EPIDEMIOLOGY

Small intestinal neoplasms are a diverse and rare group of tumors that affect the gastrointestinal tract from the duodenum to the ileum. Although the small intestine represents 75% of the length and 90% of the absorptive area of the gastrointestinal tract,¹ less than 5% of all primary gastrointestinal tract tumors originate in the small intestine.

Many types of tumors arise from the small intestine, and about 65% of them are malignant.² The four most common types of malignancies—adenocarcinomas, carcinoids, lymphomas, and sarcomas (including gastrointestinal stromal tumors or GISTs)—account for 95% of all small intestinal tumors. In most case series of Western patients, adenocarcinoma is the most common small intestinal neoplasm, followed closely by carcinoid tumor.^3,4 Adenocarcinoma (Fig. 121-1) most commonly arises in the duodenum, and carcinoid tumor and lymphoma predominate in the jejunum and ileum. Sarcoma distributes equally among all three segments of the small intestine.⁵

Figure 121-1. Endoscopic image of a mucosal neoplasm in the jejunum of a patient with metachronous small intestine adenocarcinomas.

(Courtesy of Mark A. Schattner, MD, New York.)

A review of 144 cases of malignant tumors of the small intestine showed that 64% of patients were men, with a median age of 55.7 years; 47% of the tumors were adenocarcinomas, 28% were carcinoid tumors, 13% were sarcomas, and 12% were lymphomas. Overall five-year survival was 57% and median survival was 53 months. Survival was highest for early-stage tumors and when curative resection was performed successfully.⁶ Survival was not related to location of tumor.

A recent study using the Connecticut Tumor Registry data reviewed the epidemiologic and clinical characteristics of 1260 cases of small intestinal tumors. Of these tumors, 49.8% were found in men; the mean age at presentation was 65.2 years. As for location, 25.4% occurred in the duodenum, 15.3% were in the jejunum, and 29.7% arose from the ileum; the remainder of tumors were either multifocal or their location was unspecified. By type, 33.1% were carcinoids, 30.1% were adenocarcinomas, 16.5% were lymphomas, and 7.1% were GISTs. Virtually all (99%) of the tumors were invasive. Surgery was the primary treatment in 87.7% of patients.⁷

Surveillance Epidemiology and End Results (SEER) data estimate that in the United States in 2008, small intestinal cancers were diagnosed in 3200 men and 2910 women, of whom 1110 people will die of these tumors. From data for 2001 to 2005, the median ages at diagnosis and death were 67 years and 71 years respectively. The overall five-year relative survival rate for 1996 to 2004 from 17 SEER geographic areas was 57.8%; 31% of patients had localized disease at diagnosis, 33% had locally advanced disease, and 29% had metastatic disease at presentation. The corresponding five-year relative survival rates were 77.0% with localized disease, 62.2% with locally advanced disease, 36.0% with metastatic disease, and 40.2% for patients whose stage of disease was not known.⁸

Worldwide, rates of small intestinal tumors vary; rates are higher in North America and Western Europe and lower in Asia. The Maori of New Zealand have an unusually high incidence of small intestinal tumors.⁹ Within the United States, incidence rates appear to be somewhat higher in African Americans and in men. Some have suggested an increasing incidence of small intestinal cancer over time.¹⁰

Carcinoid tumor (see Chapter 31) is the second most commonly diagnosed small intestinal malignancy, with an annual incidence of approximately three cases per million persons in the United States. The average age at diagnosis is 55 years. The most common sites of extranodal lymphomas (Fig. 121-2) are the stomach and small intestine (see Chapter 29). GISTs can be found throughout the small intestine (see Chapter 30).

Figure 121-2. Endoscopic image of a mucosal neoplasm in the duodenum in a patient with anemia and overt gastrointestinal bleeding. Pathology revealed an Epstein-Barr virus and associated B-cell lymphoma.

(Courtesy of Satish Nagula, MD, New York.)

PATHOLOGY

Neoplasms can arise from any of a wide range of epithelial and nonepithelial cells of the small intestine. Adenomas and adenocarcinomas arise from glandular mucosa; carcinoid tumors originate from argentaffin cells; lymphomas develop from clonal proliferation of lymphocytes; and GISTs have been identified as originating from the interstitial cells of Cajal, which help control the motility of the intestine and have elements of both smooth muscle and neural differentiation.¹¹ Leiomyomas arise from smooth muscle cells in the muscularis propria or muscularis mucosa, can be intra- or extraluminal, and account for about 40% of benign intestinal neoplasms. Leiomyomas with more than two mitoses per high-power field are reclassified as leiomyosarcomas. Lipomas represent approximately 20% of benign small bowel neoplasms, are most commonly intraluminal, and are found in the ileum; they rarely bleed, but they can obstruct or intussuscept (Fig. 121-3).¹² The remainder of benign neoplasms include desmoid tumors (see Chapter 122) and hemangiomas (see Chapter 36).

Figure 121-3. A, Film from an enteroclysis study that demonstrates a smooth submucosal lesion that was found to be a lipoma (arrow). B, Surgical resection specimen of a lipoma from another patient who presented with intussusception and bleeding.

(Courtesy of Igor Laufer, MD, Philadelphia.)

Small intestinal adenocarcinoma is staged using the TNM system as shown in Tables 121-1 and 121-2. Subtypes of this cancer include adenocarcinoma in situ, mucinous adenocarcinoma, signet cell carcinoma, squamous cell carcinoma, adenosquamous cell carcinoma, small cell carcinoma, medullary carcinoma, and undifferentiated carcinoma.

Table 121-1 TNM Classification

Typical patterns of distribution are seen with benign lesions of the small intestine just as with malignant lesions. The most common benign tumor is the adenoma, which can be found throughout the small intestine but is slightly more common in the duodenum and ileum. Adenomas account for about 30% of all benign small intestinal neoplasms. They are more likely to be polypoid in the ileum and sessile and villous in the duodenum. Villous adenomas tend to be somewhat larger and often occur in the second portion of the duodenum; 40% to 45% can have pathologic features of malignancy.

Benign lesions of the small intestine can often be removed by endoscopic means, after being localized using some or all of the methods described later. Techniques for resection and destruction include snare polypectomy, endoscopic mucosal resection (EMR), and argon plasma coagulation. Early duodenal cancers also have been removed using EMR with good results. Because the duodenal wall is thin, the risk of perforation with EMR is high; careful submucosal injection of the duodenum is recommended before removing a duodenal lesion.¹³ Two studies have shown EMR to be safe and effective, with the potential of reducing the need for surgical intervention for these relatively rare conditions.^14,15

Table 121-3 shows the variety of tumors that can arise in the small intestine.

Table 121-3 Some Benign and Malignant Tumors of the Small Intestine

* GIST may be a benign or malignant tumor, although all GISTs have malignant potential (see Chapter 29).

ETIOLOGY

Despite similarities in genetic mechanisms underlying adenocarcinoma of the small intestine and colon, the incidence of small intestinal adenocarcinoma is far lower than that of colonic adenocarcinoma. Given the identical genetic makeup and similar tissue anatomy of the small intestine and colon, the marked difference in cancer incidence between the two sites is difficult to explain. Both tumors in both locations likely develop via an adenoma-carcinoma sequence, and mutated K-ras, Ki-ras, TP53, DPC-4 (Smad-4), β-catenin, and mismatch repair genes are implicated in tumor progression (see Chapter 123).¹⁶ Factors that may reduce the incidence of small intestinal adenocarcinoma include higher intraluminal pH, liquidity of small intestinal content, rapid transit time of chyme, faster turnover rate of small intestinal epithelium, lower load of carcinogen-producing bacteria, and increased amounts of immunoglobulin (Ig)A-secreting lymphoid tissue surrounding the small intestinal lumen.⁷

RISK FACTORS

Despite the low incidence of malignant small intestinal tumors, several risk factors have been identified that contribute to their development (Table 121-4). A dietary study found that increased ingestion of refined carbohydrates, sugar, and red meat increased the risk of small intestinal adenocarcinoma, whereas a diet high in fish, fruits, and vegetables was protective. Alcohol consumption did not affect risk.¹⁷ A similar study also found a significantly increased risk with red meat consumption, as well as salt-cured or smoked foods, but did not show fruit and vegetable consumption to be protective.¹⁸ Tobacco use and alcohol consumption did not affect development of small intestinal cancer.¹⁸

Table 121-4 Risk Factors for Small Intestinal Tumors

Other etiologic factors for the development of small intestinal cancer include Crohn’s disease (see Chapter 111), in which the risk for both colon cancer and small intestinal adenocarcinoma is elevated.^19–21 A recent meta-analysis pooling 34 studies of 60,122 patients with Crohn’s disease found a relative risk of 28.4 (95% confidence interval [CI]: 14.46 to 55.66) for the development of small intestinal adenocarcinoma.²² Celiac disease (see Chapter 104) also is thought to be a risk factor for developing non-Hodgkin’s lymphoma (NHL) and small intestinal adenocarcinoma.²³ Another study showed an increase in esophageal cancer, melanoma, and NHL in patients with celiac disease; only the risk of NHL persisted despite patient adherence to a gluten-free diet.²⁴

Familial adenomatous polyposis (FAP) predisposes to small intestinal adenomas with associated malignant potential (see Chapter 122). Most of these FAP-associated lesions are found in the periampullary duodenum, although they can occur throughout the length of the duodenum. More than 90% of patients with FAP have a varied number of duodenal adenomas, but only 5% to 10% develop duodenal cancer.^25,26 Upper gastrointestinal polyps in patients with FAP might follow a different genetic pathway from that of colorectal cancer.²⁷ FAP mice models show overexpression of the β-catenin gene and deregulation of its signaling pathway. In these animals, a diet of chenodeoxycholate results in more significant duodenal polyposis secondary to the overexpression of β-catenin.²⁸ Bile has been proposed as a potential risk factor for small intestinal cancer,^29,30 and there is some suggestion it may be synergistic with the genetic mutations seen in patients with FAP.³¹

Hereditary nonpolyposis colon cancer (HNPCC) patients also are at increased risk for developing small intestinal cancer (see Chapter 122). HNPCC patients can present with a small intestinal adenocarcinoma as their first and only tumor.³² Screening recommendations for patients with these inherited syndromes might change with the advent of newer imaging techniques for the small intestine.^33,34

All adenomas of the small intestine, like adenomas of the colon, should be considered precancerous. Adenomas in both locations appear to progress through an adenoma-to-adenocarcinoma sequence. Malignant features are found in approximately one third of all small intestinal adenomas.³⁵ For reasons that are not clear, adenomas at the ampulla of Vater are typically villous, large, and more likely to be malignant than adenomas found elsewhere in the small intestine.²

Patients with Peutz-Jeghers syndrome develop hamartomatous polyps of the small intestine and colon (see Chapters 22 and 122), and adenocarcinoma can arise within adenomatous foci in the hamartoma, although the overall risk of this is unknown.³⁶ Other hamartomatous polyposis syndromes (see Chapter 122) include juvenile polyposis, which has an increased risk of gastrointestinal tract malignancy, also probably from adenocarcinoma arising from hamartomatous polyps. Other syndromes include Bannayan-Ruvalcaba-Riley syndrome, Cowden’s syndrome, Cronkhite-Canada syndrome, and Devon family syndrome. The gastrointestinal cancer risk in Cowden’s syndrome is well described, the others are less so.³⁷

SMALL INTESTINAL ADENOCARCINOMA