Essentials 

Cancers of the gastrointestinal tract provide a paradigm for the investigation and treatment of cancer. The relationship between basic research and 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 predisposition to neoplasia. Examples of this include sporadic colorectal carcinoma as well as the better understood genetic syndromes listed in Table 1.

There is increasing interest in the influence of genetic polymorphisms on treatment toxicity. For instance, UGT1A1 promoter polymorphisms have been demonstrated to predict early haematologic toxicity following treatment with irinotecan and fluorouracil. The microsatellite instability pathway, which involves failure of the nucleotide mismatch recognition and repair system, has been proposed as a form of genomic instability that can predict for survival and response. The consequent loss of DNA repair signals for apoptosis may confer resistance to specific chemotherapy drugs. More recently, the development of a molecular classification for gastrointestinal malignancy using genome-wide screens using C DNA or by microRNA have increased the potential for predicting prognosis and response in parallel with standard molecular techniques.

Although much of the translational work and trials using novel targeted agents have been in colorectal cancer, they are of potential relevance to all types of gastrointestinal malignancy.

Oesophageal cancer

There are approximately 12 000 new cases of oesophageal cancer in the United Kingdom per year . Mortality rates closely resemble incidence and, despite some progress in diagnosis and treatment, there has been little overall impact on the disease. The incidence of oesophagogastric carcinoma is increasing, with the male European age-standardized rate per 100 000 population rising from 7.8 to 13.4 between 1971 and 2005. The corresponding rates for women were 4.2 to 4.9. Worldwide, there is an 18-fold variation in male incidence rates between different regions and an almost 40 fold variation in female rates. There is also ethnic variation, with a six times higher rate in black men than in white men. Most cases (80–85%) of oesophageal cancer are diagnosed in developing countries, where it is the fourth most common cancer in men. The usual histology is squamous cell carcinoma, although the incidence of adenocarcinoma is increasing. This increase is likely to be environmental, although no single agent has been identified and it is uncertain whether or not it is related to the increase in Barrett’s oesophagus.

Predisposing factors

It has been proposed that the family of Napoleon Bonaparte had a predisposition to stomach cancer, although epidemiological and genetic aetiologies are somewhat wrong-footed by the conclusion that ‘An analysis of Bonaparte’s case may convince one that human predisposition to cancer is a phenomenon of an unstable, variable nature, which is easily broken by marriage’. More classically described is tylosis, a syndrome of familial oesophageal cancer and hyperkeratosis of the palms and soles, as well as thickening of the oral mucosa. For an affected family member, the estimated lifetime risk of cancer is 92% by age 70. The linkage has been localized to chromosome 17q25 and associated with down-regulation of the cytoglobin gene.

Environmental factors that may be incriminated in oesophageal cancer include smoking and high alcohol intake, also achalasia, oesophageal strictures due to ingestion of corrosives, radiotherapy, and coeliac disease. The Paterson–Kelly (Plummer–Vinson) syndrome, characterized by iron deficiency anaemia, glossitis, postcricoid webs, and dysphagia has been associated with squamous carcinoma in up to 20% of cases, most commonly in Scandinavian populations.

Clinical features

Approximately 55% of patients have cancers in the lower section of the oesophagus, 30% in the upper section, and 15% in the middle section. Middle and upper oesophageal cancers are more likely to be squamous cell carcinomas, whereas those in the lower oesophagus are commonly adenocarcinoma, potentially arising from a Barrett’s oesophagus.

Patients classically present with dysphagia, initially to solids and then to liquids. Other late symptoms such as dyspnoea, a hoarse voice, constant pain and weight loss suggest advanced disease and confer a poor prognosis. Initial diagnosis is made at upper gastrointestinal endoscopy or occasionally contrast radiology, and confirmed by endoscopic biopsy. Standard staging investigations include contrast-enhanced CT, 2-[¹⁸F] fluoro-2-deoxy-D-glucose positron emission tomography (the FDG-PET scan), and endoscopic ultrasonography.

Management

In patients who are fit and suitable for surgery, neoadjuvant chemotherapy is commonly given and confers an improvement in survival from 34% after oesophagectomy alone to 43% at 2 years. For locally advanced inoperable patients, or patients unfit for surgery chemoradiation in preference to radiation alone may confer a survival of 38% vs 10% at 2 years, although these data come from a small unrepeated study. Attempts to combine surgery and chemoradiation or neoadjuvant chemotherapy and chemoradiation have failed to demonstrate a survival advantage and there is still debate as to the best approach.

Surgery

Surgery is performed using a transhiatal or thoracic approach. There is increasing evidence to suggest that a two-phase oesophagectomy (abdomen and right or left chest approach) with a two-field lymphadenectomy (abdomen and thorax) is oncologically favoured, but this remains controversial.

Palliative approaches

Most patients with oesophageal cancer are elderly with comorbid disease and are unsuitable for curative surgery and 40% of patients present with advanced disease in whom palliation is the only option. Specific palliation for dysphagia can include laser, brachytherapy, external beam therapy, or stenting.

Laser endoscopic therapy vaporizes exophytic tumour under direct vision without mechanical stress on the oesophageal wall so that stenting is usually not required. Successful tumour recanalization can be achieved in more than 90% of appropriately selected patients, and a return to eating solids is seen in most patients after treatment. However, laser therapy needs to be repeated every 4–6 weeks as the tumour regrows. The palliation can be improved with radiation, either external beam or brachtherapy.

Palliative chemotherapy improves survival, although this remains poor with a 1 year survival of 40%. It is likely that three drug combinations offer the best results. Survival and prognosis can be predicted using microRNA arrays, but these methodologies have yet to be prospectively validated.

Stomach cancer

As for oesophageal cancer, stomach cancer occurs mainly in older people and has a striking variation in worldwide incidence. Unlike oesophageal cancer, however, the age-standardized incidence rates for males have halved from 31.0 per 100 000 in 1975 to 14.3 in 2004.

Predisposing factors

There are clear links to deprivation, Helicobacter pylori infection, tobacco, alcohol and diet. The compelling relationship between H. pylori infection and gastric neoplasia (and also gastric lymphoma) has led to proposals for national screening programmes, but few countries have implemented these in preference to investigation of symptomatic individuals. Diffuse adenocarcinoma is associated with an E-Cadherin mutation, conferring almost 100% penetrance in the inherited form of this gastric cancer, and leading to recommendations for ‘curative’ prophylactic gastrectomy in affected families.

Pathology

Most stomach cancers (around 95%) are adenocarcinomas, which may be further classified into ‘intestinal’ and ‘diffuse’ types. Intestinal-type adenocarcinomas are found in older patients, are associated with a history of atrophic gastritis, and have better survival. The incidence is falling, probably as a result of decreasing levels of H. pylori-associated gastritis.

‘Diffuse’ adenocarcinomas (also known as linitis plastica or signet cell cancers of the stomach) are more common than intestinal-type tumours, are associated with a poorer survival, and occur more frequently in women and people with blood group A.

Clinical features

Dysphagia, early satiety, and anaemia are common presenting features, 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’s sign) may be present. Metastasis occurs to the peritoneum (with ascites and sometimes ovarian involvement—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 endoscopy and biopsy. Tumour staging is by CT and, in some centres, endoscopic ultrasonography, together with careful preoperative assessment to determine fitness for surgery.

Management

Outcome is critically dependent on the success of surgery, although other significant risk factors include comorbidity and nodal status. Most authorities agree that an extensive nodal resection—meaning resection of all perigastric lymph nodes and some coeliac, splenic or splenic–hilar, hepatic artery, and cardia lymph nodes, depending on the location of the tumour in the stomach (a D2 resection)—confers an improved survival over a limited resection.

Neo-adjuvant and adjuvant treatment

In patients with resectable gastric cancer, a survival benefit has been demonstrated in large well-designed clinical trials for postoperative chemoradiation, neoadjuvant chemotherapy, and adjuvant chemotherapy. However, these studies have not escaped criticism: one was criticized for suboptimal surgery (only 10% of patients had undergone a formal D2 dissection), and the benefit of chemoradiation may not have been seen with optimal surgery; another was criticized for the inclusion of patients with oesophagogastric tumours (11%), although there was a clear overall benefit of adjuvant treatment for both oesophagogastric and gastric cancers.

Advanced disease

Palliation of proximal gastric obstruction and palliative chemotherapy is similar to that for oesophageal cancers. Malignant gastric outlet obstruction can be palliated with stenting, although this is less successful (up to a 25% migration or fracture rate) than for stents placed more proximally. Surgical bypass is an option for patients who are sufficiently fit, but postsurgical gastroparesis may be a problem, particularly in those with metastatic disease.

Small-bowel cancers

Small-bowel adenocarcinoma is rare, accounting for 0.2 to 0.3% of all malignant tumours but associated with a poor 5-year survival of around 25%. The incidence is increased in coeliac and Crohn’s disease, and there is some evidence that the incidence is increasing, particularly in black men.

Duodenal polyps are associated with several gastrointestinal polyposis syndromes, but most commonly with familial adenomatous polyposis, with transformation to duodenal carcinoma (resembling adenoma–carcinoma progression in the large bowel) the leading cause of death amongst familial adenomatous polyposis patients who have had a total colectomy. Endoscopic surveillance and prophylactic duodenal resection is recommended in this high risk group.

Hamartomatous polyps are common in the jejunum in Peutz–Jeghers syndrome: these can undergo malignant change, leading to a 500-fold relative risk of small-bowel carcinoma. Carcinoid tumours are usually found in the ileum.

The most common histological findings are of adenocarcinoma in 40%, with other histologies being lymphoma and gastrointestinal stromal tumours (GIST).

Clinical features

Presentation is with nonspecific symptoms of abdominal pain, change in bowel habit, weight loss, and anaemia. Appearances on noninvasive imaging may be nondiagnostic, hence the diagnosis is usually made at upper gastrointestinal endoscopy or laparotomy.

Management

Surgical resection offers the only opportunity of long-term survival. There is no evidence to support the use of adjuvant or palliative therapy, although this may reflect the paucity of data rather than a true lack of effect.

Colorectal cancer

Incidence and epidemiology

In the United Kingdom, approximately 36 000 people are diagnosed with colorectal cancer every year, of which 16 000 die of their disease. The incidence had been rising until 1999, since which time it has fallen slightly, and overall mortality has been falling steadily since 1975. The peak incidence of the disease is between the ages of 70 to 80, with less than 5% of cases under the age of 50 years.

There is a clear link between diet and relative risk of colorectal cancer, with subjects consuming more than one portion of red or processed meat a week having a relative risk of 1.63, and there is a strong protective influence of fish, fibre, calcium and dietary folate. This effect of a Westernized diet is supported by data demonstrating an increase in incidence of colorectal cancer in first-generation Japanese immigrants to the United States of America compared to their parents. Recent improvements in the diet of Western nations is likely to contribute to a continued decline in incidence. Other factors, but with lesser effects, may include hormone replacement therapy and oral contraceptives, obesity, alcohol intake, tobacco, aspirin, and statins.

Genetic processes and pathology

Vogelstein and colleagues described the adenoma–carcinoma pathway in which sequential inherited and acquired mutations lead to the development of colorectal cancer following waves of clonal expansion involving APC/β-catenin, KRAS/BRAF, TGF-β, PIK3CA, and TP53. However, this is clearly not the malignant process for all cancers, over 50% of which retain wild-type RAS and over 20% wild-type p53. Similarly, tumour response to agents targeted at the RAS and phosphatidylinositol 3-kinase pathways (cetuximab and panutumumab, see below) are effective only in patients with wild-type RAS and not in patients with mutated RAS.

The Dukes’ classification remains the mainstay of staging of colorectal carcinoma: stage A is confined to the bowel wall with no extension to the serosal fat; in stage B there is full thickness involvement of the bowel wall with extension through to the serosa; in stage C there is spread to local nodes (C1) or to more proximal mesenteric nodes (C2); and in stage D there is distant spread, usually to the liver. The frequency of the different Dukes’ stages, and the impact of staging on survival, are shown in Table 2.

Colorectal cancers can arise in any part of the large bowel or rectum, but are most frequent in the rectum, sigmoid colon, and caecum.

The polyposis syndromes

The known polyposis syndromes, all of which have some predisposition to malignancy, are listed in Table 3.

Familial adenomatous polyposis

Familial adenomatous polyposis (FAP) is responsible for 1% of all colorectal cancers, with a reported incidence of 1 in 7000 to 1 in 22 000 live births. The principal feature of the condition is the presence of hundreds to thousands of adenomatous polyps throughout the colon. It is inherited as an autosomal dominant condition, although about one-quarter of cases arise without a family history, thus implying a high rate of new mutations. The gene responsible for FAP—the adenomatous polyposis coli (APC) gene—is located on chromosome 5. Most mutations are nonsense mutations, resulting in a truncated protein of less than the predicted 310-kDa (2843 amino acids) wild-type APC protein. Some of these germ-line mutations correlate with phenotypic manifestations, such as retinal pigmentation, desmoids, the severity of polyposis, upper gastrointestinal malignancies, and attenuated FAP. As well as colonic polyps, adenomas are found in the duodenum in most patients, and also in the stomach and elsewhere in the small intestine.

There is a 10- to 20-year period between the appearance of an adenoma and its progression to colorectal carcinoma, but the risk of colorectal cancer developing in one of the adenomas is essentially 100% by the age of 40 years, so that this condition is fully penetrant. Adenomas usually begin to develop during the second decade, hence screening by flexible sigmoidoscopy is commenced between 12 and 14 years of age (Table 4). Biopsy of polyps detected at screening for histological diagnosis confirms the condition and allows surgery before the age of 20. Screening family members by flexible sigmoidoscopy confirms or eliminates the diagnosis.

Colectomy with ileorectal or ileoanal anastomosis, or total proctocolectomy with ileostomy, are the recommended surgical procedures. If the rectal stump is left, this will require continued surveillance as the likelihood of malignant change in high.

Surveillance programmes (Table 4) have reduced the incidence of colorectal cancer due to FAP, but the prolonged survival of patients post colectomy has highlighted other features of the condition, primarily desmoids and adenomas in the duodenum and stomach. Guidelines have been published for continued clinical management, including suggested surveillance of the duodenum, and also the management of duodenal polyposis and desmoid tumours.

Hereditary nonpolyposis colorectal cancer

Hereditary nonpolyposis colorectal cancer (HNPCC) accounts for 5% of colorectal cancer. Cancer occurs at a mean age of 45 years, with primarily right-sided colorectal cancer and an excess of synchronous colorectal cancer. There is also an excess of extracolonic cancers (endometrium, small bowel, pancreas, hepatobiliary tract, brain, and upper uroepithelial tract). Patients with HNPCC may also have sebaceous adenomas, sebaceous carcinomas, and multiple keratoacanthomas.

At-risk patients are identified using the Amsterdam criteria (Bullet list 1)

HNPCC arises as a result of the germ-line transmission of mutations and polymorphisms in six genes encoding components of the DNA mismatch repair enzyme system and the TGFβ receptor II gene. The encoded proteins repair DNA mismatches arising as a result of replication errors and are described as RER+ (positive replication error), mostly the MLH1, MSH2, and MSH6 genes. Replication of DNA is particularly prone to error in those 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. PCR-based methods are readily able to detect this to establish that a given tumour has an RER+ phenotype. The extent of microsatellite instability varies between tumours and there is some disagreement as to how many loci need to be modified before a tumour can be classified as RER+. In addition to patients with HNPCC, between 10 and 15% of sporadic colorectal cancers are also RER+.

Screening and prevention

Three randomized studies have demonstrated the potential improvement in survival of screening for colorectal cancer using guaiac faecal occult blood testing in the 50- to74-year-old population, which is now being piloted throughout the United Kingdom and Europe. The results of a trial in Nottingham (United Kingdom) showed a reduction in mortality from colorectal cancer in the intervention group of 15% at a median follow-up of 7.8 years, and there are early data to suggest a decrease in the incidence of new cancers in the general population as a result of faecal occult blood testing.

Clinical features

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 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 considerable size in the right colon without affecting faecal flow, often leading to presentation with iron-deficiency 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 attributable to colorectal cancer. The finding of an enlarged, irregular, hard liver clearly suggests metastatic disease.

Routine laboratory investigation may reveal iron-deficiency anaemia and abnormal liver blood tests, but specific investigations obviously focus on the bowel. Patients with new symptoms require endoscopy (flexible sigmoidoscopy or colonoscopy, Bullet list 2) or other imaging (barium enema or CT, including CT colonography). For rectal cancers, MRI and endoanal ultrasonography improve staging (http://www.nice.org.uk/nicemedia/pdf/CSGCCfullguidance.pdf).

Management

Surgery

Surgical resection is the primary treatment and potentially curative. There are no differences between open and laparoscopic-assisted surgery with respect to tumour and nodal status, short-term endpoints, and quality of life, hence surgery for resectable colon cancer is increasingly a laparoscopic procedure. However, although almost three-quarters of patients have no evidence of metastases at diagnosis (Table 2), about one-third of these relapse, mostly with incurable disease.

Bullet list 1 Amsterdam criteria for hereditary nonpolyposis colorectal cancer (HNPCC)

Adjuvant and neo-adjuvant therapy

In 1990, Moertel and colleaugues described a reduction in death of 33% following 12 months of adjuvant fluorouracil. Oral fluoropyrimidine is more convenient, as effective, and can obviate complications associated with central venous catheters although toxicity may be greater. There is a further improvement in survival of 4.4% with the addition of oxaliplatin, although this is accompanied by significant neurotoxicity.

Advanced disease

Fluoropyrimidine, in combination with both oxaliplatin and irinotecan, can improve survival in patients with advanced disease. Oral fluoropyrimidines have been shown to be as effective as 5-fluorouracil but incur more toxicity. Targeted agents such as the anti-vascular endothelial growth factor antibody bevacizumab and the anti-epidermal growth factor receptor cetuximab have further increased survival. Neo-adjuvant therapy and surgery for liver metastases has been shown to improve disease-free survival, and the resection of lung metastases as well as locally ablative techniques such as radioactive yttrium and radiofrequency ablation are having an impact on the long-term survival of patients once thought to have incurable disease.

Bullet list 2 Common indications for colonoscopy

The molecular genotyping of patients is likely to play an increasing role in treatment decisions, e.g. patients with a mutant kRAS are unlikely to benefit from epidermal growth factor receptor inhibition.

Palliation

Colonic stenting is an effective technique for symptoms from bowel obstruction, and in some cases can be used as a precursor to resection, allowing the performance status of the patient to improve and permit definitive surgery. Octreotide may improve symptoms in those with disease at multiple sites precluding stenting or surgery.

Rectal cancer

If the mesorectal margin is threatened or breached, chemoradiation with fluoropyrimidine as a radiosensitizer can render cancers operable. Patients in whom complete microscopic resection (R0) cannot be obtained have a universally poor prognosis. In operable cancers, a total mesorectal excison preceded by short course irradiation has been shown to reduce local relapse, although survival benefit is disputed.

Tumours that occur throughout the gastrointestinal tract

Several types of malignancy can occur throughout the gastrointestinal tract. Initial symptoms may be related to the mass effect that occurs within that site, e.g. a caecal B-cell lymphoma may present with obstruction, in which case initial management should be as for all obstructing tumours of the caecum, but subsequent treatment should be based on pathology rather than anatomy, i.e. of curative intent with lymphoma-specific combination chemotherapy rather than as the much more common adenocarcinoma of the caecum. Exceptions are the neuroendocrine malignancies that have specific management determined by primary site.

Non-Hodgkin’s lymphoma

There are two commonly occurring lymphomas of the gastrointestinal tract, mucosa-associated lymphoid tissue (MALT) and a high-grade B-cell lymphoma, the latter being managed with chemotherapy without surgery and without significant risk of perforation. 

Gastrointestinal stromal tumour

Gastrointestinal stromal tumours (GISTs) arise from the interstitial cells of Cajal, thought to be the pacemaker cells for gastric contraction. They occur throughout the gastrointestinal tract, and the most common stomach GIST frequently grows to a significant size before there are any local symptoms. They are associated with mutations within the cKIT domain, leading to constitutive activation and oncogenic development, with median survival approaching 5 years. Treatment options were limited to surgery and the prognosis was poor before the introduction of imatinib, a small molecule that inhibits tyrosine kinase domains of the cKIT and platelet derived growth factor (PDGF) receptors. Unlike chemotherapy, responses can occur many months into treatment. Patients with KIT exon 11 mutations have a higher rate of objective response (86%) than patients with exon 9 mutation (48%) or no mutations in KIT or PDGFRA (0%). GISTs are typically responsive before the development of novel mutations in further cKIT domains, responsible also for primary nonresponsiveness. Salvage therapies include other kinase inhibitors or surgery.

Melanoma

Primary melanoma occurs throughout the gastrointestinal tract, most commonly in the nasopharynx, rectum, and anus, but care must be taken to exclude metastasis from cutaneous melanoma whenever a lesion is found in the bowel. Surgery is often the first treatment, but there is no evidence-based management algorithm. Staging and treatment is usually based on that for cutaneous melanoma.

Linitis plastica

Although linitis plastica (signet cell carcinoma) occurs most frequently in the stomach, in 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

Neuroendocrine tumors are a group of neoplasms arising from neuroendocrine cells of the diffuse endocrine system. They comprise approximately 2% of all malignant tumors of the gastrointestinal tract, and are usually sporadic, but they may occur as part of multiple endocrine neoplasia 1 syndrome (MEN1), von Hippel–Lindau syndrome, neurofibromatosis, and tuberous sclerosis. Most have relatively slow tumor growth, but malignant potential, and most are diagnosed when distant (mainly liver) metastases have developed. Gastrointestinal neuroendocrine tumors (carcinoids) and neuroendocrine pancreatic tumours (islet cell tumours) make up the majority. Surgery of the primary and metastasis, where possible, remains the only chance of cure. Somatostatin analogues control symptoms in cases of functional tumors, and peptide receptor treatment, transarterial hepatic embolization (or chemoembolization), chemotherapy are options for palliative therapy. 

Sarcoma

Sarcomas of the gastrointestinal tract are exceedingly rare, with angiosarcomas of the large bowel and liposarcomas of the oesophagus being the least uncommon, and should be treated like all other sarcomas.

Small-cell carcinoma

Small-cell carcinomas have been described in all parts of the gastrointestinal tract. Treatment is as for primary small cell carcinoma of the lung, but prognosis is poor.

Metastasis

Metastasis in the gastrointestinal occurs commonly in the liver and following intracoelomic dissemination, but has been described uncommonly in pancreas. The liver is the most common site of metastatic presentation for carcinoma of unknown primary. 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