- Small bowel tumors are extremely rare and account for only 2% of all gastrointestinal malignancies. Approximately one-third of the tumors are benign and two-thirds are malignant at the time of diagnosis.
- Adenocarcinoma is the most common malignancy accounting for 40% of primary small bowel neoplasms. Other tumors are neuroendocrine tumors (carcinoid), 20–40%; lymphomas, 14%; and sarcomas, 11–13%.
- Small bowel tumors are usually asymptomatic in the early stages, but eventually patients develop symptoms due to progression of the disease. The most frequent presenting symptoms are abdominal pain, nausea, vomiting, and intestinal obstruction.
- The diagnostic strategies for detecting small tumors include conventional noninvasive imaging modalities (small bowel barium series, enteroclysis, CT scan, and MRI,) as well as endoscopic modalities (push enteroscopy, double-balloon enteroscopy, and video-capsule endoscopy. The later newer techniques had improved the diagnostic accuracy of detecting small bowel tumors.
- Small bowel cancers (SBCs) are often missed because they are not considered.
- SBC is increased in patients with Crohn’s disease, celiac disease, adenoma, familial adenomatous polyposis, and Peutz-Jeghers syndrome.
- Patients who are obese and smoke cigarettes are recognized as risk factors for SBC.
Epidemiology
Small bowel cancers (SBCs) are extremely rare and account for only 0.4% of total cancer cases, and 2% of all gastrointestinal (GI) malignancies in the Western population.1–4 Its global incidence is less than 1.0 per 100,000 population, and the mortality from SBC is even lower, accounting for only 0.2% of total cancer deaths in the Western population. The low incidence of SBC is interesting considering the fact that the small bowel comprises 75% of the length (about 6-m long and four times as long as the large intestine) and 90% of the absorptive mucosal surface area of the GI tract. Various theories have attempted to explain this resistance to carcinogenesis; among them are the short contact time between potential carcinogens, lower bacterial load, reduced intestinal concentrations of inherent potential carcinogens, protection of the stem cells that are buried deep in the mucosa, and the well-developed local immunoglobulin A (IgA)-mediated immune and lymphatic systems in the small intestine.5 Data from American as well as British registries of long-term surveillance show increased rates of SBC incidence in the recent four decades (from 1.18 in 1973 to 2.27 per 100,000 population in 2004).6 The incidence increased more than fourfold for carcinoid tumors (from 0.21 in 1973 to 0.93 in 2004) and less dramatic increases for adenocarcinomas (from 0.57 to 0.73) and lymphomas (from 0.22 to 0.44) and relatively stable for sarcomas (from 0.18 to 0.19). The increase occurred in both men and in women and in all ethnic groups, but was most pronounced among African American males.7 The reason for the increase in incidence could be due to the increase in some risk factors such as the rising prevalence of obesity, and the improved imaging of the small bowel by various techniques.
Approximately two-thirds out of all small bowel tumors are malignant at the time of diagnosis.
SBC has four major histologic subtypes: adenocarcinoma, neuroendocrine tumor (carcinoid), lymphoma, and sarcoma. Adenocarcinoma is the most common malignancy accounting for 40% of small bowel tumors. The incidence of the other tumors has been reported as follows: carcinoids tumors, 20–40%; lymphomas, 14%; and sarcomas, 11–13%.
Adenocarcinoma of the small bowel
Adenocarcinoma is the most common primary malignancy of the small bowel, accounting for 40% of SBC in the Western world.4 The reported average annual age-adjusted incidence rates in the Western population are 1.45 and 1.00, per 100,000, for males and females, respectively. Rates for American Africans were more than twice those of whites (1.29 vs. 0.63).2 The mean age at diagnosis is 57 years (median 67 years). It occurs most frequently within the duodenum (49% of cases), particularly around the ampulla of Vater, and with decreasing frequency in the jejunum (21%) and ileum (15%).8 One exception is in Crohn’s disease–associated adenocarcinoma, where 70% are present in the ileum.9
Risk factors
The risk of small bowel carcinoma is increased in the setting of several diseases including Crohn’s disease,10 familial adenomatous polyposis (FAP),11 hereditary nonpolyposis colorectal cancer (HNPCC) syndrome, Celiac disease, Peutz-Jeghers syndrome (PJS), and patients with small bowel adenomas.
Crohn’s disease: Crohn’s disease is characterized by transmural, granulomatous inflammation of the small and large bowel with a tendency to form fistulae. Crohn’s disease is recognized as an important risk factor for cancer of the small intestine, with reported relative risks between 33 and 60.12–18 Several factors have been reported to be associated with an increased risk of small bowel carcinoma in patients with Crohn’s disease. These include extended duration of the disease, distal jejunal and ileal location, male sex, small bowel bypass loops, strictures, chronic fistulous disease, and young age at diagnosis.19–21
Celiac disease: Patients with celiac disease are at elevated risk for both T-cell non-Hodgkin’s lymphoma (NHL) and for adenocarcinoma of the small intestine.22–26
The reported relative risk of adenocarcinoma of the small intestine in celiac disease patients is between 60 and 80.27–29
Most small intestinal carcinomas in celiac patients are located in the jejunum.
Small intestine adenomas: The prevalence of adenomas in the small intestine is much lower than their prevalence in the colon. However, just as in the colon, an adenoma in the small intestine appears to be a precursor of adenocarcinoma.30–32 Most of the adenomas in the small bowel occur in the duodenum. A retrospective analysis of 192 villous adenomas of the duodenum found malignant changes in 42% at the time of presentation.33 Villous histology, increasing polyp size, and a higher dysplastic grade have shown to be risk factors of neoplastic transformation from adenoma to carcinoma.34
Familial adenomatous polyposis (FAP): FAP is an autosomal-dominant genetic disorder caused by mutations in the APC gene on the long arm of chromosome 5.35 Most patients diagnosed with FAP have multiple adenomas in the small bowel, usually in the duodenum,36,37 and these patients are at increased risk of small intestinal cancer, especially duodenal cancer,38–40 around the ampulla of Vater. The prevalence of duodenal adenomatosis in FAP patients is 50–90% with 3–5% of these patients progressing to duodenal cancer; however, periampullary adenomas seem to have a high risk of malignant transformation.41
Peutz-Jeghers syndrome: PJS is an autosomal-dominant condition due to a mutation in the serine/threonine kinase 11 (STK11) gene on the short arm of chromosome 19, characterized by melanin spots on lips and buccal mucosa and multiple GI hamartomatous polyps.42,43 Polyps in PJS subjects are usually found in the small intestine and are more common in the jejunum than the ileum, followed by the duodenum.44 Patients with PJS are increased risk for both GI and non-GI cancers including breast and ovarian cancers in women; testicular tumors in males; and cancers of the pancreas, esophagus, stomach, and lung in both sexes.45–48 PJS has been clearly demonstrated to be associated with an increased risk of small intestinal adenocarcinoma.49 A meta-analysis of 210 PJS patients observed a statistically significant increase in relative risk for cancer of small bowel (RR, 520), stomach (RR, 213), colon (RR, 84), esophagus (RR, 57), pancreas (RR, 132), lung (RR, 17), breast (RR, 15.2), uterus (RR, 16.0), and ovary (RR, 27).49
Hereditary nonpolyposis colorectal cancer: HNPCC, or Lynch syndrome, is an autosomal-dominant disorder related to a germline mutation in one of several mismatch repair genes, including the Mut S homologue 2 (hMSH2), MSH6, Mut L homologue 1 (hMLH1), or PMS2.50 HNPCC is associated with a substantially increased risk of cancers of the colorectum, endometrium, stomach, ovary, small intestine, urinary tract, and brain.51–54 The relative risk of SBC in patients with HNPCC has been estimated to be more than 100 compared with the general population, with a lifetime risk of 1–7%.55 The risk for SBC has been reported to be higher in MLH1 mutation carriers than in MSH2 mutation carriers52 HNPCC-associated SBCs are mainly adenocarcinoma, occur at an earlier age, and appear to have a better prognosis than those occurring in the general population.56,57
Sporadic colorectal cancer: The demonstration of a geographical correlation between rates of SBC and colorectal cancer suggests a common etiology. Various studies have shown that the risk of SBC following primary colorectal cancer were elevated; also, in those diagnosed with primary SBC, there was a four- to fivefold risk of developing colorectal cancer.58–63 These studies suggest etiological similarities between cancers of the small intestine and colorectal cancers but, to date, potential common carcinogenic agents have not been elucidated in analytic epidemiological studies.
Other cancers: The risk of SBC has been reported to be elevated in patients with a diagnosis of NHL and cancers of the prostate, female genitalia, lung, and skin, as well as others.64–68 One study reported that SBC risk could be increased (although not statistically significant) in patients diagnosed with Merkel cell carcinoma of the skin.69
Environmental risk factors: Nutritional factors such as high intake of sugar, red meat, salt cured/smoked foods or low intake of fish, fruits, and vegetables and environmental factors such as radiation therapy have been associated with increased risk for SBC.70 Increased risk of small bowel tumors have been found among obese persons and alcohol and tobacco users.71 A recent report found that patients with an adenomatous component had a better survival than those without an adenomatous component, and that distal location of the tumor in the jejunum or ileum was associated with worse prognosis.72
Neuroendocrine tumors
This term is used for all endocrine tumors of the digestive system that derive from the diffuse intestinal neuroendocrine system.73 Other synonyms are used by clinicians and pathologists for these tumors, including “carcinoid tumor,” “APUD-oma,” “neuroendocrine tumor,” and “neuroendocrine carcinoma.” The mucosa of the GI tract contains at least 15 different endocrine cell types producing hormonal peptides and/or biogenic amines.74 Neuroendocrine tumors (NETs) can be subclassified into those with, and those without, a clinical syndrome and are accordingly termed “functionally active” and “functionally inactive” NET, respectively. Furthermore, NET can arise sporadically or as a result of genetic predisposition. NET is the second most common small bowel malignancy, representing approximately 25% of all primary SB tumors. Its average annual incidence rates per 100,000 population are 1.00 and 0.70 for men and women, respectively. These rates are higher for African Americans, and lower for Hispanics and Asians/Pacific Islanders (incidence rate ratios (IRRs) are 1.63, 0.64, and 0.29, respectively.75
NETs are more common in the ileum (mostly located within 60 cm of the ileocecal valve). These are slow-growing tumors, which first appear as submucosal nodules. Although the vast majority of these tumors occur sporadically, a subset of tumors are associated with inherited syndromes, among which multiple endocrine neoplasia type 1 (MEN1) is the most significant. The diagnostic strategies for imaging NETs include conventional noninvasive imaging modalities such as ultrasound, CT scan, MRI, capsule endoscopy (CE), and bone scanning, as well as invasive imaging modalities (angiography and selective venous sampling for hormonal gradients). Recently, somatostatin receptor scintigraphy (SRS) has gained a central role, whereas tomographic procedures such as CT and MRI serve for the completion of the oncologic workup.76
Lymphomas
The gut is the most common extralymphatic site, and up to 40% of the lymphomas arise in sites other than the lymph nodes.77 Lymphomas, whether primary or secondary, account for 15–20% of all small bowel malignancies and 20–30% of all primary GI lymphomas. The ileum is the most common site (60–65%) followed by the jejunum (20–25%), duodenum (6–8%), and other GI sites (8–9%).78 The age-adjusted incidence rates of GI lymphomas in the United States are low at 0.54 in males and 0.26 in females per 100,000.2 Several patterns of SB lymphoma have been identified and include an infiltrating pattern that appears as wall thickening, an exophytic mass; these sometimes simulate an adenocarcinoma or GI stromal tumor, multifocal submucosal nodules within the SB, or a single mass lesion, which can lead to intussusception.
Four different histological types of lymphomas may be found in the small bowel:
Sarcomas
Small intestinal sarcomas constitute only 10–15% of the malignancies seen in the small intestine.84,85 There are various benign and malignant mesenchymal tumors arising in the small intestine. The most common type of small intestinal sarcomas, representing more than 90% of sarcomas, is the gastrointestinal stromal tumors (GISTs).86–88 Other types include leiomyomas, leiomyosarcomas, lipoma, angiosarcoma, and Kaposi’s sarcoma. The reported average annual incidence rates of small intestinal sarcomas per 100,000 population are 0.24 and 0.17 for males and females, respectively, and have been found to be higher for Asians (IRR, 1.36; 95% CI, 1.13–1.62).89,4
Gastrointestinal stromal tumors
GISTs are the fourth most common malignant small bowel tumors (9%). These rare mesenchymal neoplasms derived probably from the interstitial cells of Cajal, and can occur anywhere along the GI tract, but are most common in the stomach (60–70%), followed by the small bowel (20–25%).90 They are submucosal lesions, which most frequently grow endophytically in parallel with the lumen of the affected structure, but may also manifest as exophytic extraluminal excrescences. These highly vascular tumors have been reported ranging in size from 1 cm to as large as 40 cm in diameter. Ulceration of these lesions is common and intestinal bleeding is a frequent symptom. GISTs may invade adjacent organs directly or spread via peritoneal seeding. GISTs may be benign or malignant, and compared with gastric GISTs, small bowel GISTs tend to be more aggressive and have a worse prognosis. Metastases develop in nearly 50% of patients primarily via the hematogenous route, commonly involving the liver and peritoneum. GISTs smaller than 2 cm are generally considered benign with a very low risk of recurrence. About 5% of GIST cases are multiple, and increased incidence is seen in patients with neurofibromatosis type 1 (NF1). Gain-of-function mutations in exon 11 of the c-kit proto-oncogene are associated with most GISTs.91
Clinical features
Small bowel tumors are usually asymptomatic in the early stages, but eventually symptoms do develop due to disease progression. The rareness of these tumors and the subtle presenting symptoms may delay the diagnosis. The most frequent presenting symptoms are abdominal pain, nausea, vomiting, and intestinal obstruction. Half of the patients undergo emergency surgery for intestinal obstruction.8 GISTs present more commonly with acute GI bleeding. Symptoms mainly depend on the size and location of the tumor, with lesions distal to the ligament of Treitz having a tendency to present with either obstruction or bleeding. The most common laboratory abnormality found is hypochromic microcytic anemia, and many of these patients present with a positive test for fecal occult blood. Direct hyperbilirubinemia and increased alkaline phosphatase are present usually in cases of duodenal tumors as a consequence of extrahepatic biliary obstruction.
Diagnosis
Early detection of small bowel neoplasms is desirable but challenging for both clinicians and radiologists. The detection of small intestinal tumors by traditional imaging modalities is often compromised by overlapping bowel loops and suboptimal bowel distention. There are some newer techniques described in the following sections that may improve the diagnostic accuracy of imaging.
Imaging modalities
Small Bowel Follow-Through (SBFT): This is the oldest barium study traditionally used for evaluation of the small bowel. There is a questionable role for this noninvasive test due to a reported wide range of sensitivities for tumor detection (30–90%).92 This modality is rarely used now.
Enteroclysis: This procedure is based on the intubation of nasojejunal tube under fluoroscopic guidance and administration of barium sulphate suspension followed by 0.5% methylcellulose. Enteroclysis is considered superior than SBFT due to the exquisite mucosal detail that can be demonstrated and its higher yield and sensitivity, especially when evaluating patients with bleeding of obscure origin, but it is a more difficult examination for both the radiologist and the patient, requiring nasojejunal intubation and oral administration of large volumes of contrast material. The sensitivity of enteroclysis is as high as 95% with 90% correct estimation of the actual size of the tumor. Push enteroscopy (PE) is very useful for the evaluation of the first 100 cm of small bowel.93
Multidetector CT scan: This is also named multislice spiral computed tomography, produces high-resolution cross-sectional imaging of the abdomen and the small bowel. The lumen of the small bowel must be distended with orally administered contrast to demonstrate the wall thickening that characterizes small bowel tumors on CT. It allows multiplanar visualization of small bowel tumors and demonstrates signs of small bowel obstruction as well as the mural and extramural extent of small bowel malignancies.
Multidetector CT enteroclysis: This test shares the advantages of both conventional enteroclysis and cross-sectional imaging. This technique is more sensitive than conventional barium studies and less invasive than enteroscopy, and lesions as small as 5 mm can be identified. Studies have shown 100% sensitivity and 85–95% concordance with enteroscopy.94
MRI enterography
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