CHAPTER 1: REFLUX-INDUCED CANCER: AN EPIDEMIC WE
NEED TO ADDRESS NOW 1
Epidemiology of Refl ux-Induced Cancer 2
The Problem 6
The Refl ux-to-Adenocarcinoma Sequence 10
Step 1: Squamous Epithelial Damage with Columnar Metaplasia 11
Step 2: Intestinal Metaplasia of Cardiac Mucosa 13
Step 3: Carcinogenesis in Intestinal Metaplasia 17
The Future Without Change 19
Can Refl ux-Induced Adenocarcinoma Be Prevented? 22
Step 1: Squamous Epithelial Damage and Cardiac Metaplasia 24
Step 2: Intestinal Metaplasia of Cardiac Mucosa 24
Step 3: Carcinogenesis in Intestinal Metaplasia 25
Objections to Anti-Refl ux Surgery 26
Cost 26
Surgical Mortality, Morbidity, and Failure 27
Feasibility 27
A Plea for an Aggressive Approach 27
Aggressively Understand Refl ux Disease at a Histologic Level 28
Aggressively Assess the Cancer Risk in a Given Patient 28
Aggressively Seek Patients at Highest Risk 29
Aggressively Treat High-Risk Patients 31
Barrett Esophagus with High-Grade Dysplasia 31
Barrett Esophagus with Low-Grade Dysplasia or Without
Dysplasia 32
Refl ux Disease Without Barrett Esophagus 33
Expectation of Change 34
References 34
CHAPTER 2: THE PRESENT STATE OF DIAGNOSIS OF RELUX
DISEASE 36
Presently Used Diagnostic Criteria of Refl ux Disease 36
Symptom-Based Diagnosis 36
Diagnosis by Physiologic Testing 39
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xii Table of Contents
Endoscopic Diagnosis 41
Histologic Diagnosis 48
Columnar-Lined Esophagus: An Inexplicably Ignored Diagnostic
Criterion for Refl ux Disease 52
Universally Accepted Endoscopic Conclusions 53
Universally Accepted Histologic Conclusions 54
Recommended Changes to Present Diagnostic Criteria
by Accepted Data 57
References 59
CHAPTER 3: HISTOLOGIC DEFINITION AND DIAGNOSIS OF
EPITHELIAL TYPES IN THE ESOPHAGUS AND STOMACH 61
The Importance of Histology in Understanding Disease 61
Embryologic Development 61
The Fetal Esophagus 61
The Fetal Stomach 64
Histologic Defi nition of Epithelial Types in Postnatal Esophagus
and Proximal Stomach 65
Stratifi ed Squamous Epithelium 65
Columnar Epithelia 70
Basic Structure 70
Cell Types 73
Classifi cation 77
Diagnosis of Columnar Epithelial Types 81
Gastric Oxyntic Mucosa 81
Cardiac Mucosa 85
Oxyntocardiac Mucosa 88
Case Study 89
Intestinal Metaplasia in Cardiac Mucosa 90
Application of Histologic Defi nitions 92
Problems in Differential Diagnosis Between Columnar Epithelial
Types 93
Cardiac Mucosa with Pseudo-Goblet Cells Versus Intestinal
Metaplasia in Cardiac Mucosa 95
Cardiac Mucosa Versus Oxyntocardiac Mucosa 97
Oxyntocardiac Versus Gastric Oxyntic Mucosa 98
Cardiac Mucosa Versus Normal Gastric Oxyntic Mucosa 99
Cardiac Mucosa Versus Atrophic Gastric Mucosa with
Pseudo-Pyloric Metaplasia 99
Case Study 103
Intestinal Metaplasia in Cardiac Mucosa Versus Intestinal
Metaplasia in Chronic Atrophic Gastritis Involving Gastric
Oxyntic Mucosa 104
Case Study 109
References 111
CHAPTER 4: DEFINITION OF NORMAL AND REFLUX-INDUCED
ANATOMY AND HISTOLOGY 112
Normal Anatomy 112
The Normal Esophagus 112
The Lower Esophageal Sphincter 114
The Normal Stomach: What Is the Gastric Cardia? 116
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Normal Histology of the Esophagus and Proximal Stomach 119
Discrepancy Between the Anatomic Gastric Cardia and Cardiac
Mucosa 120
The Importance of Precise Histologic Defi nitions 122
Defi nition of the Gastroesophageal Junction 123
Historical Background 123
Clinical Impact of Validated and Unvalidated Defi nitions of
the Gastroesophageal Junction 127
Defi nition of the True Gastroesophageal Junction by
Histology: The Proof 129
Pathogenesis of Refl ux Disease 132
Refl ux Versus Refl ux Disease 132
The Mechanism of Gastroesophageal Refl ux 133
The Dilated End-Stage Esophagus: The Earliest Stage of
Refl ux Disease 136
Visible Columnar-Lined Esophagus and Hiatal Hernia: The
Later Stage of Refl ux Disease 139
Anatomic Location and Signifi cance of Epithelial Types: Resolution
of Controversy 141
Squamous Epithelium 142
Gastric Oxyntic Mucosa 144
Cardiac Mucosa with and Without Intestinal Metaplasia and
Oxyntocardiac Mucosa 144
Prevalence and Extent—Present Viewpoint 145
Prevalence and Extent—New Data in Autopsy Populations 149
Prevalence and Extent—Data from Clinical Populations 151
Signifi cance of Cardiac Mucosa with and Without Intestinal
Metaplasia and Oxyntocardiac Mucosa 152
New Defi nitions of the Normal State and Gastroesophageal Refl ux
Disease 154
References 154
CHAPTER 5: CELLULAR CHANGES OF NON-NEOPLASTIC
GASTROESOPHAGEAL REFLUX DISEASE 157
Squamous Epithelial Injury 158
Sequence of Columnar Metaplasia of the Esophagus 158
Cardiac Metaplasia of Squamous Epithelium: The First Genetic
Switch 158
Cardiac Mucosa to Intestinal Metaplasia: The Second Genetic
Switch 163
Cardiac to Oxyntocardiac Mucosa: The Benign Genetic Switch 164
Distribution of Columnar Epithelial Types 165
Relationship Between Prevalence of Intestinal Metaplasia and
Length of Columnar-Lined Esophagus 166
Historical Differences in Epithelial Composition of Columnar-Lined
Esophagus 168
Mechanism of the Genetic Switches in Columnar-Lined
Esophagus 170
Case Study 176
Reversibility of Genetic Switches 179
Barrett Esophagus: Five Decades of Medical Failure 180
References 182
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CHAPTER 6: REFLUX-INDUCED ADENOCARCINOMA OF THE
ESOPHAGUS 184
Case Study 184
The Target Cell 189
The Carcinogen 190
Salivary Nitrogenous Compounds 190
Acid 191
Case Study 191
Bile 194
Interaction Between Carcinogens and Target Cells 196
Case Study 198
Factors Associated with an Increased Cancer Risk in
Gastroesophageal Refl ux Disease 201
Symptomatic Refl ux Disease 201
Demographic Factors 201
Clinical Evidence of Severity of Refl ux Disease 202
Evidence of Duodenogastroesophageal Refl ux 202
Barrett Esophagus 202
The Length of Barrett Esophagus 202
The Amount of Intestinal Metaplasia 204
The Proximity of the Intestinal Metaplasia to the
Gastroesophageal Junction 204
The Proliferative Rate of the Target Cells 205
Acid-Suppressive Drug Therapy 205
Statistical Evidence of Increased Risk with Acid-Suppressive
Drugs 205
Theoretical Considerations 206
Factors that Are Protective Against Development of Cancer
in Barrett Esophagus 207
Decreasing Gastroesophageal Refl ux 208
Ablation of Barrett Epithelium 209
Exclusion of Bile from the Refl uxate 209
Assessment of Cancer Risk in Barrett Esophagus 210
Molecular Abnormalities 212
Dysplasia 213
Criteria for Diagnosis of Dysplasia 216
The Diagnosis of High-Grade Dysplasia 216
Criteria for Diagnosis of High-Grade Dysplasia 217
Criteria for Diagnosis of Low-Grade Dysplasia 222
Prevalent Cancer in Barrett Esophagus 225
High-Grade Dysplasia 227
High-Grade Dysplasia in a Lesion that Is Visible at Endoscopy 227
Multifocal Versus Unifocal High-Grade Dysplasia 228
Extensive (Multifocal and Multilevel) Low-Grade Dysplasia 228
Non-Dysplastic Barrett Esophagus 229
Conclusion 229
References 229
CHAPTER 7: NEW HISTOLOGY-BASED DEFINITIONS AND
METHOD OF DIAGNOSIS OF REFLUX DISEASE 232
A New Histologic Defi nition of Gastroesophageal Refl ux Disease 232
Refl ux Carditis: The Perfect Defi nition of Gastroesophageal
Refl ux Disease 236
Defi nition of Refl ux Carditis 237
Table of Contents xv
Histologic Features of Refl ux Carditis 238
Gross Pathologic and Endoscopic Features of Refl ux Carditis 238
Clinical Features of Refl ux Carditis 240
Refl ux Carditis and the 24-Hour pH Test 241
Signifi cance of Refl ux Carditis 241
Differential Diagnosis of Refl ux Carditis 242
A New Defi nition of Barrett Esophagus 242
Case Study 245
A New Diagnostic Method for Refl ux Disease 249
Protocols for Histologic Assessment 249
Biopsy Protocol for Patients Who Are Endoscopically
Normal 250
Biopsy Protocol for Patients with a Visible Columnar-Lined
Esophagus 251
Quick Biopsy Protocol for the Busy Gastroenterologist 252
Biopsy Protocol for Barrett Surveillance 253
Biopsy Protocol for the Patient with a Mass Lesion 253
Protocol for Dissecting an Esophagectomy Specimen 255
Data Generated by Histologic Assessment 257
Interpretation of the Data 260
Does the Patient Have Evidence of Refl ux-Induced
Cellular Change? 261
Does the Patient Have Refl ux Disease? 263
Case Study 264
What Is the Severity of Refl ux Disease in the Patient? 267
What Is the Risk of Cancer in These Patients? 268
A Classifi cation Based on the Cellular Status as It Relates
to Gastroesophageal Refl ux 272
Assessment of Treatment of Gastroesophageal Refl ux Disease 274
Effect of Acid-Suppressive Drug Therapy 280
Effect of Mucosal Ablation 281
Effect of Anti-Refl ux Surgery 282
Decrease in the Incidence of High-Grade Dysplasia and
Adenocarcinoma 282
Reversal of Intestinal Metaplasia 283
Case Study 284
Prevention of Conversion of Cardiac Mucosa to Intestinal
Metaplasia 287
Conversion of Cardiac Mucosa to Oxyntocardiac Mucosa 287
References 289
Index 291