15.16 Cancers of the gastrointestinal tract 2977

15.16 Cancers of the gastrointestinal tract 2977

ESSENTIALS Cancers of the gastrointestinal tract are one of the most rewarding interfaces in translational medicine, leading to greater understanding of the genetic mechanisms leading to cancer and the development of novel targeted therapies. Diagnosis of gastrointestinal tract cancers is usually made or suspected at endoscopy and confirmed by biopsy. Oesophageal cancer A common cancer, usually of squamous cell histology, that is particu- larly prevalent in East Asia and Southeast Africa. Typical presentation is with dysphagia. Staging investigations include contrast-​enhanced CT, 2-​[18F] fluoro-​2-​deoxy-​d-​glucose positron emission tomography CT (FDG PET-​CT), and endoscopic ultrasonography. In patients who are fit and suitable for surgery, neoadjuvant chemotherapy improves survival, but most patients are elderly with comorbid disease and un- suitable for curative surgery, and many others present with advanced disease such that palliation with or without systemic therapy is the only option. Overall survival at 5 years is 15%. Stomach cancer Usually adenocarcinoma, this is particularly prevalent in East Asia, Eastern Europe, and Western South America. Predisposing factors include Helicobacter pylori infection, low socioeconomic status, to- bacco smoking, heavy alcohol use, and diet. Dysphagia, early satiety, and anaemia are common presenting features, with weight loss being an indication of advanced disease. Tumour staging is by CT with or without FDG PET-​CT. Best treatment, when appropriate and when possible, is by surgery with extensive nodal resection combined with perioperative chemotherapy with or without adjuvant radiotherapy. Patients with advanced disease require palliation. Overall survival at 5 years is 18.9%. Colorectal cancer This is the third most common cancer in men and second most common in women worldwide, and is predisposed to by a Western diet. Most cases arise by transformation of an adenoma to a car- cinoma by sequential inherited and acquired mutations. Typical presentations of left-​sided tumours are alteration in bowel habit, obstruction, or overt bleeding, whereas right-​sided tumours often present with iron-​deficiency anaemia. Patients are staged by CT, supplemented by liver MRI if there is doubt about hepatic spread, and pelvic MRI for rectal cancers. Surgical resection is the primary treatment and potentially curative. Neoadjuvant therapies are used in high-​risk rectal cancers and adjuvant chemotherapy in colon can- cers. Colonic stenting can relieve bowel obstruction. Overall survival at 5 years is now almost 60%. Introduction Cancers of the gastrointestinal tract provide a paradigm for the in- vestigation and treatment of cancer. The relationship between de- velopments in basic research and progress in clinical management has generated one of the most rewarding interfaces in translational medicine, particularly with respect to novel targeted therapies. This has occurred on the background of an increasing understanding of the genetic predisposition to cancer, in particular the influence of common, low-​penetrance susceptibility alleles in conferring pre- disposition to neoplasia. Examples of this include sporadic colo- rectal carcinoma as well as better understood genetic syndromes (Table 15.16.1). There is also increasing interest in the influence of genetic polymorphisms that predict toxicity from systemic treatments. For example, UGT1A1 codes for UDP-​glucuronyl transferase which is normally responsible for the conversion of unconjugated bilirubin into conjugated bilirubin but is also known to convert the breakdown products of irinotecan to their inactive form (SN-​ 38 to SN-​38G). Certain polymorphisms in this gene have been shown to be associated with a greater risk of irinotecan toxicity (diarrhoea, neutropenia) and response to therapy in metastatic colorectal cancer. Another example is the microsatellite instability pathway, which involves deficiency of the nucleotide mismatch re- pair (MMR) system. This deficiency occurs in 12 to 15% of spor- adic colorectal cancers and is associated with a more favourable prognosis than patients with intact MMR pathways. Evidence suggests that patients with stage II deficient MMR colon cancers do not benefit from adjuvant 5-​fluorouracil (5-​FU) and are best treated with surgery alone. More recently deficient MMR has been shown to define a cohort of advanced disease patients who respond to checkpoint inhibition. 15.16 Cancers of the gastrointestinal tract Peter L. Labib, J.A. Bridgewater, and Stephen P. Pereira

section 15  Gastroenterological disorders 2978 The potential benefits of such approaches to the diagnosis and treatment of gastrointestinal tumours cannot be overstated. Although much of the translational work and trials using novel tar- geted agents to date have been in colorectal cancer, they are of poten- tial relevance to all types of gastrointestinal malignancy. Oesophageal cancer Epidemiology Oesophageal cancer is the eighth most common cancer worldwide with over 450 000 new cases per annum (Fig. 15.16.1). Mortality rates parallel incidence and, despite progress in diagnosis and treat- ment, there has been little overall impact on survival. The overall trends in incidence vary significantly by country and sex, with the highest rates found in East Asia and Southeast Africa. Worldwide, there is a 21-​fold variation in the incidence rates be- tween different regions and a three to fourfold higher incidence in men compared to women. In the United Kingdom, between 2005 and 2015, age-​standardized incidence rates remained stable. Marked variation between ethnic groups has also been reported, although results are conflicting depending on the ethnic groups studied and the country in which the studied populations reside. Geographical location and ethnicity are likely to affect predisposing genetic and environmental risk factors. Squamous cell carcinoma (SCC) is the more common histological subtype in East Asia and is more closely linked to smoking and to- bacco use. Conversely, adenocarcinoma of the oesophagus is more common in the United States of America and Europe and is more closely associated with obesity, gastro-​oesophageal reflux disease (GORD), and Barrett’s oesophagus. Predisposing factors Environmental The vast majority of cases of oesophageal cancer are sporadic and related to environmental factors. Environmental risk factors for oesophageal SCC include smoking (fivefold risk increase), alcohol, chewing tobacco and betel nuts, and certain micronutrient defi- ciencies. Risk factors for oesophageal adenocarcinoma include GORD and Barrett’s oesophagus (6–​14% of patients with GORD will develop Barrett’s oesophagus, and up to 1% of these will de- velop oesophageal cancer), obesity, smoking, and diets low in fibre, fruits, and vegetables. Other risk factors include achalasia, oesophageal strictures due to ingestion of corrosives, radiotherapy, and coeliac disease. Plummer–​ Vinson syndrome, characterized by the triad of iron deficiency anaemia, dysphagia, and oesophageal webs, is associated with oe- sophageal SCC in 2 to 5% of cases. Genetic There are some rare recognized genetic syndromes. Tylosis palmoplantaris is an autosomal dominant syndrome characterized by hyperkeratosis of the palms and soles and a 40-​fold increased risk of SCC of the oesophagus; a mutation in RHBDF2 on chromosome 17q25 codes for an inactive protein (iRHOM2) that normally plays a role in epidermal growth factor receptor (EGFR) signalling. For an affected family member, the estimated lifetime risk of cancer is 95% by age 65. Up to 7% of cases of Barrett’s oesophagus and oesopha- geal adenocarcinomas occur in family clusters, although the genetic basis behind this observation remains unclear. Pathology Middle and upper oesophageal cancers are more likely to be SCC, whereas those in the lower oesophagus are more commonly adeno- carcinoma. SCC and adenocarcinoma account for most oesophageal cancers, with less than 2% being other histological types such as sar- coma, small-​cell cancer, or lymphoma. Clinical features and investigation Patients classically present with progressive dysphagia, initially to solids and then to liquids. Other late symptoms such as dyspnoea, a hoarse voice, pain, and weight loss suggest advanced disease and confer a poor prognosis. Initial diagnosis is made at upper Table 15.16.1  Gastrointestinal cancer syndromes, their molecular defects, and cancer risk Clinical syndrome Cancer risk Gene Normal gene function Cowden syndrome 9–​16% PTEN Multifunctional tumour suppressor enzyme Familial adenomatous polyposis (FAP) 100% (69% in attenuated FAP) APC Tumour suppressor protein that acts as an antagonist in the WNT signalling pathway Juvenile polyposis 38–​68% BMPR1A Transmembrane receptor that binds to ligands involved in TGFβ pathway, leading to activation of SMAD proteins SMAD4 Transcription factor and tumour suppressor Lynch’s syndrome (HNPCC) M: 27–​74% F: 22–​61% MLH1/​MSH2 DNA MMR M: 22–​69% F: 10–​30% MSH6 DNA MMR M: 20% F:15% PMS2 DNA MMR MUTYH-​associated polyposis 43–​100% MUTYH DNA base excision repair (corrects A–​G base pair mismatches) Peutz–​Jeghers syndrome 39% STK11 Tumour suppressor enzyme involved in polarization and apoptosis F, female; M, male. Adapted from Syngal S, et al. (2015). ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol, 110, 223–​62.

15.16  Cancers of the gastrointestinal tract 2979 gastrointestinal endoscopy (Fig. 15.16.2a) or occasionally by con- trast radiology, and confirmed by endoscopic biopsy. Standard sta- ging investigations include contrast-​enhanced CT (Fig. 15.16.3), 2-​[18F] fluoro-​2-​deoxy-​d-​glucose positron emission tomography (FDG PET-​CT) to exclude distant disease, and endoscopic ultrason- ography (EUS) in selected cases (Fig. 15.16.2b) to better stage the primary tumour in anticipation of surgery. Management Curative-​intent treatment For most patients with operable disease and an adequate perform- ance status, the preferred treatment is surgery combined with neoadjuvant chemotherapy or chemoradiotherapy. The surgical ap- proach depends on the site of the tumour and can be open, minimally invasive, or a combination of the two. Preoperative chemotherapy has been shown to confer an improved overall survival compared to surgery alone, with no difference in morbidity or postoperative mortality. Preoperative chemoradiotherapy leads to improved overall survival and disease-​free survival and no difference in com- plications such as anastomotic leak, but worse rates of treatment-​re- lated mortality. For early-​stage (T1aN0) disease, endoscopic mucosal resec- tion provides similar overall survival to oesophagectomy. Radical chemoradiotherapy can also be considered for selected patients with T1bN0 disease. Male Eastern Asia (a) Southern Africa Eastern Africa Less developed regions World Northern Europe South-Central Asia South America Western Europe More developed regions Australia/New Zealand Northern America Central and Eastern Europe Middle Africa Caribbean Western Asia Melanesia South-Eastern Asia Northern Africa Southern Europe Micronesia Polynesia Central America Western Africa 20 15 10 5 0 5 10 15 20 Female Incidence Mortality Fig. 15.16.1  (a) Estimated age-​standardized incidence and mortality rates per 100 000 for oesophageal cancer worldwide by sex, 2012 estimates. (b) Trends in age-​standardized incidence of oesophageal cancer in men in selected countries per 100 000 population, 2012. (c) Trends in age-​standardized incidence of oesophageal cancer in women in selected countries per 100 000 population, 2012. Reproduced with permission from Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray, F. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 2013. Available from: http://​gco.iarc. fr/​today/​home, accessed on 23 May 2018.

section 15  Gastroenterological disorders 2980 Palliative treatment Many patients with oesophageal cancer are of an advanced age with comorbidities that often make them unsuitable candidates for curative-​ intent treatment. In inoperable nonmetastatic oesophageal cancer, chemoradiotherapy confers a better overall survival than radiotherapy alone, although if high-​dose radiotherapy is not possible (e.g. the tumour cannot fit within the radiotherapy field) then chemotherapy, local treat- ments (e.g. stenting), or palliative dose radiotherapy can be considered. 15 (b) 10 5 0 15 10 5 0 1975

• = regional data 1980 1985 1990 1995 2000 2005 2010 1975 1980 1985 1990 1995 2000 2005 2010 Denmark Finland France* Slovakia Spain* England China* India* Japan* Philippines* Singapore Thailand* 10 (c) 3 4 5 6 7 8 9 0 1 2 10 3 4 5 6 7 8 9 0 1 2 1975
• = regional data 1980 1985 1990 1995 2000 2005 2010 1975 Denmark Finland France* Slovakia Spain* England China* India* Japan* Philippines* Singapore Thailand* 1980 1985 1990 1995 2000 2005 2010 Fig. 15.16.1  Continued

15.16  Cancers of the gastrointestinal tract 2981 In patients with metastatic disease and an adequate perform- ance status, first-​line chemotherapy consists of a combination of two or three agents, typically including 5-​FU or capecitabine with a platinum-​based agent. In patients with HER2-​positive adeno- carcinoma of the gastro-​oesophageal junction, the anti-​HER2 monoclonal antibody trastuzumab may be used in addition to double-​agent chemotherapy. Second-​line chemotherapy can be con- sidered in selected patients, where both taxane and irinotecan based schedules are modestly effective. Several local treatments are available for the palliative manage- ment of dysphagia. Metal stenting provides immediate relief, al- though external beam radiotherapy is associated with a greater overall survival (+77 days). However, external beam radiotherapy often temporarily worsens dysphagia and so is not always suitable as a primary treatment (although it can be offered poststenting). If external beam radiotherapy is not possible, brachytherapy can be considered if available. Other treatment options such as laser, balloon dilatation, and photodynamic therapy are possible but not widely used in clinical practice. Prognosis Despite an improvement in survival over the last four decades, overall age-​standardized 5-​year overall survival is currently 15% in the United Kingdom. The Surveillance, Epidemiology, and End Results (SEER) cancer statistics review (1975–​2014) from the National Cancer Institute (United States of America) reported a 5-​year overall survival from diagnosis of 38.5%, 20.7%, and 3.9% for local, regional, and distant disease, respectively. Stomach cancer Epidemiology Like oesophageal cancer, stomach cancer occurs mainly in older people and has a striking variation in worldwide incidence (Figs. 15.16.4a and 15.16.4b). There are an estimated 952  000 cases per annum globally, with 60% of cases occurring in just three countries—​China, Japan, and Korea. However, there has been a marked change from historical rates; 40 years ago, stomach cancer was the most common neoplasm globally, whereas now it is the fifth most common. In the United Kingdom, the incidence of stomach cancer has reduced from 31.8 per 100 000 in 1971 to 11.3 per 100 000, with a peak incidence in the ninth decade. International vari- ation is thought to be due to a combination of dietary differences, salt consumption and the prevalence and virulence of Helicobacter pylori infections in different regions. Predisposing factors Environmental Environmental risk factors are variable depending on the site of stomach cancer. Noncardia stomach cancers are associated with H. pylori infection, low socioeconomic status, high intake of smoked and salted food, and low consumption of fruit and veget- ables. Cancers of the cardia, such as oesophagogastric tumours, are associated with obesity and GORD. Risk factors common to both sites are age, male sex, smoking, heavy alcohol consumption, family history, radiation exposure, low fibre intake, and low physical ac- tivity. Ethnic differences are likely to be driven by environmental exposures; first-​generation Japanese expatriates in the United States of America have the same risk of stomach cancer as the domestic Japanese population, but their grandchildren have the same risk as their American Caucasian counterparts. Genetic Whole-​genome association studies in East Asian populations have identified several single-​nucleotide polymorphisms associ- ated with gastric cancer; these include prostate stem cell antigen (PSCA, possibly has a tumour suppressor function in the stomach), Mucin-​1 (MUC1, a membrane-​bound protein providing a barrier function), and PLCE1 (phospholipase C epsilon 1, linked to mul- tiple pathways and processes for cell survival and growth). Although the vast majority of cases are sporadic, genetic syn- dromes account for 1 to 3% of cases of stomach cancer. Hereditary diffuse gastric cancer is an autosomal dominant disorder Fig. 15.16.3  Axial CT image demonstrating circumferential thickening of the upper oesophagus (arrow), consistent with oesophageal carcinoma. Case courtesy of Dr Roberto Schubert, Radiopaedia.org. (b) (a) Fig. 15.16.2  (a) Mass arising from a Barrett’s oesophagus segment at endoscopy. Note the abnormal epithelium which lies distally and around the mass. (b) Endoscopic ultrasound examination demonstrating the mass that has not penetrated the wall of the oesophagus (short arrow) and an associated enlarged lymph node (long arrow).

section 15  Gastroenterological disorders 2982 < 3.4 3.4–5.2 5.2–7.4 7.4–10.9 ≥ 10.9 (a) No data Not applicable All rights reserved. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization / International Agency for Research on Cancer concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps represent approximate borderlines for which there may not yet be full agreement. © International Agency for Research on Cancer 2018 Data source: GLOBOCAN 2012 Map production: IARC (http://gco.iarc.fr/today) World Health Organization Fig. 15.16.4  (a) Estimated age-​standardized incidence rates per 100 000 for stomach cancer worldwide, 2012 estimates. (b) Trends in age-​standardized incidence of stomach cancer in men in selected countries per 100 000 population, 2012. (c) Trends in age-​standardized incidence of stomach cancer in women in selected countries per 100 000 population, 2012. (a) Reproduced with permission from Ervik M, Lam F, Ferlay J, Mery L, Soerjomataram I, Bray F (2016). Cancer Today. Lyon, France: International Agency for Research on Cancer. Cancer Today. Available from:
http://​gco.iarc.fr/​today, accessed on 23 May 2018. (b) and (c) Reproduced with permission from Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray, F. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 2013. Available from: http://​gco.iarc.fr/​today/​home, accessed on 23 May 2018.

15.16  Cancers of the gastrointestinal tract 2983 80 (b) 70 60 50 40 30 20 10 0 1975

• = regional data 1980198519901995200020052010 80 70 60 50 40 30 20 10 0 19751980198519901995200020052010 Denmark Finland France* Slovakia Spain* England China* India* Japan* Philippines* Singapore Thailand*

40 (c) 30 20 10 0 1975

• = regional data 1980198519901995200020052010 40 30 20 10 0 19751980198519901995200020052010 Denmark Finland France* Slovakia Spain* England China* India* Japan* Philippines* Singapore Thailand* Fig. 15.16.4  Continued

section 15  Gastroenterological disorders 2984 characterized by reduced expression of E-​cadherin (25% of fam- ilies with this condition have a mutation in the CDH1 gene that codes for cadherin) and development of a highly invasive form of diffuse gastric cancer. Hereditary diffuse gastric cancer confers a lifetime risk of stomach cancer of over 80% by age 80, with a me- dian age at diagnosis of 38. Other hereditary syndromes that increase the risk of gastric cancer are familial adenomatous polyposis (FAP), Peutz–​Jeghers syndrome, and Lynch’s syndrome (see Table 15.16.1 and ‘The polyp- osis syndromes’ below). Although there have been historical claims that the French emperor Napoléon Bonaparte’s stomach cancer was familial, a 2007 analysis suggested that his cancer was more likely sporadic with his main risk factor being H. pylori infection. Pathology Most stomach cancers (90–​95%) are adenocarcinomas, with the remaining cancers usually being lymphomas, gastrointestinal stromal tumours (GISTs), or carcinoid tumours. Macroscopically, the Borrmann classification describes gastric tumours as polypoid, fungating, ulcerating, or diffusely infiltrating. The last of these is known clinically as linitis plastica (histologically a signet-​ring cell carcinoma that is associated with poorer survival). The Lauren classification has been used for the last 50 years and divides gastric adenocarcinoma into intestinal type (54%), diffuse type (32%), and indeterminate type (15%). Intestinal type is more commonly associated with H. pylori infection and diffuse type is more common in female and younger patients. The World Health Organization classification (2010) for gastric adenocarcinoma sub- divides into four major (papillary, tubular, mucinous, signet ring cell and other poorly cohesive carcinomas) and many rarer histological variants. Clinical features and investigation Dysphagia, early satiety, and anaemia are common presenting fea- tures, with weight loss being an indication of advanced disease. Gross haematemesis is unusual. An epigastric mass is palpable in about 30% of patients, and palpable lymphadenopathy in the left supraclavicular fossa (Virchow’s node/​Troisier sign) may be present. Metastasis occurs to the peritoneum (with ascites and ovarian in- volvement known as Krukenberg’s tumour), to the liver, and in later stages to the lung and other sites. Gastric cancer is the most common malignancy to be associated with dermatomyositis or acanthosis nigricans. Diagnosis is usually made by upper gastrointestinal endos- copy (Fig. 15.16.5) and biopsy. Tumour staging is by CT scan. Patients require careful assessment to determine fitness for surgery. Occasionally, staging laparoscopy or FDG PET-​CT is used to deter- mine resectability. Management Curative-​intent treatment Radical surgery (total or subtotal gastrectomy) with lymphadenectomy can offer cure for localized gastric cancer. Depending on the tumour site, D2 lymphadenectomy (removal of all perigastric nodes and nodes surrounding major arterial trunks) has a marginal benefit in overall survival compared to D1 lymphadenectomy (removal of perigastric nodes only). Complete surgical removal plays a critical role in overall survival; patients with a negative resection margin (R0) have a greater overall survival than patients with a positive resection margin (R1), even if attempts are then made to convert the R1 to an R0 resection by extending the surgical margin (Fig. 15.16.6). Due to the high risk of locoregional and metastatic recurrence, several randomized controlled trials have investigated the role of neoadjuvant, adjuvant, and perioperative (both neoadjuvant and adjuvant) chemotherapy, with or without radiotherapy. Compared to surgery alone, there is evidence that overall survival is improved by perioperative and adjuvant chemotherapy but not neoadjuvant chemotherapy alone. Adjuvant chemoradiotherapy improves overall survival compared to adjuvant chemotherapy, but with a high risk of treatment morbidity. Based on the available evidence, the current National Institute for Health and Care Excellence (NICE) guidelines recommend offering perioperative chemotherapy for patients undergoing curative-​intent resection. If no neoadjuvant treatment was given preoperatively, patients should be offered adjuvant chemotherapy or chemoradiotherapy. Fig. 15.16.5  Endoscopic images of gastric cancer. From Jahng J, et al. (2012). Endoscopic and clinicopathologic characteristics of early gastric cancer with high microsatellite instability. World J Gastroenterol, 18, 3571–​7.

15.16  Cancers of the gastrointestinal tract 2985 Palliative treatment Palliation of proximal gastric obstruction and palliative chemo- therapy is similar to that for oesophageal cancers, including deter- mination of HER2 status and use of trastuzumab. Malignant gastric outlet obstruction can be palliated with stenting, although this is less successful (there is a 25% stent migration or fracture rate) than for stents placed more proximally. Surgical bypass is an option for patients who are sufficiently fit, but postsurgical gastroparesis is common, particularly in those with metastatic disease. Prognosis Despite an improvement in survival over the last four decades, overall age-​standardized 5-​year overall survival is currently 18.9% in the United Kingdom. The SEER cancer statistics review (1975–​2014) reported a 5-​year overall survival from diagnosis of 63.6%, 28.0%, and 4.3% for local, regional, and distant disease respectively. Small bowel cancers Epidemiology and pathology Small-​bowel cancers are rare; in the United States of America they represent 3% of gastrointestinal malignancies and 0.6% of all can- cers. Although rare in the United Kingdom (1500 cases per annum), the incidence of small-​bowel cancer has more than doubled in the last 25 years (Fig. 15.16.7). Common histological subtypes are adenocarcinoma (40%, most often in the duodenum), neuroendocrine tumours (NETs) (40%, most often carcinoid tumours in the ileum or appendix), and lymphomas (10%, most often found in the jejunum). Predisposing factors Environmental risk factors for small-​bowel adenocarcinoma in- clude alcohol consumption, smoking, and high consumption of sugar, refined carbohydrates, red meat, and smoked food. 1.0 0.8 0.6 0.4 0.2 0.0 0 Total 447 48 25 271 27 17 167 18 10 116 8 4 83 6 2 58 p=0.l4 p=0.02 PS-R1 (n = 25) FS-R1-to-PS-R0 (n = 48) PS-R0 (n = 447) 5 1 PS-R0 FS-R1-to-PS-R0 PS-R1 1 yr 2 yrs 3 yrs 4 yrs 5 yrs 12 24 36 Time (months) Overall Survival Proportion Surviving 48 60 72 Fig. 15.16.6  The effect of proximal margin status on overall survival following curative-​intent surgery for gastric cancer. PS-​R0, permanent section R0; FS-​R1-​to-​PS-​R0, frozen section R1 to permanent section R0; PS-​R1, permanent section R1. R1 margin status confers a survival disadvantage, even if attempts to extend the margin to achieve complete clearance (R0) are made. Reprinted by permission from Springer Nature: Squires MH, et al. (2014). Utility of the proximal margin frozen section for resection of gastric adenocarcinoma: A 7-​institution study of the US gastric cancer collaborative. Ann Surg Oncol, 21, 4202–​10. 3.0 2.5 2.0 1.5 1.0 Year of Diagnosis Incidence Rate per 100,000 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2014 2013 2015 Males Persons Females Fig. 15.16.7  Age-​standardized incidence rates of small bowel cancer in the UK, 1993 to 2015. Cancer Research UK (http://​www.cancerresearchuk.org/​).

section 15  Gastroenterological disorders 2986 Chronic inflammation of the small intestine also predisposes to carcinogenesis. Crohn’s disease increases the risk of small-​bowel adenocarcinoma with an estimated cumulative risk of 2.2% after 25 years. Coeliac disease is associated with both adenocarcinoma and small-​bowel lymphoma. A United Kingdom study reporting on 395 new cases of small-​bowel cancer (1998–​2000) found that 39% of new diagnoses of small-​bowel lymphoma and 13% of small-​ bowel adenocarcinoma patients had a prior diagnosis of coeliac disease. Small bowel adenocarcinoma is also associated with FAP, Lynch’s syndrome, and Peutz–​Jeghers syndrome. Although historically the primary cause of death of patients with FAP was colorectal cancer, due to improved screening and prophylactic proctocolectomy, duodenal adenocarcinoma is now the leading cause of cancer-​ related mortality in these patients. FAP patients are normally en- rolled in a duodenal surveillance programme undergoing regular duodenoscopies to monitor for duodenal polyps. Lynch’s syndrome, caused by a germline mutation of a DNA MMR gene, confers a 1% risk of small bowel adenocarcinoma. Peutz–​Jeghers syndrome, char- acterized by widespread hamartomatous polyposis and oral hyper- pigmentation, confers a 500-​fold increased risk of small-​bowel adenocarcinoma. Clinical features and investigation Symptoms are typically nonspecific and include intermittent ab- dominal pain, weight loss, nausea and vomiting, gastrointestinal bleeding, change in bowel habit, and anaemia. More distal tumours may present with small-​bowel obstruction. The diagnosis is usually made by upper gastrointestinal endos- copy or during surgery, in part due to the inaccuracy and low sensi- tivity of abdominal CT in detecting such lesions (47%). Newer and more accurate noninvasive investigations with greater diagnostic accuracy than conventional abdominal CT include CT enteroclysis, magnetic resonance enteroclysis, and capsule endoscopy. Management Localized adenocarcinomas, NETs, and GISTs are best treated with surgery, which may be as limited as a wide local excision in the distal small bowel but as extensive as a pancreaticoduodenectomy in the case of duodenal adenocarcinoma. There is a paucity of data and trials to support the use of adjuvant or palliative chemotherapy in small-​bowel tumours, although this is likely due to the impracticality of recruiting enough patients for adequately powered trials rather than a true lack of treatment ef- fect. Of note, most GISTs (>85%) have a mutation in the KIT proto-​ oncogene and the adjuvant use of the tyrosine kinase inhibitor imatinib was shown in the SSG XVIII trial to improve relapse-​free survival (66% vs 48%) and 5-​year overall survival (92% vs 82%) in high-​risk GISTs. Imatinib and other tyrosine kinase inhibitors are also used in the palliative setting, although development of treatment resistance re- mains an issue. As carcinoid metastases are often hypervascular, liver metastases are sometimes amenable to hepatic artery-​based therapies such as embolization. Somatostatin analogues may pro- vide symptomatic control of hormonally active carcinoid tumours, although this does not reduce the tumour burden. Small-​bowel lymphomas are best treated with chemotherapy. Prognosis Although complete surgical excision can achieve long-​term survival, most patients are diagnosed with advanced disease due to the nonspecific nature of symptoms. Despite this, survival is more favourable than oesophageal or stomach cancers. The SEER data- base (2007–​2013, all histological subtypes) reported a 5-​year overall survival from diagnosis of 85.3%, 73.6%, and 42.2% for local, re- gional, and distant disease, respectively. Colorectal cancer Epidemiology Colorectal cancer is the third most common cancer in men and the second most common in women worldwide. There is a 10-​fold vari- ation in incidence globally, with the highest rates in Australia and New Zealand and the lowest rates in Western Africa (Fig. 15.16.8a). In the United Kingdom, colorectal cancer is the fourth most common cancer with approximately 42  000 people diagnosed every year. The incidence rate in the United Kingdom has remained stable since the early 1990s and survival has more than doubled from 22% in 1975 to 57% in 2010 to 2011 (Fig. 15.16.8b). The peak incidence of the disease is in people aged 85 to 89, with less than 6% of cases diagnosed under the age of 50 years. Predisposing factors Environmental and dietary factors There several well-​established environmental risk factors for colorectal cancer (Fig. 15.16.9). A  high body mass index ap- pears to pose a higher risk to men than women, and it has been proposed that this may be secondary to differences in fat dis- tribution and central adiposity between males and females. Smoking and the consumption of red meat also increase the risk of colorectal cancer, although the relationship with smoking is not linear. Protective environmental factors include increased phys- ical activity and the consumption of fibre, fruit, and vegetables. Other factors include alcohol consumption (increased risk), pro- cessed meats (increased risk), hormone replacement therapy in postmenopausal women (reduced risk), and the use of aspirin and nonsteroidal anti-​inflammatory medication (reduced risk). Many of these factors are associated with a Westernized diet (e.g. high red meat and low fruit and vegetable consumption) which is thought to account in part for the global differences seen in inci- dence. Data from several population studies support this theory; for example, an analysis of census data from Canada found that the risk of colorectal cancer in the recently immigrated popula- tion was roughly half that of the Canadian-​born population (odds ratio 0.48 for men and 0.54 for women) but their risk converged as their years since migration increased, matching the Canadian-​ born population after 50 to 60 years. Medical conditions Type 2 diabetes has been shown in several meta-​analyses to increase the risk of colorectal cancer by 22 to 30% compared with nondiabetics. Due to the effect of chronic inflammation, inflammatory bowel

15.16  Cancers of the gastrointestinal tract 2987 < 4.9 4.9–8.5 8.5–14.4 14.4–26.3 ≥ 26.3 No data Not applicable (a) All rights reserved. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization / International Agency for Research on Cancer concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps represent approximate borderlines for which there may not yet be full agreement. Data source: GLOBOCAN 2012 Map production: IARC (http://gco.iarc.fr/today) World Health Organization © International Agency for Research on Cancer 2018 100 (b) 90 80 70 60 50 40 30 20 10 0 1980–1981 1980–1991 2000–2001 Period of Diagnosis Net Survival (%) 2005–2006 2010–2011 1971–1972 Men Women Adults Fig. 15.16.8  (a) Estimated age-​standardized incidence rates per 100 000 for colorectal cancer worldwide, 2012 estimates. (b) Trends in age-​standardized 10-​year net survival from colorectal cancer in the UK, 2010 to 2011. (a) Reproduced with permission from Ervik M, Lam F, Ferlay J, Mery L, Soerjomataram I, Bray F (2016). Cancer Today. Lyon, France: International Agency for Research on Cancer. Cancer Today. Available from: http://​gco.iarc.fr/​today, accessed on 23 May 2018. (b) Cancer Research UK: http://​www.cancerresearchuk.org/​.

section 15  Gastroenterological disorders 2988 disease confers a 70% increased risk of colorectal cancer compared to the normal population; the risk is the same for both ulcerative colitis and Crohn’s colitis. The risk increases with the duration and extent of disease. For all patients with Crohn’s colitis or ulcerative colitis, the cumulative risk of colorectal cancer after the first, second, and third decade of disease is 0.7%, 2.6%, and 6.6% respectively. In patients with extensive colitis, this risk increases to 2%, 12%, and 21% respectively. Genetic factors After excluding patients with FAP and Lynch’s syndrome, roughly one in five cases of colorectal cancer can be attributed to hereditary 16 .9 .6 .7 .8 .8 .9 1 .8 .9 1 .9 1 1.1 1.4 1.9 2.4 2.9 1 1.1 1.2 1.3 1.4 1 1.2 Relative Risk Relative Risk Relative Risk Relative Risk Relative Risk Relative Risk 1.4 1.6 0 0 5 10 Red Meat (servings/wk) 15 20 0 2 4 Fruit (servings/day) 6 8 10 20 40 Smoking (pack-yr) 60 80 0 2 4 Vegetable (servings/day) Standardized PA Score 6 8 0 2 3 4 5 18 20 22 24 26 28 Referent Adjusted BMI (kg/m2) 30 32 34 36 38 40 42 44 46 CRC Colon Overall RR Overall RR Cohort CC, colon CC, CRC Overall RR M, CRC M, colon F/B, CRC F/B, colon Overall RR Overall RR Overall RR (a) (b) (c) (d) (e) (f) Fig. 15.16.9  Relative risk of developing colon cancer in relation to: (a) body mass index (BMI); (b) physical activity (PA); (c) cigarette smoking; (d) vegetable consumption; (e) consumption of red meat; (f) fruit consumption. CC, case–​control studies; CRC, colorectal cancer; F/​B, female/​both sexes; M, male; RR, relative risk. Adapted by permission from Springer Nature: Johnson CM, et al. (2013). Meta-​analyses of colorectal cancer risk factors. Cancer Causes Control, 24, 1207–​22.

15.16  Cancers of the gastrointestinal tract 2989 factors. Having a family history of colorectal cancer in a first-​ degree relative more than doubles an individual’s risk (pooled risk of 2.24 in one meta-​analysis). Women under the age of 50 with BRCA1 mutations have a 4.8-​fold increased risk of colorectal cancer compared to the normal population. Polymorphisms in some genes have also been linked to increased colorectal cancer risk (e.g. SMAD7 and CYP2E1). The polyposis syndromes The known polyposis syndromes, many of which have some pre- disposition to malignancy, are listed in Table 15.16.2. Polyps can arise from either parenchymal or stromal cells within the colon, and many of the syndromes listed have a mixture or predominant polyp types rather than being exclusively featuring one type of polyp. Familial adenomatous polyposis FAP, although the most common of the polyposis syndromes, is re- sponsible for less than 1% of all colorectal cancers, but it is likely that this figure will continue to decrease due to improved disease detection and prophylactic colectomies in affected patients. FAP has a reported prevalence of 1 in 6850 to 1 in 3250 live births, with no major differences in incidence either globally or between males and females. The principal feature of the condition is the presence of hun- dreds to thousands of adenomatous polyps throughout the colon (Fig. 15.16.10). It is inherited as an autosomal dominant condition, although about one-​third of cases arise without a family history, demonstrating a high rate of de novo mutations. The gene respon- sible for FAP—​the adenomatous polyposis coli (APC) gene—​is Table 15.16.2  Polyps and polyposis syndromes affecting the colon Polyp type Polyposis syndrome Colorectal cancer risk Adenoma Familial adenomatous polyposis (FAP) 93% by age 50 Attenuated FAP 69% by age 80 MUTYH-​associated polyposis 43% by age 50 Serrated polyposis syndrome Up to 50% lifetime risk Hamartoma Peutz–​Jeghers syndrome 39% by age 64 Juvenile polyposis syndrome 68% by age 60 Cronkhite–​Canada syndrome 25% of cases PTEN hamartoma tumour syndromes (including Cowden syndrome,
Bannayan–​Riley–​Ruvalcaba syndrome and Lhermitte–​Duclos disease) 9–​16% lifetime risk Inflammatory Inflammatory polyposis of IBD Up to 21% after 30 years of active disease Mucosal prolapse syndrome No increased risk Neural Neurofibromatosis type I No evidence of increased risk Multiple endocrine neoplasia type 2B No evidence of increased risk Lymphoid Nodular lymphoid hyperplasia N/​A (lymphoproliferative disorder) Multiple lymphomatous polyposis N/​A (lymphoma) Other/​mixed Hereditary mixed polyposis syndrome Unknown IBD, inflammatory bowel disease; N/​APTEN, phosphatase and tensin homolog. Data sources: Burt RW, Jasperson KW (2016). Polyposis syndromes. In: Podolsky DK, Camilleri M, Fitz JG, Kalloo AN, Shanahan F, Wang TC (eds). Yamada’s textbook of gastroenterology, 6th edition. Chichester: Blackwell, pp. 1583–​607; Oh SH, Lee JH, Namgung H (2012). A case of rectal cancer in a patient with neurofibromatosis type 1.
J Korean Soc Coloproctol, 28, 170–​3. (a) (b) Fig. 15.16.10  Familial adenomatous polyposis: endoscopic (left) and pathological (right) appearance. Images courtesy of the National Cancer Institute, Miguel Rodriguez-​Bigas, MD, University of Texas, MD Anderson Cancer Center (Photographer).

section 15  Gastroenterological disorders 2990 located on chromosome 5q21 and normally acts as a tumour sup- pressor. Most mutations are nonsense mutations, resulting in a trun- cated protein of less than the predicted 310-​kDa (2843 amino acids) wild-​type APC protein. The site of the mutation correlates with the phenotypic manifestations of FAP, such as congenital hypertrophy of retinal pigment epithelium, desmoids, and the severity of polyp- osis (Fig. 15.16.11). As well as colonic polyps, most patients will also have adenomas in the duodenum, stomach, and elsewhere in the small intestine. Patients normally undergo prophylactic surgery by the age of 25 and are entered into upper gastrointestinal endoscopy surveillance programmes by the age of 30. Lynch’s syndrome (hereditary nonpolyposis colorectal cancer) Lynch’s syndrome, historically known as hereditary nonpolyposis colorectal cancer (HNPCC), is the most commonly inherited her- editary colon cancer syndrome and accounts for up to 4% of all cases of colon cancer and up to 10% of cases diagnosed before the age of 50. Compared to sporadic colon cancer with a median age at diagnosis of 69 for men and 73 for women, this decreases to 61 years in patients with Lynch’s syndrome. Colon cancer typically arises from an adenoma in the right hemicolon with an excess incidence of synchronous colorectal cancer at diagnosis. Lynch’s syndrome is also associated with a number of extracolonic malignancies with increased lifetime risks, including endometrium (60%), pancreatobiliary (18%), brain (1.2–​2.4%), urothelial tract (2.6–​4%), and small bowel (1–​4%). The Muir–​Torre variant of Lynch’s syndrome is characterized by the occurrence of one or more sebaceous neoplasms, such as sebaceous adenomas, sebaceous adenocarcinomas, keratoacanthomas, or squamous cell cancers. Patients who are suspected of having Lynch’s syndrome are iden- tified using the Amsterdam II criteria (Box 15.16.1), but it is im- portant to note that not all patients with Lynch’s syndrome will fulfil the criteria. The condition arises as a result of a germline mutation of at least one of the DNA MMR genes:  MLH1, MSH2, MSH6, or PMS2. MLH1, and MSH2 mutations account for 70% of the mutations seen in Lynch’s syndrome. The normal function of the MMR genes is to encode proteins that repair DNA base–​base mismatches arising as a result of replication errors. Replication errors are more common in regions of DNA known as microsatellites, where multiple short nucleotide repeat sequences occur. Loss of DNA repair function leads to the so-​called microsatellite instability of these regions, such that the allele sizes of microsatellites are different in tumours than in normal cells from the same individual. Genetic processes and pathology Our understanding of the molecular pathogenesis of colorectal cancer has exponentially increased since Fearon and Vogelstein de- scribed their genetic model for the adenoma–​carcinoma sequence for colorectal cancer in 1990. Although colorectal carcinogenesis was previously thought to occur following stepwise progressive ac- cumulation of primarily genetic mutations (such as the APC gene in the early stages of development and KRAS and TP53 in the later stages), it is now appreciated to be a much more complex process involving chromosomal instability, microsatellite instability, and epigenetic changes as well as genetic mutations. At present, four established pathway-​orientated models for spor- adic colorectal cancer have been described (Fig. 15.16.12): 157 Codon Extracolonic phenotype CHRPE Attenuated FAP Intermediate FAP Profuse FAP Desmoid tumours 412 1595 1464 1250 Fig. 15.16.11  Diagrammatic representation of the APC gene. The FAP phenotype (i.e. severity of polyposis) varies depending on the site of mutation; mutations between codons 1250 and 1464 result in severe FAP, whereas attenuated and intermediate FAP occurs following mutations outside of this region. Related extracolonic manifestations, such as desmoid tumours and congenital hypertrophy of the retinal pigment epithelium (CHRPE), are also associated with mutations in particular regions of the APC gene. CHRPE, congenital hypertrophy of the retinal pigment epithelium; FAP, familial adenomatous polyposis. Adapted from Burt RW, Jasperson KW (2016). Polyposis syndromes. In: Podolsky DK, Camilleri M, Fitz JG, Kalloo AN, Shanahan F, Wang TC (eds). Yamada’s textbook of gastroenterology, 6th edition. Chichester: Blackwell. pp. 1583–​607. Box 15.16.1  Amsterdam II criteria for the diagnosis of Lynch’s syndrome • At least three relatives with an HNPCC-​associated cancer (colorectal cancer or cancer of the endometrium, small bowel, ureter, or renal pelvis) • One must be a first-​degree relative of the other two • At least two successive generations should be affected • At least one should be diagnosed before the age of 50 • FAP should be excluded in the colorectal cancer case(s) if any • Tumours should be verified by histopathological examination Adapted from Vasen HFA, Watson P, Mecklin JP, Lynch HT (1999). New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative Group on HNPCC. Gastroenterology, 116, 1453–​6.

15.16  Cancers of the gastrointestinal tract 2991 • The traditional pathway—​this accounts for 70% of cases and fol- lows the Fearon and Vogelstein model; normal mucosa develops into colonic adenomas via gene mutations in APC and KRAS, re- sulting in tumours in the distal colon with TP53 mutations and chromosomal instability. Their prognosis is considered average. • The serrated pathway—​this accounts for 10 to 20% of cases of colo- rectal cancer; serrated adenomas and polyps form from normal mucosa due to BRAF mutations and global hypermethylation of CpG islands resulting in the silencing of several tumour suppressor genes (this is known as the CpG island methylator phenotype). Resultant tumours are found to have loss of expression of MLH1 and are characterized by high microsatellite instability. Usually found in the proximal colon, they have a favourable prognosis. • The alternative pathway—​this accounts for 10 to 30% of colorectal cancer, is less homogeneous than the traditional or serrated path- ways, and can have mutations in KRAS, APC, or BRAF and do not feature CpG hypermethylation or microsatellite instability. These tumours confer a poor prognosis and have a poor response to chemotherapy. • The ‘de novo’ pathway—​very rarely, tumours can develop without precursor lesions; these are characterized by APC and TP53 gene mutations as well as loss of heterozygosity at chromosome 3p, but rarely have KRAS mutations. Anatomically, colorectal cancers can arise in any part of the large bowel or rectum, but are most frequent in the rectum, sigmoid colon, and caecum (Fig. 15.16.13). Clinical features and investigation The site of a colorectal cancer influences the symptoms that it is likely to produce. The stool becomes more solid as it passes through the colon, hence obstruction and overt bleeding are increasingly likely with distal lesions. Blood is typically dark and mixed in with the stool, in contrast to the fresh or dripping bleeding that is often (50%–70%) (10%–30%) (10%–20%) Tubular adenoma CIN Villous adenoma SSA/P TSA CIMP-L CIMP-L CIMP-H (very rare) SSA/P MSI-L Adenocarcinoma in situ Adenocarcinoma in situ Adenocarcinoma in situ Adenocarcinoma invasive and metastatic Adenocarcinoma invasive and metastatic Adenocarcinoma invasive and metastatic Adenocarcinoma invasive and metastatic Distal colon Poor prognosis Poor response to chemotherapy Proximal colon Good prognosis Adenocarcinoma in situ Mucosa Submucosa Muscularis Propria Normal mucosa APC KRAS TP53 TGF-β β–catenin EMT Loss of E-cadherin EMT Loss of E-cadherin EMT KRAS APC BRAF MLH1 MSI-H APC TP53 LOH at chr 3p BRAF Normal mucosa Normal mucosa Normal mucosa Fig. 15.16.12  Molecular pathogenesis of colorectal cancer. APC, adenomatous polyposis coli; BRAF, B-​Raf proto-​oncogene, serine/​threonine kinase; CIMP-​H, CpG island methylator phenotype—​high; CIMP-​L, CpG island methylator phenotype—​low; CIN, chromosomal instability; EMT, epithelial-​mesenchymal transition; KRAS, Kirsten rat sarcoma viral oncogene homolog; LOH, loss of heterozygosity; MLH1, MutL homolog 1; MSI-​H, microsatellite instability—​high; MSI-​L, microsatellite instability—​low; SSA/​P, sessile serrated adenomas/​polyps; TGF-​β, transforming growth factor beta; TP53, tumour protein 53; TSA, traditional serrated adenomas. From Yamagishi H, Kuroda H, Imai Y, Hiraishi H (2016). Molecular pathogenesis of sporadic colorectal cancers. Chin J Cancer, 3, 4. © Yamagishi et al. 2016.

section 15  Gastroenterological disorders 2992 caused by haemorrhoids. Alteration of bowel habit may be in terms of frequency or increased constipation where the flow of solid stool is obstructed, which is particularly likely with left-​sided lesions. Tumours can grow to a considerable size in the right colon without affecting faecal flow, often leading to presentation with iron defi- ciency anaemia as a consequence of long-​standing but occult blood loss. Pain in a patient with colorectal cancer suggests obstructive disease or invasion, and weight loss is a late symptom suggesting advanced disease and poor prognosis. Digital rectal examination is an essential part of the physical examination of any patient with symptoms that might be attribut- able to colorectal cancer. The finding of an enlarged, irregular, hard liver clearly suggests metastatic disease. Routine laboratory investigation may reveal iron deficiency an- aemia and abnormal liver blood tests, but specific investigations focus on the bowel. Patients with suspected colorectal cancer should have a colonoscopy with biopsy unless contraindicated. In patients with comorbidities, alternative investigations are CT colonography or flexible sigmoidoscopy followed by barium/​ water-​soluble contrast enema. Box 15.16.2 summarizes current referral criteria in the United Kingdom for adults with suspected colorectal cancer. Staging Once a diagnosis of colorectal cancer is confirmed, patients require a staging CT scan to assess the extent of disease. Further local staging of rectal cancer is performed by pelvic MRI (or endorectal ultra- sonography if MRI is contraindicated). In patients with metastatic disease only located in the liver, further imaging such as MRI liver or FDG PET-​CT may be used to determine resectability. Although Dukes’ classification was historically used to stage colorectal car- cinoma, this has now been superseded by the more detailed TNM staging system (Table 15.16.3). Management Surgery Surgical resection is the primary treatment and potentially cura- tive. Colon cancers are usually treated with hemicolectomy, upper and middle rectal tumours with anterior resection, and low rectal tumours with abdominoperineal resection. Rectal cancer surgery is performed with total mesorectal excision as this reduces local recur- rence rates and improves survival. Patients with very early (T1N0) rectal cancer can be managed with transanal endoscopic microsur- gery as an alternative to major surgery in selected cases. Occasionally patients with operable left-​sided colonic tumours present with acute large-​bowel obstruction. As emergency colo- rectal cancer surgery is associated with much higher morbidity and mortality (10–​20%) than elective surgery, some patients can be ini- tially managed with a colonic stent to relieve obstruction, allowing for elective surgery following resuscitation. However, this option is not suitable for low rectal tumours, right-​sided tumours, or in pa- tients with evidence of peritonitis or perforation. Neoadjuvant treatment Although approximately 75% of patients have no evidence of metas- tases at diagnosis, 30 to 40% of patients who undergo curative-​intent surgery will develop recurrent disease. Neoadjuvant treatment for rectal cancer is guided by the pre- dicted risk of local recurrence based on the preoperative MRI find- ings. Patients with low-​risk operable rectal cancer proceed straight to surgery, moderate-​risk patients can be offered short-​course radio- therapy followed by immediate surgery, and high-​risk patients (if fit) are offered chemoradiotherapy with an interval to allow for tumour regression prior to surgery. The value of neoadjuvant chemotherapy in advanced colon cancer is not established. A recent retrospective analysis from the National Cancer Database (USA) of 27 575 patients with nonmetastatic T3 or T4 colon cancer treated with either adjuvant chemotherapy or neoadjuvant chemotherapy found that neoadjuvant chemotherapy reduced risk of death at 3 years by 23% compared to patients having adjuvant chemotherapy in patients with T4b disease (but not in pa- tients with T3 or T4a disease). Prospective trials are needed. 15% Unspecified Rectum 29% Sigmoid colon 18% Descending colon 2% Splenic flexure 2% Transverse colon 4% Hepatic flexure 2% Ascending colon 5% Caecum 13% Appendix 1% Anus 2% Rectosigmoid juction 7% Fig. 15.16.13  Anatomical distribution of adenocarcinoma within the large bowel. Box 15.16.2  Referral criteria for suspected colorectal cancer • Make urgent (within 2 weeks) referral for patients who: — are aged 40 or over with unexplained weight loss and abdominal pain — are aged 50 or over with unexplained rectal bleeding — are aged 60 or over with: • iron deficiency anaemia, or • change in bowel habit — have a positive faecal occult blood test • Consider urgent referral for patients who: — have a palpable rectal or abdominal mass — are aged under 50 with rectal bleeding and any of the following unexplained symptoms or findings: • abdominal pain • change in bowel habit • weight loss • iron deficiency anaemia • Offer faecal occult blood test to assess for colorectal cancer in adults without rectal bleeding or who have unexplained symptoms but do not meet the above-​listed criteria for referral Source:  National Institute for Health and Care Excellence (NICE) (2015). Suspected cancer:  recognition and referral (NICE guideline NG12). London: NICE [updated July 2017].

15.16  Cancers of the gastrointestinal tract 2993 Adjuvant treatment Moertel and colleagues published a seminal paper in 1990 demonstrating that adjuvant 5-​FU for stage III and high-​risk stage II colon cancer reduced disease recurrence by 41% and risk of death by 33% compared to observation alone. Further trials found that the addition of oxaliplatin to 5-​FU and folinic acid (FOLFOX regimen) significantly improved disease-​free survival and overall survival in stage II/​III colon cancer. The combination of a fluoropyrimidine with oxaliplatin is now the established standard of care, with capecitabine monotherapy being another option for patients who cannot tolerate FOLFOX. The evidence for the use of adjuvant chemotherapy is less well es- tablished for rectal cancer. A systematic review in 2015 did not find a survival benefit from adjuvant chemotherapy with 5-​FU if patients have undergone neoadjuvant radiotherapy or chemoradiotherapy. The addition of oxaliplatin, although possibly associated with an improvement in disease-​free survival, does not improve overall survival. Adjuvant chemoradiotherapy is only indicated in selected cases, such as patients with a high risk of local recurrence when no neoadjuvant radiotherapy has been given. Current NICE guidelines advise to consider offering adjuvant chemotherapy to high-​risk stage II and stage III rectal cancer to reduce the risk of local and sys- temic recurrence. Advanced disease Unlike metastatic disease in other cancers of the gastrointestinal tract, stage IV colorectal cancer is sometimes amenable to resec- tion of the primary tumour and metastatic deposits with a chance Table 15.16.3  Tumour, node, metastasis (TNM) staging of colorectal carcinoma T—​primary tumour Tx Primary tumour cannot be assessed T0 No evidence of primary tumour Tis Carcinoma in situ (invasion of lamina propria) T1 Tumour invades submucosa T2 Tumour invades muscularis propria T3 Tumour invades subserosa or into non peritonealized pericolic or perirectal tissues T4 Tumour directly invades other organs or structures and/​or perforates visceral peritoneum: T4a: tumour perforates visceral peritoneum T4b: tumour directly invades other organs or structures N—​regional lymph nodes Nx Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastasis in 1–​3 regional lymph nodes: N1a: metastasis in 1 regional lymph node N1b: metastasis in 2–​3 regional lymph nodes N1c: tumour deposit(s), i.e. satellites, in the subserosa, or in nonperitonealized pericolic or perirectal soft tissue without regional lymph node metastasis N2 Metastasis in 4 or more regional lymph nodes: N2a: metastasis in 4–​6 regional lymph nodes N2b: metastasis in 7 or more regional lymph nodes M—​distant metastasis M0 No distant metastasis M1 Distant metastasis: M1a: metastasis confined to one organ (liver, lung, ovary, nonregional lymph node(s)) without peritoneal metastases M1b: metastasis in more than one organ M1c: metastasis to the peritoneum with or without other organ involvement Stagea 0 Tis N0 M0 I T1, T2 N0 M0 II T3, T4 N0 M0 III Any T N1, N2 M0 IV Any T Any N M1 a Stage simplified for clarity. Adapted from Brierley J, Gospodarowicz M, Wittekind C (eds) (2017). TNM classification of malignant tumours, 8th edition. Chichester: John Wiley & Sons, Ltd.

section 15  Gastroenterological disorders 2994 of long-​term survival. Neoadjuvant therapy and surgery for liver metastases has been shown to improve disease-​free survival. Other ablative techniques for liver metastases such as selective internal radiotherapy and radiofrequency ablation, as well as surgical resec- tion of isolated lung metastases, are having an impact on the long-​ term survival of patients once thought to have incurable disease. Fluoropyrimidines, in combination with both oxaliplatin and irinotecan, can improve survival in patients with unresectable dis- ease. Oral fluoropyrimidines such as capecitabine have been shown to be as effective as 5-​FU but incur more toxicity. Biological ther- apies are also available; for example, the anti-​EGFR antibody cetuximab can be used in EGFR-​expressing, RAS wild-​type meta- static colorectal cancer. Patients with MMR deficiency respond well to immune modulation with antiprogrammed cell death (anti-​PD-​

1. receptor monoclonal antibodies. The molecular genotyping of pa- tients is likely to play an increasing role in future treatment decisions as our ability to characterize individual patients’ tumours leads to individualized care. Colonic stenting is an effective technique for symptoms of left-​sided bowel obstruction. Octreotide may also improve symp- toms in those with disease at multiple sites precluding stenting or surgery. Screening and prevention Four randomized controlled trials (1993–​2007) and a Cochrane re- view (2007) found that bowel cancer screening using the faecal oc- cult blood test reduced colorectal cancer mortality by 16% and also reduced colorectal cancer incidence, presumably due to the removal of benign polyps that would otherwise have progressed to malig- nancy. Biennial faecal occult blood testing (using a home testing kit) is currently offered to all adults aged 60 to 74, and on request to adults aged 75 and over. In 2010, the United Kingdom Flexible Sigmoidoscopy Screening randomized controlled trial assigned over 170 000 patients to either a single flexible sigmoidoscopy (between the ages of 55 and 64) or no intervention. Over a median follow-​up period of 11.2 years, colo- rectal cancer incidence in the screened group was reduced by 23% and colorectal cancer mortality by 31%. This benefit was confirmed in a follow-​up study of the same cohort published in 2017 (median follow-​up 17.11 years), demonstrating that screening reduced colo- rectal cancer incidence by 26% and colorectal cancer mortality by 30%. Due to these results, one-​off flexible sigmoidoscopy screening for adults at age 55 is currently being implemented across the United Kingdom. Prognosis Bowel cancer survival has more than doubled in the United Kingdom in the last 40 years, due to a combination of improved de- tection through screening, improved surgical techniques, and the establishment of evidence-​based neoadjuvant, adjuvant, and pallia- tive therapies. Five-​year overall survival, although now approaching 60%, is heavily influenced by the stage at diagnosis (Fig. 15.16.14). Tumours that occur throughout the gastrointestinal tract Several types of malignancy can occur throughout the gastrointes- tinal tract. Initial symptoms may be related to the mass effect that occurs within that site; for instance, a caecal B-​cell lymphoma may present with obstruction and a right iliac fossa mass. Initial manage- ment should be emergency surgery, as for all obstructing tumours of the caecum, but subsequent treatment should be based on the path- ology rather than the anatomy. Lymphomas should be treated as a haematological malignancy rather than as the much more common cause of obstruction, an adenocarcinoma. Exceptions are neuro- endocrine malignancies that have specific management determined by their primary site. 100 110 90 80 70 Relative Survival (%) Stage I Stage II Stage III Stage IV Stage at Diagnosis All Stages Stage Not Known 60 50 40 30 20 10 0 Men Women Fig. 15.16.14  Five-​year relative survival (%) of colorectal cancer by stage. Source: Cancer Research UK. Bowel cancer survival statistic [internet]. CRUK 2018. Available from: http://​www. cancerresearchuk.org/​ [Accessed 2018 Mar 26].

15.16  Cancers of the gastrointestinal tract 2995 Gastrointestinal lymphoma Primary lymphomas are rare, accounting for only 1 to 4% of all gastrointestinal malignancies. There are two commonly occurring lymphomas of the gastrointestinal tract, mucosa-​associated lymphoid tissue lymphoma and diffuse large B-​cell lymphoma, the latter being managed with a combination of surgery and chemo- therapy. See Chapter 15.10.4 for further discussion. Gastrointestinal stromal tumour GISTs arise from the interstitial cells of Cajal, thought to be the pacemaker cells for enteric contraction. They occur throughout the gastrointestinal tract, and gastric GIST (the most common type) frequently grows to a significant size before there are any local symptoms. Most (88%) are associated with mutations of the KIT gene, leading to constitutive activation and oncogenic devel- opment. Treatment options were limited to surgery and the prog- nosis was poor before the introduction of imatinib, a small molecule that inhibits tyrosine kinase domains of the KIT and platelet-​ derived growth factor (PDGF) receptors. Median survival is now approaching 12 years with a 5-​year overall survival of almost 80%. Unlike chemotherapy, responses can occur many months into treat- ment. Patients with KIT exon 11 mutations have a higher rate of ob- jective response (84%) than patients with exon 9 mutations (48%) or no mutations in the KIT or PDGFR receptor (0%). GISTs are typ- ically responsive before the development of novel mutations in fur- ther KIT domains, responsible also for primary nonresponsiveness. Salvage therapies include other kinase inhibitors or surgery. Gastrointestinal melanoma Primary gastrointestinal melanoma occurs throughout the gastro- intestinal tract but is most commonly found in the anorectum (54%), oropharynx (33%), and oesophagus (5.9%). Whenever a melanoma is found in the bowel, care must be taken to exclude an occult skin cancer, as the vast majority of cases of intestinal mel- anoma are metastases from a cutaneous primary. Surgery is often the first treatment, but there is no evidence-​based management algo- rithm. Staging and treatment is usually based on that for cutaneous melanoma. Signet-​ring cell carcinoma (linitis plastica) Although over 95% of cases of linitis plastica occur in the stomach, it can also occur in the colon and rectum, gallbladder, and pancreas. Such cases must be carefully differentiated from the more common scenario of a linitis plastica of the stomach with peritoneal spread. Neuroendocrine tumours NETs are a group of neoplasms arising from neuroendocrine cells of the diffuse endocrine system. They comprise approximately 2% of all malignant tumours of the gastrointestinal tract and are usually sporadic, but they may occur as part of multiple endocrine neoplasia syndromes, von Hippel–​Lindau syndrome, neurofibromatosis, and tuberous sclerosis. Most have relatively slow tumour growth but have malignant potential, and most are diagnosed when distant (mainly liver) metastases have developed. Gastroenteropancreatic (GEP) NETs make up the majority, and these can be subdivided into carcinoid tumours of the luminal tract and pancreatic NETs (traditionally called islet-​cell carcinomas). Surgery of the primary and metastases, where possible, remains the only chance of cure. As NETs are usually hypervascular, locoregional therapies for liver metastases such as selective internal radiotherapy and transarterial chemoembolization have a role. Systemic (pal- liative) therapies include somatostatin analogues for symptom control in functional tumours, peptide receptor radionuclide treat- ment, low-​dose interferon, biological therapies (e.g. bevacizumab, everolimus, and sunitinib), and chemotherapy. See Chapters 15.9.2 and 15.26.3 for further information. Sarcomas Sarcomas of the gastrointestinal tract are exceedingly rare, with leiomyosarcomas of the stomach and small bowel being the most common. Management should be as for all other sarcomas. Small-​cell carcinoma Small-​cell carcinomas have been described in all parts of the gastro- intestinal tract. Treatment is as for primary small-​cell carcinoma of the lung, but prognosis is poor. Metastasis Metastases from cancer of the gastrointestinal tract occur commonly in the liver (see Chapter 15.24.6) due to haematological spread via the portal venous system. Rectal tumours can metastasize directly to the lungs from haematological spread via the portosystemic rectal veins. Other patterns of spread include transcoelomic (more common in mucinous and signet-​cell ring adenocarcinomas) and lymphatic. The liver is the most common site of metastatic presen- tation for carcinoma of unknown primary, and metastasis must be suspected in patients with a history of prior malignancy. Biopsy and comparison with prior histopathology is essential to confirm the diagnosis where there is clinical doubt and the overall condition of the patient makes this appropriate. FURTHER READING André T, et al. (2004). Oxaliplatin, fluorouracil, and leucovorin as ad- juvant treatment for colon cancer. N Eng J Med, 350, 2343–​51. Aparicio T, et al. (2014). Small bowel adenocarcinoma: epidemiology, risk factors, diagnosis and treatment. Dig Liver Dis, 46, 97–​104. Arnal MJD, Arenas AF, Arbeloa AL (2015). Esophageal cancer: risk factors, screening and endoscopic treatment in Western and Eastern countries. World J Gastroenterol, 21, 7933–​43. Atkin W, et  al. (2017). Long-​term effects of once-​only flexible sig- moidoscopy screening after 17 years of follow-​up: the UK flexible sigmoidoscopy screening randomised controlled trial. Lancet, 389, 1299–​311. Atkin WS, et al. (2010). Once-​only flexible sigmoidoscopy screening in prevention of colorectal cancer: a multicentre randomised con- trolled trial. Lancet, 375, 1624–​33. Brenner B, et al. (2004). Small-​cell carcinoma of the gastrointestinal tract: a retrospective study of 64 cases. Br J Cancer, 90, 1720–​6. Breugom AJ, et al. (2015). Adjuvant chemotherapy after preoperative (chemo)radiotherapy and surgery for patients with rectal cancer: a systematic review and meta-​analysis of individual patient data. Lancet Oncol, 16, 200–​7.

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