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Library of Congress Cataloging-in-Publication Data
Research Fellow, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
Shazad Ashraf
Consultant Colorectal Surgeon, University Hospital, Birmingham, UK
Sujata Biswas
Gastroenterology Registrar, Translational Gastroenterology Unit, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
Emma Bracey
Surgical Fellow, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
Nicolas Buchs
Colorectal Surgeon, University Hospitals of Geneva, Geneva, Switzerland
Marcus Chow
Medical Officer, Tan Tock Seng Hospital, Singapore
Christopher Cunningham
Consultant Colorectal Surgeon, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
James East
Consultant Gastroenterologist, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
Charles Evans
Consultant Colorectal Surgeon, University Hospitals of Coventry and Warwickshire, Coventry, UK
Myles Fleming
Colorectal Surgical Fellow, Auckland Hospital, Auckland, New Zealand
Luana Franceschilli
Colorectal Surgeon, University of Rome Tor Vergata, Rome, Italy
Bruce George
Consultant Colorectal Surgeon, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
Kim Gorissen
Consultant Colorectal and Emergency Surgeon, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
Martijn Gosselink
Colorectal Surgeon, Erasmus Medical Centre, Rotterdam, The Netherlands
Richard Guy
Consultant Colorectal Surgeon, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
Roel Hompes
Consultant Colorectal Surgeon, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
Gareth Horgan
Consultant Gastroenterologist, Naas General Hospital, Dublin, Ireland
Oliver Jones
Consultant Colorectal Surgeon, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
Heman Joshi
Specialist Surgical Registrar, St Helens and Knowsley NHS Trust, Merseyside, UK
Rebecca Kraus
Colorectal Surgeon, University Hospital, Basel, Switzerland
Simon Leedham
Consultant Gastroenterologist, Translational Gastroenterology Unit, Oxford University Hospitals NHS Foundation Trust, Oxford, UK; Wellcome Trust Centre for Human Genetics, Oxford University, Oxford, UK
Ian Lindsey
Consultant Colorectal Surgeon, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
Richard Lovegrove
Colorectal Fellow, Mount Sinai Hospital, University of Toronto, Toronto, Canada
Marc Marti-Gallostra
Colorectal Surgeon, University Hospital Vall d'Hebron, Barcelona, Spain
Ami Mishra
Consultant Colorectal Surgeon, West Suffolk Hospital, Bury St. Edmunds, Suffolk, UK
Neil Mortensen
Professor of Colorectal Surgery, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
Alistair Myers
Colorectal Surgeon, Hillingdon Hospital NHS Foundation Trust, London, UK
Par Myrelid
Colorectal Surgeon, University Hospital of Linkoping, Linkoping, Sweden
Jonathan Randall
Consultant Surgeon, University Hospitals, Bristol, UK
Frederic Ris
Consultant Colorectal Surgeon, University Hospitals of Geneva, Geneva, Switzerland
Astor Rodrigues
Consultant Paediatric Gastroenterologist, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
Silvia Silvans
Colorectal Surgeon, Hospital del Mar, Barcelona, Spain
Richard Tilson
Colorectal Foundation Doctor, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
Christian Toso
Visceral Surgeon and Associate Professor, University Hospitals of Geneva, Geneva, Switzerland
Koen van Dongen
Colorectal Surgeon, Maashospital Pantein, Beugen, The Netherlands
Jon Vogel
Colorectal Surgeon and Associate Professor of Surgery, University of Colorado, Colorado, US
Lai Mun Wang
Consultant Histopathologist, Department of Cellular Pathology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
Sara Q. Warraich
Colorectal Foundation Doctor, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
Kate Williamson
Gastroenterologist, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
Massarat Zutshi
Colorectal Surgeon, Cleveland Clinic, Cleveland, US
Foreword
Mastering the art and science of surgery is becoming increasingly difficult. The explosion of knowledge and technology is a threat to even a relatively new specialty like colorectal surgery. Our medical students have little exposure to the subject and need instant tutorials, our trainees struggle with the increasing complexity of operative surgery, and consultant staff are beginning to subspecialize. Everyone is finding it difficult to keep up. If you agree then this accessible, readable, and very enjoyable book will help.
Although not in quite the same league as the Case Records of the Massachusetts General Hospital, we have a weekly academic meeting in Oxford at which one of the residents or consultant staff presents a “case of the week.” The diagnosis, management, and outcome of each are poked, prodded, and recorded so that we can address our ignorance, learn from our mistakes, and look at controversies from every point of view.
This book distils some of these cases into 52 clinical vignettes arranged into groups of colorectal cancer, inflammatory bowel disease, proctology, and emergency surgery. For each group, there is a background chapter, and then the cases are presented with a discussion point, a series of learning points, and an important paragraph, “Could we have done better?” A particularly nice touch is the Letter from America in which one of our former residents looks at how US guidelines and practice might have differed from ours.
The Editors have done a great job choosing and putting together a terrific range of cases, some of which I remember only too well. And on reflection, yes, we could have done better.
Neil Mortensen, Oxford
Section A Colorectal cancer
Bruce George
Oxford University Hospitals NHS Foundation Trust, Oxford, UK
Incidence
Colorectal cancer (CRC) is the second most common cause of cancer-related mortality in the Western world. Approximately 6% of the population will develop CRC during their lifetime.
Pathogenesis
Colorectal cancer develops through a stepwise accumulation of genetic and epigenetic alterations. There are three major molecular mechanisms involved in colorectal carcinogenesis:
chromosomal instability
microsatellite instability
CpG island methylation.
Chromosomal instability
In the late 1980s, Vogelstein et al. described a series of genetic alterations resulting in change from normal colonocytes through adenoma to carcinoma. Key genes in this process include adenomatous polyposis coli (APC), k-ras and p53, all of which code for proteins critically involved in regulation of cell turnover. APC is a tumor suppressor gene on chromosome 5q21 (long arm of chromosome 5). The APC protein controls degradation of beta-catenin which is involved in the control of epithelial cell turnover. Mutation of the APC gene results in accumulation of beta-catenin which, in turn, alters expression of several genes affecting cell proliferation, differentiation, and apoptosis. Germline mutation in the APC gene results in familial adenomatous polyposis (FAP).
Microsatellite instability
Microsatellites are short repeat nucleotide sequences found throughout the genome and are prone to errors during replication. Mutations in mismatch repair genes result in an increased risk of CRC. Tumors associated with defects in DNA mismatch repair are characterized by increased microsatellite instability. Germline mutations in mismatch repair genes result in hereditary nonpolyposis colorectal cancer (HNPCC).
CpG island methylation
More recently, epigenetic influences such as DNA methylation have been found to be involved in tumorigenesis. Normally, only about 3–4% of all cytosines in DNA are methylated and methylation only occurs at cytosines at the 5' end of guanine (CpGs). Clusters of CpGs tend to occur in the promoter region of many genes. Increased methylation of CpGs at the promoter end of tumor suppressor genes may result in reduced activation of the genes, resulting in increased tumor risk. Environmental factors may exert their influence on carcinogenesis through epigenetic mechanisms.
Awareness of the molecular changes in individual tumors is likely to become increasingly important in individualizing treatment. Sporadic tumors, for example, with features of high microsatellite instability, tend to respond poorly to 5-fluorouracil (5FU) chemotherapy.
Risk factors for colorectal cancer
Increasing age, a family history of CRC and long-term ulcerative colitis (UC) or Crohn's colitis are major risk factors for the development of CRC. Rare situations in which the risk is slightly increased include acromegaly, renal transplantation, and a history of abdominal irradiation.
Family history
Twin studies suggest that about 20% of CRC have an inherited predisposition. The mechanism of inherited risk is well characterized in patients with FAP (about 1% of all CRC) and HNPCC (about 3–5% of all CRC), but not in the remainder of those with a positive family history.
Familial adenomatous polyposis is an autosomal dominant condition resulting from mutation in the APC gene. The disease is characterized by the development of multiple polyps, usually over 100, in adolescence and, unless treated, inevitable progression to colon cancer. Extracolonic features include gastroduodenal polyps – with a lifetime risk of duodenal cancer of 12% – and desmoid tumors. The precise site of the mutation in the APC gene correlates with the clinical phenotype, for example the risk of developing desmoid tumors.
Hereditary nonpolyposis colorectal cancer is an autosomal dominant condition caused by a germline mutation in DNA mismatch repair genes. Loss of mismatch repair genes results in replication errors, increased mutations, and an increased risk of malignancy. The hallmark of HNPCC is microsatellite instability. Individuals with HNPCC tend to develop tumors at a younger age than those with sporadic tumors and are also at increased risk of other tumors, especially endometrial, gastric, ovarian, and urinary tract.
It is impractical to genetically test all family members of patients with CRC for HNPCC, and various criteria have been developed to identify patients and families likely to have HNPCC, the most common being the Amsterdam Criteria (Box A.1).
Box A.1 Amsterdam criteria for the diagnosis of HNPCC
Amsterdam I
At least three relatives with CRC, one of which should be a first-degree relative of the other two
At least two successive generations affected
At least one CRC diagnosed before the age of 50 years
FAP excluded
Tumors verified histologically
Amsterdam II
At least three relatives with an HNPCC-associated cancer, one of which should be a first-degree relative of the other two
At least two successive generations affected
At least one CRC diagnosed before age 50 years
FAP excluded
Tumors verified histologically
Diet and lifestyle
A high-fiber diet has been postulated for many years to be associated with a reduced risk of CRC, although results from several meta-analyses show conflicting results. The EPIC study suggests that a high-fiber diet is associated with a 40% risk reduction. On the other hand, red meat, smoking, alcohol, and obesity have been associated with an increased risk. Increased physical exercise has been shown to be independently associated with a reduced risk.
Long-term aspirin therapy has been shown in several studies with over 20-year follow-up to be associated with a reduced risk, although a recent consensus group felt that further research was needed before aspirin could be recommended as chemoprevention for high-risk groups [1].
