Malignant Neoplasms of the Small Intestine

Updated: Sep 26, 2019
  • Author: Ponnandai S Somasundar, MD, MPH, FACS; Chief Editor: N Joseph Espat, MD, MS, FACS  more...
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Overview

Practice Essentials

Malignant neoplasms of the small bowel are among the rarest types of cancer, accounting for 1-2% of all GI cancers. [1] Research into the natural history and prognosis of patients with small bowel cancer has been limited by the small number of cases and the heterogeneity of tumor types. Around 98% of small-bowel tumors are made up of adenocarcinomas, carcinoid tumors, lymphomas, sarcoma (most commonly leiomyosarcoma and more rarely angiosarcoma or liposarcoma) and gastrointestinal stromal tumors (GISTs). [1]   Each of these tumor subtypes has its own distinct clinical behavior and, therefore, dictates a different treatment approach.

Unfortunately, malignant lesions of the small bowel are often discovered when they have metastasized to distant sites or at surgery indicated for another diagnosis or intestinal obstruction. Thus, these patients often have in a poor prognosis. The 5-year survival rates of small intestine cancers by stage are as follows [2] :

  • Stage I - 70%
  • Stage II - 55%
  • Stage III - 30%
  • Stage IV - 5-10%

This review focuses on adenocarcinoma, as it is the most common histologic type of small-bowel malignancy in the United States. Sarcomas are also briefly discussed. For further information on carcinoid tumors, refer to Intestinal Carcinoid Tumors; for further information on GISTS, refer to Gastrointestinal Stromal Tumors (GISTs).

For patient education information, see What Is Small Intestine Cancer?

 

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Pathophysiology

Approximately 64% of all small-bowel tumors are malignant, and approximately 40% of these tumors are adenocarcinomas. Epidemiologically, small-bowel adenocarcinomas bear a striking resemblance to large-bowel adenocarcinomas. For example, although small-bowel adenocarcinomas are only one fiftieth as common as large-bowel adenocarcinomas, they share a similar geographic distribution, with predominance in Western countries. In addition, they tend to co-occur in the same individuals, with an increased risk of small-bowel adenocarcinoma in survivors of colorectal cancer and vice versa.

Furthermore, similar to adenocarcinomas in the colon, those in the small bowel arise from premalignant adenomas. This occurs both sporadically and in the context of familial adenomatous polyposis. Through a stepwise accumulation of genetic mutations, these adenomas become dysplastic and progress to carcinomas in situ and then to invasive adenocarcinomas. They then metastasize via the lymphatics or portal circulation to the liver, lung, bone, brain, and other distant sites.

Despite these similarities with colon cancer, small-bowel adenocarcinomas (SBAs) tend to cluster away from the colon, toward the gastric end of the small intestine. Approximately 50% arise in the duodenum, 30% in the jejunum, and 20% in the ileum. The duodenum is the first portion of the small bowel to be exposed to ingested chemicals and pancreaticobiliary secretions. This fact, combined with the higher prevalence of cancer in the duodenum, may indicate that the substances (ie, ingested chemicals, pancreaticobiliary secretions) may have carcinogenic properties. Animal studies have demonstrated that diverting bile decreases the prevalence of experimentally induced small-bowel cancers, which suggests that bile may be carcinogenic.

In the first large-scale genomic comparison of SBA (n = 317) with colorectal cancer (n = 6353) and gastric carcinoma (n = 889), the frequency of genomic alterations seen in SBA demonstrated distinct differences in comparison with either colorectal cancer (APC: 26.8% vs 75.9%, P <  0.001; and CDKN2A: 14.5%  vs 2.6%, P <  0.001) or gastric carcinoma (KRAS: 53.6% vs 14.2%, P <  0.001; APC: 26.8% vs 7.8%, P <  0.001; and SMAD4: 17.4% vs 5.2%, P <  0.001).  BRAF was mutated in 7.6% of colorectal cancer and 9.1% of SBA samples, but V600E mutations were much less common in SBA, representing only 10.3% of BRAF-mutated cases. The ERBB2/HER2 point mutations, microsatellite instability, and high tumor mutational burden were all enriched in SBA. [3]  

 

 

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Etiology

Genetic risk factors

Patients with familial adenomatous polyposis develop multiple adenomas throughout the small bowel and colon that may lead to adenocarcinomas. [4]  After the colon, the duodenum is the most common site of adenocarcinoma. A 1993 study from Johns Hopkins by Offerhaus et al found that patients with familial adenomatous polyposis have a relative risk of more than 300 for duodenal adenocarcinoma but no elevated risk for gastric or nonduodenal small-bowel cancer. [5]  Molecular genetic studies of duodenal polyps in patients with familial adenomatous polyposis performed by Kashiwagi et al in 1997 found a high frequency of p53 overexpression in dysplastic adenomas, although the frequency of TP53 and k-ras gene mutations was much lower. [6]

Aside from colorectal carcinoma, patients with hereditary nonpolyposis colorectal cancer also develop endometrial, gastric, small bowel, upper urinary tract, and ovarian carcinomas. The lifetime risk of small-bowel adenocarcinoma in patients with hereditary nonpolyposis colorectal cancer is 1-4%, which is more than 100 times the risk in the general population. Small bowel adenocarcinomas in persons with hereditary nonpolyposis colorectal cancer are distributed fairly evenly throughout the small bowel. They occur at younger age and appear to entail a better prognosis than sporadic small-bowel cancers. The most commonly mutated genes in the germline of patients with hereditary nonpolyposis colorectal cancer are HMLH1 and HMSH2, which are involved in DNA mismatch repair.

Environmental risk factors

A 1977 study by Lowenfels and Sonni found animal fat intake to be correlated with small-bowel cancer. [7]  Another study, in 1993 by Chow et al, reported that consumption of red meat and salt-cured or smoked foods raised the risk of small-bowel cancer 2-3 times. [8]

Studies from 1994 by Chen et al found an association between smoking and small-bowel adenocarcinoma and between alcohol consumption and small-bowel adenocarcinoma, but this has not been confirmed in other studies. [9, 10]

Predisposing medical conditions

The relative risk of small-bowel adenocarcinoma is estimated to be between 15 and more than 100 in patients with Crohn disease. Unlike most small-bowel adenocarcinomas, Crohn-related tumors generally occur in the ileum, reflecting the distribution of Crohn disease. The risk of adenocarcinoma does not begin until at least 10 years after the onset of Crohn disease, and the adenocarcinoma typically occurs more than 20 years afterwards.

Patients with celiac disease appear to be at increased risk of small-bowel lymphoma and adenocarcinoma. A 2001 survey of adult celiac disease patients in the United States performed by Green et al found a relative risk of 300 for the development of lymphoma and 67 for the development of adenocarcinoma. Small-bowel adenocarcinomas associated with celiac disease appear to have an increased incidence of defective DNA mismatch repair compared with those not associated with celiac disease and are also associated with an earlier stage at diagnosis and a better prognosis. [11]

Hemminki has reported an approximately 18-fold increase in the incidence of gastrointestinal cancers in patients with Peutz-Jeghers syndrome compared with that in the general population. [12]

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Epidemiology

The American Cancer Society estimates 10,590 new cases and 1590 deaths from small intestine cancer in the United States in 2019. [13]

In general, small-bowel cancer prevalence is lower in Asia and in less industrialized countries than in Western countries. In addition, several hospital-based series indicate that while adenocarcinomas constitute the majority of small-bowel cancers in developed countries, lymphomas predominate in less-developed countries.

Population-based studies in the United States have suggested somewhat higher prevalence rates of small-bowel cancer for blacks than for whites. According to one study, blacks have almost twice the incidence of carcinomas than whites do (10.6 versus 5.6 per million population). [14]

Males represent a slight preponderance of new cases (52%) compared with females (48%). [13] The prevalence of small-bowel cancer tends to increase with age, with a mean age at diagnosis of approximately 60 years. Adenocarcinomas, more than the other histologic subtypes, tend to be diagnosed in somewhat older patients.

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Prognosis

Adenocarcinomas

The overall 5-year survival rate for resectable adenocarcinoma is 20%. [1]

A study comparing outcomes for 2123 patients with small-bowel adenocarcinoma and 248,862 patients with colon cancer found the prognosis for small-bowel adenocarcinoma is worse than that for colon cancer, and only surgery improves survival. In contrast to colon cancer, chemotherapy did not improve overall or cancer-specific survival regardless of stage. Predictors of poor survival included advanced age, black race, advanced stage, poor tumor differentiation, high comorbidity index, and distal location. [15]

Sarcomas

The 5-year survival rate for resectable leiomyosarcoma, the most common primary sarcoma of the small intestine, is approximately 50%. [1]  Negative surgical margins after surgery improve prognosis. Intestinal bleeding is common with small-bowel sarcomas and may necessitate transfusion support and surgical intervention.

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