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Oncology: A Critical Multidisciplinary Team Approach
Janusz A. Z. Jankowski
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Textbook of Gastrointestinal Oncology Suayib Yalcin
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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
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List of Contributors , vii Preface , xvii Foreword , xviii
Section I: Upper Gastrointestinal Cancer, 1
1 Epidemiology, Microbiome, and Risk Factors Involved in Carcinogenesis of Esophagus, Gastric, and Intestine, 3
2 Genomics, Molecular Pathology, and Pathology of Esophageal and Gastric Cancer, 23
3 Screening, Surveillance, and Prevention of Esophageal and Gastric Cancers, 42
4 Management of Esophageal Dysplasia and Esophageal Adenocarcinoma, 63
5 Esophageal Squamous Cell Carcinoma, 82
6 Management of Diffuse Gastric Cancer, 116
7 Intestinal-type Gastric Cancer, 120
8 Cancer of the Small Intestine, 139
Section II: Colorectal and Anal Cancer, 145
9 Epidemiology, Microbiome, and Risk Factors Involved in Carcinogenesis of Colorectal Cancer, 147
10 Genomics, Histopathology, and Molecular Pathology of Sporadic and Hereditary Colorectal Cancer, 149
11 Screening, Surveillance, and Prevention for Colorectal Cancer, 170
12 Colorectal Cancer, 181
13 Epidemiology, Pathology, Diagnosis, Prevention, and Management of Anal Cancer, 235
Section III: Hepatobiliary and Pancreas Cancer, 249
14 Epidemiology and Risk Factors of Hepatocellular Carcinoma, 251
15 Pathology, Molecular Pathology, and Genomics of Hepatobiliary and Pancreatic Cancer, 264
16 Screening, Surveillance, and Prevention of Hepatocellular Carcinoma, 271
17 Pancreatic and Biliary Tract Cancers: Risk Factors and Etiology, Screening, Surveillance, and Biomarkers of Detection and Prognosis, 291
18 The Multidisciplinary Management of Primary Hepatocellular Carcinoma, 321
19 Management of Metastatic Liver Cancer, 347
20 Management of Primary Pancreatic Cancer, 386
21 Management of Intrahepatic and Extrahepatic Cholangiocarcinoma, 407
22 Management of Cystic Neoplasms of the Pancreas, 438
Section IV: Specialist Abdominal Cancer Management teams, 455
23 Epidemiology, Pathology, Diagnosis, Prevention, and Management of GI Stromal Tumors and Other GI Sarcomas, 457
24 Neuroendocrine Neoplasms of the Digestive System, 470
25 Epidemiology, Pathology, Diagnosis, Prevention, and Management of Unknown Primary Cancer, 538
26 Diagnosis and Management of Gastrointestinal Lymphomas, 546
27 Palliative and Supportive Medicine in Gastrointestinal Oncology, 561
28 Psychological Oncology and Wellbeing: Wellbeing (part 1) and narrative practices in child palliative care (part 2), 576
29 Nutrition for Cancer Prevention, Adjunctive Cancer Care, and Rehabilitation: Nutrition and Cancer, 587 Cancer – The Road Less Traveled, 591 Index, 593
List of Contributors
Mostafa Abasseri
Department of Gastroenterology and Hepatology St. George Hospital
Sydney
New South Wales
Australia
School of Medicine
University of New South Wales
Sydney Australia
Aidalena Abidin
Candiolo Cancer Institute
Italy
Pilar Acedo
Institute for Liver and Digestive Health
University College London
London
UK
Raja A.R. Ali
Gastroenterology Unit
Department of Medicine
Faculty of Medicine
Universiti Kebangsaan Malaysia
Kuala Lumpur
Malaysia
School of Medical and Life Sciences
Sunway University
Selangor
Malaysia
GUT Research Group
Faculty of Medicine
Universiti Kebangsaan Malaysia
Kuala Lumpur
Malaysia
Martin Anlauf
Institute of Pathology and Cytology
St. Vincenz Hospital Limburg
Limburg
Germany
Pietro Antonini
Section of Pathology
Department of Diagnostics and Public Health
University of Verona
Verona
Italy
Nadir Arber
Oncology Unit
Tel Aviv Medical Center
Israel
Middle East
Maya Balakrishnan
Gastroenterology and Hepatology Section
Department of Medicine
Baylor College of Medicine
Houston
Texas
USA
Kirill Basiliya
Consultant Gastroenterologist
Leiden Medical Centre
Belgium
Charlotte Benson Institute for Cancer Research
Royal Marsden Hospital
London
UK
Lauren E. Berninger
Division of General Internal Medicine
Department of Medicine
Palliative Care Program
Johns Hopkins Medical Institutions
Sidney Kimmel Comprehensive Cancer Center
Baltimore
Maryland
USA
Inga Boeck
Institute of Pathology and Cytology
St. Vincenz Hospital Limburg
Limburg
Germany
Jessica A.L. Borbasi
Department of Palliative Medicine
Nelune Comprehensive Cancer Centre
Prince of Wales Hospital
Randwick
New South Wales Australia
David Bowden
Department of Radiology
Addenbrooke’s Hospital
Cambridge University Hospitals NHS Foundation Trust
Cambridge UK
Ilene S. Browner
Palliative Medicine Program
Johns Hopkins Medical Institutions
Sidney Kimmel Comprehensive Cancer Center
Baltimore Maryland USA
Simon James Alexander Buczacki
Nuffield Department of Surgical Science University of Oxford Oxford UK
Amitabh Chak
Division of Gastroenterology and Hepatology
University Hospitals Cleveland Medical Center Cleveland Ohio
USA
Dedrick Kok Hong Chan
Division of Colorectal Surgery
University Surgical Cluster
National University Hospital
Singapore
Department of Surgery
Yong Loo Lin School of Medicine
National University of Singapore Singapore
Annie On On Chan
Department of Medicine
School of Clinical Medicine
The University of Hong Kong
Queen Mary Hospital
Hong Kong
China
Hong Kong Sanatorium Hospital
Hong Kong China
Yin-Kai Chao
Department of Thoracic Surgery
Chang Gung Memorial Hospital-Linkou
Chang Gung University
Taiwan
Mingyi Chen
UT Southwestern Medical Center
Dallas
Texas
USA
Ka Shing Cheung
Department of Medicine
School of Clinical Medicine
The University of Hong Kong
Queen Mary Hospital
Hong Kong
China
Department of Medicine
The University of Hong Kong-Shenzhen Hospital
Shenzhen China
Deborah Chia Hsin Chew
Gastroenterology Unit
Department of Medicine
Faculty of Medicine
Universiti Kebangsaan Malaysia
Kuala Lumpur Malaysia
Zhikai Chi
UT Southwestern Medical Center
Dallas Texas USA
Francis Chu
Department of Upper Gastrointestinal and Hepatobiliary Surgery
St. George Hospital
Sydney Australia
Wen-Yu Chuang
Department of Anatomic Pathology
Chang Gung Memorial Hospital-Linkou
Chang Gung University
Taiwan
David Church
Cancer Research UK Advanced Clinician
Scientist Fellow
Honorary Consultant Medical Oncologist
Wellcome Centre for Human Genetics
University of Oxford
Oxford
UK
D. Chamil Codipilly
Division of Gastroenterology and Hepatology
Mayo Clinic
SW Rochester MN
USA
Natalie Collier
Department of Radiation Oncology
Wollongong Hospital and University of New South Wales
New South Wales
Australia
Alicia-Marie Conway
The Christie Hospital Foundation Trust
Manchester UK
Gareth Corbett
Department of Gastroenterology
Addenbrooke’s Hospital
Cambridge University Hospitals NHS
Foundation Trust
Cambridge UK
Eithne Costello
Institute of Systems
Molecular and Integrative Biology
University of Liverpool Liverpool
UK
Philip I. Craig
Department of Gastroenterology and Hepatology
St. George Hospital Sydney and University of New South Wales Medical School
New South Wales
Australia
Brian Czito
Department of Radiation Oncology
Duke University School of Medicine
Durham
North Carolina
USA
S. Lindsey Davis
Department of Medical Oncology
University of Colorado School of Medicine
Aurora
Colorado
Justin Davies
Cambridge Colorectal Unit
Addenbrooke’s Hospital
Cambridge University Hospitals NHS
Foundation Trust
Cambridge UK
Mihir Desai
Department of Interventional Radiology
Prince of Wales Hospital
Sydney
New South Wales
Australia
Prince of Wales Clinical Campus
School of Clinical Medicine
University of New South Wales
New South Wales
Australia
Levent Dizdar
Department of Surgery
Heinrich-Heine-University and University Hospital Duesseldorf
Duesseldorf
Germany
Yardenna Dolev
Oncology Unit
Tel Aviv Medical Center
Israel
Middle East
Michail Doukas
Department of Pathology
Erasmus University Medical Center
Rotterdam
The Netherlands
Clarisse Dromain
Department of Radiology
Lausanne University Hospital (CHUV)
Rue du Bugnon 46 1011 Lausanne
Switzerland
Emad M. El-Omar
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
Australia
Hashem B. El-Serag
Gastroenterology and Hepatology Section
Department of Medicine
Baylor College of Medicine
Houston
Texas
USA
Irene Esposito
Institute of Pathology
Heinrich-Heine University and University Hospital and of Dusseldorf
Germany
Oliver M. Fisher
Department of Surgery
St. George Hospital Sydney and University of New South Wales
New South Wales
Australia
Yuman Fong
Department of Surgery
City of Hope National Medical Center
Duarte
California
USA
Giuseppe K. Fusai
Institute for Liver and Digestive Health
University College London
London
UK
Department of HPB Surgery
Royal Free Hospital
London
UK
Robert C. Gandy
Department of General Surgery
Prince of Wales Hospital
Randwick
New South Wales
Australia
School of Clinical Medicine
Faculty of Medicine & Health
UNSW Sydney
New South Wales
Australia
Andres Garcia-Sampedro
Institute for Liver and Digestive Health
University College London London
UK
Xing Gao
Department of Surgery
Erasmus MC Cancer Institute
Rotterdam the Netherlands
Department of Thoracic Surgery
Chang Gung Memorial Hospital-Linkou
Chang Gung University
Taiwan
Elena Geuna
Candiolo Cancer Institute
Italy
Ravit Geva
Oncology Unit
Tel Aviv Medical Center
Israel
Middle East
Prithwish Ghosh
Division of Gastroenterology and Hepatology
Mayo Clinic
SW Rochester MN
USA
Frederik L. Giesel
Department of Nuclear Medicine
Heinrich-Heine University and University Hospital of Düsseldorf Düsseldorf
Germany
Brooke Glessing
Division of Gastroenterology and Hepatology
University Hospitals Cleveland Medical Center
Cleveland Ohio
USA
William Greenhalf
Institute of Systems
Molecular and Integrative Biology
University of Liverpool Liverpool
UK
David Goldstein
School of Clinical Medicine
Faculty of Medicine & Health
UNSW Sydney
New South Wales
Australia
Department of Medical Oncology
Nelune Comprehensive Cancer Centre
Prince of Wales Hospital
Randwick
New South Wales
Australia
Lena Häberle
Institute of Pathology
Heinrich-Heine University and University Hospital and of Dusseldorf
Germany
Koroush S. Haghighi
Department of General Surgery
Prince of Wales Hospital Randwick
New South Wales Australia
School of Clinical Medicine
Faculty of Medicine & Health
UNSW Sydney
New South Wales
Australia
Mahnur Haider
Department of Hepatology
Cleveland Clinic
Cleveland Ohio
USA
Umar Hayat
Division of Gastroenterology and Hepatology
University Hospitals Cleveland Medical Center Cleveland Ohio
USA
Felix Ho
Department of Surgery
University of Colorado School of Medicine
Aurora Colorado
Nicholas Holt
Department of Gastroenterology and Hepatology
St. George Hospital Sydney
New South Wales
Australia
Phillip Hopley
Institute of Systems
Molecular and Integrative Biology
University of Liverpool Liverpool UK
Shakira Hoque
Department of Gastroenterology and Hepatology
St. George Hospital
Sydney New South Wales
Australia
Ta-Chen Huang
Department of Oncology
National Taiwan University Hospital
Taipei
Taiwan
Faiz Jabbar
Department of Immunology
Oxford University
Hospital NHS Foundation Trust
Oxford UK
Helena Jankowska
UCL Medical School
University College London London
UK
Izaak Jankowski
Faculty of Medicine
Imperial College London
South Kensington Campus
London UK
Janusz A.Z. Jankowski
Comprehensive Clinical Trials Unit
Institute of Clinical Trials & Methodology
University College London London
UK
Provost’s Office
Dubai Medical College
United Arab Emirates
Henning Jann
Department of Hepatology and Gastroenterology
Campus Virchow Klinikum (CVK) and Campus Charité Mitte (CCM)
Charité Universitätsmedizin Berlin
Berlin
Germany
Sri Jasti
Department of Medical Oncology
St. George Hospital
Sydney
Australia
Moritz Jesinghaus
Institute of Pathology
Phillips University Marburg and University Hospital Marburg
Marburg
Germany
Robin L. Jones
Institute for Cancer Research
Royal Marsden Hospital
London
UK
Pooja Karukonda
Department of Radiation Oncology
Duke University School of Medicine
Durham
North Carolina
USA
Atsuko Kasajima
Institute of Pathology
Technical University of Munich
Munich
Germany
Christy Kim
Department of Gastroenterology and Hepatology
St. George Hospital
Sydney
New South Wales
Australia
Günter Klöppel
Institute of Pathology
Technical University of Munich
Munich
Germany
Shahid Khan
St. Mary’s Hospital
Imperial College Healthcare NHS Trust
London
UK
Wolfram Trudo Knoefel
Department of Surgery
Heinrich-Heine-University and University Hospital Duesseldorf
Duesseldorf
Germany
John Kokkinos
Pancreatic Cancer Translational Research Group
School of Biomedical Sciences
Lowy Cancer Research Centre
UNSW Sydney
New South Wales
Australia
Björn Konukiewitz
Department of Pathology
University Hospital Schleswig-Holstein
Campus Kiel
Christian-Albrechts-Universität zu Kiel
Kiel
Germany
Magdalena Krakowska
Department of Chemotherapy
Medical University of Lodz
Copernicus Memorial Hospital
Lodz
Poland
Sjoerd Lagarde
Department of Surgery
Erasmus MC Cancer Institute
Rotterdam the Netherlands
Ngee Soon Lau
Department of Surgery
Royal Prince Alfred Hospital and University of Sydney
New South Wales Australia
Joanna Lee
Clinical Trials Centre
University of Sydney
Sydney Australia
Shao-Hsuan Lee
Department of Hematology-Oncology
Kaohsiung Chang Gung Memorial Hospital
Taiwan
Yasmin Leshem
Oncology Unit
Tel Aviv Medical Center
Israel Middle East
Winston Liauw
Department of Medical Oncology
St. George Hospital
Sydney Australia
Translational Medicine Group
Pomeranian Medical University
Szczecin
Poland
Jonathan Lindquist
Department of Interventional Radiology
University of Colorado School of Medicine
Aurora Colorado
Lisa Liu
Department of Interventional Radiology
University of Colorado School of Medicine
Aurora
Colorado
Suhrid Lodh
Department of Interventional Radiology
Prince of Wales Hospital
Sydney Australia
Claudio Luchini
Department of Diagnostics and Public Health
Section of Pathology
University of Verona Verona Italy
ARC-Net Research Center
University of Verona Verona Italy
Betania Mahler-Araujo
Cambridge Colorectal Unit
Department of Pathology
Addenbrooke’s Hospital
Cambridge University Hospitals NHS Foundation Trust
Cambridge UK
Ilaria Marinoni
Institute of Tissue Medicine and Pathology
University of Bern
Bern
Switzerland
Katalin Mattes-György
Department of Nuclear Medicine
Heinrich-Heine University and University Hospital of Düsseldorf
Düsseldorf
Germany
Lauren J. McEneaney
St. Mary’s Hospital
Imperial College Healthcare NHS Trust
London UK
Jeremy Meyer
Cambridge Colorectal Unit
Addenbrooke’s Hospital
Cambridge University Hospitals NHS Foundation Trust
Cambridge UK
Piotr Milkiewicz
Liver and Internal Medicine Unit
Medical University of Warsaw Warsaw Poland
Claire Mitchell
The Christie Hospital Foundation Trust Manchester UK
Paul Moayyedi
McMaster University Canada
Filippo Montemurro
Candiolo Cancer Institute Italy
Daniel A. Moses
Medical Imaging Department
Prince of Wales Hospital Randwick
New South Wales Australia
Graduate School of Biomedical Engineering
Faculty of Engineering
UNSW Sydney New South Wales Australia
Bianca Mostert
Department of Medical Oncology
Erasmus MC Cancer Institute
Rotterdam the Netherlands
Linda Moxley-Haegert
Department of Psychology
Shriners Hospitals for Children Montreal Quebec Canada
Andrzej Mróz
Department of Pathology
Center of Postgraduate Medical Education Warsaw Poland
Department of Pathology
Maria Sklodowska-Curie Memorial Cancer Hospital and Institute Warsaw Poland
Amrita Sen Mukherjee
Honorary Clinical Research Fellow
Imperial College London London UK
Visiting Academic
Medicine and Health Sciences
Royal College of Surgeons Ireland
Andrea Napolitano
Institute for Cancer Research
Royal Marsden Hospital London UK
Yamini Natarajan
Gastroenterology and Hepatology Section
Department of Medicine
Baylor College of Medicine
Houston
Texas USA
Khairul Najmi Muhammad Nawawi
Gastroenterology Unit
Department of Medicine
Faculty of Medicine
Universiti Kebangsaan Malaysia
Kuala Lumpur Malaysia
GUT Research Group
Faculty of Medicine
Universiti Kebangsaan Malaysia
Kuala Lumpur Malaysia
Alexander Ney
Institute for Liver and Digestive Health
University College London London UK
Emil Novruzov
Department of Nuclear Medicine
Heinrich-Heine University and University Hospital of Düsseldorf Düsseldorf Germany
Daniel C. Osei-Bordom
Institute for Liver and Digestive Health University College London London UK
Lucy Oldfield
Institute of Systems
Molecular and Integrative Biology
University of Liverpool Liverpool UK
Sean M. O’Cathail
Senior Research Fellow
School of Cancer Sciences
University of Glasgow Glasgow UK
Chandni Patel
Institute of Systems
Molecular and Integrative Biology
University of Liverpool Liverpool UK
Antonio Pea, Department of Surgery
The Pancreas Institute
University of Verona Verona Italy
Aurel Perren
Institute of Tissue Medicine and Pathology
University of Bern Bern Switzerland
Stephen P. Pereira
Institute for Liver and Digestive Health
University College London London UK
Omali Pitiyarachchi
Pancreatic Cancer Translational Research Group
School of Biomedical Sciences
Lowy Cancer Research Centre
UNSW Sydney
New South Wales
Australia
Phoebe A. Phillips
Pancreatic Cancer Translational Research Group
School of Biomedical Sciences
Lowy Cancer Research Centre
UNSW Sydney
New South Wales
Australia
Hans Prenen
University Hospital Antwerp
Belgium
Carlo Pulitano
Department of Surgery
Royal Prince Alfred Hospital and University of Sydney
New South Wales
Australia
Alessandra Pulvirenti
Department of Surgery
The Pancreas Institute
University of Verona Verona
Italy
Mohamed Rabie
Cambridge Colorectal Unit
Cambridge University Hospital NHS Foundation Trust
Cambridge UK
Praveen Ramakrishnan
UT Southwestern Medical Center
Dallas
Texas
USA
Syed Rizvi
UT Southwestern Medical Center
Dallas
Texas
USA
Christoph Roderburg
Clinic for Gastroenterology
Hepatology and Infectious Diseases
University Hospital Düsseldorf
Medical Faculty of Heinrich Heine University Düsseldorf
Düsseldorf
Germany
Stefano La Rosa Unit of Pathology
Department of Medicine and Surgery
University of Insubria and ASST Sette Laghi
Varese
Italy
Iannish Sadien
Cambridge Colorectal Unit
Department of Pathology
Addenbrooke’s Hospital
Cambridge University Hospitals NHS Foundation Trust
Heinrich-Heine-University and University Hospital Duesseldorf Duesseldorf
Germany
Johannes Schumacher Institute of Human Genetics
Philipps University of Marburg Marburg
Baldingerstraße Germany
Malin Katarina Schumacher
Department of Radiation Oncology
Wollongong Hospital and University of New South Wales
New South Wales
Australia
Bence Sipos
ENETS Center of Excellence
Department of Medical Oncology and Pneumology
University Hospital Tuebingen
Tuebingen
Germany
Private Practice of Pathology and Molecular Pathology
Stuttgart
Germany
Private Practice of Molecular Pathology
Baden-Württemberg
Germany
George Sharbeen
Pancreatic Cancer Translational Research Group
School of Biomedical Sciences
Lowy Cancer Research Centre
UNSW Sydney
New South Wales
Australia
Pram Sirimana
Department of Upper Gastrointestinal and Hepatobiliary Surgery
Royal North Shore Hospital
Sydney
New South Wales
Australia
Katrin Sjoquist
Department of Medical Oncology
St. George Hospital Sydney and Clinical Trials Centre
University of Sydney
New South Wales
Australia
Myles J. Smith
Institute for Cancer Research
Royal Marsden Hospital
London UK
Thomas J. Smith
Palliative Medicine Program
Johns Hopkins Medical Institutions
Sidney Kimmel Comprehensive Cancer Center
Baltimore
Maryland
USA
Manon C.W. Spaander
Department of Gastroenterology and Hepatology
Erasmus University Medical Center
Rotterdam the Netherlands
Camille Stewart
Department of Surgery
University of Colorado School of Medicine
Aurora
Colorado
Rebecca Strutt
School of Clinical Medicine
Faculty of Medicine & Health
UNSW Sydney
New South Wales
Australia
Department of Palliative Medicine
Nelune Comprehensive Cancer Centre
Prince of Wales Hospital
Randwick
New South Wales
Australia
Martyn Stott
Institute of Systems
Molecular and Integrative Biology
University of Liverpool Liverpool
UK
Luis F. Tapias
Division of Thoracic Surgery
Mayo Clinic
SW Rochester MN
USA
Corey X. Tapper
Division of General Internal Medicine
Department of Medicine
Palliative Care Program
Johns Hopkins Medical Institutions
Sidney Kimmel Comprehensive Cancer Center
Baltimore
Maryland
USA
Stephen R. Thompson
School of Clinical Medicine
Faculty of Medicine & Health
UNSW Sydney
New South Wales
Australia
Department of Radiation Oncology
Nelune Comprehensive Cancer Centre
Prince of Wales Hospital
Randwick
New South Wales
Australia
Chen-Kan Tseng
Proton and Radiation Therapy Center
Chang Gung Memorial Hospital-Linkou Medical Center
Department of Radiation Oncology
Chang Gung University
Taiwan
Yung-Kuan Tsou
Department of Gastroenterology and Hepatology
Chang Gung Memorial Hospital
Taiwan
Silvia Uccella
Unit of Pathology
Department of Medicine and Surgery
University of Insubria and ASST Sette Laghi Varese
Italy
Department of Biomedical Sciences
Humanitas University and Department of Pathology
IRCCS Humanitas Research Hospital
Milan Italy
Michael Vieth
Institut für Pathologie
Friedrich-Alexander-Universität Erlangen-Nürnberg
Klinikum Bayreuth
Preuschwitzer Str. 101 Bayreuth Germany
Bavarian Cancer Research Center (BZKF) Bayreuth
Germany
Nicolas Villard
Department of Radiology
Lausanne University Hospital (CHUV) Lausanne
Switzerland
Mathew Vithayathil
St. Mary’s Hospital
Imperial College Healthcare NHS Trust
London UK
James Wheeler
Cambridge Colorectal Unit
Cambridge University Hospital NHS Foundation Trust
Cambridge UK
Christopher Willett
Department of Radiation Oncology
Duke University School of Medicine
Durham North Carolina
USA
Bas P.L. Wijnhoven
Department of Surgery
Erasmus MC Cancer Institute
Rotterdam
the Netherlands
Kenneth K. Wang
Division of Gastroenterology and Hepatology
Mayo Clinic
SW Rochester
MN USA
Benjamin Chun Yu Wong
Department of Medicine
School of Clinical Medicine
The University of Hong Kong
Queen Mary Hospital
Hong Kong
China
I-Chen Wu
Department of Gastroenterology
Department of Internal Medicine
Kaohsiung Medical University Hospital
Taiwan
Tsung-Teh Wu
Division of Anatomical Pathology
Mayo Clinic
SW Rochester MN
USA
Jing Xu
UT Southwestern Medical Center
Dallas Texas
USA
Chi-Ju Yeh
Department of Anatomic Pathology
Chang Gung Memorial Hospital-Linkou
Chang Gung University
Taiwan
Chi Ho Howard Yim
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
Australia
Amany Zekry
Department of Gastroenterology and Hepatology
St. George Hospital
Sydney
New South Wales
Australia
Translational Medicine Group
Pomeranian Medical University
Szczecin
Poland
Charlène J. van der Zijden
Department of Surgery
Erasmus MC Cancer Institute
Rotterdam the 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. Jankowski JP, MBChB, MSc, MD, PhD, PCME, PGCM, PGCC, AGAF, FACG, FRCP, SFHEA Clinical Professor, University College London Non-Executive Director and Consultant, National Health Service, UK Editor in Chief, Gastrointestinal Oncology, Wiley Former Sir James Black Fellow and Professor, University of Oxford
Foreword
“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 Medicine University 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
1Gastroenterology Unit, Department of Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
2UNSW 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, Australia
3School of Medical and Life Sciences, Sunway University, Selangor, Malaysia
4GUT 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.
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. Nondysplastic 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 doseresponse 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.
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,
Figure 1 Pathways of esophageal cancer.
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 earlystage EAC cell models (Flis et al. 2021). Whether this TLR2mediated 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.
Epidemiology of Gastric Cancer
Global Burden and Time Trends
There has been a significant shift in the global epidemiology of gastric cancer (GC) (Sekiguchi et al. 2022). Gastric cancer demonstrated the second highest incidence and mortality worldwide in 1990, while in 2020 Gastric cancer has become the fifth commonest cancer and the fourth common cause of cancer death worldwide (Sung et al. 2021).
Approximately 1.1 million cases of GC (720,000 males and 370,000 females) were diagnosed globally in 2020 which resulted in 770,000 deaths (65% males) (Morgan et al. 2022a). The global age-standardized incidence decreased by 28.0% in 2017 compared to 1990 while the age-standardized mortality decreased by 48.7% with the most remarkable decrease noted in Japan and South Korea (Etemadi et al. 2020) due to the advancement in diagnosis and treatment (Rawla and Barsouk 2019). However, the decrease in GC was less pronounced in populations such as the US Caucasian population, Canada, Columbia, Denmark, Brazil, Germany, Israel, and India (Luo et al. 2017).
Human Development Index has been shown to correlate with the incidence of gastric cancer. It is estimated that 86% (885,119 of 1,033,701) of new GC cases in 2018 were diagnosed in areas with high as well as very high Human Development Index. Eastern Asia had the highest incidence rates of GC (32.1 per 100,000 men and 13.2 per 100,000 women), followed by Central and Eastern Europe which had 17.1 per 100,000 men and 7.5 per 100,000 women, and then South America which had 12.7 per 100,000 men and 6.9 per 100,000 women. North America had one of the lowest rates of GC (5.6 per 100,000 men and 2.8 per 100,000 women) followed by Africa (~5 per 100,000 men and 3–4 per 100,000 women) (Bray et al. 2018).
Gastric Cancer Survival Trends
The survival rate of gastric cancer is highly dependent upon the stage at diagnosis and also exhibits regional variability. The overall age-standardized five-year survival rate of GC was 31% in the United States (Rawla and Barsouk 2019) and 20.7% in the United Kingdom. Meanwhile, the overall age-standardized five-year survival in South Korea was reported to be 68.9% and 60.3% in Japan (Allemani et al. 2018). The overall 5-year survival has improved over time from. The survival rate for all patients diagnosed in 2000 was 18.8% and it increased to 28.0% in 2010. The survival rate for localized gastric cancer in 2000 was 46% and this increased to 60% for those diagnosed in 2010. Those with regional disease diagnosed in 2000 was 20% while this improved to 30% for those diagnosed in 2010. Unfortunately, the 5-year survival rate for patients diagnosed with distant disease remains dismal at less than 5%.
(Thrift & El-Serag, 2020). References: Thrift, A. P., & El-Serag, H. B. (2020). Burden of gastric cancer. Clinical Gastroenterology and Hepatology, 18(3), 534-542.
Risk Factors for Gastric Cancer
Gastric cancer consists of two main topographic types: Cardia gastric cancer (cancer arising at the area of the stomach next to the esophagogastric junction) and non-cardia gastric cancer (cancer arising from the distal region of the stomach) and can be divided histologically according to the Lauren classification into intestinal and diffuse. Helicobacter
pylori infection is associated with histologic subtypes and accounts for approximately 89% of non-cardia gastric cancer cases worldwide (Plummer et al. 2015). The intestinal type is the most commonly found in the high gastric cancer incidence populations and is associated with the Correa cascade of inflammation (Correa et al. 1975).
Helicobacter Pylori Infection
It has been reported that an almost a staggering 50% of the world’s inhabitants are currently infected with Helicobacter pylori (Fan et al. 2021). Helicobacter pylori is commonly found in the stomach antrum or body. Numerous elements such as adhesins, urease, flagella, and vacuolating cytotoxin (VacA) promote Helicobacter pylori activity and injury to the gastric cells (Gastli et al. 2021). Helicobacter pylori infection triggers chronic active gastritis, which, if persists, results in gastric glandular loss termed chronic atrophic gastritis. Atrophy begins in the incisura and, with time, progresses to the anterior and posterior gastric wall, where it is replaced by metaplastic cells. Metaplastic cells then transform into low-grade dysplastic cells, high-grade dysplastic cells, and subsequently, invasive carcinoma (Thrift and Nguyen 2021). On a molecular level, there is an increase in the activity of arginase which acts as a catalyst of L-arginine hydrolysis which results in the formation of ornithine and urea (Alam et al. 2018). Urea then forms ammonia which neutralizes gastric acid thereby promoting an alkaline pH which improves the survival of Helicobacter pylori allowing it to propagate (Wu et al. 2021). It has been shown that the Wnt/b-catenin pathway plays an important role in gastric epithelial cell regulation. Helicobacter pylori triggers abnormal Wnt/b-catenin pathway signaling via b catenin stabilization in gastric epithelial cells, which results in abnormal cellular proliferation which leads to carcinogenesis (X. Song et al. 2015b) (Song et al. 2015b).
The reduction in incidence and mortality of gastric cancer is due to the decrease in NGC (Rawla and Barsouk 2019), which is attributed to the improved diagnosis and treatment of Helicobacter pylori. Most Helicobacter pylori infection occurs in early childhood which is transmitted through the orofecal route (Sonnenberg 2013). Globally there has been a decrease in the prevalence of Helicobacter pylori infection (Sjomina et al. 2018). Africa (79.1%) had the highest prevalence of Helicobacter pylori infection followed by Latin American and the Caribbean (63.4%) and Asia (54.7%) while the lowest prevalence was seen in North America (37.1%) and Oceania (24.2%) (Hooi et al. 2017). A urban-rural disparity was seen in the prevalence of Helicobacter pylori infection whereby higher rates of infection were seen in the rural areas and correspondingly higher rates of gastric cancer were also observed (Wen et al. 2017). On the other hand, gastric cardia cancer incidence has been rising, particularly among developed countries (Clinton et al. 2020). This has been attributed
to the increasing rates of smoking in developed countries. Data has shown that 11% of stomach malignancies worldwide and 17% of stomach malignancies in Europe are imputed to smoking (Clinton et al. 2020).
Smoking
Tobacco smoking has been linked with a variety of malignancies including gastric cancer. The Stomach Cancer Pooling Project (StoP) has shown that active smokers had a 25% greater risk of developing gastric cancer than never-smokers (OR, 1.25; 95% CI, 1.11–1.40). There was a linear relationship between cigarettes per day (P<0.01) and duration of smoking (P<0.01) with an OR od 1.33 (95% CI: 1.14 – 1,54). For 40 years of smoking and above, the risk was seen to be more marked for cardia than non-cardia gastric cancer (Praud et al. 2018). Quitting smoking was associated with a reduced rate of GC. The risk of GC of former smokers who quit more than ten years of tobacco became similar to that of never smokers (Praud et al. 2018).
Carcinogens found in tobacco such as the N-nitroso compound are pivotal to its carcinogenesis. In vitro studies have shown that tobacco smoke has a direct carcinogenic effect in the gastric mucosa. (Tayler and Piper 1977) In endoscopic studies, Tobacco smoking was demonstrated to promote dysplasia of gastric epithelium, chronic atrophic gastritis, and intestinal metaplasia (Kneller et al. 1992). Molecular mechanisms by which tobacco smoking promotes GC may be mediated via the polymorphism in the GSTT1, SULT1A1, CYP1a1, and NAT2 genes which increase susceptibility to GC (Boccia et al. 2007). Smoking also has a compounding effect on the increased risk of susceptibility and persistence of Helicobacter pylori infection. Smoking also results in a lower efficacy of antibiotic eradication of Helicobacter pylori (Ferro et al. 2019).
Obesity and Lifestyle Factors
Obesity has also been shown to be associated with a modestly increased risk for cardia gastric cancer (X.-J. Lin et al. 2014a). Dietary factors that increase GC risk include a high salt diet (Morais et al. 2022) processed meat (Kim et al. 2019) nitrates (P. Song et al. 2015b). Excessive processed meat intake increased the risk for non-cardia GC but not cardia GC. Salt has been postulated to cause gastric mucosal damage and hypergastrinemia (Furihata et al. 1996) leading to chronic inflammation promoting H. pylori infection. Salt also potentiates the carcinogenicity of nitrates by enhancing its penetration. (Eusebi et al. 2020) Heavy alcohol consumption which is defined as more than five drinks per day increased the risk of gastric cancer (OR 3.13, 95% CI 1.15–8-64) (Laszkowska et al. 2021). A meta-analysis by Han et al. showed high total dietary fat intake more than 20 g/day correlated with an increased risk for GC (Han et al. 2015).
Genetic Risk
Hereditary cancer syndromes such as hereditary diffuse gastric cancer (HDCC), Lynch, hereditary breast and ovarian cancer (BRCA), Li-Fraumeni, familial adenomatous polyposis, and Peutz-Jeghers syndromes result in an increased risk for gastric cancer. Persons with HDCC syndrome have a 80% risk of developing GC (Hansford et al. 2015), While GC is usually sporadic, approximately 10% of GC cases have familial aggregation (Pocurull et al. 2021). HDCC is characterized by E-cadherin (CDH1) mutation results in an increased risk of early-onset diffuse gastric cancer and lobular breast cancer. HDCC is inherited in an autosomal dominant manner. The cumulative risk for gastric cancer in those with CDH1 mutations is 70% by 89 years for men and 56% for women (Hansford et al. 2015). It is recommended that any patient with two or more family members with a history of gastric cancer, irrespective of age with at least one diagnosed with gastric cancer, or anyone with a family member with diffuse gastric cancer at any age and lobular breast cancer diagnosed before the age of 70, a family history of two or more relatives with breast cancer diagnosed less than 50 years of age undergo CDH1 testing. Meanwhile, any patients who have been diagnosed with diffuse gastric cancer below the age of 50, have diffuse gastric cancer at any age who are of Maori ethnicity, have diffuse gastric cancer with a history or family history of cleft lip palate, a history of bilateral lobular breast cancer diagnosed before 70, or gastric cancer in situ signet ring or pagetoid spread of signet ring diagnosed less than 50 years of age undergo CDH1 testing (Blair et al. 2020).
Li-Fraumeni syndrome is an infrequently encountered hereditary cancer syndrome which is a result of TP53 germline mutation and is inherited in an autosomal dominant manner (Masciari et al. 2011). It is also associated with an increased risk of sarcoma, brain tumors, breast and adrenal cortical carcinomas, and breast cancer (Garber et al. 1991). Familial adenomatous polyposis (FAP) is an autosomal dominant hereditary colorectal cancer syndrome that has a prevalence of 1 in 10,000 (Plawski et al. 2013). FAP is due to a mutation in the adenomatous polyposis coli (APC) gene. The endoscopic features of patients with FAP is multiple polyposis of the stomach. There is an increased prevalence of gastric adenomas, fundic gland polyps, and polyps with high grade dysplasia in these patients. There is a high rate of duodenal adenomas in patients with FAO reaching approximately 88 to 98% with the risk of duodenal malignancy as high as 18% by the age of 75. The risk of gastric adenocarcinoma is 1.3% in patients with FAP. Polyposis usually begins around puberty therefore it is recommended that colonoscopy screening begin at the age of 12 in patients with an affected family member (Bülow et al. 2012), hence it is recommended by international guidelines that screening esophagealgastroduodenoscopy (EGDS) should commence at age 25 (Monahan et al. 2020; van Leerdam et al. 2019; Yang et al. 2020).
Peutz-Jeghers syndrome (PJS) is an autosomal dominant inherited genetic disorder that results in the development of mucocutaneous pigmentation and multiple hamartomatous polyps in the gastrointestinal tract. It is due to a mutation in the STK11 gene which is located in 19p 13.3 (Aretz et al. 2005). STK11 is a tumor suppressor gene that is responsible for cell cycle and cell proliferation pathways that regulate apoptosis and RAS-related cell transformation (Karuman et al. 2001). The development of GI malignancies in PJS occurs through the hamartoma-adenoma-carcinoma pathway. (Bosman 1999) PJS has an incidence of approximately 1 in 250,000 and carries a 15 to 18-fold increased risk of cancer compared to the general population (Kalloo and Shanahan 2016). A clinical diagnosis of PJS can be made when one of the criteria is met: two or more pathologically ascertained Peutz-Jeghers polyps, detection of Peutz-Jeghers polyps and family history of Peutz-Jeghers in a close relative, characteristic mucocutaneous pigmentation in the mouth, lips, nose, eyes, genitalia, or fingers with a family history of PJS, any PeutzJeghers polyps in a patient with a characteristic mucocutaneous pigmentation (Beggs et al. 2010). In view of the increased risk of malignancy, it is advocated that a screening EGDS be performed at eight years of age in those with PJS. If polyps are found, polypectomy should be performed and EGDs should be repeated in one to three-year intervals. If no polyps are found at baseline screening EGDs therefore the next EGD can be performed at 18 years of age (Monahan et al. 2020; van Leerdam et al. 2019).
Other Risk Factors for Gastric Cancer
Other less common risk factors for GC include Epstein-Barr virus infection, Menetrier’s disease, and autoimmune gastritis. Epstein Barr Virus was found in approximately 8% of gastric cancers; however, there is inadequate evidence for a direct causal relationship for Epstein Barr Virus in gastric carcinogenesis (Group 2012). Menetrier’s disease is a condition where hypertrophic gastropathy develops in the body of the stomach resulting in the formation of giant gastric folds, protein-losing enteropathy, and achlorhydria. Histologically, there is presence of massive foveolar hyperplasia (Toubia and Schubert 2008). Smoking increased the risk of development of Menetrier’s disease however alcohol use and Helicobacter Pylori did not increase this risk. The risk of GC was 8.9% after 10 years of the diagnosis of Menetrier’s disease and the survival was 72.7% at 5 years and 65% at 10 years (Almazar et al. 2021).
Autoimmune gastritis accounts for under 5% of chronic gastritis cases (Lahner et al. 2015). It is the result of autoimmune T-cell mediated destruction of the oxyntic mucosa of the proximal stomach which is mediated by autoantibodies against the parietal cells and intrinsic factor (Zhang et al. 2013). This results in the development of atrophy of the oxyntic gastric
mucosa with hypo- or achlorhydria. Complications of B12 malabsorption (Pernicious anemia) and iron deficiency anemia ensue (Coati et al. 2015). Pernicious anemia carries approximately seven-fold higher risk of gastric malignancy (Weise et al. 2020). It is important to note that the hypo- or achlorhydria gives rise to hypergastrinemia and enterochromaffinlike cell hyperplasia which can develop into a neuroendocrine tumor (Bordi et al. 1995). The prevalence of enterochromaffinlike cell neuroendocrine tumors in autoimmune gastritis is markedly elevated compared to Helicobacter pylori gastritis (Waldum and Fossmark 2019). The pathophysiology of gastric cancer is depicted in Figure 2.
Factors Protective of Gastric Cancer
The Mediterranean diet which incorporates vegetables, legumes, whole grains, fish, and olive oil which are high in polyunsaturated fat and low in saturated fats and nitrites have been shown to be protective against GC in those with high adherence (Álvarez-Álvarez et al. 2021). The Stomach cancer Pooling (STOP) a global epidemiological study on GC demonstrated that there was a marked decrease in GC risk in those with highest tertile consumption of fruits (0.76, CI 0.64–0.90), vegetables (OR 0.68, CI 0.56–0.84) and fruits and vegetables combined (OR 0.61, CI 0.49–0.75) compared to those in the lowest tertile (Ferro et al. 2020). Other beneficial food include whole grains and nuts (Zhang et al. 2020), Vitamin D levels above 20 ng/ml (Kwak and Paik 2020), and ascorbic acid and polyphenols found in fruits and vegetables was found to lower the risk of GC (Toh and Wilson 2020).
Microbiome and Gastric Cancer
Proteobacteria, Actinobacteria, Firmicutes, and Bacteroidetes are the major phyla present in the healthy gastric mucus layer (Fakharian et al. 2022). Prevotella, Veillonella, Streptococcus, Neisseria, Fusobacterium, and Haemophilus are the main genera present in the healthy gastric microbiota, but their abundance varies among human individuals from different geolocations (Fakharian et al. 2022). In general, the overall microbial load of the stomach is around 102–104 CFU/ml which is lower than that of the colonic microbiota (1010–1012 CFU/ml) owing to the acidic environment that limits microbial colonization (J. Yang et al. 2021b).
Helicobacter pylori (H. pylori) plays a major role in the progression from atrophic gastritis to intestinal metaplasia to gastric cancer (GC) (Stewart et al. 2020). Chronic H. pylori infection induces chronic gastric inflammation, leading to atrophic gastritis (Goldenring and Mills 2022). These effects are mediated by multiple virulence factors of H. pylori. Of these, VacA increases the mitochondrial membrane permeability, impairs endocytosis trafficking, and triggers apoptosis in gastric epithelial cells (Gauthier et al. 2005; Matsumoto et al. 2011; Willhite and Blanke 2004). It also
stimulates mast cells to produce pro-inflammatory cytokines such as IL-6 and TNF-a (Supajatura et al. 2002), leading to the H. pylori-associated gastritis. Furthermore, VacA, g-glutamyl transpeptidase and bacterial cholesterol of H. pylori induce TH17 immune responses, contributing to the development of gastritis. On the other hand, CagA and T4SS form a complex that deliver CagA to the infected host cells across the outer and inner bacterial membranes (Chung et al. 2019; Knorr et al. 2019). CagA then induces inflammatory responses and proliferation, inhibits apoptosis, impairs cellcell junctions, and leads to loss of cell polarity in the gastric epithelial cells, thus promoting gastric carcinogenesis (Bagnoli et al. 2005; Buti et al. 2020, 2011; Yang et al. 2018). This chronic inflammation induced by H. pylori virulence factors enhances the production of reactive oxygen species and reactive nitrogen species which damage DNA (Shimizu et al. 2017). H. pylori also induces DNA damage via direct adhesion of live bacteria with the host cells and impairs the DNA repair system via the host long noncoding RNAs, SNHG17 (Toller et al. 2011). The DNA damage results in genomic instability and accumulation of mutations, leading to gastric carcinogenesis.
The chronic gastric inflammation results in the death of hydrochloric acid secreting parietal cells. The hypochlorhydria allows the gastric colonization and outgrowth of oral and lower bowel microbes that are not normally present in the acidic condition of the stomach, leading to dysbiosis of the gastric microbiota. The enriched oral bacteria in the mucosa of GC includes Peptostreptococcus stomatis, Streptococcus anginosus, Parvimonas micra, Slackia exigua, and Dialister pneumosintes (Coker et al. 2018; Liu et al. 2022). This enrichment only occurs in GC but not in other early stages including superficial gastritis, atrophic gastritis, and intestinal metaplasia (Coker et al. 2018). In addition, H. pylori reduces microbial diversity, changes the microbiota composition, and weakens the interactions among gastric microbes (Liu et al. 2022). The first link between gastric dysbiosis and carcinogenesis was demonstrated by Lee et al., using the INS-GAS transgenic mouse model for gastritis with achlorhydria (Lee et al. 2008). Lee et al. treated the INS-GAS transgenic mice with three antibiotics including metronidazole, omeprazole, and clarithromycin prior to H. pylori infection (Lee et al. 2008). Killing of H. pylori by the antibiotics lowers the severity of gastric dysplasia several weeks post-infection (Lee et al.
Figure 2 Pathways of gastric cancer.
2008). Intriguingly, INS-GAS transgenic mice treated with the antibiotics and without H. pylori infection also have a reduced severity of dysplasia (Lee et al. 2008). These data suggest that antibiotics not only eradicate H. pylori but also the gastric microbiota, protecting the mice from gastric carcinogenesis. This idea is further supported by two later studies. Lofgren et al. demonstrated that germ-free INS-GAS mice have a delayed development of gastric lesions as compared to INS-GAS mice with a more complex microbiota and H. pylori infection (Lofgren et al. 2011). Lertpiriyapong et al. further examined if a diverse gastric microbiota is required for the development of gastric lesions (Lertpiriyapong et al. 2014). The risk for gastric cancer development was compared among three groups of INS-GAS mice that were germ-free, had restricted microbiota (only containing Lactobacillus, Clostridium, Bacteroides), and had complex microbiota (Lertpiriyapong et al. 2014). They found that the rate of gastric cancer development is similar in mice with a restricted and complex microbiota (Lertpiriyapong et al. 2014). However, mice with a restricted microbiota have enhanced gastric inflammation, epithelial defects, oxyntic gland atrophy, epithelial hyperplasia, and dysplasia as compared to the germ-free mice (Lertpiriyapong et al. 2014). Taken together, these results suggest that H. pylori acts synergistically with the bacterial community for potentiating gastric neoplasia development. Despite the above evidence, it remains unknown if gastric dysbiosis in humans is sufficient to induce gastric carcinogenesis. A recent study addressed this research question by transplanting the microbiota obtained from chronic superficial gastritis, intestinal metaplasia, or GC into germ-free wild type mice (Kwon et al. 2022). They found that the gastric microbiota from patients with intestinal metaplasia or GC colonized the mouse stomachs and induced premalignant lesions including loss of parietal cells, increased inflammation, and enhanced gastric cell proliferation (Kwon et al. 2022). These mice also developed gastric dysplasia after one year of transplantation (Kwon et al. 2022). These results suggest that the gastric dysbiotic microbiota from intestinal metaplasia and GC but not gastritis is sufficient to induce gastric carcinogenesis. They also explain why more than 50% of the world population are infected with H. pylori but only 1–3% of these infected individuals develop gastric cancer (Stewart et al. 2020). It is possible that H. pylori induces chronic gastritis and hypochlorhydria, providing a favorable environment for the development of gastric dysbiosis which in turn potentiates the gastric carcinogenesis with or without the synergistically carcinogenic effect by H. pylori. Further investigation is required to understand the molecular mechanism on how this gastric dysbiotic microbiota promote gastric carcinogenesis and to examine if this gastric dysbiosis could be treated to prevent gastric cancer.
Epidemiology of Colorectal Cancer
Global Burden and Time Trends of Colorectal Cancer
Colorectal cancer is ranked third in worldwide incidence of malignancies in 2020 with 1.9 million new cases diagnosed and accounted for 935,000 cancer-related deaths making it the second deadliest malignancy (Sung et al. 2021). The crude incidence rate was 24.8 per 100,000 and the age-adjusted incidence rate was 19.5 per 100,000 while the crude mortality rate was 12 per 100,000 and the age-standardized mortality rate was 9 per 100,000 (Sung et al. 2021). There is significant geographic variability in CRC incidence and a correlation with the human development index (HDI). The incidence and mortality of CRC in the past two decades in developed countries with high HDI has decreased largely due to established CRC screening programs and polypectomy (Kanth and Inadomi 2021). There has been an increase in the incidence of CRC in Eastern Europe, South America, and South Eastern and South Central Asia which is possibly associated with an affluent lifestyle encompassing higher animal-source food, higher calorie intake, reduced physical activity, and increased obesity (Sung et al. 2021). The highest age-standardized incidence rate was reported in Australasia at 48.3 per 100,000 population, while the lowest was seen in central sub-Saharan Africa at 7.7% per 100,000 (Collaborators 2022). Central Europe has the highest age-standardized mortality rate (23.6 per 100,000). On the other hand, South Asia had the lowest figure for age-standardized mortality rate (7.3 per 100,000) (Collaborators 2022).
Early-onset Colorectal Cancer
Early-onset CRC is defined as CRC occurring before the age of 50. The average age of diagnosis of CRC is 68 years of age in men and 72 years of age in women (Sung et al. 2021). However, there has been a steady increase in the incidence of early-onset CRC and a decrease in late-onset CRC. There has been a rise in early-onset CRC in the last three decades. In the United States there has been an increase of 45% of CRC in adults aged 20 to 49 years from 1992 (8.6 per 100,000) to 2016 (13.1 per 100,000) (Stoffel and Murphy 2020). There has also been an increasing trend of early CRC across Europe. CRC in ages 20 to 29 increased from 0.8 in 1990 to 2.3 per 100,000 in 2016 while in ages 30 to 39 there was an increase from 2.8 in 2006 to 6.4 per 100,000 in 2016 and in ages 40 to 49 an increase from 15.5 in 2005 to 19.2 per 100,000 in 2016 was observed (Vuik et al. 2019). A similar trend was seen in Australia and New Zealand (Siegel et al. 2019) as well as in industrialized Asian countries such as Japan, Hong Kong, South Korea, and Taiwan (Sung et al. 2021). Early onset CRC mortality has also been on the rise with an increase of 1.3% per year from 2008 and 2017 (Siegel
et al. 2019). Decreasing colorectal cancer trends were noted in three developed countries: Italy, Austria, and Lithuania. Of note Austria implemented an earlier CRC screening age commencing at 40 years of age which likely contributes to this trend (Vuik et al. 2019).
In terms of clinical presentation, early-onset CRC usually presents symptomatically in 70 to 95% of cases (Silva et al. 2019) whereas late onset CRC patients are usually diagnosed fortuitously likely during CRC screening colonoscopy (F. W. Chen et al. 2017b). Patients with early onset CRC also report a longer duration of symptoms and have a lengthier delay in diagnosis and are diagnosed at a more advanced stage compared with late-onset CRC (F. W. Chen et al. 2017b). Early onset CRC had a higher frequency of left-sided disease with more aggressive histology with approximately 27.9% having poorly or undifferentiated cancer (F. W. Chen et al. 2017b). Insights into the adenoma-carcinoma pathway have revealed that the most effective way to prevent sporadic CRC is by the removal of colorectal adenomas. According to a 20-year prediction model reported based on Cancer Tomorrow on Global Cancer Observatory (https://gco.iarc.fr), there would be 1.93 million instances of colon, rectal, and anal cancers globally in 2020, and 3.15 million in 2040 (Xi and Xu 2021). This is based on projected aging, population growth, and human advancement. The surge was ascribed to a shift in lifestyle and nutrition toward a more westernized norm (Xi and Xu 2021).
Risk Factors of Colorectal Cancer
Polyps, the Adenoma-carcinoma Sequence and the Risk of Colorectal Cancer
Colorectal cancer is divided into sporadic, colitis-associated, and hereditary colorectal cancer all of which undergo different carcinogenic pathways. It is estimated that 60 to 65% of CRC are sporadic, while 25% have a family history but no genetic cancer syndrome whereas only 5% are hereditary (Keum and Giovannucci 2019; Migliore et al. 2011). The development of CRC undergoes four key phases which encompass initiation, promotion, progression, and metastasis. The process of initiation begins with an irreparable genetic injury that results in neoplastic transformation. The promotion stage ensues when the neoplastic cells proliferate resulting in neoplastic growth. Thereafter the progression phase occurs. Genetic and epigenetic remodeling causes the cells to have a selective growth advantage which results in their metastatic ability. Metastasis then occurs via the bloodstream or lymphatic system (Keum and Giovannucci 2019).
Most CRCs begin with a polyp. There are two major subtypes of polyps: adenomatous (adenomas) and serrated polyps. Approximately 85 to 90% of CRCs arise from adenomas (Conteduca et al. 2013). However, below 10% of adenomas develop into CRC (Conteduca et al. 2013). Adenomas with
characteristics of villous histology, high-grade dysplasia, or size being more than 1 cm have been termed high-grade adenomas and possess a greater likelihood of progression to malignancy (30–50%) compared with non-advanced adenomas (1%) (Conteduca et al. 2013). An adenoma develops from mutations in APC, the tumor suppressor gene. This results in the overactivation of the Wnt/b-catenin signaling pathway and progresses to dysregulated cell proliferation forming an adenoma (Dow et al. 2015). Thereafter, KRAS mutations enhances the adenoma proliferation, and subsequent inactivation of TP53 tumor suppressor gene results in the development of CRC (Armaghany et al. 2012).
Another group of polyps, the serrated polyps encompass traditional serrated adenomas, sessile serrated adenomas, and hyperplastic polyps. The hyperplastic polyp (HP) is the predominant variant that was previously believed to be completely benign, however, recent data have shown that large polyps and/ or in the proximal colon may progress to CRC via the serrated pathway (East et al. 2017). An estimated 10–15% of sporadic CRC arise from serrated polyps (Conteduca et al. 2013). One of the critical events in this pathway is mutation of the BRAF oncogene which activates the MAPK pathway and results in the development of hyperplastic polyp. Progression to sessile serrated adenoma is propagated by CIMP (Kedrin and Gala 2015). The risk of progression can be halted by removing these adenomas via polypectomy during a colonoscopy thus reducing the CRC risk.
Inflammatory Bowel Disease
Chronic inflammation results in a different carcinogenic pathway. In chronic inflammation, TP53 mutation occurs early and low-grade dysplasia arises from chronic inflammation and usually occurs in flat mucosa and has an accelerated pathway to high-grade dysplasia and finally CRC (Itzkowitz and Yio 2004). Due to the fact that these lesions occur in flat mucosa, their detection is challenging hence chromoendoscopy or high-definition endoscopy is superior to white light imaging for dysplasia surveillance (Buchner and Lichtenstein 2016).
Risk Factors for Early-onset Colorectal Cancer
Early-onset CRC has been on the rise in highly Westernized countries. Early-onset CRC is genetically, pathologically, and molecularly diverse (Pearlman et al. 2017). An estimated 30% of early-onset CRC patients have a family history of CRC or one first-degree relative with CRC and out of that only 13% had a germline mutation (Pearlman et al. 2017). Early-onset CRC has been found to be MSI-high in 10–30% of the cases of CRC compared with ~15% of overall CRCs (Conteduca et al. 2013). The obesity epidemic among young children and adolescents parallels the rise in early-onset CRC (Keum and Giovannucci 2019). It has been shown that women with a BMI of 23 or above at the age of 18 had almost 60% increased risk
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que no podrán mil vidas esperalla.
Mas no hay tan gran peligro que me espante, ni tan fragoso y áspero camino, que me estorbe de andar siempre adelante. Siguiendo voy mi proprio desatino, voy tras la pena y busco lo que daña, y ofrezco al llanto el ánimo mezquino.
Perpetuo gozo alegra y acompaña mi vida, que penando está en sossiego, y siente en los dolores gloria extraña.
La pena me es deleite, el llanto juego, descanso el suspirar, gloria la muerte, las llagas sanidad, reposo el fuego.
Cosa no veo jamás que no despierte y avive en mí la furia del tormento, pero recibo en él dichosa suerte.
Estos males, señora, por vos siento, destas passiones vivo atormentado con la fatiga igual al
sufrimiento.
Pues muévaos á piedad un desdichado, que ofresce á vuestro amor la propia vida, pues no pide su mal ser remediado, mas sólo ser su pena conoscida.
Esta fué la carta que le escribí, y si ella fuera tan bien hecha como fué venturosa, no trocara mi habilidad por la de Homero. Llegó á las manos de Alcida, y aunque de mis razones quedó alterada, y de mi atrevimiento ofendida; pero al fin, tener noticia de mi pena hizo, según después entendí, en su corazón mayor efecto de lo que yo de mi desdicha confiaba. Comencé á señalarme su amante, haciendo justas, torneos, libreas, galas, invenciones, versos y motes por su servicio, durando en esta pena por espacio de algunos años. Al fin de los cuales Eugerio me tuvo por merescedor de ser su yerno, y por intercessión de algunos principales hombres de la tierra me ofresció su hija Alcida por mujer. Tratamos que los desposorios se hiciesen en la ciudad de Lisbona, porque el rey de lusitanos en ellos estuviesse presente; y assí, despachando un
correo con toda diligencia, dimos cuenta al rey de este casamiento, y le suplicamos que nos diesse licencia para que, encomendando nuestros cargos á personas de confianza, fuéssemos allá á solemnizarlo. Luego por toda la ciudad y lugares apartados y vecinos se extendió la fama de mi casamiento, y causó tan general placer, como á tan hermosa dama como Alcida y a tan fiel amante como yo se debía. Hasta aquí llegó mi bienaventuranza, hasta aquí me encumbró la fortuna, para después abatirme en la profundidad de miserias en que me hallo. ¡Oh, transitorio bien, mudable contento; oh, deleite variable; oh, inconstante firmeza de las cosas mundanas! ¿Qué más pude recibir de lo que recibí y qué más puedo padescer de lo que padezco? No me mandes, pastora, que importune tus oídos con más larga historia, ni que lastime tus entrañas con mis desastres. Conténtate agora con saber mi passado contentamiento, y no quieras saber mi presente dolor, porque está cierta que ha de enfadarte mi prolijidad y de alterarte mi desgracia. A lo cual respondió D : Deja, Marcelio, semejantes excusas, que no quise yo saber los sucessos de tu
vida para gozar sólo de tus placeres, sin entristecerme de tus pesares, antes quiero dellos toda la parte que cabrá en mi congojado corazón. ¡Ay, hermosa pastora, dijo M , cuán contento quedaría si la voluntad que te tengo no me forzasse á complacerte en cosa de tanto dolor! Y lo que más me pesa es que mis desgracias son tales que han de lastimar tu corazón cuando las sepas, que la pena que he de recebir en contallas no la tengo en tanto que no la sufriesse de grado á trueco de contentarte. Pero yo te veo tan deseosa de sabellas, que me será forzado causarte tristeza, por no agraviar tu voluntad. Pues has de saber, pastora, que después que fué concertado mi desventurado casamiento, venida ya la licencia del rey, el padre Eugerio, que viudo era, el hijo Polydoro, las dos hijas Alcida y Clenarda y el desdichado Marcelio, que su dolor te está contando, encomendados los cargos que por el rey teníamos á personas de confianza, nos embarcamos en el puerto de Ceuta, para ir por mar á la noble Lisbona á celebrar, como dije, en presencia del rey el matrimonio.
El contento que todos llevábamos nos hizo tan ciegos, que en el
más peligroso tiempo del año no tuvimos miedo á las tempestuosas ondas que entonces suelen hincharse, ni á los furiosos vientos, que en tales meses acostumbran embravecerse; sino que, encomendando la frágil nave á la inconstante fortuna, nos metimos en el peligroso mar, descuidados de sus continuas mudanzas é innumerables infortunios. Mas poco tiempo passó que la fortuna castigó nuestro atrevimiento, porque antes que la noche llegasse, el piloto descubrió manifiestas señales de la venidera tempestad. Comenzaron los espessos ñublados á cubrir el cielo, empezaron á murmurar las airadas ondas, los vientos á soplar por contrarias y diferentes partes. ¡Ay, tristes y peligrosas señales! dijo el turbado y temeroso piloto; ¡ay, desdichada nave, qué desgracia se te apareja, si Dios por su bondad no te socorre! Diciendo esto vino un ímpetu y furia tan grande de viento, que en las extendidas velas y en todo el cuerpo de la nave sacudiendo, la puso en tan gran peligro, que no fué bastante el gobernalle para regirla, sino que, siguiendo el poderoso furor, iba donde la fuerza de las ondas y vientos la impelía. Acabó poco á
poco á descararse la tempestad, las furiosas ondas cubiertas de blanca espuma comienzan á ensoberbecerse. Estaba el cielo abundante lluvia derramando, furibundos rayos arrojando y con espantosos truenos el mundo estremesciendo. Sentíase un espantable ruido de las sacudidas maromas, y movían gran terror las lamentables voces de los navegantes y marineros. Los vientos por todas partes la nave combatían, las ondas con terribles golpes en ella sacudiendo, las más enteras y mejor clavadas tablas hendían y desbarataban. A veces el soberbio mar hasta el cielo nos levantaba y luego hasta los abismos nos despeñaba, y á veces espantosamente abriéndose, las más profundas arenas nos descubría. Los hombres y mujeres á una y otra parte corriendo, su desventurada muerte dilatando, unos entrañables suspiros esparcían, otros piadosos votos ofrescían y otros dolorosas lágrimas derramaban. El piloto con tan brava fortuna atemorizado, vencido su saber de la perseverancia y braveza de la tempestad, no sabía ni podía regir el gobernalle. Ignoraba la naturaleza y origen de los vientos, y en un mesmo punto mil cosas
diferentes ordenaba. Los marineros, con la agonía de la cercana muerte turbados, no sabían ejecutar lo mandado, ni con tantas voces y ruido podían oir el mandamiento y orden del ronco y congojado piloto. Unos amainan la vela, otros vuelven la antena, otros añudan las rompidas cuerdas, otros remiendan las despedazadas tablas, otros el mar en el mar vacian, otros al timón socorren, y en fin todos procuran defender la miserable nave del inevitable perdimiento. Mas no valió la diligencia, ni aprovecharon los votos y lágrimas para ablandar el bravo Neptuno. Antes cuanto más se iba acercando la noche, más cargaron los vientos y más se ensañaron las tempestades. Venida ya la tenebrosa noche, y no amansándose la fortuna, el padre E , desconfiado de remedio, con el rostro temeroso y alterado, á sus hijos y yerno mirando, tenía tanta agonía de la muerte que habíamos de passar, que tanto nos dolía su congoja como nuestra desventura. Mas el lloroso viejo, rodeado de trabajos, con lamentable voz y tristes lágrimas decía de esta manera: ¡Ay, mudable Fortuna, enemiga del humano contento, tan gran desdicha le tenías guardada á mi
triste vejez! ¡Oh, bienaventurados los que en juveniles años mueren, lidiando en las sangrientas batallas, pues no llegando á la cansada edad no vienen á peligro de llorar los desastres y muertes de sus amados hijos! ¡Oh, fuerte mal; oh, triste sucesso! ¿Quién jamás murió tan dolorosamente como yo, que esperando consolar mi muerte con dejar en el mundo quien conserve mi memoria y mi linaje, he de morir en compañía de los que habían de solemnizar mis obsequias? Oh, queridos hijos, ¿quién me dijera á mí, que mi vida y la vuestra se habían de acabar á un mesmo tiempo y habían de tener fin con una misma desventura? Querría, hijos míos, consolaros; mas ¿qué puede deciros un triste padre, en cuyo corazon hay tanta abundancia de dolor y tan grande falta de consuelo? Mas consolaos, hijos; armad vuestras almas de sufrimiento, y dejad á mi cuenta toda la tristeza, pues allende de morir una vez por mí, he de sufrir tantas muertes cuantas vosotros habéis de passar. Esto decía el congojado padre con tantas lágrimas y sollozos, que apenas podía hablar, abrazando los unos y los otros por despedida, antes que llegasse la hora del perdimiento.
Pues contarte yo agora las lágrimas de Alcida, y el dolor que por ella yo tenía, sería una empresa grande y de mucha dificultad. Sólo una cosa quiero decirte: que lo que más me atormentaba, era pensar que la vida que yo tenía ofrescida á su servicio hubiesse de perderse juntamente con la suya. En tanto la perdida y maltratada nave con el ímpetu y furia de los bravos ponientes, que por el estrecho passo que de Gibraltar se nombra rabiosamente soplaban, corriendo con más ligereza de la que á nuestra salud convenía, conbatida por la poderosa Fortuna por espacio de toda la noche y en el siguiente día, sin poder ser regida con la destreza de los marineros, anduvo muchas leguas por el espacioso mar Mediterráneo, por donde la fuerza de los vientos la encaminaba.
El otro día después paresció la Fortuna querer amansarse; pero volviendo luego á la acostumbrada braveza, nos puso en tanta necessidad que no esperábamos una hora de vida. En fin, nos combatió tan brava tempestad, que la nave, compelida de un fuerte torbellino, que le dió por el izquierdo lado, estuvo en tan gran peligro de trastornarse, que tuvo ya el bordo
metido en el agua. Yo que vi el peligro manifiesto, desciñéndome la espada, porque no fuesse embarazo, y abrazándome con Alcida, salté con ella en el batel de la nave. Clenarda, que era doncella muy suelta, siguiéndonos, hizo lo mesmo, no dejando en la nave su arco y aljaba, que más que cualesquier tesoros estimaba. Polydoro abrazándose con su padre, quiso con él saltar en el batel como nosotros; mas el piloto de la nave y un otro marinero fueron los primeros á saltar, y al tiempo que Polydoro con el viejo Eugerio quiso salir de la nave, viniendo por la parte diestra una borrasca, apartó tanto el batel de la nave, que los tristes hubieron de quedar en ella, y de allí á poco rato no la vimos, ni sabemos della, sino que tengo por cierto que por las crueles ondas fué tragada, ó dando al través en la costa de España, miserablemente fué perdida. Quedando, pues, Alcida, Clenarda y yo en el pequeño esquife, guiados con la industria del piloto y de otro marinero, anduvimos errando por espacio de un día y de una noche, aguardando de punto en punto la muerte, sin esperanza de remedio y sin saber la parte donde estábamos. Pero en la mañana
siguiente nos hallamos muy cerca de la tierra, y dimos al través en ella. Los dos marineros, que muy diestros eran en nadar, no sólo salieron á nado á la deseada tierra, pero nos sacaron á todos, llevándonos á seguro salvamiento. Después que estuvimos fuera de las aguas, amarraron los marineros el batel á la ribera, y reconosciendo la tierra donde habiamos llegado, hallaron que era la isla Formentera, y quedaron muy espantados de las muchas millas que en tan poco tiempo habiamos corrido. Mas ellos tenían tan larga y cierta experiencia de las maravillas que suelen hacer las bravas tempestades, que no se espantaron mucho del discurso de nuestra navegación. Hallámonos seguros de la Fortuna, pero tan tristes de la pérdida de Eugerio y Polydoro, tan mal tratados del trabajo y tan fatigados de hambre, que no teníamos forma de alegrarnos de la cobrada vida.
Dejo agora de contarte los llantos y extremos de Alcida y Clenarda por haber perdido el padre y hermano, por passar adelante la historia del desdichado sucesso que me acontesció en esta solitaria isla; porque después que en ella fuí librado de la crueldad
de la Fortuna, me fué el Amor tan enemigo, que paresció pesarle de ver mi vida libre de la tempestad, y quiso que al tiempo que por más seguro me tuviesse, entonces con nueva y más grave pena fuesse atormentado. Hirió el maligno Amor el corazón del piloto, que Bartofano se decía, y le hizo tan enamorado de la hermosura de Clenarda, su hermana de Alcida, que por salir con su intento olvidó la ley de amicicia y fidelidad, imaginando y efectuando una extraña traición. Y fué assí, que después de las lágrimas y lamentos que las dos hermanas hicieron, acontesció que Alcida, cansada de la passada fatiga, se recostó sobre la arena, y vencida del importuno sueño se durmió. Estando en esto le dije yo al piloto: Bartofano amigo, si no buscamos qué comer, ó por nuestra desdicha no lo hallamos, podemos hacer cuenta que no habernos salvado la vida, sino que habernos mudado manera de muerte. Por esso querría, si te place, que tú y tu compañero fuéssedes al primer lugar que en la isla se os ofresciere para buscar qué comer Respondió B : Harto hizo la Fortuna, señor Marcelio, en llevarnos á tierra, aunque sea despoblada. Desengáñate de
hallar qué comer aquí, porque la tierra es desierta y de gentes no habitada. Mas yo diré un remedio para que no perezcamos de hambre. ¿Ves aquella isleta que está de frente, cerca de donde estamos? Allí hay gran abundancia de venados, conejos, liebres y otra caza, tanto que van por ella grandes rebaños de silvestres animales. Allí también hay una ermita, cuyo ermitaño tiene ordinariamente harina y pan. Mi parescer es que Clenarda, cuya destreza en tirar arco te es manifiesta, passe con el batel á la isla para matar alguna caza, pues el arco y flechas no le faltan, que mi compañero y yo la llevaremos allá; y tú, Marcelio, queda en compañía de Alcida, que será posible que antes que se despierte volvamos con abundancia de fresca y sabrosa provisión.
Muy bien nos paresció á Clenarda y á mí el consejo de Bartofano, no cayendo en la alevosía que tenía fabricada. Mas nunca quiso Clenarda passar á la isleta sin mi compañía, porque no osaba fiarse en los marineros. Y aunque yo me excusé de ir con ella, diciendo que no era bien dejar á Alcida sola y durmiendo en tan solitaria tierra, me respondió que, pues el espacio de mar era muy poco, la
caza de la isla mucha y el mar algún tanto tranquilo, porque en estar nosotros en tierra había mostrado amansarse, podíamos ir, cazar y volver antes que Alcida, que muchas noches había que no había dormido, se despertasse. En fin; tantas razones me hizo que, olvidado de lo que más me convenía, sin más pensar en ello, determiné acompañada, de lo cual le pesó harto á Bartofano, porque no quería sino á Clenarda sola, para mejor efectuar su engaño. Mas no le faltó al traidor forma para poner por obra la alevosía: porque dejada Alcida durmiendo, metidos todos en el esquife, nos echamos á la mar, y antes de llegar á la isleta, estando yo descuidado y sin armas, porque todas las había dejado en la nave, cuando salté de ella por salvar la vida, fuí de los dos marineros assaltado, y sin poderme valer, preso y maniatado.
Clenarda, viendo la traición, quiso de dolor echarse en el mar; mas por el piloto fué detenida antes; apartándola á una parte del esquife, en secreto le dijo: No tomes pena de lo hecho, hermosa dama, y sossiega tu corazón, que todo se hace por tu servicio. Has de saber, señora, que éste Marcelio, cuando llegamos á la
isla desierta, me habló secretamente y me rogó que te aconsejase que passasses para cazar á la isla, y cuando estuviéssemos en mar, encaminasse la proa hacia Levante, señalándome que estaba enamorado de ti y quería dejar en la isla á tu hermana, por gozar de ti á su placer y sin impedimento. Y aquel no querer acompañarte era por dissimulación y por encubrir su maldad. Mas yo, que veo el valor de tu hermosura, por no perjudicar á tu merescimiento, en el punto que había de hacerte la traición, he determinado serte leal y he atado á Marcelio, como has visto, con determinación de dejarle ansí á la ribera de una isla que cerca de aquí está y volver después contigo adonde dejamos á Alcida. Esta razón te doy de lo hecho; mira tú agora lo que determinas.
Oyendo esto Clenarda, creyó muy de veras la mentira del traidor, y túvome una ira mortal, y fué contenta que yo fuesse llevado donde Bartofano dijo. Mirábame con un gesto airado, y de rabia no podía hablarme palabra, sino que en lo íntimo de su corazón se gozaba de la venganza que de mí se había de tomar, sin nunca advertir el engaño que se le
hacía. Conoscí yo en Clenarda que no le pesaba de mi prisión, y ansí le dije: ¿Qué es esto, hermana? ¿tan poca pena te paresce la mía y la tuya que tan presto hicieron fin tus llantos? ¿Quizá tienes confianza de verme presto libre para tomar venganza de estos traidores? Ella entonces, brava como leona, me dijo que mi prisión era porque había pretendido dejar á Alcida y llevarme á ella, y lo demás que el otro le había falsamente recitado. Oyendo esto sentí más dolor que nunca, y ya que no pude poner las manos en aquellos malvados, los traté con injuriosas palabras; y á ella le di tal razón, que conosció ser aquella una grande traición, nascida del amor de Bartofano. Hizo Clenarda tan gran lamento, cuando cayó en la cuenta del engaño, que las duras piedras ablandara; mas no enternesció aquellos duros corazones.
Considera tú agora que el pequeño batel por las espaciosas ondas caminando largo trecho con gran velocidad habría corrido, cuando la desdichada Alcida despertándose sola se vido, y desamparada volvió los ojos al mar y no vido el esquife; buscó gran parte de la ribera, y no halló persona. Puedes pensar, pastora, lo que debió sentir en este punto.
Imagina las lágrimas que derramó, piensa agora los extremos que hizo, considera las veces que quiso echarse en el mar y contempla las veces que repitió mi nombre. Mas ya estábamos tan lejos, que no oíamos sus voces, sino que vimos que con una toca blanca, dando vueltas en el aire con ella, nos incitaba para la vuelta. Mas no lo consintió la traición de Bartofano. Antes con gran presteza caminando, llegamos á la isla de Ibiza, donde desembarcamos, y á mí me dejaron en la ribera amarrado á una anchora que en tierra estaba. Acudieron allí algunos marineros conoscidos de Bartofano, y tales como él, y por más que Clenarda les encomendó su honestidad, no aprovechó para que mirassen por ella, sino que dieron al traidor suficiente provisión, y con ella se volvió á embarcar en compañía de Clenarda, que á su pesar hubo de seguille, y después acá nunca más los he visto, ni sabido dellos.
Quedé yo allí hambriento y atado de pies y manos. Pero lo que más me atormentaba, era la necessidad y pena de Alcida, que en la Formentera sola quedaba, que la mía luego fué remediada. Porque á mis voces vinieron muchos marineros, que siendo
más piadosos y hombres de bien que los otros, me dieron qué comiesse. E importunados por mí, armaron un bergantín, donde puestas algunas viandas y armas se embarcaron en mi compañía, y no passó mucho tiempo que el velocíssimo navío llegó á la Formentera, donde Alcida había quedado. Mas por mucho que en ella busqué y di voces, no la pude hallar ni descubrir. Pensé que se había echado en el mar desesperada ó de las silvestres fieras había sido comida. Mas buscando y escudriñando los llanos, riberas, peñas, cuevas y los más secretos rincones de la isla, en un pedazo de peña hecho á manera de padrón hallé unas letras escriptas con punta de acerado cuchillo, que decían:
Soneto. Arenoso, desierto y seco prado, tú, que escuchaste el son de mi lamento, hinchado mar, mudable y fiero viento, con mis suspiros tristes alterado. Duro peñasco, en do escripto y pintado perpetuamente queda mi tormento,
dad cierta relación de lo que siento, pues que Marcelio sola me ha dejado.
Llevó mi hermana, á mí puso en olvido, y pues su fe, su vela y mi esperanza al viento encomendó, sedme testigos, Que más no quiero amar hombre nascido, por no entrar en un mar do no hay bonanza, ni pelear con tantos enemigos.
No quiero encarescerte, pastora, la herida que yo sentí en el alma cuando leí las letras, conosciendo por ellas que por ajena alevosía y por los malos sucessos de Fortuna quedaba desamado, porque quiero dejarla á tu discreción. Pero no queriendo vida rodeada de tantos trabajos, quise con una espada traspassar el miserable pecho, y assí lo hiciera si de aquellos marineros con obras y palabras no fuera estorbado. Volviéronme casi muerto en el bergantín, y condescendiendo con mis importunaciones, me llevaron por sus jornadas camino de Italia, hasta que me desembarcaron en el puerto de Gayeta, del reino de
Nápoles, donde preguntando á cuantos hallaba por Alcida, y dando las señas della, vine á ser informado por unos pastores que había llegado allí con una nave española, que passando por la Formentera, hallándola sola, la recogió, y que por esconderse de mí se había puesto en hábito de pastora. Entonces yo, por mejor buscarla, me vestí también como pastor, rodeando y escudriñando todo aquel reino, y nunca hallé rastro della hasta que me dijeron que huyendo de mí, y sabiendo que tenía della información, con una nave genovesa había passado en España. Embarquéme luego en su seguimiento, y llegué acá á España, y he buscado la mayor parte della, sin hallar persona que me diesse nuevas desta cruel, que con tanta congoja busco. Esta es, hermosa pastora, la tragedia de mi vida, esta es la causa de mi muerte, este es el processo de mis males. Y si en tan pesado cuento hay alguna prolijidad, la culpa es tuya, pues para contarle por ti fuí importunado. Lo que te ruego agora es que no quieras dar remedio á mi mal, ni consuelo á mi fatiga, ni estorbar las lágrimas que con tan justa razón á mi pena son debidas.
