Carcinoma, Small Intestine

Synonyms

Adenocarcinoma; Small Intestine

Definition

Briefly, small intestinal carcinoma is the malignant epithelial tumor of the small intestine. Though the small intestine has a larger surface area and higher rate of epithelial cell turnover, epithelial neoplasms develop less frequently than the other parts of the GI tract. Small intestinal carcinomas are most commonly located in duodenum, usually around the ampulla of Vater. Although adenocarcinomas are the most common primary tumors, small intestine is the most common part of the gastrointestinal tract for involvement by secondary tumors, which are more than twice as common as the primary neoplasm. Like colorectal carcinomas, most of the small intestine carcinomas are sporadic and develop from adenomas. Risk factors for sporadic carcinoma include smoking, alcohol consumption, and fat in diet. Chronic inflammation is an important predisposing condition, including long-standing Crohn’s disease and gluten-sensitive enteropathy (GSE). Familial adenomatous polyposis (FAP) carries the greatest increase risk for small intestinal adenocarcinoma. Other polyposis syndromes with increased risk include Peutz-Jeghers syndrome, juvenile polyposis syndrome, and hereditary nonpolyposis colon cancer syndrome (HNPCCC). Carcinoma can also develop in ileostomies, and ileal reservoirs. The most common presenting symptoms of small intestinal carcinoma are abdominal pain, obstruction, and occult gastrointestinal bleeding. Duodenal and ampullary tumors may obstruct the bile duct and cause jaundice. Most cases with distal small intestinal carcinomas present with advanced disease.

Clinical Features

• Incidence

  6.8 per million (Data from United States Surveillance, Epidemiology and End Results (SEER), 1973–2005). Overall small intestine carcinomas are rare tumors, making up 2% of GI tumors and 1% of GI cancer deaths.

• Age

  Median age is approximately 67 years.

• Sex

  Men are affected slightly more often than woman.

• Site

  Duodenum is the main site of occurrence of carcinomas. In duodenum, carcinomas are most common around the ampulla of Vater (approximately 65% of the tumors). The incidence decreases progressively through the rest of the small intestine. Crohn’s disease–associated tumors are found in the ileum, in the main site of the inflammatory pathology.

• Treatment

  Pancreaticoduodenectomy or endoscopic mucosectomy/polypectomy (for polypoid and superficial tumors) can be applied for proximally located tumors, while more distal tumors require segmental resection with accompanying mesentery. Chemotherapy and radiotherapy appear to have little proven effect on survival.

• Outcome

  Outcome of the patients is poor in all locations. In the SEER database for 1988–2001, the overall 5-year survival of small intestinal adenocarcinoma was 27% and median survival was 13.9 months. For the cases with localized tumors, the 5-year survival rate was 57%, regional disease was 34%, and metastatic disease was 3%.

Macroscopy

The macroscopic findings depend on the site of the carcinoma. Tumors may have flat, stenotic, ulcerative, infiltrative, or polypoid macroscopic appearance. Ampullary and duodenal tumors usually have small, exophytic appearance, whereas distal tumors tend to be large, constricting, and annular lesions. Stage of the tumor also affects the macroscopic appearance. Another determinant is the presence or absence of a predisposing factor, such as accompanying adenoma, GSE, Crohn’s disease, polyposis syndromes, etc. Most of the tumors have already penetrated the muscularis layer or serosal surface at the time of diagnosis. Duodenal carcinoma requires additional sampling to evaluate the involvement of the pancreas and depth of the retroperitoneal invasion.

Microscopy

Histologically, small intestine carcinomas resemble their colonic counterparts (Fig. 1). Most of the small intestine carcinomas are adenocarcinomas, while mucinous adenocarcinoma and signet ring cell carcinomas can also be seen. Carcinomas that develop in ampulla of Vater may show an intestinal or pancreaticobiliary phenotype. Differentiation of these phenotypes is important for treatment and also the prognosis of the intestinal type is better. Adenosquamous carcinoma, medullary carcinoma, squamous cell carcinoma, carcinomas with neuroendocrine cell component, and undifferentiated carcinomas are rarer types of small intestinal carcinomas.

Carcinoma, Small Intestine, Fig. 1

Moderately differentiated adenocarcinoma of the duodenum (H&E, ×100)

Immunophenotype

Small intestinal carcinomas show a different keratin 7/keratin 20 profiles; nearly half of the cases are positive for keratin 7 and keratin 20. This feature can be useful in differential diagnosis of metastatic spread of colonic carcinoma. AMACR/P504S immunostaining can be helpful as this antibody is usually positive in colon cancer, but not in primary small intestinal carcinoma. Expression of CDX2 is observed in more than half of the cases and the staining pattern is usually diffuse, similar to colorectal carcinomas.

Molecular Features

Molecular pathology is not very clear because of the relative rarity of these tumors. APC gene mutations are infrequent; however, overexpression of p53 is common. Loss of E-cadherin expression, mutation in beta-catenin, SMAD4, and KRAS genes, and activation of RAS-RAF-MAPK pathway are other genetic abnormalities that have been reported.

Differential Diagnosis

The main differential diagnostic consideration is metastatic tumor. Colorectal, breast, and lung adenocarcinoma and melanoma are among the most common secondary tumors involving the small intestine. Pancreatic and gastric cancer may directly involve the small intestine. Features favoring metastasis include the presence of multiple lesions and absence of a predisposing lesion. Immunohistochemistry is primarily used to exclude metastatic disease. Pancreaticobiliary neoplasms arising in the ampulla of Vater and periampullary area should be considered in the differential diagnosis of duodenal carcinomas. The size and the location of the tumor, determined both grossly and microscopically, are considered as useful features.