Stem Cells, Pre-neoplasia, and Early Cancer of the Upper Gastrointestinal Tract (eBook)

Professor Sir Nicholas Wright’s research is in the field of gastrointestinal stem cells and cancer. He was Professor of Pathology at the Royal Postgraduate Medical School at the Hammersmith Hospital, and then became the Dean of the Royal Postgraduate Medical School before becoming the Deputy Principal of the Imperial College School of Medicine in 1998. Sir Nicholas then served as Warden of Barts and the London, Queen Mary’s School of Medicine and Dentistry from 2001 to 2011. He as served as Group Leader at the Histopathology Unit at Cancer Research UK London Research Institute and was President of the Pathological Society of Great Britain and Ireland and the British Society of Gastroenterology. He was knighted in 2006 for services to medicine. Sir Wright has published over 427 scientific articles and received over 12,939 citations. Dr. Marnix Jansen is a histopathologist at University College London Hospital (UCLH) and Senior Clinical Fellow at Barts Cancer Institute. He a rising young star in the area of upper GI cancer research and he has published 23 scientific papers and has received over 794 citations.

Contents 5
Contributors 8
Chapter 1: Distal Esophageal Adenocarcinoma and Gastric Adenocarcinoma: Time for a Shared Research Agenda 12
References 19
Part I: Introduction 20
Chapter 2: Clonal Evolution of Stem Cells in the Gastrointestinal Tract 21
How Many Stem Cells Are in the Intestinal Crypt? 24
What Factors Determine Stem Cell Number in the Crypt? 25
Neutral Competition and the Rules of the Game 26
Dynamics in the Pyloric Glands of the Stomach Epithelium 28
Clone Behavior in Corpus Glands of Stomach Epithelia 30
References 33
Chapter 3: The Complex, Clonal, and Controversial Nature of Barrett’s Esophagus 36
Introduction 36
The Basic Unit of the Human GI Tract Mucosa Is the Gland 37
Gland Phenotypes in Barrett’s esophagus 38
The Stem Cell Niche and Niche succession in Barrett’s 40
Tracing Clonal Lineages in Barrett’s 41
Clonal Expansions in Non-dysplastic Barrett’s Esophagus 43
Clonal Dynamics and Expansion in Barrett’s Esophagus 44
Combining Clonal Labeling with Phenotype 46
Clonal Expansion Postradiofrequency Ablation (RFA) 47
Conclusion 47
References 47
Chapter 4: A New Pathologic Assessment of Gastroesophageal Reflux Disease: The Squamo-Oxyntic Gap 50
Introduction 50
Progression of GORD with Empiric PPI Therapy 52
Definition of Irreversibility in GORD: vCLO 54
Cause of GORD: Lower Esophageal Sphincter Damage 55
The Normal LOS and Consequence of Abdominal LOS Damage 55
Mechanism of LOS Damage 57
Relationship Between LOS Damage and GORD 58
Mechanism of Maintenance of LOS Pressure 61
In Search of Accurate Definitions 62
Histologic Definitions of Epithelia in the Esophagus and Stomach 63
The Squamo-Oxyntic Gap 65
Definition of the Squamo-Oxyntic Gap 66
The Length of the Squamo-Oxyntic Gap 67
The Epithelial Composition of the Squamo-Oxyntic Gap 68
The Location of the Squamo-Oxyntic Gap 69
Autopsy Studies of the GOJ 70
The Squamo-Oxyntic Gap in Different Populations 72
People Without GORD Symptoms 72
GORD Patients with No Endoscopic Abnormality 72
Patients with a vCLO at Endoscopy 74
The Distal Part of the Squamo-Oxyntic Gap Correlates with Damage to the Abdominal Los 75
Definition of the Gastroesophageal Junction (GOJ) 75
Genesis and Progression of the Squamo-Oxyntic Gap 78
Columnar Metaplasia Due to LOS Effacement Without Reflux 78
Columnar Metaplasia of the Esophageal Body Due to LOS Failure and Reflux 79
A New Pathologic Test of Los Damage 80
Measurement at Autopsy 81
Measurement in Esophago-Gastrectomy Specimens 81
Measurement at Endoscopy with Present Biopsy Forceps 81
Future Ideal Endoscopic Measurement 84
Conclusion 84
References 85
Part II: Cancer Progression in the Distal Esophagus 88
Chapter 5: Diagnosis by Endoscopy and Advanced Imaging of Barrett’s Neoplasia 89
Introduction 90
Endoscopic Diagnosis of Early Neoplasia in Barrett’s Esophagus 91
Use Best Endoscope Available 91
You Do Not Detect What You See, You Detect What You Recognize 91
Perform a Systematic Endoscopic Inspection 92
Advanced Imaging Techniques in Barrett’s Esophagus 93
Detection of Early Neoplasia 93
Chromoendoscopy 93
Optical and Digital Chromoendoscopy Techniques 95
Autofluorescence Imaging 96
Real-Time Diagnosis and Decision Making 98
Optical Chromoendoscopy 98
Confocal Laser Endomicroscopy 98
Optical Coherence Tomography 99
Recommendations for Current Clinical Practice 99
Endoscopic Surveillance 99
Workup and Treatment of Early Neoplasia 100
Future Perspectives 101
References 102
Chapter 6: Endoscopic Treatment of Early Barrett’s Neoplasia: Expanding Indications, New Challenges 107
Introduction 107
Endoscopic Treatment Methods 107
Endoscopic (Mucosal) Resection Techniques 107
Cap-ER 109
ER with a Ligation Device (ER-L) 109
Endoscopic Submucosal Dissection 110
Photodynamic Therapy 110
Radiofrequency Ablation 110
Cryoablation 112
Argon-Plasma-Coagulation 112
Special Indications for Endoscopic Treatment 113
Low-Grade Intraepithelial Neoplasia 113
Submucosal Barrett’s Adenocarcinoma 114
Conclusions 114
References 115
Chapter 7: Definition, Derivation, and Diagnosis of Barrett’s Esophagus: Pathological Perspectives 118
Introduction 118
The Definition of CLO 119
The Derivation of CLO 123
Current Theories of the Pathogenesis of CLO 124
CLO Derivation: Stem Cells and Clonal Expansion 125
Maintenance of Multilineage CLO 126
The Origin of the Initial Stem Cell in CLO 127
The Derivation of Intestinal Metaplasia 129
The Diagnosis of CLO 130
Endoscopic Diagnosis 130
Short Segment and Ultra-Short Segment CLO 131
Biopsy Protocols 131
Histological Features 132
Gastric Heterotopia 135
Hiatus Hernia 135
Immunohistochemical Findings 135
Conclusions 136
References 137
Chapter 8: What Makes an Expert Barrett’s Histopathologist? 144
Introduction 144
General Approach 145
Clonal Transitions in BO Dysplasia 146
Surface Maturation 146
Architecture 147
Cytonuclear Atypia 147
Negative for Dysplasia 148
Dysplasia 150
Low-Grade Dysplasia 152
High-Grade Dysplasia 152
Indefinite for Dysplasia 153
Controversy Regarding the “Indefinite for Dysplasia” Category 154
Making the Most of P53 IHC 155
Interobserver Variability 156
Endoscopic Treatment of High-Grade Lesions 157
Handling the Endoscopic Resection Specimen 158
The EMR Pathology Report 159
Differentiation Grade 159
Infiltration Depth 159
Resection Margins 161
Artifacts 161
(Lympho-)Vascular Invasion 162
Risk of Local Recurrence 162
References 163
Chapter 9: Staging Early Esophageal Cancer 167
Principles of Staging 167
TNM Staging System 168
Endoscopic Resection (ER) 171
Endoscopic Ultrasound (EUS) 173
Computed Tomography (CT) 176
PET 177
Staging Laparoscopy and Peritoneal Cytology 178
Future Staging Modalities: Optical Diagnosis 178
Optical Coherence Tomography (OCT) 178
Raman Spectroscopy (RS) 181
Conclusion 183
References 183
Chapter 10: Transcommitment: Paving the Way to Barrett’s Metaplasia 188
Transdifferentiation 189
Native Esophageal Squamous Progenitor Cells 191
Native Esophageal Submucosal Gland or Duct Progenitor Cells 195
Circulating Bone Marrow-Derived Stem Cells 197
Proximally Shifting Columnar Progenitor Cells 198
Transcommitment 203
Conclusions 210
References 211
Chapter 11: Studying Cancer Evolution in Barrett’s Esophagus and Esophageal Adenocarcinoma 218
Introduction 218
Cancer Models in the Age of Genome Sequencing 219
Barrett’s Esophagus and Esophageal Adenocarcinoma: A Model System for Studying the Development and Progression of Cancer In Vivo 222
The Development of Evolution Studies in BE and EA 223
Necessary Elements for a Study of Neoplastic Evolution 226
Temporal and Spatial Evolution of Somatic Chromosomal Alterations 227
Study Type 229
Epithelial Isolation 229
Use of SNP Arrays to Identify Somatic Chromosomal Alterations 229
Evaluations of Samples Over Time and Space 230
Cancer Endpoint 230
Nonprogressors 231
Progressors 232
Other Considerations 233
Questions and Implications for Future Studies of Cancer Evolution 234
References 237
Chapter 12: Genomics of Esophageal Cancer and Biomarkers for Early Detection 242
Introduction 242
Landscape of Genomic Alterations in Esophageal Adenocarcinoma 243
Genetic Aberrations in Cell Signaling Pathways 243
EGFR and HER2 243
Transforming Growth Factor-? 244
c-myc 245
Abnormalities in DNA Repair and Cell Cycle Genes 245
TP53 245
CDKN2A 246
Cyclins and Cyclin-Dependent Kinases 246
Dysregulation of Wnt Signaling and Cell Adhesion Genes 247
Gross Chromosomal Anomalies 248
Aneuploidy and Microsatellite Instability 248
Accumulation of Fragile Sites 250
Dysfunctional Homologous Recombination and Telomere Biology 251
Epigenetic Alterations in BO and OAC 251
Biomarker Development 254
p53 254
Epigenetic Biomarkers 256
Inflammation and Stress Biomarkers 256
Chromosomal Abnormality Panel 257
Imaging with Molecular Biomarkers 257
Significance of Epidemiological Risk Factors 258
Molecular Alternatives to Endoscopy 258
Serum Markers 259
Conclusion 260
References 261
Chapter 13: Common Variants Confer Susceptibility to Barrett’s Esophagus: Insights from the First Genome-Wide Association Studies 269
Introduction 269
Genome-Wide Association Studies: Motivation and Practicalities 271
Genome-Wide Association Studies Have Identified 8 Loci Associated with Risk of Barrett’s esophagus 274
Meta-Analysis of BO/OAC GWASs Has Been Limited to the Top Association Signals in Either Study 275
How Progress in Identification of Loci Associated with Barrett’s Esophagus and Esophageal Adenocarcinoma Compares with Progress for Other Selected Cancer Types 275
Lack of Evidence for the Involvement of Esophageal Squamous Cell Carcinoma Loci in Barrett’s Esophagus and Esophageal Adenocarcinoma, Apart from Those at the Major Histocompatibility Complex 276
The Involvement of Alcohol Dehydrogenase Genes in OSCC and BO/OAC 280
The Other Non-MHC Loci Associated with Risk of BO Map to Potential Enhancer Regions That May Regulate Transcription Factors Involved in Esophageal Development 282
FOXF1 282
TBX5 283
GDF7 284
Esophageal Adenocarcinoma GWAS Hits Are Also in or Near to Genes Involved in Esophageal Development 286
BARX1 286
FOXP1 287
CRTC1 287
Discussion and Concluding Remarks 288
References 290
Part III: Cancer Progression in the Stomach 295
Chapter 14: Endoluminal Diagnosis of Early Gastric Cancer and Its Precursors: Bridging the Gap Between Endoscopy and Pathology 296
Early Gastric Cancer and Its Precursors 296
Definition of Early Gastric Cancer 296
Histological Criteria 297
Endoscopic Procedures 297
Preparation 297
White Light Endoscopy 298
Dye-Based Image-Enhanced Endoscopy (Chromoendoscopy) 298
Equipment-Based Image-Enhanced Endoscopy (Narrow Band Imaging, Flexible Spectral Imaging Color Enhancement, iScan) 300
Magnifying Endoscopy 301
Endoscopic Findings 301
Normal (Helicobacter pylori Naive) Gastric Mucosa 301
Helicobacter pylori-Associated Chronic Atrophic Gastritis 302
Intestinal Metaplasia 306
Early Gastric Cancer 308
Characterization of Detected Lesions 308
Endoscopic Staging of Early Gastric Cancer 311
Macroscopic Type 311
Histological Type 312
Tumor Extent 314
Tumor Depth 314
Summary 315
References 315
Chapter 15: Endoscopic Submucosal Dissection for Early Gastric Cancer: Getting It Right! 320
Introduction 320
Indications of ESD for EGC 321
Results 321
Technical Tips Regarding ESD Performed for EGC 322
Basic Movement Is Dependent on ESD Device 322
ESD Strategy 323
Training for ESD 327
Complications 328
Perforation 328
Bleeding 329
Conclusions 330
References 331
Chapter 16: The Japanese Viewpoint on the Histopathology of Early Gastric Cancer 334
Introduction 334
Histological Diagnosis of Adenoma and Intramucosal Carcinoma in Japan 335
Group Classification for Gastric Biopsy 336
Diagnosis of “Low-Grade Adenocarcinoma” 338
Special Types of Gastric Carcinoma 340
Histological Evaluation of Endoscopically Resected Specimens 341
Helicobacter pylori–Negative Gastric Cancers 344
Concluding Remarks 346
References 346
Chapter 17: Syndromic Gastric Polyps: At the Crossroads of Genetic and Environmental Cancer Predisposition 350
Introduction 350
Familial Adenomatous Polyposis Syndrome 353
MUTYH-Associated Polyposis 356
Lynch Syndrome 356
Peutz–Jeghers Syndrome 357
Juvenile Polyposis Syndrome 359
Cowden Syndrome (PTEN Hamartoma Tumor Syndrome) 361
Gastric Adenocarcinoma and Proximal Polyposis of the Stomach 362
Neurofibromatosis Type 1 363
McCune–Albright Syndrome 365
Cronkhite–Canada Syndrome 366
Conclusion 367
References 368
Chapter 18: Histopathological, Molecular, and Genetic Profile of Hereditary Diffuse Gastric Cancer: Current Knowledge and Challenges for the Future 373
Introduction 373
Genetics of HDGC 375
Germline CDH1 Mutation and Clinical Guidelines 376
Somatic Changes in HDGC 377
Inactivation of the 2nd CDH1 Allele 377
Other Somatic Changes in HDGC 378
Histopathology of HDGC 378
Prophylactic Gastrectomy 378
Gastrectomy with Curative Intent for Advanced HDGC 379
Immunohistochemical Profile of HDGC and Its Relationship with CDH1 Mutations 380
New Insights in Morphological, Immunohistochemical, and Genetic Profile of HDGC 382
Conclusions and Practical Points 388
New Hypotheses and Further Research Directions 389
References 389
Chapter 19: Helicobacter pylori, Cancer, and the Gastric Microbiota 394
Gastric Cancer 394
H. pylori 395
H. pylori Virulence Factors That Influence Gastric Pathogenesis 395
Host and Environmental Factors That Influence Gastric Pathogenesis 397
The Human Gastric Microbiota in Gastric Pathogenesis 398
The Mongolian Gerbil Gastric Microbiota and Gastric Pathogenesis 401
The Mouse Gastric Microbiota and Disease 402
Limitations of Current Models and Alternatives to Investigate the Gastric Microbiota in Gastric Pathogenesis 404
Conclusions and Outlook 405
References 405
Chapter 20: Helicobacter pylori and Gastric Cancer: Timing and Impact of Preventive Measures 410
Gastric Cancer: Classification 410
Gastric Cancer: Epidemiological Aspects 410
H. pylori as Principal Trigger of Gastric Carcinogenesis 411
Gastric Cancer: Prevention Strategies 412
H. pylori and Other Gastrointestinal Malignancies 413
Esophageal Cancer 414
Malignancies of the Hepatobiliopancreatic Tract 415
Colorectal Neoplasms 416
Conclusion 416
References 417
Chapter 21: Genomics Study of Gastric Cancer and Its Molecular Subtypes 420
Molecular and Morphological Diversity of Gastric cancer 420
Whole-Exome and Whole-Genome Sequencing Study of Gastric Cancer 422
Mutation Spectrum 426
Structural Variants 427
Somatic Copy Number Aberration 428
DNA Methylation Profiling 429
Gene Expression Profiling 431
miRNA Expression Profiling 434
Integrative Genomic Analysis 434
Linking Genomics Changes to Therapeutic Response 436
References 436
Chapter 22: Recapitulating Human Gastric Cancer Pathogenesis: Experimental Models of Gastric Cancer 441
Overview 441
Comparative Gastric Anatomy and Physiology 442
Gastric Anatomy 442
Histology 442
Gastric Cardia 442
Gastric Fundus and Corpus 443
Gastric Antrum 445
Histologic and Molecular Classification of Gastric Cancer 446
Contribution from Invertebrate Biology 447
Signaling Pathways in Gastric Cancer 447
Signaling Pathways in the Proximal Versus Distal Stomach 448
EGRr/Ras/MapK 448
Notch Signaling 449
Hedgehog Signaling 449
Wnt/?catenin 450
Akt/PI3K 450
Mouse Models of Gastric Cancer 451
Chemical Carcinogen-Induced Models of Gastric Cancer 455
N-Nitroso Compounds (MNNG and MNU) 455
Dietary Salt 456
Other Environment-Related Agents 456
Bacterial Models 457
Helicobacter 457
Helicobacter Coinfection with Other Microorganisms 458
Epstein-Barr Virus 459
Genetically Engineered Mouse Models (GEMMs) 459
Gastrin Mutants 459
INS-GAS Mice 460
Gastrin-Deficient Mice 460
The Trefoil Factor 1 (Tff1) and gp130 Mutants 461
Parietal Cell Mutants 462
Oncogene and Tumor Suppressor Gene Mutants 462
COX-2 462
K-ras 463
p27Kip1 464
Inflammation Mediators and Cytokine Mutants 464
TGF-? Signaling 464
Autoimmune Model (TxA23 Mice) 465
Interleukin-1? 465
Models of Precancerous Change 466
Model of Bone Marrow-Derived Gastric Cancer Stem Cells 466
References 467
Erratum to: Histopathological, Molecular,and Genetic Profile of Hereditary Diffuse Gastric Cancer: Current Knowledge andChallenges for the Future 479
Index 480