Gastrointestinal Oncology - download.e-bookshelf.de€¦ · Gastro-intestinal Oncology A Critical Multidisciplinary Team Approach EDITED BY Janusz Jankowski MD, PhD, FRCP, FACG Consultant

Gastrointestinal OncologyA Critical Multidisciplinary Team Approach

Gastro-intestinal OncologyA Critical Multidisciplinary Team Approach

EDITED BY

Janusz Jankowski MD, PhD, FRCP, FACGConsultant Gastroenterologist, Digestive Diseases Centre UHL Trust, Leicester, UKJames Black Senior Fellow and Professor, University of Oxford, UKFellow and Professor, Cancer Research UK and Queen Mary University of London, UK

Richard Sampliner MDProfessor of Medicine, University of Arizona College of Medicine, USAChief of Gastroenterology, Southern Arizona VA Health Care System, USA

David Kerr CBE, MA, MD, DSc, FRCP, FMedSciRhodes Professor of Cancer Therapeutics and Clinical Pharmacology, University of Oxford, UKHead of Department of Clinical Pharmacology, University of Oxford, UK

Yuman Fong MDMurray F. Brennan Chair in Surgery, Memorial Sloan-Kettering Cancer Center, New York, USAProfessor of Surgery, Weill Cornell Medical Center, New York, USA

FOREWORD BY

Ernest Hawk MD, MPH & Jaye L. Viner MD, MPHNational Cancer Institute, Bethesda, USA

© 2008 by Blackwell PublishingBlackwell Publishing, Inc., 350 Main Street, Malden, Massachusetts 02148-5020, USABlackwell Publishing Ltd, 9600 Garsington Road, Oxford OX4 2DQ, UKBlackwell Publishing Asia Pty Ltd, 550 Swanston Street, Carlton, Victoria 3053, Australia

The right of the Author to be identifi ed as the Author of this Work has been asserted in accordance with the Copyright, Designs and Patents Act 1988.

All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the prior permission of the publisher.

First published 20081 2008

Library of Congress Cataloging-in-Publication Data

Gastrointestinal oncology : a critical multidisciplinary team approach / edited by Janusz Jankowski . . . [et al.]. p. ; cm. Includes bibliographical references and index. ISBN 978-1-4051-2783-7 (alk. paper) 1. Digestive organs–Cancer. 2. Health care teams. 3. Medical cooperation. I. Jankowski, Janusz [DNLM: 1. Gastrointestinal Neoplasms–diagnosis. 2. Gastrointestinal Neoplasms–therapy. 3. Liver Neoplasms–diagnosis. 4. Liver Neoplasms–therapy. WI 149 G257442 2008]

RC280.D5G3783 2008 616.99′43–dc22

2007048809

A catalogue record for this title is available from the British Library

Set in 9.5/12 pt Minion by SNP Best-set Typesetter Ltd., Hong KongPrinted and bound in Singapore by Markono Print Media Pte Ltd

Commissioning Editor: Alison BrownEditorial Assistant: Cathryn GatesDevelopment Editor: Helen HarveyProduction Controller: Debbie Wyer

For further information on Blackwell Publishing, visit our website:http://www.blackwellpublishing.com

The publisher’s policy is to use permanent paper from mills that operate a sustainable forestry policy, and which has been manufactured from pulp processed using acid-free and elementary chlorine-free practices. Furthermore, the publisher ensures that the text paper and cover board used have met acceptable environmental accreditation standards.

Designations used by companies to distinguish their products are often claimed as trademarks. All brand names and product names used in this book are trade names, service marks, trademarks or registered trademarks of their respective owners. The Publisher is not associated with any product or vendor mentioned in this book.

The contents of this work are intended to further general scientifi c research, understanding, and discussion only and are not intended and should not be relied upon as recommending or promoting a specifi c method, diagnosis, or treatment by physicians for any particular patient. The publisher and the author make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifi cally disclaim all warranties, including without limitation any implied warranties of fi tness for a particular purpose. In view of ongoing research, equipment modifi cations, changes in governmental regulations, and the constant fl ow of information relating to the use of medicines, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each medicine, equipment, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. Readers should consult with a specialist where appropriate. The fact that an organization or Website is referred to in this work as a citation and/or a potential source of further information does not mean that the author or the publisher endorses the information the organization or Website may provide or recommendations it may make. Further, readers should be aware that Internet Websites listed in this work may have changed or disappeared between when this work was written and when it is read. No warranty may be created or extended by any promotional statements for this work. Neither the publisher nor the author shall be liable for any damages arising herefrom.

Contents

Ablation, novel agents, and endoscopic therapy for esophageal

dysplasia and carcinoma, 87

Herbert C. Wolfsen

Prognosis and follow-up, 98

Kenneth K. Wang

5 Squamous Cancer of the Esophagus, 114 Edited by Hugh Barr

Diagnosis, 114

History and etiology, 114

Alastair Sammon & Mark Vipond

Clinical, 115

Alastair Sammon & Mark Vipond

Histopathology and staging, 116

Salim Anjarwalla, David Hewin & Neil A. Shepherd

Imaging and clinical staging, 119

David Hewin, Neil A. Shepherd & Salim Anjarwalla

Treatment, 122

Overview, 122

Hugh Barr

Surgery, 122

Ferdinandos Skoulidis, Yu Jo Chua & David Cunningham

Chemotherapy, 124


Radiotherapy, 131


Ablation of early cancer, 137

Hugh Barr

Palliation and endoscopic therapy, 138

Hugh Barr

Novel agents, 139



Hugh Barr

6 Diffuse Gastric Cancer, 146 Edited by Ilfet Songun & Cornelius van de Velde

Diagnosis, 146

List of Contributors, ix

Preface , xvi

Foreword , xvii

Part 1: Gastroesophageal CancerEdited by Richard Sampliner

1 Epidemiology of Gastroesophageal Cancer, 3 Evan S. Dellon & Nicholas J. Shaheen

2 Factors involved in Carcinogenesis and Prevention, 14

Mark R. Anderson & Janusz Jankowski

3 Molecular Biology of Gastroesophageal Cancers: the Role of Mutational Analysis in Prognosis, 21

Matthew Lovell, Chetan Bhan, Janusz Jankowski &

Stuart McDonald

4 Esophageal Adenocarcinoma, 31 Edited by Kenneth K. Wang

Diagnosis, 31

Endoscopic diagnosis of Barrett’s esophagus, 31

Vidu B. Mokkala, Navtej S. Buttar &

Louis M. Wong Kee Song

The histologic diagnosis of Barrett’s esophagus, 43

Thomas C. Smyrk & Navtej S. Buttar

Staging of esophageal cancer, 47

Ananya Das & Amitabh Chak

Treatment, 51

Overview, 51

Kenneth K. Wang

Surgical management of esophageal carcinoma, 51

Daniela Molena, Fernando Herbella & Jeffrey H. Peters

Chemotherapy for metastatic cancer of the esophagus,

gastroesophageal junction, and stomach, 65

Aminah Jatoi

Concurrent radiochemotherapy for esophageal cancer, 67

Zhongxing Liao, Luka Milas, Ritsuko Komaki & Jaffer Ajani

V

VI CONTENTS

History, 146

Ilfet Songun & Cornelius van de Velde

Clinical, 146

Annemieke Cats

Histopathology and molecular pathology, 149

Cen Si, Nicole C.T. van Grieken & Gerrit A. Meijer

Imaging and staging of gastric cancer, 152

Regina G.H. Beets-Tan & Cornelius van de Velde

Treatment, 156

Overview, 156


Surgery, 157


Chemotherapy, 160

Christopher Jackson, Naureen Starling & David Cunningham

Radiotherapy, 164

Edwin P.M. Jansen & Marcel Verheij

Novel agents, 166

Annemieke Cats



7 Intestinal Gastric Cancer, 177 Edited by Benjamin C.Y. Wong

Diagnosis: history, clinical and histopathology, 177

Annie On On Chan & Asif Rashid

Imaging and staging, 180

Annie On On Chan & Benjamin C.Y. Wong

Treatment, 181




8 Small Bowel Tumors, 189 Edited by Nadir Arber

Diagnosis, 189

Epidemiology, 189

Kerin Adelson, Eyal Sagiv, Nadir Arber &

Alfred I. Neugut

Endoscopy in the diagnosis of small bowel tumors, 196

Ian M. Gralnek & Rami Eliakim

Molecular biology of small bowel tumors, 200

Eyal Sagiv, Kerin Adelson, Alfred I. Neugut & Nadir Arber


Yulia Bronstein & Ronelle Dubrow

Treatment, 210

Surgery, 210

Ido Nachmany & Joseph M. Klausner

Other treatments, 215

Pascal Peeters, Eric Van Cutsem & Mario Dicato

9 Sarcoma and Gastrointestinal Stromal Tumors, 227 Edited by Markku Miettinen

Introduction, 227

Markku Miettinen

Pathology, prognosis and genetics of gastrointestinal stromal

tumors (GISTs), 228

Markku Miettinen & Jerzy Lasota

Imaging and staging of gastrointestinal stromal tumors, 240

Angela D. Levy

Treatment, 244

Heikki Joensuu & Ronald P. DeMatteo

10 Rare Tumors of the Abdomen, 259 Edited by Anil R. Prasad

Smooth muscle and pericytic tumors, 259

Mitual Amin, Malathy Kapali, Benjamin Paz, Sanjay Saluja &

Tomislav Dragovich

Vascular tumors, 263

Mitual Amin, Malathy Kapali, Benjamin Paz, John Fetsch &

Tomislav Dragovich

Adipose tissue tumors, 267

John Fetsch, Anil R. Prasad, Sanjay Saluja & Benjamin Paz

Neurogenic tumors, 270

Anil R. Prasad, Markku Miettenen & Benjamin Paz

Myofi broblastic and fi brous tumors, 273

John Fetsch, Malathy Kapali, Benjamin Paz, Sanjay Saluja &

Tomislav Dragovich

Mesothelial tumors, 276

Anil R. Prasad, Malathy Kapali, Sanjay Saluja &

Tomislav Dragovich

Gastric lymphomas, 280

Anil R. Prasad, Sanjay Saluja & Daniel O. Persky

Rare miscellaneous tumors and tumor-like lesions, 283

Anil R. Prasad, John Fetsch, Sanjay Saluja &

Tomislav Dragovich

Part 2: Colorectal CancerEdited by David Kerr

11 Epidemiology and Prevention of Colorectal Cancer, 293

Paul Moayyedi

12 The Molecular Pathology of Sporadic and Hereditary Colorectal Cancer, 305

Massimo Pignatelli, Nahida Banu & Zsombor Melegh

13 Screening for Colorectal Cancer, 317 Robert J.C. Steele

14 Cancer of the Colon and Rectum, 325 Edited by Rachel S. Midgley

Diagnosis, 325

Clinical presentation, 325

Omar Khan, Rachel S. Midgley & Andrew Weaver

Histopathology, 326

Daniel Royston & Bryan Warren


Margaret Betts

CONTENTS VII

Treatment, 334

Overview of therapy modalities, 334

Rachel S. Midgley

Surgery, 335

Baljit Singh & Chris Cunningham

Chemotherapy, 341

Ami Sabharwal & David Kerr

Radiotherapy for rectal cancer, 346

Robert Glynne-Jones

Surgery for liver metastases, 351

Zahir Soonwalla

Ablative treatments, 356

Fergus Gleeson

Novel therapies, 359

Carlos Escriu, Mark Middleton & Rachel S. Midgley

Stomas, 367

Ann MacArthur & Julia Liddi

Answers to case scenerios, 369

Omar Khan, Rachel S. Midgley & Andrew Weaver

15 Rare Cancers, 374 Edited by Colin McArdle

Gastrointestinal carcinoids, 374

Irwin M. Modlin, Jon Bornschein & Mark Kidd

Anorectal melanoma, 384

Gary N. Mann, Shailender Bhatia & John L. Thompson

Cancer of the anal canal, 389

Matthew Clark & Lincoln Israel

Appendiceal epithelial neoplasms, 394

Paul H. Sugarbaker

Diffuse malignant peritoneal mesothelioma, 400

Tristan D. Yan & Paul H. Sugarbaker

Part 3: Hepatobiliary CancerEdited by Yuman Fong

16 Epidemiology of Hepatocellular Carcinoma, 411 Hashem B. El-Serag, Donna L. White &

Zhannat Nurgalieva

17 Factors involved in Carcinogenesis and Prevention in Hepatobiliary Cancer, 421

Paula Ghaneh, William Greenhalf & John P. Neoptolemos

18 Molecular Biology of Hepatobiliary Cancer, 433 Knut Ketterer & Helmut Friess

19 Primary Liver Cancer, 441 Edited by Charlie Pan & Theodore Lawrence

Diagnosis, 441

History and clinical, 441

Jorge A. Marrerro & Charlie Pan

Histopathology, 443

Rebecca F. Harrison & Angus H. McGregor


Jonathon Willatt & Hero K. Hussain

Treatment, 451

Overview, 451

Charlie Pan

Surgery, 453

Shawn J. Pelletier & James A. Knol

Ablation, 456

James A. Knol

Radiotherapy, 459

Charlie Pan & Theodore Lawrence

Chemotherapy, 463

Charlie Pan & William D. Ensminger

Novel agents, 466

Charlie Pan & William D. Ensminger


Charlie Pan

20 Metastatic Liver Cancer, 469 Edited by Yuman Fong

Treatment, 469

Overview, 469

Yuman Fong

Surgical therapy for hepatic colorectal metastases, 469

Darren Carpizo & Yuman Fong

Systemic chemotherapy, 481

Nancy Kemeny

Ablative Therapy, 488

Anne M. Covey

Radiation therapy, 494

Christopher Willet & Brian G. Czito

21 Primary Pancreatic Adenocarcinoma, 498 Edited by Christopher L. Wolfgang

Diagnosis, 498

Epidemiology, history and clinical fi ndings, 498

Timothy M. Pawlik

Histopathology, 502

Ralph H. Hruban

CT imaging in pancreatic cancer, 506

Karen M. Horton & Elliot K. Fishman

Treatment, 514

Overview, 514

Christopher L. Wolfgang

Surgery, 515

Robert A. Meguid & Christopher L. Wolfgang

Chemotherapy, 523

Daniel Laheru

Radiotherapy, 526

Joseph Herman

Novel agents, 533

Manuel Hildago


Jeffrey Infante & Wells Messersmith

VIII CONTENTS

22 Cholangiocarcinoma, 543 Edited by Ravi S. Chari

Diagnosis, 543

Overview, 543

Ravi S. Chari

History, 543

T. Markley Earl, Burnett S. Kelly & Ravi S. Chari

Clinical, 545

T. Markley Earl, Burnett S. Kelly & Ravi S. Chari

Histopathology, 546

Elizabeth I. Johnston & Mary Kay Washington

Imaging and Staging, 548

Christopher D. Anderson, T. Markley Earl, Stephen J. Meranze &

Ravi S. Chari

Treatment, 551

Overview, 551

Ravi S.Chari

Surgery, 552

Christopher D. Anderson & Ravi S. Chari

Chemotherapy, 554

Laura A. Williams & Jordan Berlin

Role of radiation therapy, 557

Jayamarx Jayaraman & A. Bapsi Chakravarthy

Ablation, 561




23 Neuroendocrine Tumors, 564 Edited by Ursula Plöckinger

History and histopathology, 564

Guido Rindi & Cesare Bordi

Diagnosis, staging, prognosis and follow-up, 568

Gastric neuroendocrine tumors, 568

Gianfranco Delle Fave

Gastrinoma, 574

Frédérique Maire & Phillippe Ruszniewski

Insulinoma, 579

Wouter W. de Herder

Non-functioning endocrine tumors of the pancreas, 580

Dimitios Papdogias & Gregory Kaltsas

Rare functioning pancreatic endocrine tumors, 587

Dermot O’Toole

Midgut and appendiceal tumors, 594

Barbro Eriksson

Neuroendocrine tumors of the colon and rectum, 599

Christoph J. Auernhammer

Imaging of gastroenteropancreatic neuroendocrine tumors, 605

Anders Sundin

Treatment, 613

Overview, 613

Rudolf Arnold & Anja Rinke

Surgery: pancreatic tumors, 618

Göran Åkerström & Per Hellman

Surgery: midgut tumors, 627

Matthias Rothmund

Surgery: liver metastases, 632

Håkan Ahlman & Michael Olausson

Ablative therapy, 638

Massimo Falconi & Rossella Bettini

Radiolabeled somatostatin analogs, 645

Dik J. Kwekkeboom, Jaap J.M. Teunissen, Boen L. Kam,

Roelf Valkema, Wouter W. de Herder & Eric P. Krenning

Biotherapy and chemotherapy, 651

Ursula Plöckinger

Novel agents, 662

Marianne Pavel

24 Rare Tumors of the Liver, 669 Shantanu Bhattacharjya, Zahir Soonawalla, Rachel R. Phillips &

Peter J. Friend

25 Cystic Neoplasms of the Pancreas, 688 Edited by Peter J. Allen

Diagnosis and imaging, 688

John Mansour & Lawrence Schwartz

Treatment recommendations, 700

John Mansour & Peter J. Allen

Endoscopic assessment and treatment, 704

Mark Greaves & Mark Schattner

Index, 711

List of Contributors

Editors

Yuman Fong MDMemorial Sloan-Kettering Cancer CenterNew York, NYUSA

Janusz Jankowski MD, PhD, FRCP, FACGDepartment of Clinical PharmacologyUniversity of OxfordOxfordUK

David Kerr CBE, MA, MD, DSc, FRCP, FMedSciDepartment of Clinical PharmacologyUniversity of OxfordOxfordUK

Richard Sampliner MDUniversity of Arizona College of MedicineTuscon, AZUSA

Contributors

Kerin Adelson MDMount Sinai School of MedicineNew York, NYUSA

Håkan Ahlman MD, PhDDepartment of Clinical SciencesSahlgrenska AcademyUniversity of GöteborgSweden

Jaffer Ajani MDDepartment of Radiation OncologyUniversity of Texas MD Anderson Cancer CenterHouston, TXUSA

Goran Akerström PhD, MDDepartment of SurgeryUniversity HospitalUppsalaSweden

Peter J. Allen MDDepartment of SurgeryMemorial Sloan-Kettering Cancer CenterNew York, NYUSA

Mitual B Amin MDDepartment of Anatomic PathologyWilliam Beaumont HospitalRoyal Oak, MIUSA

Christopher D. Anderson MDSection of Abdominal Transplant SurgeryWashington University in St. LouisSt Louis, MIUSA

Mark R. Anderson MBBChir, PhD, MRCPCity HospitalBirminghamUK

Salim M. Anjarwalla MD, MBChB, MRCPathDepartment of HistopathologyGloucestershire Royal HospitalGloucesterUK

Nadir Arber MD, MSc, MHAIntegrated Cancer Prevention CenterTel Aviv Medical Center and Tel Aviv UniversityIsrael

Rudolf Arnold MD, FRCPDivision of Gastroenterology and Endocrinology Department of Internal Medicine Philipps UniversityMarburgGermany

Christoph J. Auernhammer MDMedizinische Klinik II, GrosshadernKlinikum der Ludwig-Maximilians-Universität MünchenMünchenGermany

Nahida Banu MBBS, PhDDepartment of PathologyBristol Royal Infi rmaryBristolUK

Hugh Barr MD, ChM, FRCS, FRCS, FHEACranfi eld HealthGloucestershire Royal HospitalGloucesterUK

Shantanu Battacharyja MS, FRCSEdBGS Global HospitalKengeriBangaloreIndia

Regina G.H. Beets-Tan MDUniversity Hospital MaastrictMaastrichtThe Netherlands

Jordan Berlin MDVanderbilt UniversityVanderbilt-Ingram Medical CenterNashville, TNUSA

Rossella Bettini MDChirurgia Generale BDipartimento di Scienze Chirurgiche e Gastroenterologiche Policlinico ‘GB Rossi’VeronaItaly

Margaret Betts MBChB, MRCP, FRCRJohn Radcliffe HospitalOxfordUK

IX

X LIST OF CONTRIBUTORS

Chetan Bhan MBBSDepartment of SurgeryEastbourne HospitalEastbourneUK

Shailender Bhatia MBBSDivision of Hematology-OncologyFred Hutchinson Cancer Research CenterUniversity of WashingtonSeattle, WAUSA

Cesare Bordi MDUniversita Degli Studi di ParmaParmaItaly

Jan Bornschein MDDepartment of Gastroenterological SurgeryYale University School of MedicineNew Haven, CTUSA

Yulia Bronstein MDDiagnostic RadiologyBody ImagingMD Anderson Cancer CenterHouston, TXUSA

Navtej S. Buttar MDMiles and Shirley Fiterman Center for Digestive DiseasesMayo ClinicRochester, MNUSA

Darren Carpizo MD, PhDMemorial Sloan-Kettering Cancer CenterDepartment of SurgeryNew York, NYUSA

Annemieke Cats MD, PhDNetherlands Cancer Institute/Antoni van Leeuwenhoek HospitalAmsterdamThe Netherlands

Amitabh Chak MDDivision of GastroenterologyCase Western Reserve University School of MedicineCleveland, OHUSA

A. Bapsi Chakravarthy MDRadiation OncologyVanderbilt University Medical CenterNashville, TNUSA

Annie O.O. Chan MBBS, MRCP, FHKAM, MD, PhD, FRCPDepartment of MedicineQueen Mary HospitalPokfulam RoadHong Kong

Ravi S. Chari MD, FRCSC, FACSDivision of HepatobiliarySurgery and LiverTransplantationVanderbilt University Medical CenterNashville, TNUSA

Yu Jo Chua MD, MBBSDepartment of MedicineRoyal Marsden HospitalSurreyUK

Matthew Clark MBChB, MD, FRACSUniversity of AucklandAucklandNew Zealand

Anne M. Covey MDMemorial Sloan-Kettering Cancer CenterNew York, NYUSA

Chris Cunningham MD, FRCSEdDepartment of Colorectal SurgeryJohn Radcliffe HospitalOxfordUK

David Cunningham MD, FRCPRoyal Marsden HospitalSurreyUK

Brian G. Czito MDDepartment of Radiation OncologyDuke University Medical CenterDurham, NCUSA

Ananya Das MD, FACP, FASGEAssociate ProfessorMayo Clinic ArizonaScottsdale, AZUSA

Evan S. Dellon MDCenter for Esophageal Diseases and SwallowingDivision of Gastroenterology and HepatologyUniversity of North Carolina School of MedicineChapel Hill, NCUSA

Ronald P. DeMatteo MD, FACSDepartment of SurgeryMemorial Sloan-Kettering Cancer CenterNew York, NYUSA

M. Dicato MD, FRCPHematology-Oncology ServiceLaboratory of Research on Cancer and Blood DisordersLuxembourg Medical CenterLuxembourg

Tomislav Dragovich MD, PhDArizona Cancer Center /University Medical CenterTucson, AZUSA

Ronelle Dubrow MS, MDMD Anderson Cancer CenterHouston TXUSA

T. Markley Earl MDDepartment of SurgeryVanderbilt University School of MedicineNashville, TNUSA

Rami Eliakim MDRambam Health Care CampusTechnion-Israe Institute of TechnologyHaifaIsrael

Hashem B El-Serag MD, MPHMichael E. DeBakey VA Medical Center and Baylor College of MedicineHouston, TXUSA

William D. Ensminger MDUpjohn Center SPC 5504Ann Arbor, MIUSA

Barbro Eriksson MD, PhDDepartment of Medical SciencesUppsala University Hospital’UppsalaSweden

Carlos Escriu MD, MRCPClatterbridge Centre for OncologyLiverpoolUK

Massimo Falconi MDChirurgia Generale BDipartimento di Scienze Chirurgiche e GastroenterologichePoliclinico ‘GB Rossi’VeronaItaly

Gianfranco Delle Fave MDUniversità di Roma ‘La Sapienza’RomeItaly

John Fetsch MDDepartment of Soft Tissue PathologyArmed Forces Institute of PathologyWashington, DCUSA

LIST OF CONTRIBUTORS XI

Elliot K. Fishman MDJohns Hopkins HospitalDepartment of RadiologyBaltimore, MDUSA

Peter J. Friend MA, MB, FRCS, MDNuffi eld Department of SurgeryUniversity of OxfordUK

Helmut Friess MDDepartment of SurgeryKlinikum rechts der IsarTechnical University of MunichMunichGermany

Paula Ghaneh MBChB, MD, FRCSUniversity of LiverpoolSchool of Cancer StudiesLiverpoolUK

Fergus Gleeson FRCP, FRCRDepartment of RadiologyThe Churchill HospitalOxfordUK

Ian M. Gralnek MD, MSHS, FASGEDepartment of GastroenterologyRambam Health Care CampusHaifaIsrael

Mark Greaves MDMemorial Sloan-Kettering Cancer CenterNew York, NYUSA

William Greenhalf BSc, PhDUniversity of LiverpoolSchool of Cancer StudiesLiverpoolUK

Nicole C.T. van Grieken MD, PhDDepartment of PathologyVrije Universiteit Medical CenterAmsterdamThe Netherlands

Rebecca F. Harrison BSc, MBChB, FRCPathDepartment of PathologyLeicester General HospitalLeicesterUK

Per Hellman PhD, MDDepartment of SurgeryUniversity HospitalUppsalaSweden

Fernando Herbella MDFellow, Department of SurgeryUniversity of RochesterRochester, NYUSA

Wouter W. de Herder MD PhDDepartment of Internal MedicineSector of EndocrinologyErasmus MCRotterdamThe Netherlands

Joseph Herman MD, MScDepartment of Radiation OncologySidney Kimmel Cancer CenterThe Johns Hopkins UniversityBaltimore, MDUSA

David Hewin BSc, MD, FRCSConsultant Upper Gastrointestinal SurgeonGloucestershire Royal HospitalGloucesterUK

Manuel Hidalgo MD, PhDThe Johns Hopkins University School of MedicineBaltimore, MDUSA

Karen M. Horton MDJohns Hopkins Medical InstitutionsBaltimore, MDUSA

Ralph H. Hruban MDThe Sol Goldman Pancreatic Cancer Research CenterThe Johns Hopkins Medical InstitutionsBaltimore, MDUSA

Hero K. Hussain MBChB, FRCRDepartment of Radiology / MRIUniversity of Michigan Health SystemAnn Arbor, MIUSA

Jeffrey Infante MDSarah Cannon Research InstituteNashville, TNUSA

Lincoln Israel BHB, MBChB, FRACSMiddlemore HospitalOtahuhuAucklandNew Zealand

Christopher Jackson MBChBGastrointestinal UnitRoyal Marsden HospitalSurreyUK

Edwin P.M. Jansen MDThe Netherlands Cancer Institute/Antoni van Leeuwenhoek HospitalDepartment of RadiotherapyAmsterdamThe Netherlands

Aminah Jatoi MDDepartment of OncologyMayo ClinicRochester, MNUSA

Jayamarx Jayaraman MBBS, MPHVanderbilt University Medical CenterNashville, TNUSA

Heikki Joensuu MDDepartment of OncologyHelsinki University Central HospitalHelsinkiFinland

Elizabeth I. Johnston MDDepartment of PathologyVanderbilt University School of MedicineNashville, TNUSA

Robert Glynne Jones BA, MBBS, FRCR, FRCPMount Vernon Cancer CentreUK

Gregory Kaltsas MD, FRCPDepartment of PathophysiologyNational University of AthensAthensGreece

Boen L. Kam MDNuclear Medicine PhysicianDept of Nuclear MedicineErasmus MC, Rotterdamthe Netherlands

Malathy Kapali MDUniversity of ArizonaCollege of MedicineTucson, AZUSA

Burnett S. Kelly MDDepartment of SurgeryVanderbilt University Medical CenterNashville, TNUSA

Nancy Kemeny MDMemorial Sloan-Kettering Cancer CenterGastrointestinal Solid Tumor ServiceDepartment of MedicineNew York, NYUSA

XII LIST OF CONTRIBUTORS

Knut Ketterer MDDepartment of SurgeryKlinikam rechts der IsarTechnical University of MunichMunichGermany

Omar Khan BSc, MBBS, MRCPCancer Research UKDepartment of Medical OncologyChurchill HospitalOxfordUK

Mark Kidd PhDDepartment of Gastroenterological SurgeryYale University School of MedicineNew Haven, CTUSA

Joseph M. Klausner MDDepartment of SurgeryThe Tel Aviv Sourasky Medical CenterSackler School of MedicineTel Aviv UniversityTel AvivIsrael

James A. Knol MD, FACSDivision of Gastrointestinal SurgeryUniversity of Michigan Department of SurgeryAnn Arbor, MIUSA

Ritsuko Komaki MD, FACRAnderson Cancer CenterHouston, TXUSA

Eric P. Krenning MDErasmus MCRotterdamThe Netherlands

Dik J. Kwekkeboom MD, PhDErasmus MCUniversity Hospital RotterdamDepartment of Nuclear MedicineRotterdamThe Netherlands

Daniel Laheru MDDepartment of Medical OncologyThe Johns Hopkins University School of MedicineThe Sidney Kimmel Comprehensive Cancer CenterBaltimore, MDUSA

Jerzy Lasota MD, PhDDepartment of Soft Tissue PathologyArmed Forces Institute of PathologyWashington, DCUSA

Theodore Lawrence MD, PhDDepartment of Radiation OncologyUniversity of MichiganUSA

Angela D. Levy MDUniformed Services University of the Health SciencesBethesda, MarylandUSA

Zhongxing Liao MDDepartment of Radiation OncologyThe University of Texas M. D. Anderson Cancer CenterHouston, TXUSA

Julia Liddi BScJohn Radcliffe HospitalOxfordUK

Matthew Lovell MBBSDepartment of Clinical PharmacologySt Bartholomew’s and the London School of Medicine and DentistryLondonUK

Frédérique Maire MDService de Gastroentérologie et PancréatologiePôle des maladies de l’Appareil DigestifHôpital BeaujonClichyFrance

Gary N. Mann MBBCh, FACSDepartment of SurgerySection of Surgical OncologyUniversity of Washington Medical CenterSeattle, WAUSA

John Mansour MDDepartment of SurgeryMemorial Sloan-Kettering Cancer CenterNew York, NYUSA

Jorge A. Marrero MD, MSMultidisciplinary Liver Tumor ProgramUniversity of MichiganTaubman CenterAnn Arbor, MIUSA

Colin McArdle FRCSDepartment of SurgeryRoyal Infi rmaryGlasgow, UK

Stuart McDonald BSc, PhDDepartment of Clinical PharmacologyGI Oncology GroupUniversity of OxfordOxfordUK

Angus H. McGregor MBChB, Bsc, MDDepartment of HistopathologyLeicester Royal Infi rmaryLeicesterUK

Robert A. Meguid MDDepartment of SurgeryJohns Hopkins University School of MedicineBaltimore, MDUSA

Gerrit A. Meijer MD, PhDVrije Universiteit Medical CenterAmsterdamThe Netherlands

Zsombor Melegh MD, MScDepartment of Cellular and Molecular MedicineHistopathology DivisionBristol Royal Infi rmaryBristolUK

Steven J. Meranze MDVanderbilt University Medical CenterNashville, TNUSA

Wells Messersmith MDDivision of Medical OncologyDepartment of MedicineUniversity of ColoradoAurora, COUSA

Mark Middleton MDUniversity of OxfordCancer Research UKDepartment of Medical OncologyChurchill HospitalOxfordUK

Rachel S. Midgley BSc, MB ChB, MRCP, PhDDepartment of Clinical PharmacologyUniversity of OxfordUK

Markku Miettinen MD, PhDDepartment of Soft Tissue PathologyArmed Forces Institute of PathologyWashington, DCUSA

Luka Milas MD, PhDDepartment of Experimental Radiation OncologyThe University of Texas M. D. Anderson Cancer CenterHouston, TXUSA

LIST OF CONTRIBUTORS XIII

Paul Moayyedi BSc, MB ChB, PhD, MPH, FRCP, FRCPC, FACG, AGAFDepartment of MedicineMcMaster University Medical CentreHamilton, ONCanada

Irvin M. Modlin MD, PhD, DSC, FRCSYale University School of MedicineNew Haven, CTUSA

Vidu B. Mokkala MDMiles and Shirley Fiterman Center for Digestive DiseasesMayo ClinicRochester, MNUSA

Daniela Molena MDDepartment of SurgeryUniversity of Rochester Medical CenterRochester, NYUSA

Ido Nachmany MDDepartment of SurgeryTel Aviv Sourasky Medical CenterSackler School of MedicineTel Aviv UniversityTel AvivIsrael

John P. Neoptolemos MBChB, MD, FRCS, FMedSciUniversity of LiverpoolSchool of Cancer StudiesLiverpoolUK

Alfred I. Neugut MD, PhDColumbia University Medical CenterNew York, NYUSA

Zhannat Nurgalieva MDMichael E. DeBakey VA Medical Center and Baylor College of MedicineHouston, TXUSA

Michael Olausson MDDivision of Transplantation and Liver SurgeryUniversity of GöteborgGöteborgSweden

Dermot O’Toole MD, MRCPISt James’s Hospital and Trinity College DublinDublinIreland

Charlie Pan MDDepartment of Radiation OncologyUniversity of Michigan Medical SchoolAnn Arbor, MIUSA

Dimitrios Papadogias MDGeneral Hospital ‘G. Gennimatas’AthensGreece

Marianne Pavel MDInternistin, EndokrinologinMedizinische Klinik I mit PoliklinikUniversitätsklinikum UlmenwegErlangenGermany

Timothy M. Pawlik MD, MPH, FACSDivision of Surgical OncologyDepartment of SurgeryJohns Hopkins School of MedicineBaltimore, MDUSA

Benjamin Paz MDCity of Hope National Medical CenterCalifornia, CAUSA

Pascal Peeters MDDigestive Oncology UnitUniversity Hospital GasthuisbergLeuvenBelgium

Shawn J. Pelletier MDGeneral and Transplantation SurgeryTaubman CenterUniversity of Michigan Health SystemAnn Arbor, MichiganUSA

Daniel O. Persky MDUniversity of Arizona Health Sciences CenterTucson, AZUSA

Jeffrey H. Peters MDDepartment of SurgeryUniversity of RochesterRochester, NYUSA

Rachel R. Phillips FRCP, DCH, FRCRUniversity of OxfordDepartment of RadiologyThe Churchill HospitalOxfordUK

Massimo Pignatelli MD, PhD, FRCPathDepartment of Cellular and Molecular MedicineHistopathology DivisionBristol Royal Infi rmaryBristolUK

Ursula Plöckinger MDInterdisziplinäres Stoffechsel-CentrumCharité-Universitätsmedizin BerlinCampus-Virchow-KlinikumBerlinGermany

Anil R. Prasad MD, FASCP, FCAPUniversity of Arizona Health Sciences CenterTucson, AZUSA

Asif Rashid MD, PhDDepartment of PathologyMD Anderson Cancer CenterHouston, TXUSA

Ann MacArthur Rgn EnbThe Horton HospitalOxford Radcliffe Hospitals NHS TrustOxfordUK

Guido Rindi MD, PhDAnatomic Pathology SectionDepartment of Pathology and Laboratory MedicineUniversity of ParmaParmaItaly

Anja Rinke MDPhilipps Universität MarburgMarburgGermany

Matthias Rothmund MDPhilipps Universität MarburgMarburgGermany

Daniel Royston MBChB, BMScDepartment of Cellular PathologyJohn Radcliffe HospitalOxfordUK

Philippe Ruszniewski MD, PhDBeaujon HospitalClichyUniversité Denis DiderotParisFrance

Ami Sabharwal MDDepartment of Clinical PharmacologyUniversity of OxfordOxfordUK

Eyal Sagiv PhDTel Aviv Medical CenterTel AvivIsrael

XIV LIST OF CONTRIBUTORS

Sanjay Saluja MDDepartment of RadiologyYale University School of MedicineNew Haven, CTUSA

Alastair Sammon MD, FRCSDepartment of General SurgeryGloucestershire Hospitals NHS Foundation TrustGloucesterUK

Mark Schattner MD, FACPGastroenterology and Nutrition ServiceMemorial Sloan-Kettering Cancer CenterNew York, NYUSA

Lawrence Schwartz MDMemorial Sloan-Kettering Cancer CenterNew York, NYUSA

Nicholas J. Shaheen MD, MPHUniversity of North Carolina School of MedicineChapel Hill NCUSA

Neil A. Shepherd DM, FRCPathDepartment of HistopathologyGloucestershire Royal HospitalGloucesterUK

Cen Si MDDepartment of PathologyVrije Universiteit Medical CenterAmsterdamThe Netherlands

Baljit Singh FRCS, DPhilNuffi eld Department of SurgeryJohn Radcliffe HospitalOxfordUK

Ferdinandos Skoulidis MD, MRCPMRC/Hutchison Research CentreUniversity of CambridgeUK

Thomas C. Smyrk MDDepartment of Lab medicine and PathologyMayo ClinicRochester, MNUSA

Louis M. Wong Kee Song MDMiles and Shirley Fiterman Center for Digestive DiseasesMayo ClinicRochester, MNUSA

Ilfet Songun MD, PhDLeiden University Medical CenterDepartment of SurgeryLeidenThe Netherlands

Zahir Soonawalla FRCS, MS, DNBJohn Radcliffe HospitalOxfordUK

Naureen Starling MBBS, BSc, MRCPGastrointestinal UnitDepartment of MedicineRoyal Marsden HospitalSurreyUK

Robert J. C. Steele MD, FRCSNinewells Hospital and Medical SchoolDundeeUK

Paul H. Sugarbaker MDPeritoneal Surface Malignancy ProgramWashington Cancer InstituteWashington Hospital CenterWashington DCUSA

Anders Sundin MD, PhDDepartment of RadiologyKarolinska University Hospital SolnaStockholmSweden

Jaap J.M. Teunissen MDErasmus MCUniversity Hospital RotterdamDepartment of Nuclear MedicineRotterdamThe Netherlands

John L. Thompson MDFred Hutchinson Cancer Research CenterUniversity of WashingtonSeattle, WAUSA

Roelf Valkema MD, PhDDepartment of Nuclear MedicineErasmus MCRotterdamThe Netherlands

Eric Van Cutsem MD, PhDDigestive Oncology UnitUniversity Hospital GasthuisbergLeuvenBelgium

Cornelius J.H. van de Velde FRCS, FRCPS, MD, PhDLeiden University Medical CenterDepartment of SurgeryLeidenThe Netherlands

Marcel Verheij MD, PhDDepartment of Radiation OncologyThe Netherlands Cancer Institute/ Antoni van Leeuwenhoek HospitalAmsterdamThe Netherlands

Mark Vipond MS, FRCSGloucestershire Royal NHS Foundation TrustGloucesterUK

Kenneth K. Wang MDMayo ClinicDepartment of Gastroenterology and HepatologyRochester, MNUSA

Bryan F. Warren MBChB, FRCP, FRCPathJohn Radcliffe HospitalOxfordUK

Mary Kay Washington MD, PhDVanderbilt University Medical CenterNashville, TNUSA

Andrew Weaver MD, MRCP, FRCRJohn Radcliffe HospitalOxfordUK

Donna White PhDBaylor College of MedicineHouston, TXUSA

Bertram WiedenmannUniversity Medicine Berlin, ChariteDepartment of Internal MedicineDivision of Hepatology and GastroenterologyBerlinGermany

Jonathon Willatt MBChB, FRCRRadiology DepartmentUniversity of MichiganAnn Arbor, MIUSA

Christopher Willett M.D.Duke University Medical CenterDepartment of Radiation OncologyDurham, NCUSA

Laura A. Williams MDVanderbilt UniversityVanderbilt-Ingram Medical CenterNashville, TNUSA

Christopher L. Wolfgang MD, PhD, FACSJohns Hopkins HospitalBaltimore, MDUSA

LIST OF CONTRIBUTORS XV

Herbert C. Wolfsen MDMayo Clinic College of MedicineRochester, MNUSA

Benjamin C.Y. Wong MD, PhDDepartment of MedicineUniversity of Hong KongHong Kong

Tristan D. Yan BSc, MBBSPeritoneal Surface Malignancy ProgramWashington Cancer InstituteWashington Hospital CenterWashington DCUSA

Preface

The book is divided up into specifi c tumour areas for imme-diate and easy access and then subdivided into the specialities relating to an individual tumour. The unique advantage is that an expert in one area can refresh his knowledge in one area while quickly grasping the fundamentals in related clinical spe-cialities. The task of getting the worlds’ experts to write and submit their texts to such an exceptional standard is due in part to the excellent publishing team. We hope you enjoy this book and feel sure that your patients will benefi t time and again from the tried and tested effective advice as well as help to manage recalcitrant disease. As doctors we are tasked on a daily basis to make a real difference to every one of our patients each day. This book will help make this privilege manageable for the individual doctor and will allow doctors to think and act as a team. If one expert is not available then the book will provide the expertise needed – the immortal cancer specialist.

Janusz JankowskiLeicester, 2008

Gastrointestinal Oncology: A Critical Multidisciplinary Team Approach takes an entirely novel approach to the management of cancer. Since we accept that cancer medicine has changed over the last decade so must the approach to learning in this complex area, nowhere more so than the many multidisci-plinary needs of the single patient. The rationale for the book is as the reference text for multidisciplinary meetings dealing with esophageal, gastric, intestinal, colonic, hepatobiliary, pan-creatic and other GI tumors. It recapitulates the many expert opinions that are needed to weigh up the best management for a particular cancer sufferer. This text book will enable the expert not only to stay up to date with their speciality, but also make themselves experts in allied disciplines. This compendium is also aimed at those in training as we have used an evidence based approach to prioritise the themes of each chapter. There-fore, anyone who is a gastroenterologist, oncologist, radiologist, pathologist, GI surgeon or clinical scientist should refer to this book so their conceptual understanding is given breadth and depth.

XVI

Foreword

XVII

As a group, gastrointestinal (GI) cancers are the most frequent cause of cancer-related mortality worldwide. Recent data sug-gest that annual deaths exceed an estimated 2.4 million, and incident cases number more than 3.2 million. Even though rela-tively preventable, mortality rates approach incidence rates because GI cancers typically come to attention only at advanced clinical stages when current therapies are of limited benefi t.

GI cancers vary greatly in their pathogenesis and global occur-rence. For example, cancers of the esophagus, stomach, and liver occur more commonly in men and in economically developing countries, whereas colorectal cancer typically occurs without preference to gender, but is more common in industrialized countries. Variations in GI cancer—and changing patterns observed in migrant populations that tend to assume the cancer risks of their host countries, often within one generation—suggest a prominent role for environmental infl uences at most sites. In some cases, signifi cant environmental contributors have been identifi ed, such as Helicobacter pylori infection (stomach cancer), chronic viral hepatitis B and C and alcohol abuse (liver cancer), and alcohol abuse and tobacco exposure (esophageal squamous cell carcinoma). Our understanding of etiologic asso-ciations for other GI cancers is less complete and/or the associa-tions appear to be more complex. Colorectal cancer risk, for example, is infl uenced by a broad range of lifestyle and environ-mental factors, such as dietary nutrients, dietary fi ber, physical activity, tobacco exposure, and diabetes mellitus.

Key cellular and molecular derangements underlying the development of GI cancer are becoming clearer, and this knowl-edge is informing advances in cancer risk assessment, screening, early detection, and diagnosis. Molecular data have already translated into more effective and less toxic approaches to prevent, treat, and palliate certain GI cancers. Now, in all but the earliest clinical settings, a multidimensional approach has proven most effective for clinical management. Multi-disciplinary approaches draw upon the expertise of gastro-enterologists, surgeons, radiologists, radiotherapists, medical oncologists, specialized nurses, and supportive health specialists and have paved the way for multi-specialty clinics that attend to the diverse needs of patients with GI cancer.

Despite these conceptual and practical advances, many patients suffer serious morbidity from their disease and/or its management, and advanced GI cancer remains highly lethal. This underscores the critical role that basic, translational, and clinical research play in improving patient care. Indeed, as genetic susceptibility, molecular characterization, and tailored interventions play an expanding role in clinical decision making, molecular biologists, cancer geneticists, and other translationally-oriented researchers are increasingly integrated into multidisciplinary teams.

Finally, our improved molecular understanding of GI cancers suggests that we might one day be able to reduce their incidence altogether. This possibility has already been realized in colorec-tal carcinoma, where screening, polypectomy, and most recently, chemoprevention have not only proven to be feasible, but more importantly, effective. Furthermore, colorectal cancer screening of average risk individuals has demonstrated that issues of long-term health risks/benefi ts and cost-effectiveness ultimately drive dissemination of medical approaches. This fi nal hurdle may prove the most diffi cult to overcome, particularly if such advances are to be extended across all sectors of the population. Nevertheless, high-quality research offers the best opportunity to provide care for our patients, and to generate data that improve options for future generations.

This text, edited by Janusz Jankowski, Richard Sampliner, David Kerr and Yuman Fong, provides a timely and compre-hensive summary of our knowledge of GI cancer from a multi-disciplinary perspective—highlighting its pathogenesis, as well as its translation into clinical measures that can be applied by health care practitioners to benefi t those at risk for, or living with, GI cancers. In addition, it provides insights into pressing discovery needs that may guide bench researchers, clinical researchers, and population scientists in the search for more effective, safe, and cost-effective interventions.

Ernest Hawk MD, MPH & Jaye L. Viner MD, MPHNational Cancer Institute, Bethesda, USA

2008

1 Gastroesophageal CancerEdited by Richard Sampliner

1 Epidemiology of Gastroesophageal CancerEvan S. Dellon & Nicholas J. Shaheen

While there has been a substantial increase in the number of ACEs, there has been a relative decline in the incidence of SCC such that the overall burden of esophageal cancer has increased only slightly in the US. The 14,550 estimated cases of esophageal cancer in the US in 2006 were responsible for approximately 13,770 deaths, making esophageal cancer the 19th most common cancer, but the sixth leading cause of cancer death in men and the 16th cause in women (Jemal et al. 2006). Compared to 1970 when approximately 5% of new diagnoses of esophageal cancer were ACE, over half now are ACE with the remainder largely comprised of SCC (Devesa et al. 1998). The overall 5-year sur-vival rate for esophageal cancer of 15% is poor and has not signifi cantly improved over the past quarter-century (Eloubeidi et al. 2003; Jemal et al. 2006).

Risk factors for adenocarcinoma of the esophagus

DemographicMultiple risk factors for ACE have been established (see Table 1.1), and these also pertain to adenocarcinoma of the gastric cardia (see below). The incidence of ACE increases with increas-ing age, with a mean onset in the seventh and eighth decade of life; males are two to four times more likely to be affected than females, and Caucasians are approximately 5 times more likely than African-Americans to develop ACE; an association with socioeconomic status has not yet been seen (Blot et al. 1991; Daly et al. 1996; Devesa et al. 1998). There is regional variation in both incidence and ethnicity (Kubo & Corley 2002) but it has yet to be determined whether this is related to geographical factors or to issues pertaining to detection and diagnosis. Finally, to date, a strong heritable component of ACE has yet to be described, though in limited familial studies it appears that host factors are important (Chak et al. 2002).

ObesityWith the ongoing obesity epidemic in the US, there has been interest in obesity as a risk factor for malignancy. Several studies have linked increasing body mass index (BMI) with a stepwise

Malignancies of the esophagus and stomach represent a diverse group of disease processes. The epidemiology of these condi-tions has changed substantially over the last half-century, likely due to interactions between genetic predisposition and environ-mental factors. The goal of this chapter is to provide a review of the epidemiology of the major forms of gastroesophageal cancer. The fi rst part of the chapter will focus on the two major forms of esophageal neoplasm: adenocarcinoma and squamous cell carcinoma. In the second part of the chapter, gastric malig-nancies including adenocarcinoma, lymphoma, and stromal tumors will be discussed.

Epidemiology of esophageal cancer

Esophageal cancer is the eighth most common malignancy worldwide, responsible for an estimated 462,000 incident cases in 2002, and squamous cell carcinoma (SCC) is felt to be the most common subtype (Parkin et al. 2005). During the fi rst part of the twentieth century, SCC was also the most prevalent form in the US, but over the past several decades the incidence of adenocarcinoma of the esophagus (ACE) has risen dramatically (Jemal et al. 2006). In fact, the rate of increase has been faster than that of any other type of cancer (see Fig. 1.1) and has been measured at between 4 and 10% per year, with an overall increase of 300–500% (Daly et al. 1996; Devesa et al. 1998). While the cause of this shift is not fully understood, it may be a combination of factors such increasing obesity, alteration in known risk factors including treatment of Helicobacter pylori, and changes in the US population from the standpoint of aging and immigration (Daly et al. 1996; Devesa et al. 1998). Misclas-sifi cation bias from improved detection alone does not appear to explain this fi nding (Pohl & Welch 2005). Specifi c risk factors for each subtype of esophageal cancer will be discussed sepa-rately below.

3

Gastrointestinal Oncology: A Critical Multidisciplinary Team Approach. Edited by J. Jankowski, R. Sampliner, D. Kerr, and Y. Fong. © 2008 Blackwell Publishing, ISBN: 978-1-4501-2783-7

4 1 GASTROESOPHAGEAL CANCER

Fig. 1.1 Comparison of relative rates of increase of esophageal adenocarcinoma (solid black line) and other malignancies in the US (red short dashed line, melanoma; red thin solid line, prostate cancer; red dashed line, breast cancer; grey dotted line, lung cancer; black dashed and dotted line, colorectal cancer). From Pohl and Welch (2005).

Esophageal adenocarcinoma Esophageal squamous cell carcinoma

Gastric adenocarcinoma

Geographic location* Geographic location* Geographic location*

Demographics

Increasing age

Male

White

Demographics

Increasing age

Male

Ethnic minorities

Low socioeconomic status

Demographics

Increasing age (except

where H. pylori is

endemic)

Male

Ethnic minorities

Low socioeconomic status

Diet, nutrition, and habits

Tobacco

Obesity

High fat diet

Increased acid exposure


Tobacco

Alcohol

Few fruits and vegetables

Low selenium or zinc

Vitamin defi ciency*


Tobacco

Alcohol

Few fruits and vegetables

Vitamin defi ciency*

Barrett’s esophagus H. pylori infection

Heritability possible Heritability not established Heritability established

Other

Cholecystectomy

Other

Achalasia

Caustic injury

Radiation

Plummer–Vinson

Zenker’s diverticulum

Tylosis palmaris

Human papillomavirus

Other

Partial gastrectomy

Pernicious anemia

Epstein–Barr virus

Ménétrier’s disease

* See text.

Table 1.1 Risk factors for the major types of esophageal and gastric cancers.

increase in ACE risk (Chow et al. 1998b; Lagergren et al. 1999b). This fi nding is more prominent in men than women, and appears to be most directly related to central (visceral) adipos-ity. Additionally, a high-fat diet has been associated with increased risk of ACE (Mayne et al. 2001).

Acid exposureAcid exposure is pertinent to the pathogenesis of ACE (direct injury) and is also a well-established risk factor. A number of investigations have linked gastroesophageal refl ux disease (GERD) to ACE, demonstrating that the risk increases with increasing severity and duration of GERD symptoms (Lager-gren et al. 1999a; Farrow et al. 2000; Ye et al. 2001). However, it should be noted that in these same studies, as many as 40–50% of patients eventually diagnosed with ACE did not have previous symptoms of GERD. In a similar vein, medications that reduce the pressure of the lower esophageal sphincter (LES) such as anticholinergics, nitrates, and others, have also been associated with ACE (Lagergren et al. 2000). The role of Helicobacter pylori will be discussed below.

Barrett’s esophagusBarrett’s esophagus (BE), defi ned as metaplasia of the normal esophageal squamous mucosa to specialized (intestinalized)

19750

1

2

3

4

5

6

7

Rate

rat

io (r

elat

ive

to 1

975)

1980 1985 1990 1995 2000

1 EPIDEMIOLOGY OF GASTROESOPHAGEAL CANCER 5

columnar epithelium with goblet cells present, is a widely studied risk factor for ACE (Sharma et al. 2004). There is sig-nifi cant interest in this condition because it appears that ACE frequently arises in an area of BE, and that BE can progress from metaplasia, to dysplasia, and fi nally to carcinoma (Hameete-man et al. 1989; Shaheen & Ransohoff 2002). As noted above, while GERD and obesity are risk factors for ACE, they have also been found to be risk factors for BE (Avidan et al. 2002; El-Serag et al. 2005). These relations, however, do not explain the entire association; other studies show that a signifi cant proportion of subjects without GERD also have BE (Rex et al. 2003; Ronkainen et al. 2005). While an interaction between genetic predisposition and environmental exposures is implied, specifi c genes have not yet been identifi ed.

A large number of studies provide estimates that BE increases the risk of ACE 30 to 400 times, but more accurate projections place the increased risk at between 30 and 60 times (Lagergren 2005). The current best estimate of the rate of progression from non-dysplastic BE to ACE is approximately 0.5% per year in the USA but 1% in the UK (Shaheen et al. 2000). In BE with high-grade dysplasia (HGD), however, the rate of progression is sub-stantially higher at 10–30% per year (Miros et al. 1991; Buttar et al. 2001) and synchronous cancers are often found on esophagectomy specimens (Heitmiller et al. 1996; Cameron & Carpenter 1997).

The relation between BE, dysplasia, and ACE is not straight-forward, and the dysplasia to carcinoma pathway is not inevi-table. Observations of the natural history of BE and from structured treatment trials have repeatedly demonstrated cases of spontaneous regression from BE to normal squamous epi-thelium, HDG to low-grade dysplasia (LGD), and LGD to non-dysplastic Barrett’s mucosa (Schnell et al. 2001; Overholt et al. 2005; Shaheen 2005). The presence of BE has not been shown to affect mortality or life expectancy, and even in cases of BE where ACE develops, because ACE is a disease of the elderly competing comorbidities are often the cause of death (van der Burgh et al. 1996; Eckardt et al. 2001; Anderson et al. 2003).

OtherSeveral other risk factors for ACE have also been studied. Ciga-rette smoking likely increases the risk of ACE, but the results of population-based studies have been mixed (Brown et al. 1994; Zhang et al. 1996). Similarly, alcohol consumption has not been shown to be a strong risk factor (Brown et al. 1994). One study, which has yet to be replicated, found that cholecystectomy was associated with ACE (Freedman et al. 2001).

Possible preventive factors

While a number of risk factors for ACE have been identifi ed, there are also several factors that may be potentially protective, though these have not been rigorously tested in clinical trials. As summarized in a recent meta-analysis, multiple studies have reported that non-steroidal anti-infl ammatory drugs (NSAIDs)

reduce the risk of BE and ACE (Hur et al. 2004). The use of these medications specifi cally for BE, however, is not currently recommended outside of ongoing clinical trials which will defi ne the relative merits of chemoprevention with aspirin alone or in combination with proton pump inhibitors (PPIs). Several studies have also found that PPIs were associated with regression of BE and reduction of incidence of dysplasia (Sharma et al. 1997; El-Serag et al. 2004). Though there are no direct data showing that PPIs prevent ACE, given their favorable risk–benefi t profi le many experts now recommend that all patients with BE should be treated with PPIs. The value of aspirin as a chemoprevention agent is being tested in the world’s largest BE brial, ASPECT (Aspirin Chemoprevention Trial). Last, limited data suggest that the presence of H. pylori may decrease the development of dysplasia, so routine testing and treatment for this microorganism in refl ux and BE may not be warranted (Chow et al. 1998a, Ye et al. 2004).

Risk factors for squamous cell carcinoma of the esophagus

GeographicWhile some risk factors between the two major forms of esopha-geal cancer overlap, in general the risk factors for SCC are distinct (see Table 1.1). Incidence of SCC varies much more substantially by global geographic region that does ACE, with low rates (1–5 cases per 100,000) reported in the US and Western European countries and higher rates (50–200 cases per 100,000) in sections of Asia, India, and Africa (Parkin et al. 2005). While country of origin is a non-modifi able risk factor, this information may be useful in risk stratifi cation.

DemographicSimilar to ACE and other gastrointestinal malignancies, SCC of the esophagus is most frequently diagnosed in the 7th and 8th decades of life (Engel et al. 2003). White males are 2–4 times more likely to be affected than white women, and African-Americans are at 4–5 times higher risk for SCC than Caucasians (Gammon et al. 1997). Low socioeconomic status has also been related to elevated risk of SCC (Gammon et al. 1997).

Tobacco and alcoholTobacco and alcohol have repeatedly been shown not only to increase the risk of SCC in a dose-dependent manner, but also to act synergistically. The majority of studies report an elevated risk of 2–10 times, but some fi nd increases as high as 25 times (Brown et al. 1997; Thun et al. 1997). While there is a dose-dependent relationship between smoking and cancer risk, the total quantity of alcohol consumed, rather than the specifi c type, is likely the more important measure.

Diet and nutritionThe wide geographic variability in SCC of the esophagus may be explained, in part, by environmental factors such as diet and nutrition. Higher rates of SCC have been associated with


consumption of foods rich in N-nitrosamines, which in turn can cause either direct esophageal toxicity, DNA damage, or both (Siddiqi et al. 1988). Similarly, local practices such as the Iranian custom of imbibing extremely hot tea (Ghadirian 1987) or betel nut chewing in Asia (Pickwell et al. 1994) have been associated with SCC. An increased risk of SCC has also been associated with defi ciencies in a number of micronutrients, such as vitamins A, C, and E, folate, ribofl avin, B12, selenium, and zinc (Santhi Swaroop et al. 1989; Blot et al. 1993; Mark et al. 2000).

Non-malignant esophageal diseaseNon-malignant processes affecting the esophagus have also been associated with SCC. Though the mechanism is not fully understood, patients with achalasia are 15–30 times more likely to develop SCC of the esophagus compared with expected cancer registry rates (Sandler et al. 1995). Caustic ingestions (Appelqvist & Salmo 1980), radiation exposure (Ogino et al. 1992), Plummer–Vinson syndrome (Larsson et al. 1975), and Zenker’s diverticula (Huang et al. 1984) have been linked to SCC as well.

OtherA number of miscellaneous diseases are also thought to be associated with SCC. Infection with human papillomavirus (HPV) has been implicated in SCC, just as it has been in neo-plastic transformation of squamous epithelium of the anus and cervix (Chang et al. 2000). There is also a very strong link between tylosis palmaris and SCC of the esophagus, with as many as 50% of patients affected by this autosomal dominant disorder developing a malignancy by age 45, and 95% doing so by age 65 (Iwaya et al. 1998). Because of this, screening with upper endoscopy is recommended for all patients with tylosis starting at age 30 (Brown & Shaheen 2004).

Epidemiology of gastric cancer

Gastric cancer is the fourth most common malignancy world-wide (behind lung, breast, and colorectal cancers) and the second most common cause of cancer death (behind only lung cancer), responsible for an estimated 934,000 new cases and 700,000 deaths in 2002 (Parkin et al. 2005). This burden of disease falls most heavily on developing countries, where two-thirds of incident cases occur, and on China, where 42% of all cases are diagnosed (Parkin et al. 2005). Over the past several decades, however, there has been a general decline in the age-adjusted incidence rate of gastric cancer (Parkin et al. 1988). As with the rapidly evolving epidemiology of ACE, this decline implies a changing environmental milieu interacting with host factors rather than primary changes in genetics. Potential causes of this decline including sanitation and refrigeration, diet, and H. pylori will be discussed below.

In the US the epidemiology of gastric cancer does not refl ect the global picture. Incidence of gastric cancer has declined by more than 60–80% since 1930 (see Fig. 1.2). In 2006, 22,280 new cases were estimated to occur, accounting for 11,430 deaths

and making gastric cancer the 14th most common cancer and the 15th cause of cancer death (Jemal et al. 2006). Additionally, the 5-year survival rate has increased from 15% for the period 1974–1976 to 23% for the period 1995–2001 (Jemal et al. 2006). It is important to note that these trends are representative of non-cardia (or distal) gastric cancer, and will be the focus of this section. Because adenocarcinoma of the gastric cardia is felt to be closely related to ACE, risk factors for this disease are similar to those for ACE.

Gastric adenocarcinoma (GAC) comprises 90% of all non-cardia gastric cancer pathologic subtypes, with lymphomas, stromal tumors, and rare malignancies accounting for the remainder (Fuchs & Mayer 1995; Crew & Neugut 2006). GAC has been further subdivided into two histologic classes: an intes-tinal type which tends to maintain a distinct glandular structure and develops in the setting of atrophic gastritis, and a diffuse type which is generally poorly differentiated, features signet-ring cells, and arises in non-atrophic gastritis (Lauren 1965; Crew & Neugut 2006). It appears that the incidence of intesti-nal-type tumors is falling noticeably, while that of diffuse-type tumors is stable or rising slowly (Lauren & Nevalainen 1993; Kaneko & Yoshimura 2001; Henson et al. 2004). The specifi c characteristics of these individual types of cancer will be dis-cussed in further detail in Chapters 6 and 7. The general epide-miology of GAC is discussed below, and any signifi cant differences between the intestinal and diffuse types are noted. The chapter concludes with a discussion of the epidemiology of gastric lymphomas and stromal tumors.

Risk factors for gastric adenocarcinoma

GeographicA large number of studies have investigated risk factors for GAC, and while some of these overlap with esophageal cancer,

100 Lung and bronchus

Stomach

Colon and rectumProstate

Pancreas

Leukemia

Year of death

Liver

Rate

per

100

,000

pop

ulat

ion

90

80

70

60

50

40

30

20

10

01930 1940 1950 1960 1970 1980 1990 2000

Fig. 1.2 Decline in the annual age-adjusted cancer death rate from gastric cancer (pink line) for males; a similar trend has been seen in females as well (graph not shown). From Jemal et al. (2006).


many are unrelated (see Table 1.1). First, there is a substantial amount of geographic variability in the worldwide incidence of gastric cancer (see Fig. 1.3). In North America and selected regions of Africa and South Asia, rates are low (less than 10 per 100,000). By contrast, Japan has the highest rates in the world for both males and females (62 and 26 per 100,000, respectively), with comparatively high rates (approximately 20 per 100,000 or higher) also seen in China, Eastern Europe, and Central and South America (Parkin et al. 2005).

These wide differences in incidence almost certainly point to environmental factors placing inhabitants of certain regions at higher risk for GAC. Studies of migrants who emigrated from regions of high to low incidence help to confi rm this theory in multiple population types (McMichael et al. 1980; Kamineni et al. 1999). Specifi cally, when subjects emigrate from areas of high GAC incidence to low GAC incidence, they initially retain their ‘native’ incident rate. However, over time and especially over subsequent generations, descendants acquire the GAC incidence rate of their adopted country.

DemographicIn the US and other areas with a low incidence of GAC, the diagnosis of gastric cancer is most commonly made between the

ages of 50 and 70. In high-incidence areas such as East Asia and parts of Central America, however, diagnosis may be made at a much earlier age (Fuchs & Mayer 1995; Crew & Neugut 2006). In general, males are approximately 2 times more likely to be affected than females, as are certain ethnic minorities including African-Americans, Hispanic-Americans, and Native Ameri-cans (Fuchs & Mayer 1995). Low socioeconomic class has also been associated with an increased risk of GAC (Barker et al. 1990).

Helicobacter pylori and gastritisInfl ammation, especially when related to H. pylori, is likely central to GAC pathogenesis (see Chapters 2 and 3). There appears to be a progression from gastritis, to atrophic gastritis, to intestinal metaplasia, to gastric dysplasia, and fi nally to car-cinoma (Correa 2005). Epidemiologic studies of the role of H. pylori support this association in several ways. First, preva-lence rates of H. pylori correlate with GAC incidence rates (Dooley et al. 1989; Parkin 2006). In other words, areas of the world in which H. pylori prevalence is high and infection is acquired at an early age are the same geographic areas in which some of the highest incidence rates of GAC can be found.

While the overlap of these distributions is suggestive, further investigations have confi rmed the association. A number of

Japan

China

Eastern Europe

South America

Southern Europe

Western Europe

Northern Europe

Western Asia

Australia/New Zealand

South-Eastern Asia

Southern Africa

Eastern Africa

Northern America

South Central Asia

Melanesia

Northern Africa

Western Africa

70 60 50 40 30 20

Age-standardized incidence per 100,000

10 10

3.63.4

2.5

4.6

3.6

3.4

5.5

3.7

4.5

4.2

6.4

5.9

6.6

12.6

6.7

10.8

8.3

8.7

12.2

12.8

19.2

26.1

Males Females

4.4

6.3

6.9

7.4

7.4

8.2

8.5

9.9

11.6

12.4

12.8

13.4

13.6

15.2

15.7

18.0

24.2

29.6

41.4

62.1

20 30 40 50 60 700

Micro/Polynesia

Central America

Caribbean

Middle Africa

Fig. 1.3 Distribution of age-standardized incidence rates of gastric cancer by gender and location. From Parkin et al. (2005).


case–control studies report associations between H. pylori and non-cardia GAC of both intestinal and diffuse types with odds ratios (ORs) in the 2.5–4 range (Hansson et al. 1993; Hu et al. 1994; Kokkola et al. 1996). Nested case–control studies in both prospective and retrospective cohorts have been convincing as well. ORs in selected studies ranged from 2.7 to 6.0 and a meta-analysis found the pooled OR to be 2.5 (Danesh 1999). More recently, a prospective cohort of 1526 Japanese patients with either peptic ulcer disease, non-ulcer dyspepsia, or gastric hyperplasia were followed for a mean of 7.8 years to fi nd 36 GACs (Uemura et al. 2001). All of the 36 malignancies occurred in the 2.9% of patients with prior H. pylori; none were detected in patients without H. pylori. Taken together, the preponder-ance of the evidence strongly associates H. pylori infection with non-cardia GAC.

While H. pylori is a strong risk factor, it is also very common; perhaps 50% of the population worldwide are infected, and the majority of patients with H. pylori infection do not develop GAC. Ostensibly, host factors interact with bacterial and environmental factors to make progression to malignancy more or less likely. While this topic will be discussed in more detail in Chapter 2, one example involves the H. pylori virulence factor cytotoxin-associated gene A (cagA) (Al-Marhoon et al. 2004). Multiple case–control studies have shown that the presence of this virulence factor increases the risk for GAC above the risk of H. pylori alone, and a recent meta-analysis reported an overall OR of approximately 2.0 (Huang et al. 2003). Further, new data suggest that the presence of the cagA virulence factor interacts with host factors such as severity of atrophic gastritis to further modulate risk of GAC (Sasazuki et al. 2006).

While there are strong data to support the role of H. pylori in the development of GAC, whether the presence of gastric ulcer in the absence of H. pylori infection is a risk factor for GAC remains controversial (Hansson et al. 1996).

Diet and nutritionBecause the role of environment is so important in understand-ing GAC epidemiology, dietary factors have been well studied. Early investigations found that the use of refrigeration was a protective factor, suggesting that either preservatives or break-down products in spoiling food might be risk factors for GAC (Coggon et al. 1989; La Vecchia et al. 1990). Subsequent inves-tigations focused on the role of salt. A multinational ecologic study linked increasing salt intake to countries with higher inci-dences of GAC (Joossens et al. 1996), and case–control studies as well as animal models suggest that high-salt diets are a risk factor (Kono & Hirohata 1996). A recent large prospective cohort study also supports this, with ORs in the 2–3 range (Shikata et al. 2006).

A different type of preservative, N-nitroso compounds in meat, has been shown to be a risk factor for GAC. The same ecologic study evaluating the role of salt also examined rates of nitrate intake (Joossens et al. 1996). It found that increasing

nitrate consumption was associated with increased risk of GAC, and that the risk was additive to the risk of a high-salt diet. Case–control studies have also found an association between nitrates and GAC (Fraser et al. 1980; Kato et al. 1992). More recently, a multicenter prospective cohort demonstrated that both increased meat intake and increased processed meat intake were linked to an increased risk of GAC (Gonzalez et al. 2006). This study further showed that high levels of meat consumption acted synergistically with H. pylori to elevate risk.

A wide range of studies have looked at the role of fruit, veg-etables, and micronutrients in GAC risk. While some of the results of these studies have been confl icting, consumption of fruit and vegetables is felt to be protective, and vitamin C, beta-carotene, vitamin A, and vitamin E have also been found to decrease risk; consistent fi ndings have not been reported for other minerals (Kono & Hirohata 1996; Jenab et al. 2006a,b). While obesity has been linked to EAC and gastric cardia neoplasms, it has not been associated with non-cardia GAC (Lindblad et al. 2005).

Tobacco and alcoholUse of tobacco has clearly been shown to be related to GAC in a dose-dependent fashion in a number of studies, with ORs in the 1.5–2.5 range (Nomura et al. 1990; Kneller et al. 1991; Kato et al. 1992; Tredaniel et al. 1997; Gonzalez et al. 2003; Koizumi et al. 2004). The relation of alcohol to GAC, however, has not been clearly established. Most studies support either a minimal association (Kato et al. 1992) or no association (Nomura et al. 1990; D’Avanzo et al. 1994), while one recent retrospective cohort suggested that wine intake could be protective (Barstad et al. 2005).

Genetics and heritabilityThe role of genetics and heritability in gastric malignancy will be fully addressed in Chapters 2 and 3. However, early epide-miologic work associating GAC with blood group A (Hoskins et al. 1965) and other heritable cancer syndromes such as hereditary non-polyposis colorectal cancer (HNPCC or Lynch syndrome), familial adenomatous polyposis (FAP), and Peutz–Jeghers (Fuchs & Mayer 1995) highlighted the importance of host factors and laid the groundwork for current genomic and molecular research. Epidemiologic studies have also demon-strated that GAC likely has a heritable component (Palli et al. 1994; Zhao et al. 1994) and that this risk is independent from a shared environmental factor such as H. pylori (Brenner et al. 2000; Yatsuya et al. 2004). A recently described syndrome of hereditary diffuse gastric cancer has been linked to a germline mutation of the E-cadherin gene and confers a lifetime risk of GAC of 67% in males and 83% in females by the age of 80 (Blair et al. 2006). Finally, ongoing studies are examining the effect of inherited polymorphisms in interleukin-1-beta (El-Omar et al. 2003) and the interferon gamma receptor (Thye et al. 2003) on the host response in gastric infl ammation and H. pylori infection.


OtherIn addition to the major risk factors for GAC discussed above, a number of other associations have been reported. Two meta-analyses found that approximately 15 years after partial gastrec-tomy for benign gastric conditions, the risk of subsequent GAC was elevated by 1.5–3 times (Stalnikowicz & Benbassat 1990; Tersmette et al. 1990). A retrospective cohort found that this risk continued to increase as time from surgery increased (Tersmette et al. 1991).

While pernicious anemia is more frequently associated with gastric carcinoid (see Chapter 10), it has also been associated with GAC, potentially through a common pathway of atrophic gastritis. Two studies have found that GAC was 2–3 times more likely to develop in the setting of pernicious anemia (Brinton et al. 1989; Hsing et al. 1993). Of note, long-term use of anti-secretory therapy has not been associated with GAC (Moller et al. 1992; Klinkenberg-Knol et al. 1994).

Other associations that have been reported include infection with Epstein–Barr virus (EBV) (Levine et al. 1995), and hyper-trophic gastropathy conditions such as Ménétrier’s disease (Fuchs & Mayer 1995).

Risk factors for other gastric neoplasias

Of the 10% of non-GAC gastric malignancies, the majority are comprised of gastric lymphomas and gastric stromal tumors. These are discussed in detail in Chapters 9 and 10. Because they are less common than GAC, their epidemiology is correspond-ingly less well studied.

Gastric lymphomaComprising a diverse group of malignancies, gastric lympho-mas account for 3–5% of all gastric cancers and approximately 10% of all lymphomas, and the stomach is the most common site for extranodal lymphoma (Parsonnet et al. 1994; Al-Akwaa et al. 2004). In general, the peak incidence is between 50 and 65 years of age, and a small male predominance has been reported (Koch et al. 2001; Al-Akwaa et al. 2004).

As for GAC, the best-studied risk factor for gastric lymphoma is infection with H. pylori. In particular, a number of studies have reported a strong association between this bacterium and mucosa-associated lymphoid tissue (MALT) lymphoma, now termed extranodal marginal zone B-cell lymphoma (Parsonnet et al. 1994; Eck et al. 1997). In general, H. pylori is detected in nearly all patients with MALT lymphoma, and a large nested case–control study demonstrated an OR of greater than 6 (Parsonnet et al. 1994).

In addition to H. pylori, different types of gastric lymphoma have been associated with immunosuppression from medica-tions used in the post-transplant setting (Aull et al. 2003) as well as immunosuppression from the human immunodefi ciency virus (HIV) (Powitz et al. 1997; Srinivasan et al. 2004). Lastly, infection with EBV has been associated with gastric lymphoma (Thompson & Kurzrock 2004).

Gastric stromal tumorsGastric stromal tumors account for up to 3% of all gastric neo-plasias, but comprise approximately 60% of all gastrointestinal stromal tumors (GISTs) (Trent & Benjamin 2006). The peak incidence is between 50 and 70 years of age, and there may be a very slight male predominance (Miettinen et al. 2005; Nilsson et al. 2005; Trent & Benjamin 2006). While a substantial amount of research has focused on the pathogenesis of GISTs, and spe-cifi cally on the role of an activating mutation in the Kit tyrosine kinase receptor, little to no epidemiologic research has yet been done to identify specifi c population-based risk factors (Trent & Benjamin 2006).

Conclusions

This chapter has reviewed the epidemiology of gastroesophageal cancers, a diverse group of conditions with a correspondingly varied epidemiology and set of risk factors. While esophageal malignancies are less common, gastric adenocarcinoma in par-ticular exerts a large burden of disease worldwide. Additionally, the epidemiology of both types of tumors has changed substan-tially in recent decades. While the incidence of ACE has been rising quickly and the worldwide incidence of GAC continues a slow decline, the decline of GAC in the US has been particu-larly dramatic. Explanations for these changing epidemiologic patterns involve an interaction between environmental, host, and genetic factors that differ for each disease. In GAC and gastric lymphoma, infection with H. pylori is of particular importance, both for understanding pathogenesis and for pro-viding a target for treatment and prevention. For ACE, obesity, GERD, and BE play a major role, but do not account for all cases. And for most of the conditions discussed in this chapter, modifi able risk factors such as diet, nutrition, and tobacco use remain signifi cant. Ongoing research will likely clarify the role of genetics and heritability for all of these conditions, and help to further our knowledge of these processes.

Box 1.1 Level 1 evidence* for prevention of upper GI malignancies

Esophageal cancers

There is no level 1 evidence for prevention of either adenocarcinoma

of the esophagus or squamous cell carcinoma of the esophagus but

aspirin is being tested in a large RCT ASPECT.

Gastric cancers

There is no level 1 evidence for prevention of gastric adenocarcinoma.

*Level 1 evidence is defi ned as a signifi cant effect either in one or more

randomized controlled trials or in a meta-analysis of randomized controlled

trials without heterogeneity.


Referencesal-Akwaa AM, Siddiqui N, Al-Mofl eh IA. (2004) Primary gastric lym-

phoma. World J Gastroenterol 10: 5–11.

Al-Marhoon MS, Nunn S, Soames RW. (2004) The association between

cagA+ H. pylori infection and distal gastric cancer: a proposed model.

Dig Dis Sci 49: 1116–22.

Anderson LA, Murray LJ, Murphy SJ et al. (2003) Mortality in

Barrett’s oesophagus: results from a population based study. Gut 52:

1081–4.

Appelqvist P, Salmo M. (1980) Lye corrosion carcinoma of the esopha-

gus: a review of 63 cases. Cancer 45: 2655–8.

Aull MJ, Buell JF, Peddi VR et al. (2003) MALToma: a Helicobacter pylori-

associated malignancy in transplant patients: a report from the Israel

Penn International Transplant Tumor Registry with a review of pub-

lished literature. Transplantation 75: 225–8.

Avidan B, Sonnenberg A, Schnell TG, Chejfec G, Metz A, Sontag SJ.

(2002) Hiatal hernia size, Barrett’s length, and severity of acid refl ux

are all risk factors for esophageal adenocarcinoma. Am J Gastroenterol

97: 1930–6.

Barker DJ, Coggon D, Osmond C, Wickham C. (1990) Poor housing in

childhood and high rates of stomach cancer in England and Wales.

Br J Cancer 61: 575–8.

Barstad B, Sorensen TI, Tjonneland A et al. (2005) Intake of wine, beer

and spirits and risk of gastric cancer. Eur J Cancer Prev 14: 239–43.

Blair V, Martin I, Shaw D et al. (2006) Hereditary diffuse gastric cancer:

diagnosis and management. Clin Gastroenterol Hepatol 4: 262–75.

Blot WJ, Devesa SS, Kneller RW, Fraumeni JF Jr. (1991) Rising incidence

of adenocarcinoma of the esophagus and gastric cardia. JAMA 265:

1287–9.

Blot WJ, Li JY, Taylor PR et al. (1993) Nutrition intervention trials in

Linxian, China: supplementation with specifi c vitamin/mineral com-

binations, cancer incidence, and disease-specifi c mortality in the

general population. J Natl Cancer Inst 85: 1483–92.

Brenner H, Arndt V, Sturmer T, Stegmaier C, Ziegler H, Dhom G. (2000)

Individual and joint contribution of family history and Helicobacter

pylori infection to the risk of gastric carcinoma. Cancer 88: 274–9.

Brinton LA, Gridley G, Hrubec Z, Hoover R, Fraumeni JF Jr. (1989)

Cancer risk following pernicious anaemia. Br J Cancer 59: 810–3.

Brown A, Shaheen NJ. (2004) Screening for upper gastrointestinal tract

malignancies. Semin Oncol 31: 487–97.

Brown LM, Silverman DT, Pottern LM et al. (1994) Adenocarcinoma of

the esophagus and esophagogastric junction in white men in the

United States: alcohol, tobacco, and socioeconomic factors. Cancer

Causes Control 5: 333–40.

Brown LM, Hoover R, Gridley G et al. (1997) Drinking practices and risk

of squamous-cell esophageal cancer among Black and White men in

the United States. Cancer Causes Control 8: 605–9.

van der Burgh A, Dees J, Hop WC, Van Blankenstein M. (1996) Oesopha-

geal cancer is an uncommon cause of death in patients with Barrett’s

oesophagus. Gut 39: 5–8.

Buttar NS, Wang KK, Sebo TJ et al. (2001) Extent of high-grade dysplasia

in Barrett’s esophagus correlates with risk of adenocarcinoma. Gastro-

enterology 120: 1630–9.

Cameron AJ, Carpenter HA. (1997) Barrett’s esophagus, high-grade dys-

plasia, and early adenocarcinoma: a pathological study. Am J Gastro-

enterol 92: 586–91.

Chak A, Lee T, Kinnard MF et al. (2002) Familial aggregation of

Barrett’s oesophagus, oesophageal adenocarcinoma, and oesoph-

agogastric junctional adenocarcinoma in Caucasian adults. Gut 51:

323–8.

Chang F, Syrjanen S, Shen Q, Cintorino M, Santopietro R, Tosi P,

Syrjanen K. (2000) Human papillomavirus involvement in esophageal

carcinogenesis in the high-incidence area of China. A study of 700 cases

by screening and type-specifi c in situ hybridization. Scand J Gastroen-

terol 35: 123–30.

Chow WH, Blaser MJ, Blot WJ et al. (1998a) An inverse relation between

cagA+ strains of Helicobacter pylori infection and risk of esophageal

and gastric cardia adenocarcinoma. Cancer Res 58: 588–90.

Chow WH, Blot WJ, Vaughan TL et al. (1998b) Body mass index and risk

of adenocarcinomas of the esophagus and gastric cardia. J Natl Cancer

Inst 90: 150–5.

Coggon D, Barker DJ, Cole RB, Nelson M. (1989) Stomach cancer and

food storage. J Natl Cancer Inst 81: 1178–82.

Correa P. (2005) New strategies for the prevention of gastric cancer:

Helicobacter pylori and genetic susceptibility. J Surg Oncol 90: 134–8;

discussion 138.

Crew KD, Neugut AI. (2006) Epidemiology of gastric cancer. World J

Gastroenterol 12: 354–62.

D’Avanzo B, La Vecchia C, Franceschi S. (1994) Alcohol consumption

and the risk of gastric cancer. Nutr Cancer 22: 57–64.

Daly JM, Karnell LH, Menck HR. (1996) National Cancer Data Base

report on esophageal carcinoma. Cancer 78: 1820–8.

Danesh J. (1999) Helicobacter pylori infection and gastric cancer: system-

atic review of the epidemiological studies. Aliment Pharmacol Ther 13:

851–6.

Devesa SS, Blot WJ, Fraumeni JF Jr. (1998) Changing patterns in the

incidence of esophageal and gastric carcinoma in the United States.

Cancer 83: 2049–53.

Dooley CP, Cohen H, Fitzgibbons PL, Bauer M, Appleman MD, Perez-Perez

GI, Blaser MJ. (1989) Prevalence of Helicobacter pylori infection and his-

tologic gastritis in asymptomatic persons. N Engl J Med 321: 1562–6.

Eck M, Schmausser B, Haas R, Greiner A, Czub S, Muller-Hermelink HK.

(1997) MALT-type lymphoma of the stomach is associated with Heli-

cobacter pylori strains expressing the CagA protein. Gastroenterology

112: 1482–6.

Eckardt VF, Kanzler G, Bernhard G. (2001) Life expectancy and cancer

risk in patients with Barrett’s esophagus: a prospective controlled

investigation. Am J Med 111: 33–7.

El-Omar EM, Rabkin CS, Gammon MD et al. (2003) Increased risk of

noncardia gastric cancer associated with proinfl ammatory cytokine

gene polymorphisms. Gastroenterology 124: 1193–201.

El-Serag HB, Aguirre TV, Davis S, Kuebeler M, Bhattacharyya A,

Sampliner RE. (2004) Proton pump inhibitors are associated with

reduced incidence of dysplasia in Barrett’s esophagus. Am J Gastroen-

terol 99: 1877–83.

El-Serag HB, Kvapil P, Hacken-Bitar J, Kramer JR. (2005) Abdominal

obesity and the risk of Barrett’s esophagus. Am J Gastroenterol 100:

2151–6.

Eloubeidi MA, Mason AC, Desmond RA, El-Serag HB. (2003) Temporal

trends (1973–1997) in survival of patients with esophageal adenocar-

cinoma in the United States: a glimmer of hope? Am J Gastroenterol

98: 1627–33.

Engel LS, Chow WH, Vaughan TL et al. (2003) Population attributable

risks of esophageal and gastric cancers. J Natl Cancer Inst 95: 1404–13.

Farrow DC, Vaughan TL, Sweeney C et al. (2000) Gastroesophageal refl ux

disease, use of H2 receptor antagonists, and risk of esophageal and

gastric cancer. Cancer Causes Control 11: 231–8.


Fraser P, Chilvers C, Beral V, Hill MJ. (1980) Nitrate and human cancer:

a review of the evidence. Int J Epidemiol 9: 3–11.

Freedman J, Ye W, Naslund E, Lagergren J. (2001) Association between

cholecystectomy and adenocarcinoma of the esophagus. Gastroenterol-

ogy 121: 548–53.

Fuchs CS, Mayer RJ. (1995) Gastric carcinoma. N Engl J Med 333:

32–41.

Gammon MD, Schoenberg JB, Ahsan H et al. (1997) Tobacco, alcohol,

and socioeconomic status and adenocarcinomas of the esophagus and

gastric cardia. J Natl Cancer Inst 89: 1277–84.

Ghadirian P. (1987) Thermal irritation and esophageal cancer in north-

ern Iran. Cancer 60: 1909–14.

Gonzalez CA, Pera G, Agudo A et al. (2003) Smoking and the risk of

gastric cancer in the European Prospective Investigation Into Cancer

and Nutrition (EPIC). Int J Cancer 107: 629–34.

Gonzalez CA, Jakszyn P, Pera G et al. (2006) Meat intake and risk of

stomach and esophageal adenocarcinoma within the European Pro-

spective Investigation Into Cancer and Nutrition (EPIC). J Natl Cancer

Inst 98: 345–54.

Hameeteman W, Tytgat GN, Houthoff HJ, Van Den Tweel JG. (1989)

Barrett’s esophagus: development of dysplasia and adenocarcinoma.

Gastroenterology 96: 1249–56.

Hansson LE, Engstrand L, Nyren O et al. (1993) Helicobacter pylori infec-

tion: independent risk indicator of gastric adenocarcinoma. Gastroen-

terology 105: 1098–103.

Hansson LE, Nyren O, Hsing AW et al. (1996) The risk of stomach cancer

in patients with gastric or duodenal ulcer disease. N Engl J Med 335:

242–9.

Heitmiller RF, Redmond M, Hamilton SR. (1996) Barrett’s esophagus

with high-grade dysplasia. An indication for prophylactic esophagec-

tomy. Ann Surg 224: 66–71.

Henson DE, Dittus C, Younes M, Nguyen H, Albores-Saavedra J. (2004)

Differential trends in the intestinal and diffuse types of gastric carci-

noma in the United States, 1973–2000: increase

Documents

Gastrointestinal Oncology - download.e-bookshelf.de€¦ · Gastro-intestinal Oncology A Critical Multidisciplinary Team Approach EDITED BY Janusz Jankowski MD, PhD, FRCP, FACG Consultant