Introduction

Epithelial neoplasms develop far less frequently in the small intestine than in the colon, despite the fact that the small intestine has a larger epithelial surface area and a higher rate of cellular turnover. Overall, only 2% of all malignant neoplasms of the gastrointestinal (GI) tract occur in the small intestine.¹ In contrast, 57% of neoplasms arise in the colon. A number of hypotheses have been proposed to explain the relative rarity of small bowel adenomas and carcinomas.² First, the transit time of substances through the small intestine is relatively short compared with the colon, resulting in brief contact time between the mucosa and the luminal contents. Second, unlike the colon, the small intestine does not contain a large quantity of bacteria. Bacteria are known to convert bile salts into potential carcinogens. Third, the luminal contents are more liquid in the small intestine than in the colon. As a result, potentially carcinogenic luminal substances are diluted and the risk of mechanical trauma is reduced. Fourth, the small intestine is rich in lymphoid tissue, which provides a potentially high level of immunosurveillance against neoplastic cells. Finally, mucosal enzymes may help detoxify potentially carcinogenic substances in the luminal contents.²

Epithelial tumors in the small intestine are most commonly located in the duodenum, usually in the vicinity of the ampulla of Vater.^3–5 This finding suggests that biliary or pancreatic secretions may play a role in their development, possibly as a result of the carcinogenic effect of bile. Alternatively, constant influx of alkaline bile or acidic pancreatic juice may cause cell damage. Epithelial neoplasms also occur in the jejunum and in the ileum, but much less commonly.⁶ A number of diseases predispose individual patients to the development of small-intestinal adenomas and car­cinomas, including familial adenomatous polyposis (FAP), Crohn’s disease (CD),⁷ and celiac disease.^8,9 The risk for small-intestinal carcinomas may also be increased in individuals with Peutz-Jeghers syndrome^10,11 or juvenile polyposis syndrome,^12,13 and in patients with long-standing ileostomies.^14,15

Small-intestinal epithelial tumors are most commonly glandular, although other forms of neoplasia are also seen. Tumors arising in the ampulla of Vater are separately classified from those arising elsewhere in the small intestine because significant treatment and prognostic differences exist for this group of tumors. Boxes 26.1 and 26.2 summarize the World Health Organization’s (WHO) histologic classification of epithelial tumors of the small intestine and the ampullary region, respectively.¹⁶

FAP is associated with adenomatous polyps of the intestinal tract, as well as fundic gland polyps of the stomach. In the small intestine, most FAP-associated lesions arise in the duodenum and tend to cluster around the ampulla of Vater.^17–19 They are usually multiple and may be numerous (>20 to 50) in some patients.²⁰ Adenomas are often small, sessile, and tubular, usually measuring less than 1 cm in diameter.¹⁹ A “serrated” ampullary adenoma in a patient with FAP has been reported,²¹ but this morphology is not typical of small-intestinal adenomas. Ileal adenomas also occur in patients with FAP.²²

Patients with FAP who have multiple duodenal adenomas have a 100- to 300-fold increased lifetime risk for duodenal or periampullary cancer compared with the general population.^23,24 In fact, periampullary adenocarcinoma is the most common extracolonic malignant neoplasm in FAP. As a result, patients with known FAP should undergo endoscopic surveillance with biopsy examination of grossly normal duodenal and ampullary mucosa to identify potential early precancerous lesions.²⁵ Patients who have only a small number of adenomas should be screened at least every 3 years. In patients whose lesions are numerous or large, the screening interval should be shortened to 1 year.

Adenomatous Polyps

Small-intestinal adenomas are rare,³⁵ accounting for fewer than 0.05% of all intestinal adenomas. Adenomas peak in incidence in the seventh decade of life but may occur at any age. Most adenomas are asymptomatic. They are usually discovered incidentally in individuals who have undergone endoscopic examination for other reasons. Adenomas that are symptomatic typically involve the region of the ampulla of Vater and manifest with biliary colic and obstruction, acute cholangitis, or pancreatitis.³⁵ Intestinal obstruction, bleeding, nausea, vomiting, anorexia, weight loss, pain, or intussusception may also develop, depending on the size and location of the lesion.³⁶ Small-intestinal adenomas resemble those that arise in the colon in gross and microscopic characteristics (Fig. 26.1). They are usually lobulated and soft, and they may be sessile, pedunculated, villous, or tubular. A higher proportion of small-intestinal lesions tend to be villous compared with adenomas of the colon; this is most likely a reflection of the underlying villous architecture of the small bowel. Tubular adenomas tend to be small, varying from 0.5 to 3 cm in maximum diameter. Villous adenomas are often larger, sometimes reaching 8 cm or larger. Small-intestinal adenomas are usually single³⁶ but can be multiple. The finding of multiple adenomas in the small intestine is rare in patients without a hereditary polyposis syndrome. As a result, identification of multiple lesions should raise a suspicion of FAP (Fig. 26.2).

Histologically, small-intestinal adenomas may demonstrate tubular, tubulovillous, or villous growth patterns. They are composed of tall columnar epithelial cells with elongated, crowded, hyperchromatic nuclei arranged in a “picket fence” pattern. Immature goblet cells may be present. In addition, endocrine cells, squamous cells, and particularly Paneth cells may be numerous (Fig. 26.3). Mitoses, normally seen only in the base of the crypts, may occur at all levels of the adenomatous crypts and villi. Normal-appearing lamina propria is usually present between the neoplastic crypts.

Small-intestinal adenomas can display varying degrees of dysplasia, ranging from low to high grade, and may show intramucosal or invasive carcinoma. While the degree of dysplasia increases, one also tends to see an increased ratio of nucleus to cytoplasm in the cells, loss of cell polarity, and an increased mitotic rate. Prominent crypt budding, nuclear stratification, and loss of mucinous differentiation may herald progression to malignancy.

It is important to distinguish regenerative atypia associated with surface erosion from an adenoma (Fig. 26.4). Regenerating cells tend to mature toward the surface, whereas adenomas do not. The presence of Paneth or endocrine cells in the superficial portions of the lesion is almost always associated with a neoplastic alteration. Prominent acute inflammation with congested capillaries and fibrin deposition, especially when superficial, should alert the examiner to the possibility of regenerative atypia.

Preinvasive Ampullary Neoplasia

Most preinvasive neoplasms in the region of the ampulla of Vater represent intestinal-type adenomas, and approximately 80% of all small-intestinal adenomas arise at this site.³⁵ Ampullary adenomas resemble their nonampullary counterparts, as described earlier.

Pancreaticobiliary-type ampullary adenocarcinomas are thought to arise from noninvasive papillary and flat intraductal neoplasia reminiscent of that seen in the bile duct and pancreas (Fig. 26.5). These preinvasive lesions are encountered infrequently and are usually associated with a coexisting invasive carcinoma. The clinical features of these intraductal papillary lesions are not well characterized, primarily because of their rarity. Histologically, these neoplasms consist of complex, arborizing papillary structures lined by variably atypical epithelial cells. Almost all pancreaticobiliary noninvasive papillary neoplasms have focal high-grade dysplasia, and many have an associated invasive carcinoma.^37–39 The invasive component most commonly has a tubular growth pattern and is of pancreaticobiliary type, although intestinal type adenocarcinomas may occasionally arise from these papillary precursors.

Although most ampullary adenocarcinomas probably arise from preexisting adenomas or pancreaticobiliary noninvasive papillary neoplasms, a small subset appear to arise from areas of flat high-grade intraductal neoplasia (dysplasia). Microscopically, the dysplastic epithelium may have a truly flat architecture, or it may have a micropapillary growth pattern. Flat dysplasia is almost always found adjacent to invasive adenocarcinoma and is rarely seen in isolation.^40,41

Small-Intestinal Adenocarcinoma

Clinical Features and Associations

More than half of all small-intestinal carcinomas arise in the duodenum, even though this organ constitutes only 4% of the entire length of the small intestine.^5,42,43 The incidence of duodenal adenocarcinoma has risen in recent years, most likely because of the increased use of upper endoscopy⁴⁴ and the development of newer techniques such as video capsule endoscopy, double-balloon enteroscopy, and computed tomographic (CT) enterography.^45–47 Most small-intestinal carcinomas arise in the region of the ampulla of Vater. A smaller percentage of tumors arise in the jejunum, particularly in the first 30 cm distal to the ligament of Treitz. Ileal carcinomas are the least common, except in patients with CD. Small-intestinal carcinomas occur more frequently in men than in women and affect blacks more often than whites.^3,44

Some diseases (e.g., FAP) are associated with an increased incidence of small-intestinal carcinomas (Box 26.3). Cancers that arise in the upper GI tract, and especially in the periampullary region, represent a major cause of death in these patients. As discussed previously, patients with hereditary polyposis and familial cancer syndromes including FAP, Lynch syndrome, and Peutz-Jeghers syndrome are at increased risk for the development of small-intestinal tumors. In addition, patients with celiac disease have an 80-fold increased incidence of small-intestinal adenocarcinomas compared with the general population.⁸ In one study of 175 patients with adenocarcinoma of the small bowel, 13% had celiac disease.⁹ The diagnosis of celiac disease preceded that of adenocarcinoma in 63% of these patients. Tumors in these patients often arise in the jejunum.⁴⁷

Box 26.3

Conditions Associated with an Increased Risk for Small-Intestinal Carcinoma

Sporadic adenomatous polyps

Congenital anomalies

Long-standing ileostomy

Crohn’s disease

Celiac disease

Alpha chain disease

Familial adenomatous polyposis

Gardner syndrome

Peutz-Jeghers syndrome

Hereditary nonpolyposis colon cancer syndrome (Lynch syndrome)

Juvenile polyposis syndrome

Ileal adenocarcinomas develop with increased frequency in individuals with long-standing CD (see later discussion). However, in these patients, adenocarcinomas typically arise in the setting of dysplasia (flat or polypoid) rather than in preexisting adenomas.⁴⁸

Most small-intestinal carcinomas manifest in patients between 60 and 70 years of age.^49,50 However, most tumors that arise in the setting of a hereditary cancer syndrome are seen in younger individuals. Patients may have presenting symptoms of intestinal obstruction, bleeding, intussusception, or perforation. Ampullary carcinomas often manifest with bile duct obstruction, pancreatitis, and jaundice. Pancreatitis may also develop secondary to pancreatic outflow obstruction.

Pathologic Features

Small-intestinal carcinomas may have a flat, stenotic, ulcerative, infiltrative, or polypoid gross appearance (Fig. 26.6). Tumors typically range from 1 to 15 cm in diameter. Larger lesions tend to be found in the more distal portions of the small bowel, because lesions in that area often fail to produce symptoms until they are advanced.

Small-intestinal adenocarcinomas are similar, histologically, to those that develop elsewhere in the GI tract. However, because small-intestinal cancers usually arise from preexisting adenomas, one may see residual adenomatous changes in the adjacent or overlying epithelium, particularly in smaller lesions. More often, the cancer has overgrown the adenomatous component at the time of diagnosis, especially in tumors that arise in sites other than the ampulla of Vater. Identification of an associated preinvasive lesion allows one to be relatively certain that the tumor is primary to that location. However, some metastatic carcinomas induce significant cytologic atypia in adjacent non-neoplastic small-intestinal epithelium that can resemble adenomatous change (Fig. 26.7).

Adenocarcinomas are characterized by cellular and nuclear pleomorphism, loss of epithelial polarity, gland-in-gland architecture, and invasion into adjacent tissues. Most small-intestinal adenocarcinomas are moderately differentiated and demonstrate variable degrees of mucin production. Approximately 20% of tumors are poorly differentiated and contain signet ring cells. Other tumors display a prominent extracellular mucinous component. Neoplasms in which more than 50% of the tumor is mucinous should be designated as mucinous adenocarcinomas, because these tumors tend to have a poorer prognosis than typical gland-forming lesions. Neoplastic endocrine cells and Paneth cells are often present. Squamous cells may also be identified but are less common. The presence of endocrine, Paneth, or squamous cells in a carcinoma has no prognostic significance.

Immunohistochemical Features

Small-intestinal adenocarcinomas show more variable expression of cytokeratin 7 (CK7) than do colorectal carcinomas. In one study, diffuse positive CK7 immunoreactivity was identified in 54% of nonampullary small-intestinal adenocarcinomas, and focal positivity was present in the remaining 46% of cases.⁵¹ In the same study, 67% of cases expressed CK20. Expression of MUC1, MUC2, and MUC5AC occurs in 53%, 57% and 40% of small bowel adenocarcinomas, respectively.⁵² Expression of villin is observed in 67% of cases, but the staining is often focal. CDX2 staining is identified in 60% of small-intestinal adenocarcinomas, and the pattern of staining is usually diffuse, similar to colorectal carcinomas.⁵² Ninety-six percent of small-intestinal adenocarcinomas are negative for alpha methylacyl–coenzyme A racemase (AMACR).⁵³

Ampullary Adenocarcinomas

The ampulla of Vater represents the site in the small intestine where most carcinomas arise. The incidence of cancers at this site has increased in the past 4 decades. Ampullary adenocarcinomas are more common in men than in women.⁵⁴ Patients most often have painless jaundice at presentation. Because even small tumors in this location can result in biliary obstruction, many tumors arising in this site are diagnosed at a relatively early stage.

Histologic Features

The ampulla is an area in which two types of epithelium converge, that of the duodenum and that of the common bile duct. As a result, carcinomas that arise in this region may be of either intestinal or pancreaticobiliary type. Intestinal-type cancers represent the most common histologic type of ampullary carcinoma, accounting for 85% of cases.⁵⁵ The pancreaticobiliary type is the most common of the remaining tumors, although other unusual histologic tumor types may occur, including mucinous, signet ring cell, adenosquamous, clear cell, and neuroendocrine carcinomas. Distinction between the two major histologic types of ampullary adenocarcinoma is important, because many studies have shown a significantly poorer prognosis in tumors of the pancreaticobiliary type.^54,56–58

Intestinal-type ampullary adenocarcinomas are histologically indistinguishable from adenocarcinomas that occur elsewhere in the small intestine or colon (Fig. 26.8). The histologic pattern varies, from well-formed glandular or tubular structures to cribriform areas or solid nests of tumor cells. As in their colonic counterparts, the glands often contain necrotic or apoptotic debris, so-called dirty necrosis.

Pancreaticobiliary ampullary carcinomas closely resemble pancreatic ductal adenocarcinomas or primary adenocarcinomas of the extrahepatic bile ducts. These tumors consist of small, simple or branched glands surrounded by abundant desmoplastic stroma (Fig. 26.9). The cells lining the neoplastic glands are usually cuboidal to low columnar in shape, and they are typically arranged in a single layer. Intraluminal necrotic debris is infrequently present. Most tumors demonstrate well-formed glandular structures, although less differentiated tumors may contain small clusters and solid nests of tumor cells.

Immunohistochemical Features

The immunoprofile of ampullary adenocarcinoma varies depending on whether the tumor is of the intestinal or the pancreaticobiliary histologic type. Intestinal-type ampullary adenocarcinomas are usually CK20 positive (80% to 91%) and CK7 negative (73% to 82%).^59–61 In addition, 100% of these tumors are positive for CDX2.⁶² They variably express MUC1 (18% to 60%), MUC2 (47% to 82%),^61,62 and carcinoembryonic antigen (CEA; 53%).⁶¹ Forty percent express CA19-9.

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