Small Intestine Cancer

Introduction

Malignant neoplasms of the small bowel are among the rarest types of cancer, accounting for only 2% of all GI cancers. 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, including adenocarcinomas, carcinoids, sarcomas, and lymphomas. Each of these tumor subtypes has its own distinct clinical behavior and, therefore, dictates a different treatment approach. Unfortunately, malignant lesions are often discovered when they have metastasized to distant sites or at surgery when indicated for other diagnosis or intestinal obstruction.

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. Carcinoid tumors and lymphomas are described in other articles of this journal (eg, Carcinoid Tumor, Intestinal). Around 98% of small bowel tumors are made up of adenocarcinomas,carcinoid tumors, lymphomas or sarcoma/gastrointestinal stromal tumors (GISTs).

Pathophysiology

Approximately 64% of all small-bowel tumors are malignant, and approximately 40% of these tumors are adenocarcinomas. Epidemiologically, small-bowel adenocarcinomas have 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 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 addition, genetic analyses of sporadic small-bowel adenocarcinomas suggest similarities and differences from the pathogenesis from colorectal carcinomas. Although K-ras mutation and p53 overexpression appear to be as common in small-bowel adenocarcinoma as in colorectal carcinoma, mutation of the APC tumor suppressor gene, which is characteristic of colorectal carcinoma, does not commonly occur in small-bowel adenocarcinoma.The SMAD4/DPC4 gene, which is often mutated in pancreatic and colorectal carcinomas, also appears to be inactivated in small-bowel adenocarcinomas.

Sarcomas account for approximately 15% of small-bowel malignancies in the United States. While some may exhibit clear histologic features of smooth muscle origin, many tumors display only partial differentiation with incomplete expression of muscle-associated antigens. Because they are mesenchymal neoplasms believed to be derived from the interstitial cells of Cajal in the GI tract, they have recently been named with the more general term GI stromal tumors (GISTs). Recent studies have demonstrated that nearly all GISTs, unlike true sarcomas, express a growth-factor receptor with tyrosine kinase activity encoded by the proto-oncogene c-kit. As reported by Miettinen et al in 1999, mutations in c-kit that cause constitutive tyrosine kinase activity and result in uncontrolled cell proliferation have been detected in approximately 60% of GISTs and appear to play a central role in tumorigenesis.

While most GISTs are located in the stomach, 30% of GISTs are found in the small bowel. These tumors are distributed more evenly throughout the small bowel compared with adenocarcinomas, and they tend to grow extraluminally. Because they are highly vascular lesions that commonly ulcerate, intestinal bleeding is a frequent symptom. Compared with gastric GISTs, small-bowel GISTs tend to be more aggressive and have a worse prognosis. Metastases develop primarily via the hematogenous route, commonly involving the liver and lungs. GISTs also may invade adjacent organs directly or spread via peritoneal seeding. Lymphatic metastases are rare but are believed to be a marker for more widespread metastatic disease.

Frequency United States

The incidence of small-bowel cancers in the United States in 2007 was projected to be 5640 cases, of which 2940 cases were projected to be in males and 2700 were projected to be in females. An estimated 1090 persons (males 570; females 520) were projected to die of the disease in 2007.

International

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 a predominance of lymphomas in less developed countries.

Mortality/Morbidity

The 5-year overall survival rate for patients with adenocarcinoma has been estimated to be 30-35%. The 5-year survival rate for patients with small-bowel sarcomas is approximately 25%.

Race

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).

Sex

Men have higher rates of all types of small bowel cancer than women do, with a male-to-female ratio of 1.4:1.

Age

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.

Clinical History

Small-bowel cancer is typically asymptomatic in its early stages, but more than 90% of patients eventually develop symptoms as the disease progresses. This unfortunately reflects advanced disease.

• Because of the nonspecific nature of symptoms, a significant delay between the onset of symptoms and diagnosis often occurs, averaging 6-8 months.
• Nausea, vomiting, and intestinal obstruction are common presenting symptoms. Half of these patients undergo emergency surgery for intestinal obstruction.
• Abdominal pain and weight loss complicate the clinical presentation.
• Bleeding is less common.
• The few published series on small bowel neoplasms that are available cannot be used as generalizations for presentation of the individual histologic subtypes. However, it does appear that adenocarcinomas are more frequently associated with pain and obstruction when compared to sarcomas and carcinoids. Sarcomas (GIST) present more commonly with acute GI bleeding.

Physical

Patients with small-bowel malignancies may present with fairly unremarkable physical examination findings.

• A tender and distended abdomen may be found due to obstruction.
• Peritoneal signs indicate perforation.
• Jaundice from biliary obstruction or liver metastases may occur rarely.
• Guaiac-positive stool or acute GI bleeding, suggests intestinal bleeding, although this occurs more frequently in persons with benign small-bowel tumors.

Causes

• Genetic risk factors
  • Familial adenomatous polyposis: Patients with this condition develop multiple adenomas throughout the small bowel and colon that may lead to adenocarcinomas. 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.9 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.
  • Hereditary nonpolyposis colorectal cancer: Aside from colorectal carcinoma, patients with this genetic syndrome 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 have 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
  • Diet: A 1977 study by Lowenfels and Sonni found animal fat intake to be correlated with small-bowel cancer.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.
  • Tobacco and alcohol: 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.
• Predisposing medical conditions
  • Crohn disease: 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.
  • Celiac disease (nontropical sprue): 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.
  • Peutz-Jeghers syndrome: Hemminki has reported an approximately 18-fold increase in the incidence compared to that in the general population.

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