The Epidemiology and Pathogenesis of Neoplasia in the Small Intestine
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.
Section snippets
Morphology and Molecular Characteristics of Enteric Neoplasms
The mucosal layer of the small intestine is replaced in 4–7 days (12) and consists of absorptive, glandular, and neuroendocrine cells that line the crypts and villi. The crypt epithelium functions in cell proliferation and cell renewal. Pluripotential stem cells are located at the base of each crypt, from which undifferentiated reserve cells migrate toward the lumen and differentiate into absorptive cells or enterocytes, or into mucin-secreting goblet cells, before undergoing apoptosis 13, 14.
Tobacco and Alcohol
Risk factors such as the regular use of tobacco 81, 82, excessive alcohol consumption and the interaction with folate deficiency (83), obesity 84, 85, and nutrition 86, 87, 88 have been studied extensively in patients with colon cancer. In contrast, studies of patients with adenocarcinoma or malignant carcinoid tumors of the small intestine have been constrained because of the rarity and biologic heterogeneity of the major types of tumor. Studies of tobacco and alcohol that were based solely on
Chronic Inflammation and a Cascade of Cytokines
Chronic inflammatory bowel disease includes two clinically and pathologically distinctive autoimmune entities, Crohn disease (CD) and ulcerative colitis. Crohn disease is a chronic inflammatory condition presenting principally in the distal small intestine, but may involve the colon, mainly the proximal colon, rectum, anus, and perianal tissues, other digestive organs, and tissues outside of the digestive tract. Nearly 50% of patients manifest inflammatory disease that involves both ileum and
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