when EUS-guided choledochoduodenostomy is not possible.161,162 For this, a dilated biliary branch in the left lobe is punctured by a 19-gauge needle under EUS guidance. Next, a guidewire is advanced, and the needle is removed. A cystotome is introduced over the wire to create a fistulous tract by the use of electrocautery. Successful longterm drainage has been reported with plastic stents and covered metal stents. In conclusion, in case of ERCP failure, EUS-guided biliary drainage has emerged as a viable alternative to percutaneous tranhepatic drainage. Local expertise, logistics, and cost should be taken into consideration in the planning of the therapeutic algorithm in cases of ERCP failure.

KEY REFERENCES 1. American Cancer Society: Key statistics for pancreatic cancer. April 2016. Available at http://www.cancer.org/cancer/pancreaticcancer/ detailedguide/pancreatic-cancer-key-statistics. (Accessed 26 October 2016). 11. Sapisochin G, Fernandez de Sevilla E, Echeverri J, Charco R: Liver transplantation for cholangiocarcinoma: current status and new insights, World J Hepatol 7(22):2396–2403, 2015. 17. Navaneethan U, Njei B, Lourdusamy V, et al: Comparative effectiveness of biliary brush cytology and intraductal biopsy for detection of

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CHAPTER 63 Palliation of Malignant Pancreaticobiliary Obstruction

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A complete reference list can be found online at ExpertConsult .com

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CHAPTER 63 Palliation of Malignant Pancreaticobiliary Obstruction

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indeterminate biliary strictures: results of a prospective multicenter international study, Gastrointest Endosc 81(2):282–290, 2015. Finkelberg DL, Sahani D, Deshpande V, Brugge WR: Autoimmune pancreatitis, N Engl J Med 355(25):2670–2676, 2006. Vitali F, Hansen T, Kiesslich R, et al: Frequency and characterization of benign lesions in patients undergoing surgery for the suspicion of solid pancreatic neoplasm, Pancreas 43(8):1329–1333, 2014. Arvanitakis M, Rigaux J, Toussaint E, et al: Endotherapy for paraduodenal pancreatitis: a large retrospective case series, Endoscopy 46(7):580–587, 2014. Arora A, Rajesh S, Mukund A, et al: Clinicoradiological appraisal of ‘paraduodenal pancreatitis’: pancreatitis outside the pancreas!, Indian J Radiol Imaging 25(3):303–314, 2015. Kadiyala V, Lee LS: Endosonography in the diagnosis and management of pancreatic cysts, World J Gastrointest Endosc 7(3):213–223, 2015. Speer AG, Cotton PB, Russell RC, et al: Randomised trial of endoscopic versus percutaneous stent insertion in malignant obstructive jaundice, Lancet 2(8550):57–62, 1987. Smith AC, Dowsett JF, Russell RC, et al: Randomised trial of endoscopic stenting versus surgical bypass in malignant low bileduct obstruction, Lancet 344(8938):1655–1660, 1994. Freeman ML, Nelson DB, Sherman S, et al: Complications of endoscopic biliary sphincterotomy, N Engl J Med 335(13):909–918, 1996. Ballinger AB, McHugh M, Catnach SM, et al: Symptom relief and quality of life after stenting for malignant bile duct obstruction, Gut 35(4):467–470, 1994. Abraham NS, Barkun JS, Barkun AN: Palliation of malignant biliary obstruction: a prospective trial examining impact on quality of life, Gastrointest Endosc 56(6):835–841, 2002. Lai EC, Mok FP, Fan ST, et al: Preoperative endoscopic drainage for malignant obstructive jaundice, Br J Surg 81(8):1195–1198, 1994. Sewnath ME, Birjmohun RS, Rauws EA, et al: The effect of preoperative biliary drainage on postoperative complications after pancreaticoduodenectomy, J Am Coll Surg 192(6):726–734, 2001. Martignoni ME, Wagner M, Krahenbuhl L, et al: Effect of preoperative biliary drainage on surgical outcome after pancreatoduodenectomy, Am J Surg 181(1):52–59, discussion 87, 2001. van der Gaag NA, Rauws EA, van Eijck CH, et al: Preoperative biliary drainage for cancer of the head of the pancreas, N Engl J Med 362(2): 129–137, 2010. Tol JA, van Hooft JE, Timmer R, et al: Metal or plastic stents for preoperative biliary drainage in resectable pancreatic cancer, Gut 65(12):1981–1987, 2016. Coene PP, Groen AK, Cheng J, et al: Clogging of biliary endoprostheses: a new perspective, Gut 31(8):913–917, 1990. Leung JW, Ling TK, Kung JL, Vallance-Owen J: The role of bacteria in the blockage of biliary stents, Gastrointest Endosc 34(1):19–22, 1988. Speer AG, Cotton PB, Rode J, et al: Biliary stent blockage with bacterial biofilm. A light and electron microscopy study, Ann Intern Med 108(4): 546–553, 1988. Speer AG, Cotton PB, MacRae KD: Endoscopic management of malignant biliary obstruction: stents of 10 French gauge are preferable to stents of 8 French gauge, Gastrointest Endosc 34(5):412–417, 1988. Pereira-Lima JC, Jakobs R, Maier M, et al: Endoscopic biliary stenting for the palliation of pancreatic cancer: results, survival predictive factors, and comparison of 10-French with 11.5-French gauge stents, Am J Gastroenterol 91(10):2179–2184, 1996. Kadakia SC, Starnes E: Comparison of 10 French gauge stent with 11.5 French gauge stent in patients with biliary tract diseases, Gastrointest Endosc 38(4):454–459, 1992. Siegel JH, Pullano W, Kodsi B, et al: Optimal palliation of malignant bile duct obstruction: experience with endoscopic 12 French prostheses, Endoscopy 20(4):137–141, 1988. Rey JF, Maupetit P, Greff M: Experimental study of biliary endoprosthesis efficiency, Endoscopy 17(4):145–148, 1985.

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SECTION III

Pancreaticobiliary Disorders

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67. Ghosh S, Palmer KR: Prevention of biliary stent occlusion using cyclical antibiotics and ursodeoxycholic acid, Gut 35(12):1757–1759, 1994. 68. Barrioz T, Ingrand P, Besson I, et al: Randomised trial of prevention of biliary stent occlusion by ursodeoxycholic acid plus norfloxacin, Lancet 344(8922):581–582, 1994. 69. Halm U, Schiefke, Fleig WE, et al: Ofloxacin and ursodeoxycholic acid versus ursodeoxycholic acid alone to prevent occlusion of biliary stents: a prospective, randomized trial, Endoscopy 33(6):491–494, 2001. 70. Luman W, Ghosh S, Palmer KR: A combination of ciprofloxacin and Rowachol does not prevent biliary stent occlusion, Gastrointest Endosc 49(3 Pt 1):316–321, 1999. 71. Sung JY, Shaffer EA, Lam K, et al: Hydrophobic bile salt inhibits bacterial adhesion on biliary stent material, Dig Dis Sci 39(5):999–1006, 1994. 72. Lee SP, Carey MC, LaMont JT: Aspirin prevention of cholesterol gallstone formation in prairie dogs, Science 211(4489):1429–1431, 1981. 73. Smit JM, Out MM, Groen AK, et al: A placebo-controlled study on the efficacy of aspirin and doxycycline in preventing clogging of biliary endoprostheses, Gastrointest Endosc 35(6):485–489, 1989. 74. Frakes JT, Johanson JF, Stake JJ: Optimal timing for stent replacement in malignant biliary tract obstruction, Gastrointest Endosc 39(2):164– 167, 1993. 75. Prat F, Chapat O, Ducot B, et al: A randomized trial of endoscopic drainage methods for inoperable malignant strictures of the common bile duct, Gastrointest Endosc 47(1):1–7, 1998. 76. Loew BJ, Howell DA, Sanders MK, et al: Comparative performance of uncoated, self-expanding metal biliary stents of different designs in 2 diameters: final results of an international multicenter, randomized, controlled trial, Gastrointest Endosc 70(3):445–453, 2009. 77. Davids PH, Groen AK, Rauws EA, et al: Randomised trial of selfexpanding metal stents versus polyethylene stents for distal malignant biliary obstruction, Lancet 340(8834-8835):1488–1492, 1992. 78. Knyrim K, Wagner HJ, Pausch J, Vakil N: A prospective, randomized, controlled trial of metal stents for malignant obstruction of the common bile duct, Endoscopy 25(3):207–212, 1993. 79. Carr-Locke D, Ball TJ, Conners PJ: Multicenter randomized trial of Wallstent biliary prosthesis versus plastic stents, Gastrointest Endosc 39:310–316, 1993. 80. Yang MJ, Kim JH, Yoo BM, et al: Partially covered versus uncovered self-expandable nitinol stents with anti-migration properties for the palliation of malignant distal biliary obstruction: a randomized controlled trial, Scand J Gastroenterol 50(12):1490–1499, 2015. 81. Yoon WJ, Lee JK, Lee KH, et al: A comparison of covered and uncovered Wallstents for the management of distal malignant biliary obstruction, Gastrointest Endosc 63(7):996–1000, 2006. 82. Fumex F, Coumaros D, Napoleon B, et al: Similar performance but higher cholecystitis rate with covered biliary stents: results from a prospective multicenter evaluation, Endoscopy 38(8):787–792, 2006. 83. Isayama H, Komatsu Y, Tsujino T, et al: A prospective randomised study of “covered” versus “uncovered” diamond stents for the management of distal malignant biliary obstruction, Gut 53(5):729–734, 2004. 84. Nakai Y, Isayama H, Komatsu Y, et al: Efficacy and safety of the covered Wallstent in patients with distal malignant biliary obstruction, Gastrointest Endosc 62(5):742–748, 2005. 85. Artifon EL, Sakai P, Ishioka S, et al: Endoscopic sphincterotomy before deployment of covered metal stent is associated with greater complication rate: a prospective randomized control trial, J Clin Gastroenterol 42(7):815–819, 2008. 86. Jo JH, Park BH: Suprapapillary versus transpapillary stent placement for malignant biliary obstruction: which is better?, J Vasc Interv Radiol 26(4):573–582, 2015. 87. Prat F, Chapat O, Ducot B, et al: Predictive factors for survival of patients with inoperable malignant distal biliary strictures: a practical management guideline, Gut 42(1):76–80, 1998. 88. Kaassis M, Boyer J, Dumas R, et al: Plastic or metal stents for malignant stricture of the common bile duct? Results of a randomized prospective study, Gastrointest Endosc 57(2):178–182, 2003.

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CHAPTER 63 Palliation of Malignant Pancreaticobiliary Obstruction 89. Pereira-Lima JC, Jakobs R, Maier M, et al: Endoscopic stenting in obstructive jaundice due to liver metastases: does it have a benefit for the patient?, Hepatogastroenterology 43(10):944–948, 1996. 90. Yeoh KG, Zimmerman MJ, Cunningham JT, Cotton PB: Comparative costs of metal versus plastic biliary stent strategies for malignant obstructive jaundice by decision analysis, Gastrointest Endosc 49(4 Pt 1): 466–471, 1999. 91. Arguedas MR, Heudebert GH, Stinnett AA, Wilcox CM: Biliary stents in malignant obstructive jaundice due to pancreatic carcinoma: a cost-effectiveness analysis, Am J Gastroenterol 97(4):898–904, 2002. 92. Moss AC, Morris E, Leyden J, MacMathuna P: Do the benefits of metal stents justify the costs? A systematic review and meta-analysis of trials comparing endoscopic stents for malignant biliary obstruction, Eur J Gastroenterol Hepatol 19(12):1119–1124, 2007. 93. Soderlund C, Linder S: Covered metal versus plastic stents for malignant common bile duct stenosis: a prospective, randomized, controlled trial, Gastrointest Endosc 63(7):986–995, 2006. 94. Soehendra N, Maydeo A, Eckmann B, et al: A new technique for replacing an obstructed biliary endoprosthesis, Endoscopy 22(6):271– 272, 1990. 95. Dumas R, Demuth N, Buckley M, et al: Endoscopic bilateral metal stent placement for malignant hilar stenoses: identification of optimal technique, Gastrointest Endosc 51(3):334–338, 2000. 96. Lee JH, Kang DH, Kim JY, et al: Endoscopic bilateral metal stent placement for advanced hilar cholangiocarcinoma: a pilot study of a newly designed Y stent, Gastrointest Endosc 66(2):364–369, 2007. 97. Neuhaus H, Gottlieb K, Classen M: The “stent through wire mesh technique” for complicated biliary strictures, Gastrointest Endosc 39(4):553–556, 1993. 98. Kawakubo K, Kawakami H, Kuwatani M, et al: Single-step simultaneous side-by-side placement of a self-expandable metallic stent with a 6-Fr delivery system for unresectable malignant hilar biliary obstruction: a feasibility study, J Hepatobiliary Pancreat Sci 22(2):151–155, 2015. 99. Law R, Baron TH: Bilateral metal stents for hilar biliary obstruction using a 6Fr delivery system: outcomes following bilateral and side-by-side stent deployment, Dig Dis Sci 58(9):2667–2672, 2013. 100. Kim KM, Lee KH, Chung YH, et al: A comparison of bilateral stenting methods for malignant hilar biliary obstruction, Hepatogastroenterology 59(114):341–346, 2012. 101. Naitoh I, Hayashi K, Nakazawa T, et al: Side-by-side versus stent-instent deployment in bilateral endoscopic metal stenting for malignant hilar biliary obstruction, Dig Dis Sci 57(12):3279–3285, 2012. 102. Tan DM, Lillemoe KD, Fogel EL: A new technique for endoscopic removal of uncovered biliary self-expandable metal stents: stent-in-stent technique with a fully covered biliary stent, Gastrointest Endosc 75(4):923–925, 2012. 103. Tringali A, Blero D, Boskoski I, et al: Difficult removal of fully covered self expandable metal stents (SEMS) for benign biliary strictures: the “SEMS in SEMS” technique, Dig Liver Dis 46(6):568–571, 2014. 104. Bismuth H, Corlette MB: Intrahepatic cholangioenteric anastomosis in carcinoma of the hilus of the liver, Surg Gynecol Obstet 140(2):170–178, 1975. 105. Deviere J, Baize M, de Toeuf J, Cremer M: Long-term follow-up of patients with hilar malignant stricture treated by endoscopic internal biliary drainage, Gastrointest Endosc 34(2):95–101, 1988. 106. Ducreux M, Liguory C, Lefebvre JF, et al: Management of malignant hilar biliary obstruction by endoscopy. Results and prognostic factors, Dig Dis Sci 37(5):778–783, 1992. 107. Polydorou AA, Cairns SR, Dowsett JF, et al: Palliation of proximal malignant biliary obstruction by endoscopic endoprosthesis insertion, Gut 32(6):685–689, 1991. 108. Stoker J, Lameris JS, Jeekel J: Percutaneously placed Wallstent endoprosthesis in patients with malignant distal biliary obstruction, Br J Surg 80(9):1185–1187, 1993. 109. Gordon RL, Ring EJ, LaBerge JM, Doherty MM: Malignant biliary obstruction: treatment with expandable metallic stents–follow-up of 50 consecutive patients, Radiology 182(3):697–701, 1992.

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110. Paik WH, Park YS, Hwang JH, et al: Palliative treatment with selfexpandable metallic stents in patients with advanced type III or IV hilar cholangiocarcinoma: a percutaneous versus endoscopic approach, Gastrointest Endosc 69(1):55–62, 2009. 111. Rerknimitr R, Angsuwatcharakon P, Ratanachu-ek T, et al: Asia-Pacific consensus recommendations for endoscopic and interventional management of hilar cholangiocarcinoma, J Gastroenterol Hepatol 28(4):593–607, 2013. 112. Dowsett JF, Vaira D, Hatfield AR, et al: Endoscopic biliary therapy using the combined percutaneous and endoscopic technique, Gastroenterology 96(4):1180–1186, 1989. 113. Vienne A, Hobeika E, Gouya H, et al: Prediction of drainage effectiveness during endoscopic stenting of malignant hilar strictures: the role of liver volume assessment, Gastrointest Endosc 72(4):728–735, 2010. 114. Chang WH, Kortan P, Haber GB: Outcome in patients with bifurcation tumors who undergo unilateral versus bilateral hepatic duct drainage, Gastrointest Endosc 47(5):354–362, 1998. 115. De Palma GD, Galloro G, Siciliano S, et al: Unilateral versus bilateral endoscopic hepatic duct drainage in patients with malignant hilar biliary obstruction: results of a prospective, randomized, and controlled study, Gastrointest Endosc 53(6):547–553, 2001. 116. Hintze RE, Abou-Rebyeh H, Adler A, et al: Magnetic resonance cholangiopancreatography-guided unilateral endoscopic stent placement for Klatskin tumors, Gastrointest Endosc 53(1):40–46, 2001. 117. Freeman ML, Overby C: Selective MRCP and CT-targeted drainage of malignant hilar biliary obstruction with self-expanding metallic stents, Gastrointest Endosc 58(1):41–49, 2003. 118. Sawas T, Al Halabi S, Parsi MA, Vargo JJ: Self-expandable metal stents versus plastic stents for malignant biliary obstruction: a meta-analysis, Gastrointest Endosc 82(2):256–267, e7, 2015. 119. Wagner HJ, Knyrim K, Vakil N, Klose KJ: Plastic endoprostheses versus metal stents in the palliative treatment of malignant hilar biliary obstruction. A prospective and randomized trial, Endoscopy 25(3):213– 218, 1993. 120. Cheng JL, Bruno MJ, Bergman JJ, et al: Endoscopic palliation of patients with biliary obstruction caused by nonresectable hilar cholangiocarcinoma: efficacy of self-expandable metallic Wallstents, Gastrointest Endosc 56(1):33–39, 2002. 121. Perdue DG, Freeman ML, DiSario JA, et al: Plastic versus self-expanding metallic stents for malignant hilar biliary obstruction: a prospective multicenter observational cohort study, J Clin Gastroenterol 42(9):1040– 1046, 2008. 122. van den Hazel SJ, Speelman P, Dankert J, et al: Piperacillin to prevent cholangitis after endoscopic retrograde cholangiopancreatography. A randomized, controlled trial, Ann Intern Med 125(6):442–447, 1996. 123. Sauter G, Grabein B, Huber G, et al: Antibiotic prophylaxis of infectious complications with endoscopic retrograde cholangiopancreatography. A randomized controlled study, Endoscopy 22(4):164–167, 1990. 124. Harris A, Chan AC, Torres-Viera C, et al: Meta-analysis of antibiotic prophylaxis in endoscopic retrograde cholangiopancreatography (ERCP), Endoscopy 31(9):718–724, 1999. 125. Motte S, Deviere J, Dumonceau JM, et al: Risk factors for septicemia following endoscopic biliary stenting, Gastroenterology 101(5):1374– 1381, 1991. 126. Deviere J, Motte S, Dumonceau JM, et al: Septicemia after endoscopic retrograde cholangiopancreatography, Endoscopy 22(2):72–75, 1990. 127. Watanapa P, Williamson RC: Surgical palliation for pancreatic cancer: developments during the past two decades, Br J Surg 79(1):8–20, 1992. 128. van der Schelling GP, van den Bosch RP, Klinkenbij JH, et al: Is there a place for gastroenterostomy in patients with advanced cancer of the head of the pancreas?, World J Surg 17(1):128–132, discussion 132-133, 1993. 129. Wong YT, Brams DM, Munson L, et al: Gastric outlet obstruction secondary to pancreatic cancer: surgical vs endoscopic palliation, Surg Endosc 16(2):310–312, 2002.

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SECTION III

Pancreaticobiliary Disorders

130. Nevitt AW, Vida F, Kozarek RA, et al: Expandable metallic prostheses for malignant obstructions of gastric outlet and proximal small bowel, Gastrointest Endosc 47(3):271–276, 1998. 131. Soetikno RM, Lichtenstein DR, Vandervoort J, et al: Palliation of malignant gastric outlet obstruction using an endoscopically placed Wallstent, Gastrointest Endosc 47(3):267–270, 1998. 132. Venu RP, Pastika BJ, Kini M, et al: Self-expandable metal stents for malignant gastric outlet obstruction: a modified technique, Endoscopy 30(6):553–558, 1998. 133. van Halsema EE, Rauws EA, Fockens P, van Hooft JE: Self-expandable metal stents for malignant gastric outlet obstruction: a pooled analysis of prospective literature, World J Gastroenterol 21(43):12468–12481, 2015. 134. Jeurnink SM, Steyerberg EW, Hof G, et al: Gastrojejunostomy versus stent placement in patients with malignant gastric outlet obstruction: a comparison in 95 patients, J Surg Oncol 96(5):389–396, 2007. 135. Barthet M, Binmoeller KF, Vanbiervliet G, et al: Natural orifice transluminal endoscopic surgery gastroenterostomy with a biflanged lumen-apposing stent: first clinical experience (with videos), Gastrointest Endosc 81(1):215–218, 2015. 136. Khashab MA, Kumbhari V, Grimm IS, et al: EUS-guided gastroenterostomy: the first U.S. clinical experience (with video), Gastrointest Endosc 82(5):932–938, 2015. 137. Itoi T, Tsuchiya T, Tonozuka R, et al: Novel EUS-guided doubleballoon-occluded gastrojejunostomy bypass, Gastrointest Endosc 83(2):461–462, 2016. 138. Kaw M, Singh S, Gagneja H: Clinical outcome of simultaneous self-expandable metal stents for palliation of malignant biliary and duodenal obstruction, Surg Endosc 17(3):457–461, 2003. 139. Mutignani M, Tringali A, Shah SG, et al: Combined endoscopic stent insertion in malignant biliary and duodenal obstruction, Endoscopy 39(5):440–447, 2007. 140. Khashab MA, Fujii LL, Baron TH, et al: EUS-guided biliary drainage for patients with malignant biliary obstruction with an indwelling duodenal stent (with videos), Gastrointest Endosc 76(1):209–213, 2012. 141. Cotton PB, Lehman G, Vennes J, et al: Endoscopic sphincterotomy complications and their management: an attempt at consensus, Gastrointest Endosc 37(3):383–393, 1991. 142. Masci E, Toti G, Mariani A, et al: Complications of diagnostic and therapeutic ERCP: a prospective multicenter study, Am J Gastroenterol 96(2):417–423, 2001. 143. Foutch PG: A prospective assessment of results for needle-knife papillotomy and standard endoscopic sphincterotomy, Gastrointest Endosc 41(1):25–32, 1995. 144. Enns R, Eloubeidi MA, Mergener K, et al: ERCP-related perforations: risk factors and management, Endoscopy 34(4):293–298, 2002. 145. Stapfer M, Selby RR, Stain SC, et al: Management of duodenal perforation after endoscopic retrograde cholangiopancreatography and sphincterotomy, Ann Surg 232(2):191–198, 2000. 146. Mangiavillano B, Arena M, Morandi E, et al: Successful closure of an endoscopic ultrasound-induced duodenal perforation using an over-the-scope-clip, Endoscopy 46(Suppl 1 UCTN):E206–E207, 2014.

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