The Epidemiology and Pathogenesis of Neoplasia in the Small Intestine

Purpose

The mucosa of the small intestine encompasses about 90% of the luminal surface area of the digestive system, but only 2% of the total annual gastrointestinal cancer incidence in the United States.

Methods

The remarkable contrast in age-standardized cancer incidence between the small and large intestine has been reviewed with respect to the cell type patterns, demographic features, and molecular characteristics of neoplasms.

Results

Particularly noteworthy is the predominance of adenocarcinoma in the colon, which exceeds 98% of the total incidence by cell type, in contrast to that of 30% to 40% in the small intestine, resulting in an age-standardized ratio of rates exceeding 50-fold. The prevalence of adenomas and carcinomas is most prominent in the duodenum and proximal jejunum. The positive correlation in global incidence rates of small and large intestinal neoplasms and the reciprocal increases in risk of second primary adenocarcinomas suggest that there are common environmental risk factors. The pathophysiology of Crohn inflammatory bowel disease and the elevated risk of adenocarcinoma demonstrate the significance of the impaired integrity of the mucosal barrier and of aberrant immune responses to luminal indigenous and potentially pathogenic microorganisms.

Conclusion

In advancing a putative mechanism for the contrasting mucosal susceptibilities of the small and large intestine, substantial differences are underscored in the diverse taxonomy, concentration and metabolic activity of anaerobic organisms, rate of intestinal transit, changing pH, and the enterohepatic recycling and metabolism of bile acids. Experimental and epidemiologic studies are cited that suggest that the changing microecology, particularly in the colon, is associated with enhanced metabolic activation of ingested and endogenously formed procarcinogenic substrates.

Introduction

Neoplasms of the small intestine are rare throughout the world. Global incidence is generally less than 1.0 per 100,000, ranging from 0.3 to 2.0 per 100,000, when age-standardized to the world population. In the United States, cancers of the small intestine represent 0.4% of total cancer cases and 0.2% of cancer deaths (1). The small intestine, an elongated tube consisting of the duodenum, jejunum and ileum, represents 75% of the length (i.e., about 5–6 meters), extending from the pylorus to the ileocecal valve, and 90% of the absorptive surface area of the esophago-gastrointestinal system. Remarkably only 2% of the total annual cancer incidence of the digestive system occurs in the small intestine. In contrast, approximately 57% of cancers in the digestive system are diagnosed each year in the large intestine, which measures about 1.5 meters in length.

The average annual age-adjusted incidence per 100,000 for cancer of the small intestine, when age-standardized to the U.S. 2000 population, is 1.9 in men, and 1.4 in women. From 1975 to 2000, the rates increased by almost 50%. This trend reflected increases for adenocarcinomas, malignant carcinoid tumors, and lymphomas in men, and for carcinoid tumors and lymphomas in women (2). The age-specific incidence increases for carcinoid tumors, adenocarcinomas, and lymphomas after age 30, whereas the incidence of sarcomas seems to level off after age 70. The incidence of carcinoid tumors and adenocarcinomas are slightly higher in blacks compared with whites, and the reverse is true for lymphomas and sarcomas (3). Adenocarcinomas are most common in the duodenum and proximal jejunum, whereas lymphomas and carcinoid tumors predominate in the ileum and distal jejunum (4). The international incidence of adenocarcinoma of the small intestine is positively correlated with the distribution of colon cancer incidence. The pattern of increased risk of second primary cancers of the small and of the large intestine suggest similar causal mechanisms, rather than the effects of surveillance bias or the carcinogenic effects of treatment of the index primary cancer 5, 6. The U.S. Surveillance, Epidemiology and End Results (SEER) cohort of male and female patients who had survived 5 or more years after the diagnosis of cancer of the small intestine, experienced more than a two-fold increase in risk (risk ratio [RR] =2.62; 95% confidence interval [CI] = 1.77, 3.75) of colon cancer. Similarly, the cohort of patients with colon cancer exhibited an increased risk (RR = 3.44; 95% CI = 3.00, 3.95) of cancer of the small intestine (7). The reciprocal increases in risks were amplified in subcohorts in whom the index primary cancer was diagnosed before 60 years of age, suggesting interactions with genetic susceptibility factors (8). The increases in risk of second primary colorectal cancer have been described in association with a prior diagnosis of adenocarcinoma or carcinoid tumor in the small intestine 9, 10, 11.