Gastrointestinal Oncology E-Book
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- Sprache: Englisch
GASTROINTESTINAL ONCOLOGY
Blends quality research findings with advanced educational techniques in a uniquely comprehensive approach
Written and edited by leading international experts in the field, Gastrointestinal Oncology: A Critical Multidisciplinary Team Approach is an indispensable reference for clinicians, medical practitioners, and trainees involved in the investigation, diagnosis, and treatment of esophageal, gastric, intestinal, colonic, hepatobiliary, pancreatic, and other gastrointestinal tumors. Drawing on the most current evidence-based knowledge, this comprehensive resource reflects the current care of GI cancer patients, enabling effective clinical decision making and patient management.
Setting the standard in clinical practice, Gastrointestinal Oncology remains the only truly multidisciplinary reference designed for the diverse team of clinicians responsible for different stages of cancer treatment. Specially structured clinical chapters, each representing a different role in the multidisciplinary team (MDT), allow clear presentation and quick reference of the contents. This is supported by a wealth of high-quality color photographs, line drawings, and diagrams.
Now in its second edition, this authoritative reference is fully updated to reflect groundbreaking research in multiple medical fields, including the explorative use of A.I. New sections on palliative care and nutrition are accompanied by new sub-sections on molecular characterization, new targeted small molecule, receptor options, and immunological therapies for each cancer. This edition places renewed emphasis on the most ubiquitous conditions, such as colon cancer, liver cancer, and gastro-esophageal cancer.
Covering the oncology of the entire gastrointestinal tract, Gastrointestinal Oncology: A Critical Multidisciplinary Team Approach is a must-have reference for the entire MDT, including gastroenterologists, hepatologists, GI surgeons, medical oncologists, radiation therapists, interventional radiologists, pathologists, nutritionists, palliative care and specialist nurses, as well as clinical scientists.
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Veröffentlichungsjahr: 2024
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Gastrointestinal Oncology
A Critical Multidisciplinary Team Approach
EDITED BY
Professor Janusz A. Z. Jankowski JP
MBChB (Glasgow) MSc (Oxford) MD (Dundee) PhD (London)PCME (Cambridge) PGCM (C Lancs.) PGCC (Warwick)AGAF (USA). FACG (USA) FRCP (Edinburgh & London) SFHEA (UK)
Clinical ProfessorUniversity College London, London, UK
Non-Executive DirectorTavistock and Portman NHS Foundation Trust, London
Consultant Physician and GastroenterologistNational Health Service, UK
Provost, Dubai Medical College, United Arab Emirates
&
Former Sir James Black Senior FellowUniversity of Oxford, Oxford, UK
SECOND EDITION
This edition first published 2024
© 2024 John Wiley & Sons Ltd
Edition History
Blackwell Publishing (1e, 2008)
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The right of Janusz A. Z. Jankowski to be identified as the author of the editorial material in this work has been asserted in accordance with law.
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The contents of this work are intended to further general scientific research, understanding, and discussion only and are not intended and should not be relied upon as recommending or promoting scientific method, diagnosis, or treatment by physicians for any particular patient. In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow 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. While the publisher and authors have used their best efforts in preparing this work, they make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of merchantability or fitness for a particular purpose. No warranty may be created or extended by sales representatives, written sales materials or promotional statements for this work. The fact that an organization, website, or product is referred to in this work as a citation and/or potential source of further information does not mean that the publisher and authors endorse the information or services the organization, website, or product may provide or recommendations it may make. This work is sold with the understanding that the publisher is not engaged in rendering professional services. The advice and strategies contained herein may not be suitable for your situation. You should consult with a specialist where appropriate. Further, readers should be aware that websites listed in this work may have changed or disappeared between when this work was written and when it is read. Neither the publisher nor authors shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages.
A catalogue record for this book is available from the Library of Congress
Hardback ISBN: 9781119756392; ePub ISBN: 9781119756415; ePDF ISBN: 9781119756408; oBook ISBN: 9781119756422
Cover images: CT imaging courtesy of Prof P. Milkiewicz, Dr K. Korzeniowski and Dr G. Rosiak; Dietary interventions courtesy of Helena Jankowska; Neuroendocrine histology courtesy of Atsuko Kasajima, Günter Klöppel, Stefano La Rosa
Cover design by Wiley
Set in 9.5/12 pts Minion Pro by Integra Software Services Pvt. Ltd, Pondicherry, India
Contents
Cover
Title Page
Copyright Page
List of Contributors
Preface
Foreword
Section I: Upper Gastrointestinal Cancer
1 Epidemiology, Microbiome, and Risk Factors Involved in Carcinogenesis of Esophagus, Gastric, and Intestine
2 Genomics, Molecular Pathology, and Pathology of Esophageal and Gastric Cancer
3 Screening, Surveillance, and Prevention of Esophageal and Gastric Cancers
4 Management of Esophageal Dysplasia and Esophageal Adenocarcinoma
5 Esophageal Squamous Cell Carcinoma
6 Management of Diffuse Gastric Cancer
7 Intestinal-type Gastric Cancer
8 Cancer of the Small Intestine
Section II: Colorectal and Anal Cancer
9 Epidemiology, Microbiome, and Risk Factors Involved in Carcinogenesis of Colorectal Cancer
10 Genomics, Histopathology, and Molecular Pathology of Sporadic and Hereditary Colorectal Cancer
11 Screening, Surveillance, and Prevention for Colorectal Cancer
12 Colorectal Cancer
13 Epidemiology, Pathology, Diagnosis, Prevention, and Management of Anal Cancer
Section III: Hepatobiliary and Pancreas Cancer
14 Epidemiology and Risk Factors of Hepatocellular Carcinoma
15 Pathology, Molecular Pathology, and Genomics of Hepatobiliary and Pancreatic Cancer
16 Screening, Surveillance, and Prevention of Hepatocellular Carcinoma
17 Pancreatic and Biliary Tract Cancers: Risk Factors and Etiology, Screening, Surveillance, and Biomarkers of Detection and Prognosis
18 The Multidisciplinary Management of Primary Hepatocellular Carcinoma
19 Management of Metastatic Liver Cancer
20 Management of Primary Pancreatic Cancer
21 Management of Intrahepatic and Extrahepatic Cholangiocarcinoma
22 Management of Cystic Neoplasms of the Pancreas
Section IV: Specialist Abdominal Cancer Management teams
23 Epidemiology, Pathology, Diagnosis, Prevention, and Management of GI Stromal Tumors and Other GI Sarcomas
24 Neuroendocrine Neoplasms of the Digestive System
25 Epidemiology, Pathology, Diagnosis, Prevention, and Management of Unknown Primary Cancer
26 Diagnosis and Management of Gastrointestinal Lymphomas
27 Palliative and Supportive Medicine in Gastrointestinal Oncology
28 Psychological Oncology and Wellbeing: Wellbeing(part 1) and narrative practices in child palliative care (part 2)
29 Nutrition for Cancer Prevention, Adjunctive Cancer Care, and Rehabilitation: Nutrition and Cancer
Cancer – The Road Less Traveled
Index
End User License Agreement
List of Tables
CHAPTER 02
Table 1 Hereditary cancer...
Table 2 Criteria for the...
Table 3 Selection of published...
CHAPTER 03
Table 1 Non-modifiable...
Table 2 Barrett’s...
CHAPTER 04
Table 1a Cancer staging...
Table 1b Clinical stage...
CHAPTER 05
Table 1 Cancer staging...
Table 2 Lymph node groups...
Table 3 Pathologic stage...
Table 4 Morbidity after...
Table 5 An overview of...
Table 6 An overview of...
Table 7 An overview of...
Table 8 Clinical trials...
CHAPTER 07
Table 1 TNM classification...
Table 2 Clinical, pathological...
CHAPTER 10
Table 1 Amsterdam and Bethesda...
Table 2 Histological features...
Table 3 WHO criteria for the...
Table 4 Summary of rare...
Table 5 Summary of BSG/ACPGBI...
Table 6 Most commonly used...
Table 7 Suggested markers...
CHAPTER 12
Table 1 TNM classification...
Table 2 Example of standardized...
Table 1 Commonly used chemotherapy...
CHAPTER 13
Table 1 UICC TNM (8th edition)...
Table 2 UICC pTNM (8th edition)...
Table 3 Randomized studies...
Table 4 Overall survival...
CHAPTER 16
Table 1 A summary of the...
Table 2 Summary of LI-RADS...
CHAPTER 17
Table 1 Summary of risk...
CHAPTER 18
Table 1 Causes of liver...
Table 2 Barcelona Clinic...
Table 3 Child-Pugh classification...
Table 4 European Cooperative...
Table 5 The emerging role...
Table 6 Landmark...
Table 7 Side effects of...
Table 8 Potential...
CHAPTER 19
Table 1 Natural history of...
Table 2 Results of hepatic...
Table 3 Advantages and...
Table 4 Sites of initial...
Table 5 Results of repeat...
Table 6 Molecular targeted...
Table 7 Drugs for hepatic...
Table 8 Rationale for...
CHAPTER 21
Table 1 TNM-staging/AJCC...
Table 2 Criteria...
Table 3 Selected...
Table 4 Selected...
Table 5 Table of...
Table 6 Radiotherapy...
Table 7 Eligibility...
Table 8 Meta-analyses...
Table 9 Biliary drainage...
CHAPTER 22
Table 1 Characteristic...
CHAPTER 23
Table 1 Risk assessment...
Table 2 Key principles...
CHAPTER 24
Table 1 WHO classification...
Table 2 Immunohistochemical...
Table 3 Classification and...
Table 4 Clinical features...
Table 5 Molecular genetics...
Table 6 Prognostic factors...
Table 7 TNM staging for...
Table 8 Useful immunohistochemical...
Table 9 Distribution of...
Table 10 Expression of...
Table 11 Somatostatin...
Table 12 The sensitivity...
Table 13 Recommended...
Table 14 Summarizing...
CHAPTER 25
Table 1 For cancer...
CHAPTER 26
Table 1 Lugano staging...
CHAPTER 27
Table 1 Medication...
Table 2 Starting doses...
Table 3 Opioid analgesic...
Table 4 Long-acting...
Table 5 Non-opioid...
Table 6 Commonly...
Table 7 Examples...
Table 8 Diagnostic...
Table 9 Characteristics...
Table 10 Pharmacotherapy...
Table 11 Communication...
CHAPTER 29
Table 1 The role of macronutrients...
List of Illustrations
CHAPTER 01
Figure 1 Pathways of esophageal cancer.
Figure 2 Pathways of gastric cancer.
Figure 3 Pathways of colorectal...
CHAPTER 02
Figure 1 Overview of the...
Figure 2 Subtype classification...
Figure 3 Subtype classification...
Figure 4 The genetic architecture...
Figure 5 Steps in the cascade...
Figure 6 Criteria for...
Figure 7 Esophageal m2...
Figure 8 Barrett’s...
Figure 9 (Adapted from...
Figure 10 (Adapted from...
Figure 11 (Adapted after...
Figure 12 H&E of lateral...
Figure 13 (Adapted after...
CHAPTER 03
Figure 1 Endoscopic view...
Figure 2 Using image-enhanced...
CHAPTER 04
Figure 1 Histological feature...
Figure 2 Duplicated muscularis...
Figure 3 Barrett mucosa...
Figure 4 Barrett mucosa...
Figure 5 Barrett...
Figure 6 Submucosal...
Figure 7 Barrett...
Figure 8 Genetic...
Figure 9 Band-ligation...
Figure 10 Endoscopic...
Figure 12 Chemotherapeutic...
Figure 11 Radiofrequency...
CHAPTER 05
Figure 1 Station...
Figure 2a High-grade...
Figure 2b Low-grade...
Figure 3a Well-differentiated...
Figure 3b Moderately...
Figure 3c Poorly differentiated...
Figure 4a Depressed fibrotic...
Figure 4b Cross section...
Figure 5a Residual ulcerative...
Figure 5b Cross section...
Figure 6 Survival...
Figure 7 Survival...
Figure 8 Postneoadjuvant...
Figure 9 Summary of...
CHAPTER 10
Figure 1 On edge view...
Figure 2 Schematic...
Figure 3 Proposed...
Figure 4 Top 20 cancer...
Figure 5 Example of a...
Figure 6 Case of inflammatory...
Figure 8 Tubulovillous...
Figure 9 Tubular adenoma...
Figure 7 Tubular adenoma...
Figure 10 (A) Microvesicular...
Figure 11 (A) Sessile serrated...
Figure 12 Substaging of T1...
Figure 13 Tumor budding, single...
Figure 14 Flowchart of...
CHAPTER 11
Figure 1 Adenoma detected...
CHAPTER 12
Figure 1 (A) Laterally...
Figure 2 Endoscopically...
Figure 1 Axial (A) and...
Figure 3 (A, C) Axial...
Figure 2 (A) Coronal...
Figure 4 Axial CT image...
Figure 5 Axial CT Colonoscopy...
Figure 6 (A) Endorectal...
Figure 7 Axial oblique...
Figure 8 Sagittal (A)...
Figure 9 Locally...
Figure 10 (A) Mesorectal...
Figure 11 EMVI. Sagittal...
Figure 12 Same patient...
Figure 13 Enlarging liver...
Figure 14 (A) Axial CT...
Figure 15 Metastatic lateral...
Figure 1 Colonic resections...
Figure 1 Loop ileostomy.
Figure 2 Stoma Retraction.
Figure 3 Parastomal Hernia.
Figure 4 Stoma Prolapse.
Figure 1 The parallel...
CHAPTER 13
Figure 1 Anal cancer risk...
Figure 3 Treatment algorithm...
Figure 2 Diagnostic algorithm...
Figure 4 Treatment algorithm...
CHAPTER 14
Figure 1 Regional variations...
Figure 2 Trends in hepatocellular...
Figure 3 Cirrhosis, Age,...
Figure 4 Annual incidence...
Figure 5 HCC Incidence...
Figure 6 Screening for...
Figure 7 The cumulative...
CHAPTER 15
Figure 1 Cholangiocarcinoma...
Figure 2 Adenocarcinoma...
Figure 3 Ductal adenocarcinoma...
Figure 4 Adenocarcinoma...
Figure 5 Adenosquamous...
CHAPTER 16
Figure 1 Diagram...
Figure 2 Image demonstrating...
Figure 3 Summary...
CHAPTER 17
Figure 1 Summary...
Figure 2 A summary...
Figure 3 Cholangiocarcinoma...
Figure 4 Evolving...
CHAPTER 18
Figure 1 Arterially...
Figure 2 Dilation of...
Figure 3 Arterially...
Figure 4 Assessment...
Figure 5 Downstaging...
Figure 6 Representative...
Figure 7 Barcelona Clinic...
Figure 8 Multiple areas...
Figure 9 Filling defect...
CHAPTER 19
Figure 2 Fong Clinical...
Figure 3 Kaplan-Meier...
Figure 4 Typical radiologic...
Figure 1 Unadjusted...
Figure 5 Axial, sagittal,...
Figure 6 Radiation beam...
CHAPTER 20
Figure 1 A new model...
Figure 2 Systemic therapy...
CHAPTER 21
Figure 1 Cartoon...
Figure 2 A likely...
Figure 3 EUS FNA...
Figure 4 Biliary...
Figure 5 Approach to...
Figure 6 Mayo Clinic...
Figure 7 Perihilar...
Figure 8 Intrahepatic...
Figure 9 Pie chart of...
Figure 10 Endobiliary RFA...
CHAPTER 22
Figure 1 Main duct IPMN...
Figure 2 A) Large IPMN...
Figure 3 Suggested...
CHAPTER 23
Figure 1 Frequency of...
Figure 2 Frequency and...
Figure 3 Treatment algorithm...
Figure 4 GIST metastases...
Figure 5 Treatment algorithm...
CHAPTER 24
Figure 1 Practical algorithm...
Figure 2 Different type...
Figure 3 Histological...
Figure 4 PanNET. A: Intraoperative...
Figure 5 Morphological...
Figure 6 Molecular genetics...
Figure 7 Immunohistochemical...
Figure 8 Intraoperative...
Figure 9 Ileal NET. A: Small...
Figure 10 Practical algorithm...
Figure 11 Liver metastasis...
Figure 12 Liver biopsy showing...
Figure 13 Liver biopsy showing...
Figure 14 Comparison between...
Figure 15 Better detection of...
Figure 16 Well-differentiated...
Figure 17 Poorly differentiated...
Figure 18 Schematic design...
Figure 19 Comparison of alpha...
Figure 20 Luthatera treatment...
Figure 21 A large hepatic...
Figure 22 Therapy response...
Figure 23 228Th decay chain...
Figure 24 A. A classic example...
CHAPTER 25
Figure 1 Investigation...
Figure 2 Immunohistochemistry...
Figure 3 CUP management...
CHAPTER 26
Figure 1 Gastric DLBCL. The...
Figure 2 Early stage...
Figure 3 Colon Burkitt...
Figure 4 Monomorphic...
Guide
Cover
Title Page
Copyright Page
Table of Contents
List of Contributors
Preface
Foreword
Begin Reading
Cancer – The Road Less Traveled
Index
End User License Agreement
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List of Contributors
Mostafa AbasseriDepartment of Gastroenterology and Hepatology St. George HospitalSydneyNew South WalesAustralia
School of MedicineUniversity of New South WalesSydneyAustralia
Aidalena AbidinCandiolo Cancer InstituteItaly
Pilar AcedoInstitute for Liver and Digestive HealthUniversity College LondonLondonUK
Raja A.R. AliGastroenterology UnitDepartment of MedicineFaculty of MedicineUniversiti Kebangsaan MalaysiaKuala LumpurMalaysia
School of Medical and Life SciencesSunway UniversitySelangorMalaysia
GUT Research GroupFaculty of MedicineUniversiti Kebangsaan MalaysiaKuala LumpurMalaysia
Martin AnlaufInstitute of Pathology and CytologySt. Vincenz Hospital LimburgLimburgGermany
Pietro AntoniniSection of PathologyDepartment of Diagnostics and Public HealthUniversity of VeronaVeronaItaly
Nadir ArberOncology UnitTel Aviv Medical CenterIsraelMiddle East
Maya BalakrishnanGastroenterology and Hepatology SectionDepartment of MedicineBaylor College of MedicineHoustonTexasUSA
Kirill BasiliyaConsultant GastroenterologistLeiden Medical CentreBelgium
Charlotte BensonInstitute for Cancer ResearchRoyal Marsden HospitalLondonUK
Lauren E. BerningerDivision of General Internal MedicineDepartment of MedicinePalliative Care ProgramJohns Hopkins Medical InstitutionsSidney Kimmel Comprehensive Cancer CenterBaltimoreMarylandUSA
Inga BoeckInstitute of Pathology and CytologySt. Vincenz Hospital LimburgLimburgGermany
Jessica A.L. BorbasiDepartment of Palliative MedicineNelune Comprehensive Cancer CentrePrince of Wales HospitalRandwickNew South WalesAustralia
David BowdenDepartment of RadiologyAddenbrooke’s HospitalCambridge University Hospitals NHSFoundation TrustCambridgeUK
Ilene S. BrownerPalliative Medicine ProgramJohns Hopkins Medical InstitutionsSidney Kimmel Comprehensive Cancer CenterBaltimoreMarylandUSA
Simon James Alexander BuczackiNuffield Department of Surgical ScienceUniversity of OxfordOxfordUK
Amitabh ChakDivision of Gastroenterology and HepatologyUniversity Hospitals Cleveland Medical CenterClevelandOhioUSA
Dedrick Kok Hong ChanDivision of Colorectal SurgeryUniversity Surgical ClusterNational University HospitalSingapore
Department of SurgeryYong Loo Lin School of MedicineNational University of SingaporeSingapore
Annie On On ChanDepartment of MedicineSchool of Clinical MedicineThe University of Hong KongQueen Mary HospitalHong KongChina
Hong Kong Sanatorium HospitalHong KongChina
Yin-Kai ChaoDepartment of Thoracic SurgeryChang Gung Memorial Hospital-LinkouChang Gung UniversityTaiwan
Mingyi ChenUT Southwestern Medical CenterDallasTexasUSA
Ka Shing CheungDepartment of MedicineSchool of Clinical MedicineThe University of Hong KongQueen Mary HospitalHong KongChina
Department of MedicineThe University of Hong Kong-Shenzhen HospitalShenzhenChina
Deborah Chia Hsin ChewGastroenterology UnitDepartment of MedicineFaculty of MedicineUniversiti Kebangsaan MalaysiaKuala LumpurMalaysia
Zhikai ChiUT Southwestern Medical CenterDallasTexasUSA
Francis ChuDepartment of Upper Gastrointestinal and Hepatobiliary SurgerySt. George HospitalSydneyAustralia
Wen-Yu ChuangDepartment of Anatomic PathologyChang Gung Memorial Hospital-LinkouChang Gung UniversityTaiwan
David ChurchCancer Research UK Advanced ClinicianScientist FellowHonorary Consultant Medical OncologistWellcome Centre for Human GeneticsUniversity of OxfordOxfordUK
D. Chamil CodipillyDivision of Gastroenterology and HepatologyMayo ClinicSW RochesterMNUSA
Natalie CollierDepartment of Radiation OncologyWollongong Hospital and University of New South WalesNew South WalesAustralia
Alicia-Marie ConwayThe Christie Hospital Foundation TrustManchesterUK
Gareth CorbettDepartment of GastroenterologyAddenbrooke’s HospitalCambridge University Hospitals NHSFoundation TrustCambridgeUK
Eithne CostelloInstitute of SystemsMolecular and Integrative BiologyUniversity of LiverpoolLiverpoolUK
Philip I. CraigDepartment of Gastroenterology and HepatologySt. George Hospital Sydney and University of New South Wales Medical SchoolNew South WalesAustralia
Brian CzitoDepartment of Radiation OncologyDuke University School of MedicineDurhamNorth CarolinaUSA
S. Lindsey DavisDepartment of Medical OncologyUniversity of Colorado School of MedicineAuroraColorado
Justin DaviesCambridge Colorectal UnitAddenbrooke’s HospitalCambridge University Hospitals NHSFoundation TrustCambridgeUK
Mihir DesaiDepartment of Interventional RadiologyPrince of Wales HospitalSydneyNew South WalesAustralia
Prince of Wales Clinical CampusSchool of Clinical MedicineUniversity of New South WalesNew South WalesAustralia
Levent DizdarDepartment of SurgeryHeinrich-Heine-University and University Hospital DuesseldorfDuesseldorfGermany
Yardenna DolevOncology UnitTel Aviv Medical CenterIsraelMiddle East
Michail DoukasDepartment of PathologyErasmus University Medical CenterRotterdamThe Netherlands
Clarisse DromainDepartment of RadiologyLausanne University Hospital (CHUV)Rue du Bugnon 461011 LausanneSwitzerland
Emad M. El-OmarUNSW Microbiome Research CentreSt. George and Sutherland Clinical CampusesSchool of Clinical MedicineFaculty of Medicine and HealthUniversity of New South WalesSydneyNew South WalesAustralia
Hashem B. El-SeragGastroenterology and Hepatology SectionDepartment of MedicineBaylor College of MedicineHoustonTexasUSA
Irene EspositoInstitute of PathologyHeinrich-Heine University and University Hospital and of DusseldorfGermany
Oliver M. FisherDepartment of SurgerySt. George Hospital Sydney and University of New South WalesNew South WalesAustralia
Yuman FongDepartment of SurgeryCity of Hope National Medical CenterDuarteCaliforniaUSA
Giuseppe K. FusaiInstitute for Liver and Digestive HealthUniversity College LondonLondonUK
Department of HPB SurgeryRoyal Free HospitalLondonUK
Robert C. GandyDepartment of General SurgeryPrince of Wales HospitalRandwickNew South WalesAustralia
School of Clinical MedicineFaculty of Medicine & HealthUNSW SydneyNew South WalesAustralia
Andres Garcia-SampedroInstitute for Liver and Digestive HealthUniversity College LondonLondonUK
Xing GaoDepartment of SurgeryErasmus MC Cancer InstituteRotterdamthe Netherlands
Department of Thoracic SurgeryChang Gung Memorial Hospital-LinkouChang Gung UniversityTaiwan
Elena GeunaCandiolo Cancer InstituteItaly
Ravit GevaOncology UnitTel Aviv Medical CenterIsraelMiddle East
Prithwish GhoshDivision of Gastroenterology and HepatologyMayo ClinicSW RochesterMNUSA
Frederik L. GieselDepartment of Nuclear MedicineHeinrich-Heine University and University Hospital of DüsseldorfDüsseldorfGermany
Brooke GlessingDivision of Gastroenterology and HepatologyUniversity Hospitals Cleveland Medical CenterClevelandOhioUSA
William GreenhalfInstitute of SystemsMolecular and Integrative BiologyUniversity of LiverpoolLiverpoolUK
David GoldsteinSchool of Clinical MedicineFaculty of Medicine & HealthUNSW SydneyNew South WalesAustralia
Department of Medical OncologyNelune Comprehensive Cancer CentrePrince of Wales HospitalRandwickNew South WalesAustralia
Lena HäberleInstitute of PathologyHeinrich-Heine University and University Hospital and of DusseldorfGermany
Koroush S. HaghighiDepartment of General SurgeryPrince of Wales HospitalRandwickNew South WalesAustralia
School of Clinical MedicineFaculty of Medicine & HealthUNSW SydneyNew South WalesAustralia
Mahnur HaiderDepartment of HepatologyCleveland ClinicClevelandOhioUSA
Umar HayatDivision of Gastroenterology and HepatologyUniversity Hospitals Cleveland Medical CenterClevelandOhioUSA
Felix HoDepartment of SurgeryUniversity of Colorado School of MedicineAuroraColorado
Nicholas HoltDepartment of Gastroenterology and HepatologySt. George Hospital SydneyNew South WalesAustralia
Phillip HopleyInstitute of SystemsMolecular and Integrative BiologyUniversity of LiverpoolLiverpoolUK
Shakira HoqueDepartment of Gastroenterology and HepatologySt. George HospitalSydneyNew South WalesAustralia
Ta-Chen HuangDepartment of OncologyNational Taiwan University HospitalTaipeiTaiwan
Faiz JabbarDepartment of ImmunologyOxford UniversityHospital NHS Foundation TrustOxfordUK
Helena JankowskaUCL Medical SchoolUniversity College LondonLondonUK
Izaak JankowskiFaculty of MedicineImperial College LondonSouth Kensington CampusLondonUK
Janusz A.Z. JankowskiComprehensive Clinical Trials UnitInstitute of Clinical Trials & MethodologyUniversity College LondonLondonUK
Provost’s OfficeDubai Medical CollegeUnited Arab Emirates
Henning JannDepartment of Hepatology and GastroenterologyCampus Virchow Klinikum (CVK) and Campus Charité Mitte (CCM)Charité Universitätsmedizin BerlinBerlinGermany
Sri JastiDepartment of Medical OncologySt. George HospitalSydneyAustralia
Moritz JesinghausInstitute of PathologyPhillips University Marburg and University Hospital MarburgMarburgGermany
Robin L. JonesInstitute for Cancer ResearchRoyal Marsden HospitalLondonUK
Pooja KarukondaDepartment of Radiation OncologyDuke University School of MedicineDurhamNorth CarolinaUSA
Atsuko KasajimaInstitute of PathologyTechnical University of MunichMunichGermany
Christy KimDepartment of Gastroenterology and HepatologySt. George HospitalSydneyNew South WalesAustralia
Günter KlöppelInstitute of PathologyTechnical University of MunichMunichGermany
Shahid KhanSt. Mary’s HospitalImperial College Healthcare NHS TrustLondonUK
Wolfram Trudo KnoefelDepartment of SurgeryHeinrich-Heine-University and University Hospital DuesseldorfDuesseldorfGermany
John KokkinosPancreatic Cancer Translational Research GroupSchool of Biomedical SciencesLowy Cancer Research CentreUNSW SydneyNew South WalesAustralia
Björn KonukiewitzDepartment of PathologyUniversity Hospital Schleswig-HolsteinCampus KielChristian-Albrechts-Universitätzu KielKielGermany
Magdalena KrakowskaDepartment of ChemotherapyMedical University of LodzCopernicus Memorial HospitalLodzPoland
Sjoerd LagardeDepartment of SurgeryErasmus MC Cancer InstituteRotterdamthe Netherlands
Ngee Soon LauDepartment of SurgeryRoyal Prince Alfred Hospital andUniversity of SydneyNew South WalesAustralia
Joanna LeeClinical Trials CentreUniversity of SydneySydneyAustralia
Shao-Hsuan LeeDepartment of Hematology-OncologyKaohsiung Chang Gung Memorial HospitalTaiwan
Yasmin LeshemOncology UnitTel Aviv Medical CenterIsraelMiddle East
Winston LiauwDepartment of Medical OncologySt. George HospitalSydneyAustralia
Jonathan LindquistDepartment of Interventional RadiologyUniversity of Colorado School of MedicineAuroraColorado
Lisa LiuDepartment of Interventional RadiologyUniversity of Colorado School of MedicineAuroraColorado
Suhrid LodhDepartment of Interventional RadiologyPrince of Wales HospitalSydneyAustralia
Claudio LuchiniDepartment of Diagnostics and Public HealthSection of PathologyUniversity of VeronaVeronaItaly
ARC-Net Research CenterUniversity of VeronaVeronaItaly
Betania Mahler-AraujoCambridge Colorectal UnitDepartment of PathologyAddenbrooke’s HospitalCambridge University Hospitals NHSFoundation TrustCambridgeUK
Ilaria MarinoniInstitute of Tissue Medicine and PathologyUniversity of BernBernSwitzerland
Katalin Mattes-GyörgyDepartment of Nuclear MedicineHeinrich-Heine University and University Hospital of DüsseldorfDüsseldorfGermany
Lauren J. McEneaneySt. Mary’s HospitalImperial College Healthcare NHS TrustLondonUK
Jeremy MeyerCambridge Colorectal UnitAddenbrooke’s HospitalCambridge University Hospitals NHSFoundation TrustCambridgeUK
Piotr MilkiewiczTranslational Medicine GroupPomeranian Medical UniversitySzczecinPolandLiver and Internal Medicine UnitMedical University of WarsawWarsawPoland
Claire MitchellThe Christie Hospital Foundation TrustManchesterUK
Paul MoayyediMcMaster UniversityCanada
Filippo MontemurroCandiolo Cancer InstituteItaly
Daniel A. MosesMedical Imaging DepartmentPrince of Wales HospitalRandwickNew South WalesAustralia
Graduate School of Biomedical EngineeringFaculty of EngineeringUNSW SydneyNew South WalesAustralia
Bianca MostertDepartment of Medical OncologyErasmus MC Cancer InstituteRotterdamthe Netherlands
Linda Moxley-HaegertDepartment of PsychologyShriners Hospitals for ChildrenMontrealQuebecCanada
Andrzej MrózDepartment of PathologyCenter of Postgraduate Medical EducationWarsawPoland
Department of PathologyMaria Sklodowska-Curie Memorial Cancer Hospital and InstituteWarsawPoland
Amrita Sen MukherjeeHonorary Clinical Research FellowImperial College LondonLondonUK
Visiting AcademicMedicine and Health SciencesRoyal College of SurgeonsIreland
Andrea NapolitanoInstitute for Cancer ResearchRoyal Marsden HospitalLondonUK
Yamini NatarajanGastroenterology and Hepatology SectionDepartment of MedicineBaylor College of MedicineHoustonTexasUSA
Khairul Najmi Muhammad NawawiGastroenterology UnitDepartment of MedicineFaculty of MedicineUniversiti Kebangsaan MalaysiaKuala LumpurMalaysia
GUT Research GroupFaculty of MedicineUniversiti Kebangsaan MalaysiaKuala LumpurMalaysia
Alexander NeyInstitute for Liver and Digestive HealthUniversity College LondonLondonUK
Emil NovruzovDepartment of Nuclear MedicineHeinrich-Heine University and University Hospital of DüsseldorfDüsseldorfGermany
Daniel C. Osei-BordomInstitute for Liver and Digestive HealthUniversity College LondonLondonUK
Lucy OldfieldInstitute of SystemsMolecular and Integrative BiologyUniversity of LiverpoolLiverpoolUK
Sean M. O’CathailSenior Research FellowSchool of Cancer SciencesUniversity of GlasgowGlasgowUK
Chandni PatelInstitute of SystemsMolecular and Integrative BiologyUniversity of LiverpoolLiverpoolUK
Antonio Pea,Department of SurgeryThe Pancreas InstituteUniversity of VeronaVeronaItaly
Aurel PerrenInstitute of Tissue Medicine and PathologyUniversity of BernBernSwitzerland
Stephen P. PereiraInstitute for Liver and Digestive HealthUniversity College LondonLondonUK
Omali PitiyarachchiPancreatic Cancer Translational Research GroupSchool of Biomedical SciencesLowy Cancer Research CentreUNSW SydneyNew South WalesAustralia
Phoebe A. PhillipsPancreatic Cancer Translational Research GroupSchool of Biomedical SciencesLowy Cancer Research CentreUNSW SydneyNew South WalesAustralia
Hans PrenenUniversity Hospital AntwerpBelgium
Carlo PulitanoDepartment of SurgeryRoyal Prince Alfred Hospital and University of SydneyNew South WalesAustralia
Alessandra PulvirentiDepartment of SurgeryThe Pancreas InstituteUniversity of VeronaVeronaItaly
Mohamed RabieCambridge Colorectal UnitCambridge University Hospital NHS Foundation TrustCambridgeUK
Praveen RamakrishnanUT Southwestern Medical CenterDallasTexasUSA
Syed RizviUT Southwestern Medical CenterDallasTexasUSA
Christoph RoderburgClinic for GastroenterologyHepatology and Infectious DiseasesUniversity Hospital DüsseldorfMedical Faculty of Heinrich Heine University DüsseldorfDüsseldorfGermany
Stefano La RosaUnit of PathologyDepartment of Medicine and SurgeryUniversity of Insubria and ASST Sette LaghiVareseItaly
Iannish SadienCambridge Colorectal UnitDepartment of PathologyAddenbrooke’s HospitalCambridge University Hospitals NHS Foundation TrustCambridgeUK
Anna Schneider-FuchsInstitut für PathologieFriedrich-Alexander-Universität Erlangen-NürnbergKlinikum BayreuthPreuschwitzer Str. 101BayreuthGermany
Matthias SchottDivision for Specific EndocrinologyHeinrich-Heine-University and University Hospital DuesseldorfDuesseldorfGermany
Johannes SchumacherInstitute of Human GeneticsPhilipps University of MarburgMarburgBaldingerstraßeGermany
Malin Katarina SchumacherDepartment of Radiation OncologyWollongong Hospital and University of New South WalesNew South WalesAustralia
Bence SiposENETS Center of ExcellenceDepartment of Medical Oncology and PneumologyUniversity Hospital TuebingenTuebingenGermany
Private Practice of Pathology and Molecular PathologyStuttgartGermany
Private Practice of Molecular PathologyBaden-WürttembergGermany
George SharbeenPancreatic Cancer Translational Research GroupSchool of Biomedical SciencesLowy Cancer Research CentreUNSW SydneyNew South WalesAustralia
Pram SirimanaDepartment of Upper Gastrointestinal and Hepatobiliary SurgeryRoyal North Shore HospitalSydneyNew South WalesAustralia
Katrin SjoquistDepartment of Medical OncologySt. George Hospital Sydney and Clinical Trials CentreUniversity of SydneyNew South WalesAustralia
Myles J. SmithInstitute for Cancer ResearchRoyal Marsden HospitalLondonUK
Thomas J. SmithPalliative Medicine ProgramJohns Hopkins Medical InstitutionsSidney Kimmel Comprehensive Cancer CenterBaltimoreMarylandUSA
Manon C.W. SpaanderDepartment of Gastroenterology and HepatologyErasmus University Medical CenterRotterdamthe Netherlands
Camille StewartDepartment of SurgeryUniversity of Colorado School of MedicineAuroraColorado
Rebecca StruttSchool of Clinical MedicineFaculty of Medicine & HealthUNSW SydneyNew South WalesAustralia
Department of Palliative MedicineNelune Comprehensive Cancer CentrePrince of Wales HospitalRandwickNew South WalesAustralia
Martyn StottInstitute of SystemsMolecular and Integrative BiologyUniversity of LiverpoolLiverpoolUK
Luis F. TapiasDivision of Thoracic SurgeryMayo ClinicSW RochesterMNUSA
Corey X. TapperDivision of General Internal MedicineDepartment of MedicinePalliative Care ProgramJohns Hopkins Medical InstitutionsSidney Kimmel Comprehensive Cancer CenterBaltimoreMarylandUSA
Stephen R. ThompsonSchool of Clinical MedicineFaculty of Medicine & HealthUNSW SydneyNew South WalesAustralia
Department of Radiation OncologyNelune Comprehensive Cancer CentrePrince of Wales HospitalRandwickNew South WalesAustralia
Chen-Kan TsengProton and Radiation Therapy CenterChang Gung Memorial Hospital-Linkou Medical CenterDepartment of Radiation OncologyChang Gung UniversityTaiwan
Yung-Kuan TsouDepartment of Gastroenterology and HepatologyChang Gung Memorial HospitalTaiwan
Silvia UccellaUnit of PathologyDepartment of Medicine and SurgeryUniversity of Insubria and ASST Sette LaghiVareseItaly
Department of Biomedical SciencesHumanitas University and Department of PathologyIRCCS Humanitas Research HospitalMilanItaly
Michael ViethInstitut für PathologieFriedrich-Alexander-Universität Erlangen-NürnbergKlinikum BayreuthPreuschwitzer Str. 101BayreuthGermany
Bavarian Cancer Research Center (BZKF)BayreuthGermany
Nicolas VillardDepartment of RadiologyLausanne University Hospital (CHUV)LausanneSwitzerland
Mathew VithayathilSt. Mary’s HospitalImperial College Healthcare NHS TrustLondonUK
James WheelerCambridge Colorectal UnitCambridge University Hospital NHS Foundation TrustCambridgeUK
Christopher WillettDepartment of Radiation OncologyDuke University School of MedicineDurhamNorth CarolinaUSA
Bas P.L. WijnhovenDepartment of SurgeryErasmus MC Cancer InstituteRotterdamthe Netherlands
Kenneth K. WangDivision of Gastroenterology and HepatologyMayo ClinicSW RochesterMNUSA
Benjamin Chun Yu WongDepartment of MedicineSchool of Clinical MedicineThe University of Hong KongQueen Mary HospitalHong KongChina
I-Chen WuDepartment of GastroenterologyDepartment of Internal MedicineKaohsiung Medical University HospitalTaiwan
Tsung-Teh WuDivision of Anatomical PathologyMayo ClinicSW RochesterMNUSA
Jing XuUT Southwestern Medical CenterDallasTexasUSA
Chi-Ju YehDepartment of Anatomic PathologyChang Gung Memorial Hospital-LinkouChang Gung UniversityTaiwan
Chi Ho Howard YimUNSW Microbiome Research CentreSt. George and Sutherland Clinical CampusesSchool of Clinical MedicineFaculty of Medicine and HealthUniversity of New South WalesSydneyNew South WalesAustralia
Amany ZekryDepartment of Gastroenterology and HepatologySt. George HospitalSydneyNew South WalesAustralia
Translational Medicine GroupPomeranian Medical UniversitySzczecinPoland
Charlène J. van der ZijdenDepartment of SurgeryErasmus MC Cancer InstituteRotterdamthe Netherlands
Preface
Why this book, and why now? This invited reference book is aimed at a wide spectrum of readers from patients and carers as well as practitioners, specialists and students.
This new volume is unique and aims to satisfy the immediate needs of each reader, while allowing scope and depth for further learning. The editing process for the contributions also works on the premise that information rapidly progresses, so having links to trusted web sources is key to maintain knowledge in an innovative way.
The first edition of this book was awarded many plaudits and reviews including; “written by the leading international experts in the field, it sets the standard in clinical practice” and “the authorship is a mark of quality, this book is a must read”. In the intervening 15 years so much has changed in cancer management and these advances have been reflected in this invited second edition. Specifically, new sections now include the following: the pathophysiology of cancer including sections on diet, probiotics, carcinogens, and genomics; improvements in cancer screening including non-invasive markers, endoscopic imaging as well as histopathological biomarkers; sequential use of advanced imaging modalities; surgical, radiotherapy, chemotherapy and advanced targeted/biological therapies; new psychological and palliative care interventions; new chapters such as sarcoma/stromal tumours, liver transplant, and unknown primary and GI lymphomas.
Each chapter has new boxes for ‘key take home messages’, ‘areas where research and the evidence base is weak’ and an extensive’ reading list of trusted websites for further information’.
In summary this book pushes the training envelope and aims to be both comprehensive in the detail as well as holistic in its management of the patient and their carers. Furthermore, the layout is designed to be easy for fast reference and access by phone or bedside devices for immediate impact at the consultation.
I want to thank all the contributors who have worked tirelessly during the Covid-19 pandemic. They still made time for delivery of uptodate superb contributions, which as so relevant to the post-pandemic world.
So, in ending, I hope you feel purchasing this book, is more of why not?
Prof. Janusz A. Z. JankowskiJP, MBChB, MSc, MD, PhD, PCME, PGCM, PGCC, AGAF,FACG, FRCP, SFHEAClinical Professor, University College LondonNon-Executive Director and Consultant,National Health Service, UKEditor in Chief, Gastrointestinal Oncology, WileyFormer Sir James Black Fellow and Professor,University of Oxford
Preface
“The paradigm of a journey from observation to hypothesis testing and then onward to fulfil Koch’s postulates.”
The discovery 40 years ago of the Helicobacter Pylori organism was a paradigm shift in many ways. Perhaps most importantly as it indicated that the host and the organism have a complex interaction which can lead to disease, not only chronic infection, autoimmunity, but also several forms of cancer. As an adjunctive benefit it showed that we should question any disease causation assumptions which are not evidence based, “Psychiological stress” as a common cause of peptic ulcer disease being the best example.
The journey was long in that it took time to assemble the epidemiological, bacteriological, clinical, oncological teams.
The result was, and still is, to provide the only cure for a condition in gastroenterology, peptic ulcer disease. The benefits also included alleviation of dyspepsia, cures of low-grade gastric MALTOMAs, and prevention of epithelial tumors of the gastric antrum.
This discovery has spawned new interest in fields of research outside the infection-inflammation-cancer sequence, including probiotics, antibiotic resistance, and modulation of host–bacterial interactions.
As I reflect on my career’s narrative above, I am therefore glad to see such a large array of multidisciplinary experts working together in this endeavor of Gastrointestinal Oncology: A Critical Multidisciplinary Team Approach.
Barry Marshall, December 2022
Nobel Laureate MedicineUniversity of Western Australia
Section I Upper Gastrointestinal Cancer
1 Epidemiology, Microbiome, and Risk Factors Involved in Carcinogenesis of Esophagus, Gastric, and Intestine
Deborah Chia Hsin Chew1, Chi Ho Howard Yim2, Raja A.R. Ali1,3,4 & Emad M.El-Omar2
1 Gastroenterology Unit, Department of Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia2 UNSW Microbiome Research Centre, St. George and Sutherland Clinical Campuses, School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, New South Wales, Australia3 School of Medical and Life Sciences, Sunway University, Selangor, Malaysia4 GUT Research Group, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
[Aspects of genomic risk factors are covered in Chapter 2].
[Aspects of relevant colorectal data are covered in Chapter 9].
Introduction
Cancers of the gastrointestinal tract (GIT) encompassing esophagus, stomach, and colorectum make up a significant proportion of cancers diagnosed worldwide and contribute to a considerable burden of disability-adjusted life years and years of life lost. (Kocarnik et al. 2022) The increase of GIT malignancies has been linearly associated with the human development index (HDI), likely due to the adoption of an affluent lifestyle with an increase in the consumption of processed meat, fast food, sedentary lifestyle, smoking, and increasing alcohol consumption. Obesity has become a worldwide pandemic and has been linked to the development of GIT cancers through multiple genetic and epigenetic microenvironment changes. Excess adipokines in obesity mediate a state of chronic inflammation resulting in the activation of multiple pathways that promote carcinogenesis. The understanding of the epidemiology and predisposing factors to GIT cancers is crucial in the development of early detection strategies. Screening efforts such as colonoscopy has reduced the burden of CRC worldwide. Similarly, screening of gastric cancers which has been adopted in Japan and Korea has reduced the numbers as well as improved the survival of gastric cancer.
In this chapter, we will discuss the epidemiology, global time trends, burden of disease, risk factors of esophageal, gastric and intestinal cancer, and strategies to reduce the incidence of these malignancies.
Esophageal Cancer
Epidemiology of Esophageal Cancer
Global Burden and Time Trends of Esophageal Cancer
Esophageal cancer (EC) is the seventh most common cancer globally (Huang et al. 2021) and the sixth leading cause of cancer mortality (Sung et al. 2021). The rates of EC worldwide have increased in the last two decades from 319,969 cases in 1990 to 319,969 cases in 2019 with a relative increase of 67.07% (Li et al. 2021). In 2020 there were 604,100 new cases of EC worldwide with a corresponding age-standardized incidence of 6.3 per 100,000 (Morgan et al. 2022b). The five-year survival of EC remains dismal at less than 20%, owing largely to its late stage of diagnosis (Then et al. 2020). Mortality from EC demonstrated a relative increase of 55.97% from 1990 till 2019 (Li et al. 2021) and resulted in 544,100 deaths in 2020 with a corresponding age-standardized mortality of 5.6 per 100,000 (Morgan et al. 2022b). The highest incidence of EC was observed in East Asia accounting for 59.2% of all EC cases out of which 53.7% occurred in China. EC mortality was observed to be highest in Eastern Asia, accounting for 58.7% of EC-related deaths.
Distribution of Esophageal Adenocarcinoma and Esophageal Squamous Carcinoma
Histologically, EC is divided into adenocarcinoma (EAC) and squamous cell carcinoma (ESCC). The subtype of esophageal cancers varies according to geographic region. ESCC accounts for more than 85% of esophageal cancer cases worldwide (Arnold et al. 2015). There has been a change in the geographic distribution of EC with a rise in EAC, but a reduction in ESCC was noted in Western countries. The incidence rate of ESCC was double in males at 7.8 per 100,000 compared to females at 3.2 per 100,000 (Morgan et al. 2022b). This subtype is commonly seen in regions with the highest EC rates, such as Eastern Asia, Southern and Eastern Africa where it constitutes 90% of the EC cases (Zheng et al. 2019). Meanwhile, in American and European countries EAC is predominantly seen (Ilson and van Hillegersberg 2018). The incidence of ESCC is declining, however the incidence of EAC has been increasing in the last decade (Li et al. 2021) primarily due to the increase in the rate of obesity. The commonest anatomical locations of EAC are gastroesophageal junction and cardia (Pohl et al. 2010). The geographic variation demonstrates the multi-hit theory that ethnicity, lifestyle, and genetic factors culminate in the development of EC.
Gender Distribution of Esophageal Cancer
There is a male predominance of EC with 70% of EC occurring in males (Sung et al. 2021). The age-standardized rate (ASR) for EC in males is 9.3 per 100,000 and 3.6 per 100,000 for females globally while the ASR mortality is 8.3 for males and 3.2 for females (Sung et al. 2021). Mortality rates were also observed to be two to three times higher in males, a finding that was most pronounced in Eastern Asia whereby rates of male mortality were eight times higher compared to females (Morgan et al. 2022b). Of note, the male-to-female ratio is highest at ages 50 to 54 and then declines thereafter (Mathieu et al. 2014) suggesting a correlation between androgens and EC and a protective effect of estrogen (Thrift 2021). Androgen receptor expression has been demonstrated in EAC tissue (Kim) (Sukocheva et al. 2015) as well as ESCC tissues (Sukocheva et al. 2015) and may be related to the propagation of its growth. A study by Petrick et al. found a high ratio of androgens to estrogen in patients with EAC. Patients with the highest quartile of androgen to estrogen had 2.4 times increased odds of EAC (Petrick et al. 2018).
Risk Factors for Esophageal Cancer
Barrett’s Esophagus and Obesity
The incidence of Barrett’s esophagus and obesity has been increasing worldwide which parallels the increase in EAC (Alexandre et al. 2014). Visceral obesity is a significant risk factor for gastroesophageal reflux disease (GERD), Barrett’s esophagus (BE) and esophageal adenocarcinoma. Obesity is a state of chronic low-grade inflammation termed meta-inflammation whereby there is an increase in acute phase reactants such as leptin and TNF-a which have mitogenic properties and propagate the progression of Barrett’s esophagus to EAC (Corley et al. 2007; Roberts et al. 2010). Adipose tissue had been shown to contain inflammatory cells which synthesize reactive oxygen species which have mitogenic properties (Kim et al. 2012). Leptin, an adipokine, also plays a crucial role in the pathogenesis of obesity induced carcinogenesis. Leptin enhanced cell mitosis and reduced cellular apoptosis via extracellular signal-regulated kinase, p38 mitogen-activated protein kinase, phosphatidylinositol 3′ kinase/Akt and Janus tyrosine kinase 2-dependent activation of cyclooxygenase-2 and prostaglandin E2 production in Barrett’s derived EAC lineage of cells (Ogunwobi et al. 2006). Chronic inflammation is associated with epithelial metaplasia and promotes carcinogenesis by creating a microenvironment favorable for tumor development as well as progression (Jankowski et al. 2000). Obesity also exerts mechanical consequences promoting GERD.
GERD has a prevalence of 50% in patients with morbid obesity (El‐Serag and Thrift 2021). GERD is the strongest risk factor for the development of Barrett’s esophagus. The frequency of GERD symptoms influenced the risk of development of EAC whereby weekly symptoms increased the risk by five-fold (OR 4.92, 95% CI 3.90–6.22) and daily symptoms increased the risk seven-fold (OR 7.40, 95% CI 4.94–11.1) (Rubenstein and Taylor 2010). Barrett’s esophagus is defined as the replacement of normal squamous epithelium in the lower esophagus by columnar epithelium with evidence of intestinal metaplasia, the hallmark of which is acid mucin-containing goblet cells. Molecularly, this cellular change heightens the risk of EAC through chronic inflammation. Non-dysplastic BE has the lowest risk of progression to EAC with a rate or progression of 0.3% per year (Hvid-Jensen et al. 2011). Once low-grade or high-grade dysplasia develop, the risk increases. Genomic profiling of BE tissue next to EAC revealed that BE cells have a mutational burden that is only marginally reduced than the median burden for EAC (Alexandrov et al. 2013). Telomere length is altered in chronic inflammation and in patients with BE a shorter telomere length was associated with a higher risk of progression to EAC (Vaughan and Fitzgerald 2015). Obesity and BE have synergistic factors on the development of EAC which explains the rise in the incidence of EAC in the recent years.
Smoking and Alcohol Consumption
Smoking also contributes to the risk of EAC with a robust dose-response association with the number of pack years of smoking (Singh et al. 2013). The risk factors for ESCC differ between Western and Asian population. Cigarette smoking and heavy alcohol consumption are risk factors for ESSC in the West (Pandeya et al. 2013). The OR of ESCC in those who smoked more than 30 pack years was 4.1 (95% CI, 2.7 – 6.2) with the rate being higher in men compared to women (5.5 vs 4.0) (Pandeya et al. 2013), whereas in South East Asia these risk factors were less common; instead, consumption of hot tea, opium, betel chewing, poor diet, low socioeconomic status, and inhalation of aromatic hydrocarbons, a by-product of indoor air pollution, are significant risk factors for the development of ESCC in this region (Sheikh et al. 2019). Heavy alcohol intake defined as more than 170 g per week markedly increased the risk of ESCC but not EAC with a similar dose-response relationship (Pandeya et al. 2009). Concomitant smoking further compounded this risk (Pandeya et al. 2009). Ethanol is the main component of alcohol and is broken down into acetaldehyde which has been classified as a human carcinogen by IAARC (Lachenmeier 2007) and is also a local irritant that promotes DNA methylation thereby promoting carcinogenesis.
Dietary Factors
Dietary risk factors associated with ESCC are increased consumption of N-nitroso compounds in men but not in women (Keszei et al. 2013). The N-nitroso compounds are carcinogenic and produce alkyl adducts in the DNA thus promoting mutagenesis (Guttenplan 1990). The risk of ESCC increases in micronutrient deficiencies such as vitamin C, E, folate, (Uhlenhopp et al. 2020) selenium (Steevens et al. 2010), and zinc. Zinc deficiency potentiates the carcinogenic effect of nitrosamines thereby promoting ESCC (Abnet et al. 2005). Other environmental factors that contribute to the development of ESCC are opium smoking, exposure to air pollutants, as well as the frequent consumption of hot beverages and a low intake of fruits and vegetables (Morgan et al. 2022b), and a high intake of red and processed meat (Nucci et al. 2021). These risk factors, were commonly observed in areas of high incidence of EC with the intake of hot beverages compounding the effects of smoking and alcohol intake (He et al. 2010).
Genetic Risks
Genomic-profiling of EAC has shown that this malignancy has an elevated mutational burden with one of the most mutated malignancy types (Alexandrov et al. 2013). Somatic mutation in TP53 was found in more than 83% of ESCC specimens (Song et al. 2014). Genetic mutations that regulate the cell cycle (CDKN2A, RB1, NFE2L2, CHEK1, and CHEK 2) and NOTCH 1 and NOTCH 3 mutations have been detected in 1–10% of ESCCs (D.-C. Lin et al. 2014a). Epidermal growth factor receptor (EGFR) was also found to be overexpressed in 59.76% of patients with ESCC and denotes a poor prognosis (Zhang et al. 2014). Single-nucleotide polymorphism DNA microarray has shown that 19% of patients with EAC demonstrate CCNE1 gene amplification. Raised levels of cyclin E were found in BE (5.8%), low-grade dysplasia (19.0%), high-grade dysplasia (35.7%), and EC (16.7%) (Zhou et al. 2014). The pathophysiology of esophageal cancer is depicted in Figure 1.
Figure 1 Pathways of esophageal cancer.
Esophageal Microbiome and Carcinogenesis
Dysbiosis in the Esophageal Adenocarcinoma cascade
The normal distal esophagus harbors a distinct microbiota that includes six major phyla: Firmicutes, Bacteroides, Actinobacteria, Proteobacteria, Fusobacteria, and TM7 (Pei et al. 2004). It also includes five major genera: Streptococcus, Prevotella, Veillonella, Haemophilus, Neisseria (Sharma et al. 2022). However, patients with gastroesophageal reflux disease (GERD) and Barret’s esophagus (BE) have increased abundances of gram-negative bacteria such as Prevotella, Neisseria, Campylobacter, Leptotrichia, and Fusobacterium and decreased abundance of gram-positive bacteria as compared to the normal esophagus (Blackett et al. 2013; Deshpande et al. 2018; Zhou et al. 2020).
The enrichment of gram-negative bacteria including Campylobacter, Leptotrichia, Fusobacterium, Rothia, and Capnocytophaga are comparable in the esophageal microbiome of GERD and BE patients. When comparing to the microbiome at the normal mucosa adjacent to the metaplastic tissue of BE, there is decreased abundance of Prevotella, Selenomonas, Campylobacter, and Fusobacterium decreased in the latter (Lopetuso et al. 2020). An increasing density of microbial networks were found along the progression of normal esophagus to GERD and BE (Deshpande et al. 2018). This suggests that bacteria become more dependent on each other to sustain their growth along the progression of the disease stages from GERD to BE.
Decreased microbial diversity was found in patients with esophageal adenocarcinoma (EAC) as compared to healthy individuals (Elliott et al. 2017; Snider et al. 2019). While Elliott et al. found that Lactobacillus fermentum and lactic acid bacteria were enriched in EAC, Snider et al. found that high grade dysplasia and EAC had increased abundance of Enterobacteriaceae and Akkermansia muciniphila and decreased abundance of Veillonella (Elliott et al. 2017; Snider et al. 2019). In contrast, a recent study showed that Veillonella and other bacterial genera including Atopobium, Actinomyces, Ralstonia, Burkholderia, and Lautropia progressively enriched along the GERD, BE and EAC sequence. These discrepancies of microbial composition in EAC may be caused by the low resolution of 16S rRNA sequencing which is only able to identify bacteria at genus level. It is possible that the species within the same genus may positively or negatively associate with EAC, thus resulting in apparent differences at the higher genus levels.
Apart from bacteria, presence of human papillomavirus (HPV) was more prevalent in dysplasia and EAC but not in BE as compared to healthy controls (Rajendra et al. 2013). The virus was mostly detected at the transformation zone (Rajendra et al. 2013). Moreover, the viral oncogene was highly associated with disease severity in dysplasia and EAC patients with viral positivity than those with viral negativity (Rajendra et al. 2013). This suggests that HPV may contribute to esophageal carcinogenesis.
Dysbiosis and EAC Carcinogenesis
Toll-like receptors (TLR), that recognize pathogen associated molecular patterns, have been suggested to interact with the esophageal microbiota. For example, TLR2 is expressed in the basal keratinocytes in normal squamous esophagus (Verbeek et al. 2016). However, its expression is around the papillae high up in the epithelium in reflux esophagitis (Verbeek et al. 2016). In BE, TLR2 is expressed mostly in superficial epithelial cells and deeper crypts, and in lamina propria as well (Verbeek et al. 2016). In EAC, TLR2 is highly expressed as compared to normal esophagus, reflux esophagitis and BE and its expression is diffuse throughout the biopsy (Verbeek et al. 2016). Interestingly, long term activation of TLR2 together with bile salts in BE epithelial cells (BAR-T) results in higher expression of mitochondrial and lysosomal enzymes and other factors regulating the endocytosis as compared to the cells exposed to bile salt only. Furthermore, TLR2 also heterodimerizes with TLR1 or TLR6 to recognize a wider range of microbial components. Consistent with this, the expression of TLR1 and TLR6 is also increased in BE and EAC (Huhta et al. 2016). This suggests that a wide range of bacteria from the dysbiotic esophageal microbiota may activate the TLR2 signaling pathway under stress conditions, leading to inflammation. This is supported by a recent study that TLR2 stimulation results in induction of proinflammatory cytokines, chemokines, and factors that activate the inflammasome in macrophages in BE organoid and early-stage EAC cell models (Flis et al. 2021). Whether this TLR2-mediated inflammation contributes to the EAC progression requires further investigation in in vivo models.
Apart from TLR2, TLR4 has been implicated in EAC carcinogenesis. The expression of TLR4 is increased in reflux esophagitis, BE and EAC as compared to the normal squamous esophagus (Verbeek et al. 2014). Inhibition of TLR4 activation by an inhibitory peptide or by TLR4 gene mutation reduces the expression of inflammatory markers including intercellular adhesion molecule-1 and IL-8, and the development of hyperplastic and proliferative response of the esophageal mucosa in the surgical reflux mouse model (Gergen et al. 2021). This suggests that TLR4 activation promotes inflammation in reflux esophagitis, and BE, leading to the progression of EAC. This TLR4 activation could have resulted from LPS, a bacterial cell wall component, present in the dysbiotic esophageal microbiota. LPS has been shown to induce NFkB activation and IL-8 secretion in the BE cell line (BAR-T) via TLR4 (Verbeek et al. 2014). It also induces IL-8 secretion and cyclooxygenase-2 (COX2) expression in ex vivo BE cultures (Verbeek et al. 2014). Consistent with this, increased COX2 expression is found in BE mucosa (Buttar et al. 2002) and COX2 inhibitor decreases esophageal inflammation and the risk of EAC development in a BE rat models (Buttar et al. 2002). Taken together, these studies suggest that LPS from the dysbiotic esophageal microbiota activates TLR4 signaling pathway and COX2 expression in the esophageal epithelium. This leads to chronic inflammation and the progression of EAC.
