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A 65-year-old man with a history of colon cancer that was resected 10 years ago presented with small bowel obstruction. During emergency laparotomy, two stenotic, napkin ring-like lesions were seen within a 50.0 cm loop of small bowel that was subsequently resected. There was no intraoperative evidence of tumor elsewhere. Immunostains show the tumor cells to be positive for cytokeratin and CDX-2, and negative for chromogranin and synaptophysin.
Archive Case and Diagnosis:
This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2008, and Case 6 is adenocarcinoma of the small bowel, arising in celiac disease.
Criteria for Diagnosis and Comments:
Microscopic sections show an invasive adenocarcinoma of the small bowel, as supported by the above immunoperoxidase studies. The tumor is poorly differentiated with an infiltrating front and a mild lymphocytic peritumoral response. Adjacent non-neoplastic small bowel shows lamina propria inflammation, subtotal villous blunting, and increased intraepithelial lymphocytes, consistent with celiac disease.
The small intestine comprises more than 90% of the mucosal surface of the gastrointestinal tract; yet primary small bowel adenocarcinoma (SBCa) represents only about 0.5% of all bowel neoplasms. Compared to the neighboring segments of the gastrointestinal tract, the small bowel appears to be relatively resistant to the development of tumors. Several mechanisms have been proposed to explain this phenomenon, including short food transit time, dilution of carcinogens by the large volume of secretions, lack of procarcinogenic bacterial degradation of bile salts, and rapid proliferation of small bowel mucosal cells which may competitively inhibit the growth of malignant cells.
SBCa accounts for 40% of all malignant tumors in this anatomic location, and the annual incidence in the U.S. is 3.9 per million with a mean age between 60 and 70 years. SBCa is an aggressive, often fatal disease with an overall 5-yr survival rate of 30%. The poor prognosis is dictated in large part by advanced stage at the time of diagnosis, since clinical manifestations are usually nonspecific and appear late in the course of the disease. At present, the primary treatment modality for SBCa is surgery, but emerging data indicate that some SBCa may be sensitive to radiochemotherapy. The majority of SBCa are histologically moderately to well-differentiated, and are found in decreasing order of frequency in the duodenum, jejunum, and ileum. Although the duodenum only accounts for a small portion of total length of small bowel, more than 45% of SBCa arise in this area, and especially in the periampullary region. Bile acids seem to play a major role in pathogenesis, since the frequency of SBCa declines with increasing distance from the common bile duct.
Several epidemiological and pathological similarities have been identified between colorectal adenocarcinomas and SBCa, leading to the hypothesis that some genetic mechanisms responsible for colorectal cancer might, to some degree, also be involved in the development of SBCa. Both tumor types usually arise from preexisting adenomas, with an estimated one-third of solitary small bowel adenomas transforming into invasive carcinoma. Adenomas in familial polyposis disease also seem to have similar behavior in both small and large intestine. Patients with SBCa are at increased risk for large bowel adenocarcinoma and vice versa.
SBCa occur more frequently in patients with a history of Crohn disease, celiac disease, and hereditary gastrointestinal cancer syndromes such as familial adenomatous polyposis (FAP), hereditary nonpolyposis colorectal cancer syndrome (HNPCC), and Peutz-Jeghers syndrome (PJS).
Duodenal adenomas occur in 31–92% of patients afflicted with FAP, and the duodenum represents both the second most common site of malignant disease and the leading cause of cancer-related death in this patient population. SBCa is also one of the most frequently observed extra-colonic malignancies in patients with HNPCC. These tumors can be the presenting neoplasm and are sometimes the only expression of malignant disease. Similar to colorectal cancer in HNPCC, SBCa appear to have a better prognosis in this patient group. The lifetime risk of developing an HNPCC-related SBCa is about 100 times the general population risk. PJS is an autosomal dominant disease characterized by hamartomatous polyps in the gastrointestinal tract, mucocutaneous melanin pigmentation and a tumor suppressor STK11/LKB1 gene defect on chromosome 19. PJS carries a significantly increased risk for SBCa.
There is 12-fold increased risk of SBCa in patients with Crohn disease (CD) compared to the general population. Risk factors for SBCa among patients with CD include male sex, surgical by-pass loops, chronic fistulous disease, and long-standing CD. Tumors appear at a younger age than in the general population, mirror the distribution of CD in the digestive system, and often occur within an inflammatory stricture. Multifocal SBCa have been reported in CD patients.
Celiac disease carries an increased risk of T-cell non-Hodgkin lymphoma, termed enteropathy-associated T-cell lymphoma (EATL). This neoplasm is primarily localized in the gut and is associated with poor prognosis. The association between celiac disease and EATL is less common than previously thought, with a relative risk of approximately 3.0, likely due to increased diagnosis and treatment of celiac disease. Celiac disease also predisposes to SBCa, which can occur even after a long period of gluten-free diet. SBCa associated with celiac disease are characterized by proximal location (duodenum and jejunum), high frequency of defective mismatch repair proteins (especially MLH1), and better survival, compared to patients with SBCa and no gluten sensitivity.
K-ras mutations play an early and important role in SBCa development, especially in the duodenum. Similarly to colorectal cancer, p53 appears as a late event in SBCa development. Overexpression of Cyclin D1 and p27, as well as down-regulation of p16 and p21, appear early in the development of SBCa. Defects in one or more mismatch repair protein genes result in the microsatellite instability phenotype in colorectal cancer, which can be associated with HNPCC. Similar molecular changes probably contribute to SBCa tumorigenesis as well. Some genetic events appear to be distinct between SBCa and colorectal cancer. Alterations of the APC and DCC genes are frequent early events in colorectal carcinogenesis, but occur rarely in SBCa. Similarly, SBCa shows frequent β-catenin alterations, without associated APC gene defect as one sees in colorectal cancer.