An Overview of Adenocarcinoma of the Small Intestine
An Overview of Adenocarcinoma of the Small Intestine
Small intestinal epithelial cells are remarkably resistant to the development of benign or malignant neoplasms. Why small-bowel adenocarcinomas are so rare compared to colorectal adenocarcinomas is unknown. Thus, the work of Neugut et al is important, as they provide an excellent overview of the current knowledge of this unique tumor, and the problems and limitations encountered in such research.
The incidence of cancers of the small intestine in the Western Hemisphere is 0.5 to 1.0 per 100,000 people. One would expect the small bowel to be a relatively frequent site of cancer because it contains some of the body's most rapidly proliferating cells, is bathed by many potential carcinogens in the diet, and is bordered by the stomach and colon, which are common sites of cancer.1 Although the small intestine constitutes 90% of the absorptive area of the gastrointestinal tract, malignant tumors of the colon and rectum are 50 times more common. Moreover, between 50% to 75% of these very rare malignancies are located in the duodenum, which comprises only 4% of the length of the small bowel. This finding suggests that biliary and pancreatic secretions may rarely act as carcinogens on the entire small- bowel mucosa, but rather, may have a direct genotoxic effect on the duodenal mucosa. Alternatively, the constant influx of alkaline bile and/or pancreatic secretions into the duodenum could explain this finding.
The authors state that small-bowel adenocarcinomas are more common in males and specifically in black males. There is no good explanation for this finding. Nevertheless, it suggests genetic, occupational, lifestyle, and socioeconomic variables as risk factors.
It is worth emphasizing that there is a trend over time for an increasing incidence of small-bowel tumors, specifically, adenocarcinoma, carcinoid tumor, and lymphoma. This may possibly be due to changes in diet, lifestyle, or to AIDS.
Worldwide, the incidence of small- intestinal adenocarcinomas parallels that of colorectal cancers. Both small intestinal and colorectal cancers share many epidemiologic features, such as an association with cholecystectomy, alcohol consumption, and fat and protein intake. They also have similar therapeutic approaches and share the adenoma-carcinoma sequence. In addition, individuals with colorectal cancer are at increased risk for adenocarcinomas of the small intestine, and vice versa.
Very little is known about the biologic and molecular abnormalities of these tumors. Our group has researched this field, and interestingly, we found that genetic abnormalities frequently identified in colonic neoplasms are also seen in small-bowel tumors. These include activating mutations in the c-K-ras oncogene in about half of thecases, and increased expression of cyclin D1 (40%) in both adenomatous polyps and adenocarcinomas. Increased detection of p53 protein was seen in up to 70% of the tumors, with higher rates in adenocarcinomas compared to adenomatous polyps.
Thus, cyclin D1 overexpression and c-K-ras mutations appear to be early events in small-bowel tumorigenesis and do not significantly increase in the transition from adenoma to carcinoma. This contrasts with p53 detection, which increases in adenoma-to-carcinoma transition. We also found that increased expression of cyclin D1 and p53 are closely related, and each is associated with a decrease in 3-year survival. We speculate, therefore, that small- and large-bowel adenocarcinomas share the same frequencies and order of appearance of several important oncogenes, and, as in colon cancer, increased expression of cyclin D1, p53, and c-K-ras may perturb cell-cycle control in benign adenomas of the small bowel, thereby enhancing tumor progression.
In the 21st century, we should have a higher index of suspicion for this rare disease whose incidence increases, especially in high-risk patients, ie, those with familial adenomatous polyposis, Peutz-Jeghers syndrome, Crohn's disease, celiac sprue, immunosuppressive states, ileostomies, and duplications of the small bowel. Appropriate use of enteroclysis, push enteroscopy, and CT should facilitate diagnosis at an early stage, when surgery is still curable.
The authors comprehensively discuss why small-bowel tumors are so rare and offer a few explanations. Probably, the most significant of these is a higher level of apoptosis in the small bowel as compared to the large bowel. This is due mainly to increased expression of the pro-apoptotic gene bak and lack of expression of the anti-apoptotic gene bcl-2.
1. Chow J, Chen C, Ahsan H, et al: A population-based study of the incidence of malignant small bowel tumours: SEER, 1973-1990. Int J Epidemiol 25(4):722-728, 1996.
2. Neugut A, Santos J: The association between cancers of the small and large bowel. Cancer Epidemiol Biomarkers 2:551-553, 1993.
3. Sutter T, Arber N, Moss SF, et al: Frequent c-K-ras mutations in small bowel adenocarcinomas. Dig Dis Sci 41:115-118, 1996.
4. Arber N, Hibshosh H, Moss SF, et al: Increased expression of cyclin D1 is a common and early event in gastrointestinal cancers. Gastroenterology 110:485A, 1996.