Adenocarcinoma of the Small Intestine

Pathogenesis and Risk Factors

The small intestine and large intestine share similarities in structure as well as function but can display dramatically different patterns of malignancy. The duodenum and small intestine account for more than 90% of the absorptive surface of the GI system and about 75% of its length, yet malignancy is about 50 times less common in this region than in the colorectum. Several hypotheses have been presented to explain this disparity. First, as the small intestine is traversed, bacterial concentrations increase but remain substantially lower than those in the colon. This variation in gut microbiota confers different carcinogenic potential. Additionally, in healthy individuals, transit time is faster through the small intestine than the large intestine, which decreases exposure of the mucosa to potentially harmful bacteria. Although digestive enzymes are protective in portions of the GI tract, the highest concentration of digestive enzymes is in the proximal small intestine, namely the duodenum, which has the highest incidence of small intestinal adenocarcinoma. The interaction of pancreatic, biliary, and gastric secretions has been implicated in the higher incidence of adenocarcinoma of the duodenum, possibly through the development of reactive oxygen species during activation of bile acid receptors. Although this occurs throughout the small intestine, the large variations in acid content in the duodenum make it less able to repair cell damage, as compared with the jejunum and ileum.

Dietary and behavioral risk factors have also been examined. Heavy alcohol intake increases the risk of small intestinal adenocarcinoma in some cohorts. Smoking, obesity, dietary fiber intake, and dietary fat intake have been investigated with varying results.

Analyses of national and multi-institutional databases suggest that Crohn disease increases the risk of developing small intestinal cancer by about 60-fold. In one review of more than 12,000 patients with Crohn disease, the mean interval between onset of Crohn symptoms and diagnosis of carcinoma was 9 years, yet the absolute risk of small intestinal cancer was only marginally higher for Crohn patients than for non-Crohn patients.

Familial adenomatous polyposis (FAP) reflects a germline mutation in the adenomatous polyposis coli (APC) gene. Virtually all patients with FAP will develop duodenal polyps, and polyps carry a 100- to 330-fold higher risk of duodenal cancer in FAP patients than in non-FAP patients. In fact, FAP patients with duodenal polyps have a 5% to 10% estimated cumulative risk of developing duodenal cancer by 60 years of age. These neoplasms are adenocarcinomas or desmoid tumors. Increased awareness of the link between FAP and colon cancer has increased the number of prophylactic colectomies; as a result, duodenal cancer now confers the highest risk of death in FAP. Several management strategies have been proposed for patients with FAP. Upper endoscopy screening increases identification of polyps but does not improve overall survival because the optimal treatment strategy is still controversial. Several issues exist in this regard primarily because most duodenal polyps are broad-based and thus are not as amenable to endoscopic resection as are colonic polyps. As such, many clinicians are left to determine whether a duodenal resection is needed in the absence of a proven malignancy. The Spigelman classification scores the severity of duodenal polyposis on a scale of 0 to IV. According to this scoring system, the risk of duodenal malignancy is 2.3%, 2.4%, and 36% for patients with stage II, III, and IV polyposis, respectively.

Other high-risk factors include celiac sprue; however, the exact magnitude of the increased risk is unclear. In a collaborative study performed more than 30 years ago, Rampertab et al. determined that the risk of small bowel adenocarcinoma in patients with celiac disease was equivalent to the risk of colon cancer in normal populations. However, many patients in this study might have been noncompliant with their gluten-free diets. Nevertheless celiac disease remains a widely accepted risk factor for adenocarcinoma development.

Duodenal Adenocarcinoma