Updated 3 October 2007

There are a number of theories currently invoked to explain the low risk of malignancy in the small bowel. These include:

1. Rapid turnover of small intestine cells (1 g every 16 minutes)
2. Relatively low levels of bacteria in small gut
3. Rapid transit of small bowel contents
4. Chyme protection to mucosa
5. Reduced formation of nitrosamines by alkaline environment
6. Well developed local IG-A mediated immunity
7. Reduced expression of bcl-2 gene in small intestine crypts
8. Fewer stem cells in the small bowel, located deep in crypts
9. Duodenum contains a water-soluble tumour inhibiting substance
10. The small bowel contains low levels of pre-carcinogen activating enzymes

There are, however, a number of risk factors known to contribute to the development of small bowel malignancies.

Behavioural

Diet

Dietary intake studies have suggested higher risks with the intake of animal fat and protein, refined carbohydrates, red meat, salt cured or smoked foods.

Tobacco/ Alcohol

Evidence from case-control studies is inconsistent regarding the influence of either tobacco or alcohol.

Occupation/ Socio-economic

No correlations noted to date.

Genetics

Familial Adenomatous Polyposis (FAP)

FAP is an autosomal dominant disorder caused by mutations of the tumour suppressor gene, APC, located on the long arm of chromosome 5 (5q21). Members of families with FAP are at high risk for the development of multiple small bowel adenomas with an increased risk of duodenal adenomas and the development of adenocarcinomas, periampullary carcinoma in particular. The prevalence of duodenal adenomatosis or polyposis is approximately 50-90%. The estimated risk of duodenal carcinoma is between 3-5 %. A similar risk is estimated for those patients with Peutz-Jeghers syndrome, associated with mucocutaneous pigmentation and multiple hamartomas.

FAP and Duodenal Adenomatosis or Polyposis

Information from a number of large FAP registries suggests that FAP members have a risk of developing multiple adenomas in the duodenum of between 20-100% depending on a variety of factors, including endoscopic methods (side viewing versus end viewing), tissue sampling (biopsy of visible lesions versus random biopsies) and frequency of endoscopic surveillance. The prevalence of duodenal or periampullary carcinoma in FAP patients ranges from 1-12% with lifetime risks by age 70 of between 3-4% based on the Dutch and Danish registries.

Hereditary Non-polyposis Colon Cancer (HNPCC)

HNPCC is also an autosomal dominant genetic condition associated with mutations in a number of genes involved in DNA repair (MSH2, MLH1, PMS1, PMS2, and MSH6). The lifetime risk of developing small bowel carcinoma for those with HNPCC is estimated at between 1 and 4%. The locations within the small bowel differ from that seen in the general population, with tumours being evenly distributed amongst the duodenum, jejunum and ileum. The median age at onset in one series was 49 years, significantly younger than in the general population. 33% of patients may present with small bowel carcinoma as the only manifestation of HNPCC.

Cystic Fibrosis

Within 2 cohorts of patients with cystic fibrosis, the risk of small bowel cancer was reported to be higher than expected compared to the general population.

Celiac Disease

Although the risk of small bowel lymphoma is known to be higher with celiac disease, small bowel carcinoma as well has been reported in association with sprue.

Small Bowel Adenomas and Molecular Genetics

Epidemiologic evidence has suggested that the sequence of adenoma-carcinoma noted in the development of large bowel carcinoma also occurs in the small bowel.

Recent studies into the molecular genetics of small bowel malignancies have demonstrated a variety of altered gene products such as k-ras and p185neu as well as over expression of other proteins such as cyclin D1 and p53.

Data from FAP patients suggests that FAP bile may contain a mutagen, activated at low pH, which affects duodenal mucosa, creating DNA adducts. These may be incompletely repaired leading to further “second-hit” mutations in other genes such as APC, k-ras and TP53.

Radiation Therapy

Data from large series of patients undergoing radiation therapy for cancer of the cervix found a small increase in the relative risk (RR 1.8) of small bowel cancer remaining elevated out to 30 years follow up.