GERD. Reflux to Esophageal Adenocarcinoma

Transcription

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2 GERD Reflux to Esophageal Adenocarcinoma

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4 GERD Reflux to Esophageal Adenocarcinoma PARAKRAMA T. CHANDRASOMA KECK School of Medicine, University of Southern California, Los Angeles, California, USA TOM R. DEMEESTER KECK School of Medicine, University of Southern California, Los Angeles, California, USA Amsterdam Boston Heidelberg London New York Oxford Paris San Diego San Francisco Singapore Sydney Tokyo

5 Academic Press is an imprint of Elsevier 30 Corporate Drive, Suite 400, Burlington, MA 01803, USA 525 B Street, Suite 1900, San Diego, California , USA 84 Theobald s Road, London WC1X 8RR, UK This book is printed on acid-free paper. Copyright 2006, 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 photocopy, recording, or any information storage and retrieval system, without permission in writing from the publisher. Permissions may be sought directly from Elsevier s Science & Technology Rights Department in Oxford, UK: phone: (+44) , fax: (+44) , permissions@elsevier.com. You may also complete your request on-line via the Elsevier homepage ( by selecting Support & Contact then Copyright and Permission and then Obtaining Permissions. Library of Congress Cataloging-in-Publication Data Application Submitted British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library. ISBN 13: ISBN 10: For information on all Academic Press publications visit our Web site at Printed in the United States of America

6 DEDICATION To all those patients with gastroesophageal reflux disease who paid the ultimate price for our lack of understanding.

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8 Contents Preface xv Prevalence of Reflux-Induced Adenocarcinoma 6 1 Overview of Gastroesophageal Reflux Disease Physiological versus Pathological Reflux 3 Prevalence of Gastroesophageal Reflux Disease 3 Histologic Definition of Gastroesophageal Reflux Disease 5 Prevalence of Barrett Esophagus 6 Management of Barrett Esophagus 6 2 The Past, Present, and Future of Columnar-Lined (Barrett) Esophagus The History of Columnar-Lined Esophagus 12 The Reasons for Confusion 27 Historical Evolution of Columnar-Lined (Barrett) Esophagus 31 The State of the Art and Today s Problems 35 Solutions of the Problem and What We Hope to Show 36 vii

9 viii Contents 3 Fetal Development of the Esophagus and Stomach The Study of Embryology of the Foregut 42 Early Development of the Gastrointestinal Tract 43 Early Development of the Foregut 45 Epithelial Development in the Fetal Esophagus 45 Epithelial Development in the Fetal Stomach 49 Epithelial Development in the Fetal Gastroesophageal Junction 51 Summary of Epithelial Development of the Esophagus 59 Control of the Foregut Epithelial Development 59 The Meaning of Endoscopic/Gross Landmarks 74 Present Definition of the Gastroesophageal Junction 75 What Is the Cardia? Let s Remove This Term from Our Vocabulary 83 The Logical Conclusion That Should Be Tested 86 5 Histologic Definitions and Diagnosis of Epithelial Types Definitions 89 Problems with the Definitions 98 Diagnosis of Different Epithelial Types Normal Anatomy; Present Definition of the Gastroesophageal Junction Anatomy and Physiology 65 Endoscopic/Gross Landmarks 72 6 Cardiac Mucosa What Is Cardiac Mucosa? 107 Where Is Cardiac Mucosa Located? 111 Is Cardiac Mucosa Present in Everyone? 117

10 Contents ix What Is Oxyntocardiac Mucosa, and Where Is It? 124 How Much Cardia and Oxyntocardiac Mucosa Are Present? 127 What Does the Presence/Absence and Amount of Cardiac Mucosa Mean? 128 What Does Increasing Length of Cardiac Mucosa Mean? 130 A Human Experiment 131 Summary Statement Regarding Cardiac Mucosa New Histologic Definitions of Esophagus, Stomach, and Gastroesophageal Junction Let Us Establish Common Ground in Histology 135 Let Us Understand the Problem 141 Normal Histology of the Esophagus and Stomach: A Statement of Fact and New Histologic Definitions 142 Application of These Definitions to Practice Pathology of Reflux Disease at a Cellular Level: Part 1 Damage to Squamous Epithelium and Transformation into Cardiac Mucosa Reflux-Induced Damage of the Squamous Epithelium 149 Columnar Metaplasia of the Squamous Epithelium 159 Summary The Pathology of Reflux Disease at a Cellular Level: Part 2 Evolution of Cardiac Mucosa to Oxyntocardiac Mucosa and Intestinal Metaplasia Histologic Composition of Columnar- Lined Esophagus 169 Cardiac to Oxyntocardiac Mucosa: The Benign Genetic Switch 176

11 x Cardiac Mucosa to Intestinal Metaplasia: The Second Genetic Switch 179 Contents Cause of Carcinogenesis in Barrett Esophagus Pathology of Reflux Disease at a Cellular Level: Part 3 Intestinal (Barrett) Metaplasia to Carcinoma Carcinogenesis in Intestinal Metaplasia 201 Does Adenocarcinoma Arise in Esophagus without Intestinal (Barrett) Metaplasia? 202 Natural History of Dysplasia: Surveillance for Barrett Esophagus 207 Does Dysplasia Reverse? 218 Theoretical Considerations Relating to Adenocarcinoma Distribution in the Columnar-Lined Esophagus 218 Assessment of Cancer Risk in Barrett Esophagus 221 Clinically Useful Molecular Tests Pathology of Reflux Disease at an Anatomic Level Identification and Validation of the True Gastroesophageal Junction 241 The Anatomical Changes Associated with Sliding Hiatal Hernia 246 Stages between Normal and Sliding Hiatal Hernia: The Reflux-Damaged Distal Esophagus Defining the End-Stage Esophagus 247 Relationship of the Dilated End-Stage Esophagus to Columnar-Lined Esophagus 259 The Discrepancy Has Now Disappeared 261 Anatomy and Histology of a Sliding Hiatal Hernia 261 The Great Historical Misunderstanding Continues to the Present 262

12 Contents xi 12 Reflux Disease Limited to the Dilated End-Stage Esophagus: The Pathologic Basis of NERD Gastroesophageal Reflux versus Reflux Disease 267 Reflux Disease Limited to the Dilated End-Stage Esophagus 268 A New Look at Intestinal Metaplasia of the Gastric Cardia 282 A New Look at Adenocarcinoma of the Gastric Cardia Definition of Gastroesophageal Reflux Disease and Barrett Esophagus Presently Used Criteria for Defining Gastroesophageal Reflux Disease 297 Definitions Based on Quantiating Gastroesophageal Reflux 302 Proposed New Criterion for Defining Gastroesophageal Reflux Disease 305 Reflux Carditis: A New Entity That Defines Gastroesophageal Reflux Disease with Perfection 307 A New Definition of Barrett Esophagus Diagnosis of Gastroesophageal Reflux Disease, Barrett Esophagus, and Dysplasia A New Diagnostic Method for Reflux Disease 334 The Diagnosis of Reflux Carditis and Barrett Esophagus 341 The Diagnosis of Dysplasia in Barrett Esophagus Research Strategies for Preventing Reflux-Induced Adenocarcinoma Mechanisms of Cellular Changes in Reflux Disease 357

13 xii The Mechanism of Metaplasia: Epithelia Do Not Move 359 The Reflux-Adenocarcinoma Sequence 360 Recognition of Different Risk Levels in the Epithelia of Columnar-Lined Esophagus 364 The State of Present Pharmaceutical Intervention in Reflux Disease 366 Acid Suppressive Drugs Promote Esophageal Adenocarcinoma 367 Proposed New Pharmaceutical Research Targets Aimed at Preventing Adenocarcinoma 369 Research into Surgical Methods of Preventing Adenocarcinoma 372 Identifying Factors in Gastric Juice Responsible for Molecular Events 373 Molecular Research into Carcinogenesis Rationale for Treatment of Reflux Disease and Barrett Esophagus The Present Rationale for Treatment of Reflux Disease 381 Contents Acid Suppression with Drugs as Treatment for Reflux Disease 382 Does Acid Suppressive Drug Therapy Increase the Risk of Adenocarcinoma? 391 Antireflux Surgery as Treatment for Reflux Disease 393 Ablation as Treatment for Barrett Esophagus Treatment Strategies for Preventing Reflux-Induced Adenocarcinoma Asymptomatic versus Symptomatic Patients 412 Present Treatment of Reflux Disease 412 Outcome of Present Treatment Regimens 417 Reflux Disease Is the Premalignant Phase of Cancer 417 Antireflux Surgery Can Prevent Progression in the Reflux to the Adenocarcinoma Sequence; Cancer Can Be Prevented 418 Definition of the Biopsy Protocol for Index Diagnosis 421 Classification of Risk Based on Biopsy Results 423

14 Contents xiii Recommendations for Treatment of Biopsy-Defined Groups 423 Recommended Changes in the Treatment of Defined Patient Groups 426 Cost of Antireflux Surgery 434 Resources Needed to Implement Recommended Changes 435 Summary of Recommended Changes 436 Index 439 Color Plates between Pages 352 and 353

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16 Preface Failure to understand a disease has consequences to the patient. In the sixteenth century, belief that illhumors in the body were responsible for disease led to many patients being purged and bled as part of their treatment while their diseases progressed to their natural outcome. The purging and bleeding often caused harm rather than good. For patients with reflux disease, the naive and false belief that all facets of their disease are caused by acid has resulted in every person with reflux disease being prescribed acid suppressive drugs. Physicians declare this treatment to be a success of modern medicine, yet the mortality of patients with reflux disease has increased exponentially. This is the result of reflux-induced adenocarcinoma. While we know that esophageal adenocarcinoma is caused by reflux, we do not understand this relationship. To be correctly understood, a disease must be characterized by its cellular and ultimately its molecular and biochemical events. In gastroesophageal reflux disease, we are far from this ideal. The present management of patients with reflux is confusing and full of contradictions. We define a patient as having reflux when they have symptoms, but recognize that many asymptomatic patients develop reflux induced complications such as Barrett's esophagus and adenocarcinoma. We define reflux by the presence of erosions but recognize the entity of "non-erosive reflux disease". We define reflux by the amount of reflux or acid exposure by impedance and 24-hour ph tests but recognize that no disease should be defined by its etiology rather than its cellular change. There is no histologic definition of reflux. In our ignorance, all we do is feed the patient with reflux disease acid suppressive drugs and hope in vain for a cure. Are acid suppressive drugs the equivalent of purging and bleeding of the sixteenth century? This book provides a theoretical basis of how acid suppressive drugs promote reflux-induced adenocarcinoma. We have unwittingly been guilty of violating the primary edict in medicine of: "Physician, do no harm." Our work is based on the careful clinical study of over 10,000 patients over the past 15 years at the Keck School of Medicine at the University of Southern California. Patients have been examined clinically and by a range of tests, always including biopsy by a standard protocol of every patient who undergoes endoscopy. This has permitted us to describe the changes of reflux disease at a histologic level from cell to cell and millimeter to millimeter. Our translational molecular research on these patients has given us the ability to characterize the observed cellular events in their most fundamental molecular and genetic terms. It is hoped that the increased understanding of reflux disease generated by this book will result in improved patient care, measured by a reversal of the incidence of reflux-induced cancer. Reflux induced adenocarcinoma is preceded by histologically recognizable precursor lesions for many decades. We presently ignore these and simply wait for cancer to occur, often too late to prevent death. Recognizing these early precursor changes, and aggressively detecting and treating them can prevent cancer. We have provided practical methods of achieving this. Our hope is that the information contained within this book will prevent misery and death caused by reflux induced esophageal adenocarcinoma, at least in the patients whose treatment will be changed by people who read it. XV

17 C H A P T E R 1 Overview of Gastroesophageal Reflux Disease Gastroesophageal reflux disease is the classical good news-bad news story. The availability of amazingly effective acid suppressive drugs has improved the quality of life for patients by controlling pain, curing erosive esophagitis, and dramatically reducing the incidence of serious ulcers and strictures. The bad news, however, is that the incidence of adenocarcinoma induced by reflux is rapidly increasing in the United States, Western Europe, Australia, and New Zealand (1). Since the mid-1970s, the incidence of esophageal adenocarcinoma has shown the greatest increase when compared with all other cancer types (Fig. 1.1). The detection, diagnosis, and management of patients with Barrett esophagus (BE), the precursor lesion for reflux-induced adenocarcinoma, are in a state of confusion and total disarray. It is an entity without consensus regarding definition, diagnosis, and management. This was shown very well at a recent American Gastroenterology Association workshop (2). This workshop consisted of 18 experts in the field (15 gastroenterologists, 2 surgeons, and 1 pathologist) from four countries. This group developed 42 statements on the subject of Barrett esophagus. They individually and collectively evaluated the available evidence for each statement, and after discussion they ascribed a numerical grade for the nature of the evidence (graded I to V, I being best) and level of subgroup support for the statement based on the presented evidence (A to E, A being best). After further discussion, each expert voted his or her level of support for each statement. The grading was as follows: A = accept recommendation com- pletely; B = accept with some reservation; C = accept with major reservation; D = reject with reservations; E = reject completely. Table 1.1 sets out the results for the 10 statements we selected as most important. The lack of consensus among the world's most recognized experts for the most basic and crucial of statements regarding Barrett esophagus is astounding. There was a lack of consensus even about the most accepted of these statements such as the need for biopsy-proven intestinal metaplasia for a diagnosis of Barrett esophagus, which received a C; only 5 of 18 experts agreed completely with this statement, and 2 rejected it. Even more amazing is the assessment of the experts regarding the nature of the evidence that exists in the literature. The experts looked at the best evidence relating to these statements and concluded that a grade IV or V was appropriate in 30 of 41 questions (grade V = insufficient evidence to form an opinion; grade IV = opinions of respected authorities based on clinical experience, descriptive studies, or reports of expert committees; grade III = evidence obtained from case series, case reports, or flawed clinical trials). The conclusion reflects an appalling state of affairs, given that these 42 statements represent the most critical that this group could come up with. Further, the wide disparity of opinion rather than consensus among the 18 experts on these important issues makes it fair to say that the understanding of this disease is in a state of total disarray and profound confusion. The impression that we get when we read the summary of the workshop is one of great futility. Criteria for diagnosis are not agreed on, screening for the GERD: REFLUX TO ESOPHAGEAL ADENOCARCINOMA 1

18 2 GERD: Reflux to Esophageal Adenocarcinoma to 5 CO -~ 4...._o 3 n,, 2 1 S " "" "" " FIGURE 1.1 Relative change in incidence of esophageal adenocarcinoma and other malignancies in the period 1975 to Data from the NCI's SEER program. Solid black line = esophageal adenocarcinoma; dashed line = breast cancer; line = prostate cancer; other lines represent melanoma, lung cancer, and colorectal cancer. Reproduced with permission from Pohl H, Welch G. The role of overdiagnosis and reclassification in the marked increase of esophageal adenocarcinoma incidence. J Nat Cancer Inst 2005;97:143. disease is generally felt to be worthless and costineffective, the enthusiasm for the value of surveillance for Barrett esophagus is tepid at best (although this is a standard recommendation for patients diagnosed with Barrett esophagus), and all of today's available treatment methods (acid suppression, antireflux surgery, and ablation) are considered ineffective in preventing adenocarcinoma. These experts seem to be telling us that we really do not clearly know what Barrett esophagus is; we do not want to do anything to detect it even though we know it is the precursor of adenocarcinoma; once we detect it we really do not want to even do what we are doing now (surveillance); and we clearly have nothing to offer the patient in terms of preventing cancer. We have a word of caution here: there was a huge predominance of gastroenterologists among the experts. We know it is possible to gather a group of surgeons who would agree with statement 39 that "antireflux surgery has not been proven to have a major effect against the development of esophageal adenocarcinoma," but they would immediately add that it has TABLE 1.1 Results of Workshop Voting for Selected Statements out of the Total of 42" Statement Nature of Subgroup evidence support A Group Grading B C D E 1. Esophageal intestinal metaplasia documented by histology is a prerequisite criterion for tile diagnosis of BE. Z The proximal margin of the gastric rugal folds is a reliable endoscopic marker for the gastroesophageal junction. 9. The normal appearing and normally located squamocolumnar junction should not be biopsied. 12. Routine endoscopic screening for the detection of BE should be recommended for all adults >50yrs of age. 16. Endoscopic screening for BE and dysplasia should be performed in all adults >50yrs of age with heartburn. 22. Endoscopic surveillance in patients with BE has been shown to prolong survival. 23. Endoscopic surveillance detects curable neoplasia in patients with BE. 35. Normalization of esophageal acid exposure by acid suppression reduces the risk for development of adenocarcinoma. 39. In patients with BE, antireflux surgery has not proven to have a major effect against the development of adenocarcinoma. 41. Mucosal ablation with acid suppression/antireflux surgery prevents adenocarcinoma in patients with BE without dysplasia. IV C IV C IV C 14 4 C) 0 0 V D IV D III B III B V D III A IV E "The statements are selected as being the most important. The group grading represents the number of experts voting for each level of support for the statement (the number is expressed as a percentage in the publication and has been converted into an absolute number).

19 Overview of Gastroesophageal Reflux Disease 3 never been tested. If properly tested, it is likely that antireflux surgery would have a greater effect against the development of cancer than acid suppressive drug therapy. The penalty for this confusion is paid by patients who develop and die from reflux-induced adenocarcinoma. This is the most rapidly increasing cancer type in the United States and Western Europe (Fig. 1). Expressed in another way, we are floundering in the midst of an epidemic of reflux-induced cancer without offering the population at large any hope that we can do anything to stop it. In this book, we will show that the careful application of basic principles of cellular pathology to gastroesophageal reflux disease has the ability to provide understanding of the mechanism of the disease, develop accurate and reproducible criteria for definition and diagnosis of the disease, and lead to appropriate research to find logical methods of controlling the disease and potentially decreasing mortality. Many of these principles are derived from the study of cellular pathology, using the time-honored technique of microscopy. PHYSIOLOGICAL VERSUS PATHOLOGICAL REFLUX Gastroesophageal reflux is one of the most common human afflictions, ranking with atherosclerosis in being almost ubiquitous in the Western world. If a detection system (such as a ph electrode or an impedance catheter) is placed in the lower esophagus, virtually everyone will have sporadic evidence of a retrograde entry of gastric contents into the esophagus. The prevalence of gastroesophageal reflux is therefore close to 100% in the part of the human race living in the United States and Western Europe. Gastroesophageal reflux can be considered to be a physiological event designed to vent a stomach that becomes distended with swallowed air. This is belching; the gas-distended stomach causes the lower esophageal sphincter to relax (transient relaxation), permitting the air to escape into the esophagus. The anatomy of the stomach is such that swallowed air collects immediately below the gastroesophageal junction, and belching therefore is limited to the reflux of air into the esophagus. The occasional reflux of liquid gastric contents into the esophagus is probably a normal physiological occurrence. Consequently, we must draw strict guidelines as to the level reflux must reach before we consider it a disease. A physiological event does not produce a pathologic lesion. "Physiological reflux" must be carefully defined in a manner that is designed to exclude any pathologic abnormality that can be ascribed to reflux. The danger to this is that there may be pathologic changes in cells that we cannot see by present technology or do not recognize because of faulty understanding. We know that reflux causes dilated intercellular spaces that may be visible only by electron microscopy (3). The fact that our methods do not permit us to see these minimal pathologic changes does not make the reflux "physiological." The better term is "subclinical" because this is a moving definition; as our ability to detect abnormalities improves, the definition of what is pathologic will change. Perhaps the safest course is to regard all liquid reflux into the esophagus as being pathologic rather than physiological. The concept of regarding a pathologic lesion as "physiological" or "normal" has been used commonly and with much detrimental effect in reflux disease. Long-segment columnar lined esophagus was ignored until 1953 because physicians defined the esophagus as ending at the squamocolumnar junction (4). Later, when properly described by Allison and Johnstone in 1953 (5) and confirmed by Barrett in 1957 (6), it was initially passed off as an insignificant congenital anomaly. When it was recognized as being caused by reflux, physicians devised an imaginary 2 cm of "normal" columnar lining in the esophagus to ignore short-segment Barrett esophagus for three decades (7). Presently, there is a disturbing trend in gastroenterology to believe that things that are not visible to the endoscope do not exist. Thus, Barrett esophagus is presently defined as intestinal metaplasia occurring in a biopsy taken from an endoscopically visible columnar lined esophagus. By this reasoning, the presence of intestinal metaplasia in a biopsy taken from an endoscopically normal person is not Barrett esophagus. A definition is a human device that is frequently wrong. We have seen the definition of Barrett esophagus change many times depending on the opinion of the moment. Surely, there must be a stage of Barrett esophagus that precedes the ability of the endoscope to detect it. The fact that we ignore patients who truly have Barrett esophagus just because they do not fit the definition of the moment does not mean that they are not at risk to develop carcinoma. PREVALENCE OF GASTROESOPHAGEAL REFLUX DISEASE The prevalence of gastroesophageal reflux disease is unknown because there is presently no definition of gastroesophageal reflux disease. This is an amazing statement

20 4 GERD: Reflux to Esophageal Adenocarcinoma of fact. Any definition of reflux disease must include all patients who have any pathologic abnormality resulting from gastroesophageal reflux and who are at risk of developing complications of reflux disease in the future. The most commonly used definition of gastroesophageal reflux to assess prevalence is the presence of classical symptoms such as heartburn and regurgitation at some frequency defined by the whim of the investigator (9). Despite the fact that this is a hopelessly flawed definition, no better definition has ever been proposed. Population-based studies report that 4% to 9% of adults experience daily heartburn; an additional 10% to 15% have heartburn at least once a week; and an additional 10% to 15% have heartburn once a month (10, 11). In Nebel et al.'s study, the incidence of symptomatic gastroesophageal reflux was evaluated by a questionnaire in 446 hospitalized and 558 nonhospitalized subjects. Of 385 control subjects, 7% experienced heartburn daily, 14% noted heartburn weekly, and 15% experienced it once a month, meaning that a total of 36% of subjects had heartburn at least monthly. Daily heartburn occurred at a significantly greater rate for 246 medical inpatients (14%) and for 121 patients seen in an outpatient gastroenterological clinic (15%). Pregnant women seen in uncomplicated obstetrical clinics had symptoms of significantly greater incidence, as 25% reported daily heartburn and 52% experienced heartburn at least once monthly. Experts have never agreed on the exact frequency of heartburn and regurgitation that defines reflux disease. Another way to assess the prevalence of reflux is to study trends in the use of acid suppressive drugs, though this assumes that acid suppression is used mainly for reflux disease, which is only partially true. Acid suppressive drugs are commonly prescribed. In a study of pharmacy billing data for two insurers within a large eastern Massachusetts provider network, 4684 of 168,727 patients (2%) were prescribed chronic (>90 day) acid suppressive drugs; 47% were taking H2 receptor antagonists and 57% were taking proton pump inhibitors (4% were taking both). Diagnostic testing was uncommon in these patients, as only 19% of the patients on acid suppressive drugs had undergone esophagogastroduodenoscopy within the prior 2 years (12). When one adds shorter term use of prescribed acid suppressive drugs and the massive unregulated use of over-the-counter antacids by patients who do not seek medical treatment, the clinical problem of gastroesophageal reflux disease is enormous. It is estimated that the use of acid suppressive drugs has a cost of more than $10 billion per year in the United States. Television abounds in direct marketing of acid suppressive agents to the consumer, and the shelves of drugstores are replete with a wide array of drugs that induce the population to cure themselves of heartburn using self-medication with the most powerful acid suppressive agents (Figs. 1.2 and 1.3). FIGURE 1.2 The antacid section of a local pharmacy showing the shelf space devoted to over-the-counter acid suppressive drugs.