▪ GENERAL FEATURES OF SMALL INTESTINAL TUMORS
Benign and malignant small intestinal tumors are uncommon. Most small bowel malignancies are metastases from tumors arising elsewhere (1
). Primary small bowel tumors constitute only 1% to 3% of all primary GI malignancies (1
) and less than 2% of all human malignancies (1
). The major malignant tumors that arise in this location include adenocarcinomas, lymphomas (discussed in Chapter 18
), neuroendocrine tumors (discussed in Chapter 17
), and GI stromal tumors (discussed in Chapter 19
). Data from the surveillance, epidemiology, and end results (SEER) Program found that small bowel tumors had an annual average incidence rate of 9.9 per million people (4
). Carcinoid tumors and adenocarcinomas were the commonest histological types with an average annual incidence rate of 3.8 and 3.7 per million people respectively followed by stromal tumors and lymphomas (4
). The small intestine also gives rise to a number of benign lesions including Brunner gland lesions, adenomas, and a variety of polyps that are often a component of a polyposis syndrome (see Chapter 12
). Neoplasms of the small intestine are classified separately as ampullary and nonampullary due to treatment and prognostic differences between tumors arising in these sites. The WHO classification of small intestinal tumors (nonampullary) and tumors of the ampullary region is shown in Tables 7.1
, respectively (5
▪ PROLIFERATIVE BRUNNER GLAND LESIONS
Enlarged Brunner gland lesions present endoscopically as a submucosal mass. The enlargement most commonly results from hyperplasia, although rare neoplastic lesions also develop (Fig. 7.1
). Brunner gland hamartomas and true Brunner gland adenomas do exist, but adenomas are much less common than reported in the literature. In fact, the terms Brunner gland hamartoma and Brunner gland adenoma are often used synonymously, making these lesions difficult to fully understand. Brunner gland proliferative lesions generally affect older individuals and are more common in the duodenal bulb in some reports (7
), but not in others (8
). They are usually asymptomatic and are detected as incidental findings at the time of upper endoscopy. Occasionally, however, they become symptomatic causing vomiting, bleeding, or obstruction. Both hamartomas and adenomas usually retain their lobular architecture (Fig. 7.1
). Hamartomas are characterized by fibrous septa coursing between hyperplastic lobules of Brunner glands. Hamartomas may be accompanied by ciliated cysts and prominent adipose tissue (9
). Prominent ducts can be seen as well.
The diagnosis of Brunner gland adenoma is based on both architectural and cytological features. There may be mild architectural distortion, and the glands appear more crowded than usual (Fig. 7.2
). Cytologically, the nuclei are enlarged, and they may be overlapping. These neoplastic cells merge imperceptibly with more normal-appearing epithelial cells. Mitotic figures are rare. This lesion may associate with peptic duodenitis (Fig. 7.2
). Rarely, Brunner gland adenomas develop atypical hyperplasia (Fig. 7.2
) or undergo malignant transformation (10
▪ INTESTINAL ADENOMAS
Small intestinal adenomas are rare, constituting less than 0.05% of all gastrointestinal adenomas (12
). In one large series of 800,000 patients undergoing esophagogastroduodenoscopy (EGD), duodenal adenoma was diagnosed at a rate of one per 5,000 EGDs and one per 1,000 duodenal biopsies (13
). Small intestinal adenomas may be sporadic, but also arise in the setting of one of the genetically inherited polyposis syndromes (see Chapter 12
) or in the presence of an underlying condition (Table 7.3
Patients with small intestinal adenomas range widely in age, but the peak incidence is in the sixth and seventh decades (13
). Patients with adenomas are generally younger than are those with carcinomas or adenomas containing carcinoma (14
). Adenomas occur more commonly in males than females (13
). Many small adenomas remain asymptomatic, only to be discovered incidentally at the time of upper endoscopy for other reasons. They may also be found in those undergoing endoscopic surveillance because they have a polyposis syndrome or have a family history of a polyposis or hereditary cancer syndrome. Larger lesions frequently become symptomatic, particularly those located near the ampulla of Vater. Patients with ampullary adenomas present with biliary colic, biliary obstruction, cholangitis, jaundice, pancreatitis, and/or pain (12
). Partial or total intestinal obstruction, low-grade bleeding, cramps, vomiting, nausea, anorexia, weight loss, intussusception, or hemorrhage may also develop depending on adenoma size and location. Villous adenomas tend to be larger and are more likely to become symptomatic than are smaller tubular adenomas. Rare patients with secretory villous adenomas present with mucorrhea and electrolyte imbalance (15
TABLE 7.2 WHO CLASSIFICATION OF EPITHELIAL TUMORS OF THE AMPULLARY REGION (NONENDOCRINE)
Noninvasive pancreatobiliary papillary neoplasm with low-grade dysplasia (low-grade intraepithelial neoplasia)
Noninvasive pancreatobiliary papillary neoplasm with high-grade dysplasia (high-grade intraepithelial neoplasia)
Flat intraepithelial neoplasia (dysplasia), high grade
Invasive intestinal type
Clear cell carcinoma
Invasive papillary adenocarcinoma
Signet-ring cell carcinoma
Squamous cell carcinoma
FIG. 7.1 Histologic features of hyperplastic Brunner glands. The lesion presented as a mass lesion. Note the retained lobular architecture with fibrous septa coursing through the lesion. Each of the lobules, especially the deeper ones, appear markedly expanded. The hyperplastic lobules occupy a widened submucosa and extend toward the luminal surface.
Adenomas appear as soft, lobulated, pedunculated or sessile, single or multiple lesions (Fig. 7.3
). The mucosa may have a discolored granular appearance, but without erosions or ulcers (16
). Evenness of the granularity helps distinguish adenomas from cancers. Sessile adenomas are more frequent than are pedunculated ones. Tubular adenomas vary in size from 0.5 to 3 cm in maximum diameter. Villous adenomas are usually larger and may attain a size of ≥8 cm. Large villous adenomas may encircle the bowel lumen and appear as a cauliflowerlike lobulated sessile polypoid mass. Villous adenomas may also be encountered in the jejunum. The presence of multiple small intestinal adenomas suggests that the patient has a polyposis syndrome (see Chapter 12
FIG. 7.2 Brunner gland adenoma. A: There is a large expansion of the Brunner gland epithelium. Note that the fibrous septa are lacking in some areas. B: The lack of the septa is more obvious in this slightly higher-power picture. There is no lobulation present in this area. The overlying mucosa is affected by peptic duodenitis. C: Some of the glands contain cells with an increased nuclear:cytoplasmic ratio. D: Isolated cells lose the semilunar basal shape of the nuclei.
TABLE 7.3 CONDITIONS THAT PREDISPOSE PATIENTS TO DEVELOP SMALL INTESTINAL EPITHELIAL NEOPLASMS
Multiple cancer syndrome (familial cancer syndrome)
Juvenile polyposis syndrome
Peptic ulcer disease
Smoking and alcohol use
Adenomas are benign neoplasms that display varying degrees of dysplasia. Adenomas may be tubular (Fig. 7.4
), tubulovillous, or villous (Fig. 7.5
) in nature, resembling their colonic counterparts. Tall, immature columnar, pseudostratified epithelial cells displaying a typical “picket fence” pattern line the neoplastic tubules (Figs. 7.5
). Goblet cells that exhibit variable degrees of differentiation lie among the immature enterocytes. Sometimes the goblet cells appear to be dystrophic as evidenced by the presence of intraepithelial signet ring-type cells. Small intestinal adenomas may also contain endocrine cells (Fig. 7.6
), Paneth cells (Fig. 7.7
), and squamous cells (Fig. 7.7
), attesting to their origin from multipotential crypt stem cells. Paneth cells may be quite numerous, especially in patients with familial polyposis. Variable degrees of nuclear atypia affect all cell types present within adenomas, supporting the concept that each represents an inherent neoplastic component of the lesion and not entrapped normal cells. In small lesions, the adenomatous epithelium may be confined to the surface and not involve the crypts. Normal lamina propria separates the neoplastic glands (Figs. 7.4
A small villous component may be present on the surface, but most of the lesion should consist of tubules to classify it as a tubular adenoma (Fig. 7.4
). Villous adenomas consist
of fingerlike villous or papillary processes containing central thin cores of lamina propria lined by a neoplastic epithelium resembling that seen in tubular adenomas (Fig. 7.5
). Occasionally, one sees mixed tubulovillous adenomas.
FIG. 7.3 Gross appearance of small intestinal adenomas. A: A semisessile polypoid adenoma arising in the second portion of the duodenum (arrow). The red tissue to the right of the duodenal mucosa as well as above it represents gastric mucosa that was resected at the same time. It shows severe hemorrhagic gastritis. B: Jejunal adenoma presenting as a discrete polypoid mass.
FIG. 7.4 Duodenal adenoma. A: Note the focal adenomatous proliferation present in the duodenum (arrows). B: Tubular adenoma. Note the presence of pseudostratified penicillate nuclei and the paucity of goblet cells. Numerous mitoses are present. C: Junction of immature adenomatous epithelium (below arrow) with normal small intestinal surface epithelium (above arrow). The nuclei appear pseudostratified in a way that produces the characteristic “picket-fence” pattern.
FIG. 7.5 Sessile villous adenoma. A: Adenomatous epithelium extends along the duodenal villi and replaces the preexisting normal epithelium. B: Higher magnification of a different villous lesion demonstrating a slightly higher degree of dysplasia as evidenced by the focal loss of the normal epithelial polarity. Neoplastic cells have completely replaced the normal epithelium.
A full spectrum of neoplasia can be seen in small intestinal adenomas, ranging from low-grade dysplasia to highgrade dysplasia to invasive carcinoma. High-grade dysplasia occurs in almost 2% of adenomas, a frequency similar to that encountered in colonic adenomas (13
). The degree of dysplasia that is present should be described in the diagnosis. In villous lesions, high-grade dysplasia is characterized by the finding of markedly dysplastic stratified epithelial cells lining the villi with secondary gland formation. In glandular areas, similar cells are found lining the glands. The glandular lumens often contain necrotic cells. The probability of finding areas of carcinoma depends on the size and location of the lesion (17
). The larger the tumor, the more likely one is to find associated invasive cancer, and the less likely one is to see residual adenoma. As the degree of dysplasia increases, the nuclear/cytoplasmic ratio increases, epithelial polarity disappears, and the cells demonstrate increased mitotic activity (Figs. 7.8
). The nuclei consistently approach the glandular lumens in high-grade dysplasia. Marked glandular budding with loss of nuclear polarization and variable loss of mucinous differentiation heralds the development of malignancy.
FIG. 7.6 Chromogranin immunostaining of small intestinal adenoma demonstrating the presence of numerous neuroendocrine cells (dark brown cells).
Sporadic and FAP-related duodenal adenomas share similar molecular features regardless of their anatomic location. APC
mutations are frequently identified, while BRAF mutations, p53 alterations, and DNA mismatch repair abnormalities are rare (18
FIG. 7.7 Cell types in adenomas. A: Dysplastic Paneth cells (arrowheads) in this adenoma appear more eosinophilic and granular than their neighbors. The granules are larger than the smaller subnuclear eosinophilic endocrine cell granules. B: Lysozyme immunostain (dark brown) highlights the numerous Paneth cells within the lesion. C: Squamous morule (SM) in an adenoma. It abuts on the adjacent adenomatous epithelium. The squamous epithelium has a bland histologic appearance.
FIG. 7.8 High-grade dysplasia in a duodenal adenoma. A: The cells contain rounded nuclei rather than penicillate nuclei and some lose their polarity. B: Note the extreme stratification of the nuclei of the cells lining the glands. Some of the cells have begun to lose their normal polarity. Normal lamina propria separates the neoplastic glands.
FIG. 7.9 Duodenal villous adenoma. A: Low magnification showing the overall architecture of the lesion. B: Higher magnification showing the complex surface tufting and multilayering of the epithelium that covers the lamina propria core of the villous structures. High-grade dysplasia is present, but there is no invasion into the underlying lamina propria.
▪ PREINVASIVE AMPULLARY NEOPLASIA
Most preinvasive neoplasms that arise at or near the ampulla of Vater represent intestinal-type adenomas. Overall, approximately 80% of all small intestinal adenomas arise in this region (12
). Grossly and histologically, ampullary adenomas resemble their nonampullary counterparts. These adenomas give rise to the intestinal-type ampullary adenocarcinomas.
The pancreatobiliary-type ampullary adenocarcinomas are thought to arise from papillary and flat intraductal neoplasia similar to that seen in the bile ducts and pancreas (Fig. 7.10
). These preinvasive lesions are encountered only rarely in biopsy material and are usually only seen associated with a coexisting invasive carcinoma in resection specimens. The clinical features of these intraductal papillary lesions are not well characterized, primarily because they are so rarely recognized prior to the development of invasive carcinoma. Histologically, they are made up of complex, arborizing papillary structures lined by variably atypical epithelial cells. Almost all pancreatobiliary-type noninvasive papillary lesions have focal high-grade dysplasia, and many are associated with a coexisting invasive carcinoma (19
). The invasive component usually is of pancreatobiliary type with a tubular growth pattern. Occasionally, intestinal-type adenocarcinomas may arise from these papillary precursor lesions.
FIG. 7.10 Intraductal neoplasia associated with an invasive ampullary adenocarcinoma. A: Ampullary ducts adjacent to a nearby invasive pancreaticobiliary-type ampullary adenocarcinoma are lined by epithelial cells with nuclear enlargement and prominent nucleoli. The cells appear disorganized without the normal polarity. B: Another duct with a vaguely papillary-type architecture.
Although the majority of ampullary adenocarcinomas are thought to arise from preexisting adenomas or papillary pancreatobiliary intraepithelial neoplasms, a small subset appears to arise from areas of flat high-grade intraductal neoplasia (dysplasia). Microscopically, the dysplastic epithelium may appear flat or may display a micropapillary growth pattern. Flat dysplasia almost always occurs adjacent to an invasive adenocarcinoma and is rarely seen as an isolated pathologic finding (22
▪ SERRATED POLYPS
Serrated polyps are rare in the small intestine, but they do occur. Both hyperplastic and traditional serrated adenomalike polyps have been described (25
). Serrated duodenal polyps are usually identified incidentally in patients undergoing upper endoscopy for other reasons (18
). The median age for patients with hyperplasticlike polyps is 52 years, while those with traditional serrated adenomalike lesions tend to be older (18
) Histologically, hyperplasticlike duodenal polyps resemble the microvesicular hyperplastic polyps that are commonly encountered in the colon (25
). In addition, like colonic hyperplastic polyps, they express MUC6, MUC5AC, and MUC2 and may contain BRAF
Duodenal polyps resembling traditional serrated adenomas of the colon also resemble their colonic counterparts. These adenomas have serrated lumens lined by eosinophilic appearing cells that contain pseudostratified nuclei with prominent nucleoli (Fig. 7.12
). Goblet cells are typically not well developed in these lesions. Associated high-grade dysplasia or invasive adenocarcinoma has been reported in almost one half of reported cases (26
mutation occurs in approximately 20% to 40% of cases, and unlike colonic serrated adenomas, BRAF
mutations are not identified (18
). One half of reported serrated adenomalike polyps show a CPG island methylator (CIMP-high) phenotype (26
FIG. 7.11 Pyloric gland adenoma. A: Low-power photomicrograph demonstrating a polyp with a vaguely lobulated appearance. It is composed of tightly packed pyloric gland-type tubules. B: Higher-magnification view showing tubules lined with a monolayer of cuboidal to low columnar epithelial cells containing pale to eosinophilic cytoplasm. The nuclei are round and contain small nucleoli. No dysplastic changes are present in this polyp.
▪ INTERPRETATION OF BIOPSIES WITH AREAS SUSPICIOUS FOR EPITHELIAL NEOPLASIA
Typically, the initial diagnosis of a duodenal neoplasm involves interpretation of small biopsy specimens that yield only a small sample of the superficial parts of the neoplastic lesion. The degree of dysplasia often varies from one biopsy fragment to another. In this setting, the degree of dysplasia is classified according to the most severe alterations that are present. The deeper parts of an adenoma, where an invasive tumor is most likely to develop, are often not present in the biopsy. In one study of duodenal villous adenomas, biopsies missed areas of malignancy in 56% of cases, indicating the poor sensitivity of biopsies in detecting an invasive cancer (31
). Generally, the best that one can do is to recognize that the lesion is neoplastic and, to provide an accurate assessment of the degree of dysplasia that is present, state whether there is invasion into the lamina propria and whether or not one sees lymphovascular invasion or desmoplasia. One can also state whether or not submucosal tissue is present to be evaluated for the presence of invasion. The absence of identifiable lamina propria surrounding glands and the presence
of large vessels near the tumor cells, a desmoplastic response and intravascular or intralymphatic invasion, all support a diagnosis of invasive cancer. Tumors with high-grade dysplasia or a villous morphology are more likely to harbor an invasive carcinoma than adenomas lacking these features (31
). Larger, ulcerated lesions that are fixed or cause obstruction usually contain invasive cancer.
FIG. 7.12 Duodenal serrated adenoma. A: Low-power illustration of the lesion, which at this magnification appears densely crowded but otherwise not unlike other duodenal adenomas. B: Higher magnification of the lesion discloses the characteristic eosinophilic epithelium and saw-toothed pattern of a serrated adenoma.
Biopsies of periampullary epithelial lesions are not always reliable in assessing either the presence of neoplasms or invasion in carcinomas. Special caution must be used in evaluation of ampullary lesions because the anatomy of this area is quite complex and numerous small branched submucosal glands normally reside in this region (see Chapter 6
). A significant diagnostic dilemma results when high-grade dysplasia involves these submucosal glands (Figs. 7.13
). It is easy to confuse involvement of ampullary glands with invasive disease, and care needs to be taken not to overdiagnose invasive malignancy in this setting. If one sees a lobular glandular architecture with lamina propria surrounding the glands, invasive malignancy is unlikely. Further, if the
glands are round and not angulated, the lesion is more likely to be benign. The lack of desmoplasia also favors a benign lesion. It is important not to mistake regenerative atypia present on the eroded surface of an adenoma for high-grade dysplasia or an invasive cancer. Areas of acute inflammation containing prominent capillaries and fibrin deposits, especially when superficial, should alert the examiner to the possibility of reparative atypia in the setting of surface erosion.
FIG. 7.13 Ampullary tumor. A: Whole mount section through the tumor demonstrates the relationship of the pancreas (P) to the muscularis propria of the duodenal wall (MP) and surrounding normal small intestinal mucosa (SI). A complex neoplasm involves the ampullary region and surface of the duodenum (arrows). B: This figure represents a higher magnification of the lesion illustrated in (A). One can see residual normal-appearing ducts (D) as well as nonneoplastic glandular epithelium (arrows). In other areas, the ductal epithelium is replaced by changes that variously appear papillary, clear, hyperplastic, and dysplastic. Normal-appearing lamina propria and muscle fibers separate the various glandular components, and there is no evidence of invasion by the neoplastic epithelium. The muscularis mucosa is indicated by MM and the muscularis by MP. C: The nonneoplastic glands display angular features easily misinterpreted as neoplastic.
Higher magnification of the lesion illustrated in Figure 7.11
Stratified epithelium lines the glandular spaces. The glands are separated by normal-appearing lamina propria. In some foci, the epithelium appears more dysplastic than in others (arrow
). These same glands also lack normal mucinous differentiation. B:
This area of the tumor demonstrates areas of glandular hyperplasia (H
) as well as foci of adenoma (A
). One of the adenomatous glands contains an area of intramucosal carcinoma (arrows
). Normal lamina propria separates the hyperplastic and adenomatous glands (stars
). Note the absence of desmoplastic stroma. This neoplasm is of the hepatobiliary type.
Another common area of diagnostic error is the presence of the marked reactive atypia that can be present in the duodenum, especially in the area surrounding the ampulla of Vater in patients with sclerosing papillitis. Patients who have had stents or who have had cholelithiasis may exhibit significant ampullary inflammation, often accompanied by a marked papillary hyperplasia with significant reactive atypia. The papillary hyperplasia can appear polypoid and may even obstruct the ampulla, leading to secondary alterations in the biliary tree or pancreatic ducts. These circumstances lead to the strong clinical impression that the patient has a neoplasm. If one is unable to distinguish a reactive from a neoplastic process, a diagnosis of indefinite for dysplasia is appropriate.