Clinical and Endoscopic Features

Brunner glands are lobular collections of tubular glands within the duodenum; they are predominantly located in the duodenal submucosa. However, in the first part of the duodenum, Brunner glands commonly transgress the muscularis mucosae and extend into the lamina propria. Brunner glands within the lamina propria are less frequently observed in the middle to distal duodenum.

Occasionally, Brunner glands proliferate, creating small polypoid excrescences or imparting a nodular appearance to the mucosal surface ( Fig. 21.5 ). These Brunner gland proliferative lesions are most commonly encountered in the duodenal bulb, usually as an incidental finding at endoscopy performed for other indications. However, they may be seen as one of a constellation of findings, including villous shortening and gastric foveolar mucous cell metaplasia of the villous epithelium, that are indicative of peptic injury of the duodenum (peptic duodenitis). Proliferative Brunner gland lesions have also been associated with end-stage renal disease and uremia.

Brunner gland hyperplasia. Numerous polypoid excrescences are present within the duodenal bulb, imparting a nodular quality to the mucosal surface in a resection specimen (A), which may be endoscopically apparent (B) .

The nomenclature of Brunner gland proliferative lesions is not well established, and a number of diagnostic terms, including Brunner gland hyperplasia, Brunner gland adenoma, and Brunner gland hamartoma, have been used. The distinction between these diagnoses is arbitrary. No well-documented cases of either true glandular dysplasia or carcinoma arising in proliferative Brunner glands have been reported. Careful review of the limited literature reports of Brunner gland adenocarcinoma and dysplasia reveals that the dysplastic glandular epithelium involves the surface epithelium with likely secondary involvement of the underlying hyperplastic Brunner glands. In other cases, the adenocarcinomas appear to arise from pyloric gland adenomas and not from hyperplastic Brunner glands. Therefore, the term Brunner gland adenoma is potentially misleading, and we prefer to use the term Brunner gland hyperplasia to limit confusion among our clinicians and to highlight the non-neoplastic nature of the entity.

Some authors distinguish between Brunner gland hyperplasia and Brunner gland hamartoma based on the size of the lesion. However, the size cutoff between these two entities is arbitrary and not well established in the literature. The distinction is of no clinical significance, and a diagnosis of Brunner gland hyperplasia/hamartoma is usually sufficient in large polypoid lesions.

Pathologic Features

Brunner glands are composed of neutral, mucin-secreting, cuboidal to columnar cells with basally located nuclei; they are arranged in lobules containing thin, fibrous septa. Brunner glands are histologically indistinguishable from pyloric glands of the distal gastric mucosa. Indeed, biopsies of the gastroduodenal junction may demonstrate a gradual transition of these epithelial types. The predominantly submucosal location of Brunner glands helps to identify the biopsy as duodenal in origin.

The diagnostic criteria for Brunner gland hyperplasia are subjective, because Brunner glands may be normally seen in the lamina propria of the duodenum, particularly within the duodenal bulb. In addition, proliferation of Brunner glands is commonly observed in peptic-type duodenal injury. We reserve the term Brunner gland hyperplasia for those endoscopically visible duodenal nodules that are found to contain lobules of Brunner glands within the mucosa in at least 50% of the length of a biopsy specimen ( Fig. 21.6, A ). Brunner gland hyperplasia may manifest as solitary or multiple nodules that are typically small (<1 cm) and characterized by lobules of glands that are increased in both size and number. The lobules extend into the mucosa and are separated by delicate fibrous septa. Cystic dilatation of Brunner glands may occur, and rare cases of Brunner gland cysts have been reported. The cells are cytologically bland with abundant neutral mucin and small, basally located nuclei with minimal to absent mitotic activity.

Brunner gland hyperplasia. A, At low power, lobules of Brunner glands expand the submucosa, extending into and filling the lamina propria. The hyperplastic Brunner glands are separated by delicate fibrous septa. B, Brunner glands may become artifactually distorted and contain spindled, compressed epithelial cells.

Large polyps (>2 cm) composed of Brunner glands may produce symptoms of obstruction, intussusceptions, melena, and anemia requiring endoscopic resection. Such polyps typically display more abundant fibromuscular stroma, likely the result of mucosal prolapse-type changes. For such large polyps, the diagnosis of Brunner gland hyperplasia/hamartoma may be appropriate, because it recognizes the arbitrary distinction between these two diagnoses.

In mucosal biopsy specimens, Brunner glands are commonly crushed, imparting a spindle cell appearance to the epithelial cells (see Fig. 21.6, B ). Crushed Brunner glands may be mistaken for histiocytic collections, raising concern for Whipple disease, particularly given their intense positive reaction on periodic acid–Schiff (PAS) staining. The spindled appearance of crushed Brunner glands may also raise concern for a mesenchymal lesion. Careful histologic evaluation with comparison of adjacent partially crushed lobular collections of Brunner glands will allow for identification of this distortion artifact.

Differential Diagnosis

Histologic features of peptic-type injury of the duodenum include any of the following: active inflammation within the lamina propria or epithelium, Brunner gland hyperplasia ( Fig. 21.7, A ), gastric foveolar metaplasia of the surface epithelium (see Fig. 21.7, B ), and hemorrhage and edema. Nodular duodenitis is frequently observed in patients with a history of peptic ulcer disease. In the setting of histologic findings indicative of peptic-type duodenal injury, the presence of Brunner gland hyperplasia should be attributed to peptic duodenitis.

Nodular peptic-type duodenitis. A, Hyperplastic Brunner glands fill the lamina propria, imparting a nodular appearance to the mucosa. Partial villous shortening and increased lamina propria chronic inflammation are also seen, indicative of duodenitis. B, Foveolar-type metaplasia is present on the villous surface of the duodenum. In contrast to the absorptive and goblet cells, the metaplastic cells contain small apical vacuoles, similar to gastric foveolar cells.

Pyloric gland adenoma is a relatively recently described adenoma subtype that can occur in the duodenum and not infrequently evolves into invasive adenocarcinoma. The distinction between pyloric gland adenoma and Brunner gland hyperplasia/hamartoma is difficult (see later discussion). Both express the mucin core peptide MUC6; however, pyloric gland adenomas usually also demonstrate labeling with MUC5AC, which is not typical of Brunner glands.

Clinical and Endoscopic Features

Gastric heterotopias in the duodenum are most commonly identified in the bulb and are usually incidental, small (<1.0 cm) nodules that may be multiple. Patients are typically asymptomatic, but larger polyps may manifest as masses and cause obstruction or intussusception. Peptic ulceration due to heterotopic oxyntic glands in the proximal duodenum is rare because the acid secretions are quickly diluted by the alkaline duodenal contents derived from the pancreatobiliary system. However, rare cases of massive GI bleeding have been reported, particularly in patients with extensive heterotopias. Gastric heterotopia is also associated with concurrent fundic gland polyps of the stomach, suggesting that the increased use of proton pump inhibitors (PPIs) in the general population may enhance its endoscopic detection.

Pathologic Features

Biopsies of gastric heterotopias display well-organized oxyntic glands composed of chief and parietal cells ( Fig. 21.8, A ). The overlying surface often exhibits gastric foveolar-type mucinous epithelium with adjacent normal duodenal intestinal villi. Gastric heterotopia in the duodenum may harbor the same pathologic processes that affect the stomach, including Helicobacter pylori infection (see Fig. 21.8, B ). Large gastric heterotopias may exhibit secondary mucosal prolapse-type changes including prominence of the muscularis mucosae, submucosal fibrosis, cystic dilatation of the oxyntic and mucinous glands, and surface epithelial hyperplasia.

Gastric heterotopia. A, The duodenal mucosa contains tightly packed aggregates of gastric glands composed of chief and parietal cells. The villous surface of the duodenum also demonstrates gastric foveolar-type metaplasia. B, Helicobacter pylori organisms can be present with gastric heterotopia, particularly in those cases in which gastric foveolar-type cells replace the normal duodenal surface epithelium.

Differential Diagnosis

Gastric heterotopia differs from gastric foveolar metaplasia, which is hypothesized to be a response to inflammation caused by peptic injury associated with gastric H. pylori infection ( Table 21.1 ). Histologically, peptic-type injury of the duodenum typically results in active inflammation within the lamina propria or epithelium and erosion or ulceration. The metaplastic gastric foveolar epithelium is not associated with the oxyntic glands characteristic of gastric heterotopia.

Clinical and Endoscopic Features

Pancreatic heterotopia represents the presence of pancreatic tissue outside the normal pancreas without any anatomic or vascular connection to the pancreas. It is synonymous with the terms pancreatic rest and ectopic pancreas . Pancreatic heterotopia of the small intestine is most commonly located in the proximal duodenum and can be seen either confined to the mucosa or within the muscularis propria. Pancreatic tissue may be normally identified in the region of the minor papilla and does not necessarily qualify as heterotopia. In most cases, pancreatic heterotopia is asymptomatic and only incidentally detected. Mural heterotopias develop most commonly in the peraampullary region and are more likely to be symptomatic due to duodenal obstruction, intussusception, and stricture or stenosis of the ampulla. Symptomatic mural pancreatic heterotopias often mimic a neoplastic process, leading to surgical resection, and an endoscopic biopsy diagnosis is not possible given the location of the lesion.

Pathologic Features

Pancreatic heterotopia may be composed of pancreatic acini, ducts, or islets, either alone or in combination ( Fig. 21.9 ). Most frequently, pancreatic ducts are identified, with a variable number of acinar cells and islets and no relationship between symptoms and the cell type present. Mural lesions are often histologically indistinguishable from normal pancreas. Most mucosal-based lesions are unassociated with inflammation, being present in otherwise normal mucosa of the duodenum. Rarely, ductal adenocarcinoma, mucinous neoplasms, and NETs have been reported to develop in pancreatic heterotopia.

A, Pancreatic heterotopia. A, The duodenal submucosa contains rounded aggregates of pancreatic acini. B, Lobules of pancreatic acini are associated with ducts and tubules lined by pancreatic ductal epithelium, similar to the parenchyma of the normal pancreas.

Differential Diagnosis

Peraampullary duodenal wall cyst (groove pancreatitis) is not often confused with mural pancreatic heterotopias. Although both may contain pancreatic ducts, acini, and islets, peraampullary duodenal wall cyst has characteristic clinicopathologic features. Most patients are young to middle-aged men who report alcohol use and typically present with pain and vomiting due to duodenal stenosis. Jaundice may also be seen late in the disease course as the result of compression of the common bile duct. The lesion typically involves the area of the minor papilla where pancreatic tissue may normally be identified. Fibrosis and inflammation occur in the “groove” between the superior aspect of the pancreatic head, the common bile duct, and the duodenum. In addition to groove pancreatitis, alternative names include cystic dystrophy of the duodenal wall and paraduodenal pancreatitis . Most cases are characterized by multiple or solitary cysts varying in size from 1 to 10 cm within the duodenal wall and pancreas ( Fig. 21.10 ). “Solid” types have also been described and are characterized by fibrotic thickening of the duodenal wall with small (<1 cm) cysts. A reactive myofibroblastic spindle cell proliferation is usually present in the duodenal wall, whereas the fibrosis in the groove area is more paucicellular and hyalinized. Cystically dilated ducts partially lined by ductal epithelium and containing inspissated eosinophilic material are characteristic ( Fig. 21.11 ). Squamous metaplasia, granulation tissue, calcium deposition, and giant cell reaction are also frequently encountered. It has been speculated that this disorder is a localized form of alcohol-induced pancreatitis occurring in pancreatic tissue present in the area of the minor papilla.

Paraduodenal pancreatitis (cystic dystrophy of heterotopic pancreas). The cut surface is heterogeneous, with cystic and solid areas that correspond to cysts lined by biliary-type epithelium enmeshed within a stroma rich in smooth muscle.

Paraduodenal pancreatitis. A, Numerous lobules of ductules are present in association with a prominent proliferation of smooth muscle in the submucosa of the duodenum. B, The ductules are lined by bland cuboidal and columnar cells containing mucin typical of biliary or pancreatic ductal-type epithelial cells.

Clinical and Endoscopic Features

PJS is an autosomal dominant hamartomatous polyposis syndrome with a prevalence of 1 in 200,000. The majority of patients have positive family histories; however, 25% of cases develop de novo. A diagnosis of PJS should be considered if one of the following criteria is met: (1) three or more histologically confirmed Peutz-Jeghers polyps, (2) any number of Peutz-Jeghers polyps with a family history of PJS, (3) characteristic mucocutaneous pigmentation with a family history of PJS, or (4) any number of Peutz-Jeghers polyps and characteristic mucocutaneous pigmentation. More than 90% of patients with PJS develop small intestinal polyps, most commonly in the jejunum, followed by the ileum and the duodenum. PJS patients are often diagnosed at an early age (approximately 20 years), because these polyps often cause abdominal pain, obstruction due to intussusception, and bleeding. Surgical intervention often occurs in these settings. Indeed, patients are at risk for short gut syndrome due to the numerous GI surgeries undertaken to resect these polyps. Patients with PJS have a significantly increased risk of intestinal adenocarcinoma, particularly of the colon (cumulative risk of 40%) but also of the small bowel (13% cumulative risk). For this reason, patients are enrolled in an endoscopic screening protocol at a very young age. Affected individuals are also at increased risk for other tumors: breast (54% cumulative risk for females), endometrial, cervical (adenoma malignum), pancreatic (36% cumulative risk), ovarian (sex cord/stromal tumor with annular tubules), and testicular (large-cell calcifying Sertoli cell tumor). The cumulative lifetime risk for any cancer approaches 90%.

Peutz-Jeghers polyps have an irregular, multilobulated endoscopic appearance and lack the velvety texture typical of adenomas ( Fig. 21.12 ). Because they contain prominent smooth muscle, they are tightly anchored to the bowel. Unlike juvenile polyps, they rarely autoamputate.

Peutz-Jeghers polyps of the duodenum. A, The endoscopic appearance of Peutz-Jeghers–type polyps is characteristic. These lesions are variable in size and shape but typically are multinodular and contain a smooth surface and thick stalk. B, Gross appearance of a Peutz-Jeghers polyp.

In 1998, the gene responsible for the majority of sporadic and inherited cases of PJS was identified as STK11 (also known as LKB1 ), a serine/threonine kinase located on chromosome 19p13.3. STK11 is a tumor suppressor gene that is involved in a wide spectrum of cellular functions, including cellular proliferation, cell polarity, and apoptosis. STK11 has been shown to interact with other tumor suppressors, including TP53 and PTEN .

There have been case reports of sporadic Peutz-Jeghers polyps, but this is somewhat controversial. In a study at a tertiary care center, three patients with potential sporadic Peutz-Jeghers polyps were identified, but two of them had other features suggestive of PJS, although strict clinical criteria were not met. The authors concluded that if sporadic Peutz-Jeghers polyps do exist, they are extremely rare.

Pathologic Features

The hamartomatous polyps of PJS are histologically distinctive and consist of disorganized mucosa with prominent smooth muscle bundles. The smooth muscle fibers of the muscularis mucosae form thick cores and permeate the polyps in an arborizing fashion ( Fig. 21.13, A ). The epithelium lining these polyps is similar to the normal mucosa in that there are goblet cells, absorptive enterocytes, endocrine cells, and Paneth cells (see Fig. 21.13, B ). Rarely, metaplastic bone formation has been reported in these polyps. As much as 10% of Peutz-Jeghers polyps have foci of misplaced epithelium, in which the epithelium is located within the submucosa or the muscularis propria or both. This phenomenon is encountered more frequently in polyps larger than 3 cm in diameter (see Fig. 21.13, C ).

Peutz-Jeghers polyp of the duodenum. A, The polyp is composed of complex, arborizing fronds lined by absorptive cells, goblet cells, and endocrine cells. B, Under higher power, the stroma is seen to be rich in smooth muscle fibers arising from the muscularis mucosae. C , Misplacement of the epithelium within the submucosa and muscularis propria is common in Peutz-Jeghers polyps.

The development of Peutz-Jeghers polyps is the subject of some controversy. Given the prominent smooth muscle in these polyps and the presence of misplaced epithelium, some authors suggest that patients with PJS are prone to mucosal prolapse. Indeed, the differential diagnosis of Peutz-Jeghers polyps, particularly in the colon, is mucosal prolapse polyps. However, hemorrhage and hemosiderin deposits, commonly seen in prolapse polyps, are not prominent in Peutz-Jeghers polyps.

The sequence of events that results in GI dysplasia and carcinoma is also unclear in relation to Peutz-Jeghers polyps. One occasionally encounters dysplasia and even carcinoma in a Peutz-Jeghers polyp; however, in a study of 2461 Peutz-Jeghers polyps from 63 patients, only 6 polyps contained foci of dysplasia. These results argue that the hamartoma-adenoma-carcinoma hypothesis proposed by some authors rarely occurs. Peutz-Jeghers polyps have also been shown to be polyclonal, arguing against the possibility of malignant potential. Given these results, it is possible that carcinoma develops in surrounding mucosa that may have an accelerated pathway to dysplasia and carcinoma.

In any case, when one encounters dysplasia in a Peutz-Jeghers polyp, the dysplasia should be classified according to a two-tiered system (i.e., low- or high-grade dysplasia). Care must be taken to not interpret misplaced epithelium as invasive adenocarcinoma. The misplaced epithelium should not have desmoplastic stroma or an infiltrative growth pattern. The epithelial cells should have a similar cytology to other parts of the polyps, and the glands should be invested with lamina propria.

Clinical and Endoscopic Features

Juvenile polyps of the small intestine are rare and occur in two polyposis syndromes: juvenile polyposis syndrome and PTEN hamartoma tumor syndrome. Juvenile-type polyps can also be seen in Cronkhite-Canada syndrome, an extremely rare, noninherited disorder associated with diffuse GI polyposis. Juvenile polyps tend to be friable and undergo autoamputation. Endoscopically, they appear smooth and often have evidence of hemorrhage. As a result, patients typically present with complaints related to bleeding, such as occult blood loss, hematochezia, fatigue, or anemia.

First described in 1964, juvenile polyposis syndrome is an extremely rare (1 per 100,000 births), autosomal dominant polyposis syndrome with variable penetrance. Three clinical phenotypes of juvenile polyposis syndrome have been described: infantile juvenile polyposis, juvenile polyposis coli, and generalized juvenile polyposis. Infantile juvenile polyposis syndrome, the most severe type, is characterized by early and diffuse involvement of the entire GI tract. Because these hamartomatous polyps have surface erosion, affected patients usually present with GI bleeding and anemia. Juvenile polyposis syndrome is also associated with a significantly increased risk of adenocarcinoma in involved GI sites. The colon is the site most commonly involved by disease, and the cumulative lifetime risk for colorectal cancer is 40%, with a median age at onset of 44 years. The lifetime risk of developing carcinomas of the stomach, small intestine, or pancreas is approximately 10% to 15%. Prevention of intestinal adenocarcinoma mandates intensive screening, with colonoscopy and upper GI endoscopy every 2 years, beginning at age 15. Severe GI bleeding may necessitate immediate surgery. Progression to dysplasia in a polyp is not necessarily an indication for surgery, provided that it can be completely removed. Given the increased risk of adenocarcinoma, genetic screening of family members of affected individuals is essential.

Approximately 25% of patients with juvenile polyposis syndrome have a negative family history, and their polyps presumably arise from a de novo mutation. Mutations in two genes have been described in patients with juvenile polyposis: SMAD4 (also known as MADH4 or DPC4 ) and BMPR1A (also known as ALK3 ). The proteins encoded by these genes are involved in the transforming growth factor-β (TGF-β) signal transduction pathway. Because the TGF-β signaling pathway mediates growth inhibitory signals, proteins in this pathway function as tumor suppressors. Mutations in SMAD4 have been shown to be more common in patients with upper GI polyps, whereas patients with BMPR1A mutations are more likely to present at a younger age than those with mutations in SMAD4 .

The term PTEN hamartoma tumor syndrome was coined to encompass all hamartoma syndromes that arise through mutations in the tumor suppressor, PTEN . This term encompasses Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome (BRRS), and Proteus syndrome, among others. Patients with these syndromes have a wide variety of GI, skin, and soft tissue tumors and an increased risk for carcinomas of the colorectum, thyroid, breast, or endometrium. Cowden syndrome is 50% less common than juvenile polyposis syndrome and is characterized by multiple hamartomatous tumors of endodermal, mesodermal, and ectodermal origin. The most distinctive lesions are mucocutaneous—in particular, trichlemmomas, acral keratosis, subcutaneous lipomas, palmarplantar keratoses, oral cobblestoning, and oral papillomas. Colonic polyps in Cowden syndrome are common and range from ganglioneuromas to adenomas, lipomas, hyperplastic polyps, and juvenile polyps. Polyps of the small intestine are more rare but do occur, with frequencies between 37% and 66%. BRRS is also associated with juvenile polyps of the GI tract (mostly limited to ileum and colon); however, these patients also have neurologic findings, including macrocephaly and slowed psychomotor development. Some BRRS patients also develop extraintestinal hamartomatous tumors similar to those seen in patients with Cowden syndrome.

Pathologic Features

Juvenile polyps are pedunculated and are histologically characterized by abundant lamina propria, dilated mucin-filled crypts, active inflammation, and surface erosion ( Fig. 21.14 ). The epithelium in these polyps can contain adsorptive cells, goblet cells, endocrine cells, and Paneth cells. Often, eosinophils are prominent. Unlike Peutz-Jeghers polyps, juvenile polyps lack prominent smooth muscle bundles. Juvenile polyps in the small bowel are very similar to inflammatory-type polyps. The distinction between these two polyps is mostly based on the clinical context in which they arise. In a patient with a known polyposis syndrome, the diagnosis of a juvenile polyp is appropriate. In cases where multiple inflammatory or juvenile polyps are seen, the possibility of a polyposis syndrome should considered. If a single juvenile or inflammatory polyp is encountered, one should be cautious in suggesting a polyposis syndrome.

Juvenile polyp from a patient with juvenile polyposis syndrome. A, The polyp demonstrates an expanded, edematous lamina propria with a mixed inflammatory cell infiltrate. Dilated glands with crypt abscesses are seen. Unlike Peutz-Jeghers polyps, there are no prominent smooth muscle bundles. B, Areas of low-grade dysplasia characterized by epithelial cells with pseudostratified, enlarged, and hyperchromatic nuclei are seen focally.

Clinical and Endoscopic Features

Adenomas account for approximately 25% of benign neoplasms of the small intestine and demonstrate a distinct predilection for the ampulla and the peraampullary region. Most are sporadic lesions occurring in older individuals, but they also occur in patients with adenomatous polyposis syndromes, including familial adenomatous polyposis (FAP) and MUTYH -associated polyposis (MAP). Approximately 17% of patients with MAP have duodenal polyposis, and their lifetime risk of duodenal cancer is 4%. Small bowel adenomas also occur in Lynch syndrome. Unlike adenomas in MAP and FAP, those in Lynch may not have such a strong predilection for the proximal small bowel and ampulla. As in MAP, the lifetime risk of small bowel adenocarcinoma in Lynch syndrome is 4%. Given that adenomas may not be amenable to upper endoscopy, capsule endoscopy has been used to identify occult adenomas and carcinomas in Lynch syndrome ; however, this is currently not recommended for routine screening.

Although some adenomas located distal to the ampulla produce luminal obstructive symptoms or occult blood loss, most are asymptomatic and clinically silent until complicated by the development of carcinoma. In contrast, ampullary and peraampullary adenomas can produce obstructive jaundice before malignant transformation and become symptomatic earlier in their evolution.

Pathologic Features

With the exception of some ampullary neoplasms, most adenomas of the small intestine are endoscopically and histologically similar to those of the colon. Larger adenomas (>1 cm) are more likely to harbor areas of high-grade dysplasia, and approximately 50% have a villous component, consisting of long papillary projections lined by columnar, mucin-depleted epithelial cells with enlarged, hyperchromatic nuclei. Paneth cells and endocrine cells are often more numerous in adenomas of the small intestine compared with those of the colon. The criteria for grading dysplasia in adenomas of the small intestine are similar to those for colonic adenomas. Low-grade dysplasia is defined as nuclear stratification confined to the lower half of the cells in the absence of complex architectural changes ( Fig. 21.15, A and B ). High-grade dysplasia is characterized by the presence of marked nuclear enlargement with loss of nuclear polarity and irregular nuclear membranes. These nuclear changes are often accompanied by complex architectural abnormalities such as cribriforming and glandular crowding (see Fig. 21.15, C ). The terms severe dysplasia and carcinoma in situ should no longer be used to describe these changes.

Adenomas of the small intestine. A, The glands of this adenoma are reminiscent of those seen in colonic adenomas, containing crowded neoplastic cells with enlarged, hyperchromatic and pencillate nuclei. The adenomatous glands lack marked cytologic or architectural atypia. B, Many adenomas of the small intestine have prominent Paneth cells. C, Adenoma of the small intestine with high-grade dysplasia. Architectural abnormalities including cribriform glandular spaces and crowded glands with loss of intervening stroma are present. Areas of marked nuclear enlargement with loss of polarity are seen.

Unlike adenomas of the colon, but similar to those of the esophagus and stomach, the lamina propria in adenomas of the small intestine contains a rich lymphatic network. When dysplastic epithelial cells break through the basement membrane and infiltrate the lamina propria, the term intramucosal adenocarcinoma is appropriate. Intramucosal adenocarcinoma of the small intestine carries a risk of lymph node metastasis and is staged as pT1a carcinoma, according to the seventh edition of the Cancer Staging Manual of the American Joint Committee on Cancer.

Clinical and Endoscopic Features

Ampullary adenomas typically occur in older adults (mean age, 64 years), and most are sporadic (see also Chapter 41 ). Small adenomas of the ampulla and peraampullary region appear as polypoid excrescences or as a subtle prominence of the ampulla, whereas larger adenomas are velvety, flat lesions (“carpet adenomas”) at high risk for the development of invasive adenocarcinoma ( Fig. 21.16 ). Several investigators have postulated that the ampulla may be prone to neoplastic transformation because it is chronically irritated by pancreatic juices and bile salts, resulting in long-standing injury to the mucosa and culminating in epithelial cell dysplasia.

Villous adenomas of the ampulla. These lesions may appear as “carpet” adenomas composed of velvety papillary and polypoid excrescences surrounding the ampulla ( A ) or as a mucosal prominence ( B ). C and D, Intestinal type tubulovillous adenoma involving the ampulla. The epithelial cells are columnar with pseudostratified and enlarged nuclei.

Pathologic Features

Adenomas of the ampulla can be divided into intestinal and pancreaticobiliary types (although mixed lesions also occur). The intestinal-type adenomas are more common (~75%) and resemble colonic and peraampullary/duodenal adenomas ( Fig. 21.16, C and D ). Pancreaticobiliary-type adenomas—or neoplasms, as preferred by the current World Health Organization (WHO) classification —often have prominent papillary architecture and resemble intraductal papillary neoplasms of the pancreatic duct. The papillary projections are lined by a monolayer of cuboidal epithelial cells with round nuclei and eosinophilic cytoplasm (see Fig. 21.17, A and B ). These lesions are often high-grade with complex architecture including extensive arborization of the papillae, cribriforming, and marked nuclear atypia. Some authors have used immunohistochemistry to differentiate these histologic subtypes. Intestinal-type adenomas express apomucin MUC2 and the transcription factor CDX2. Pancreaticobiliary-type neoplasms express MUC1, MUC5AC, and MUC6. However, there is considerable overlap in the expression of these proteins in these lesions, limiting their clinical utility.

Ampullary adenoma, pancreaticobiliary type. A and B, The adenoma is characterized by a complex papillary proliferation of columnar to cuboidal cells, reminiscent of biliary epithelial cells. The epithelial cells have open chromatin and prominent nucleoli. C, As is common with these neoplasms, there is an associated invasive carcinoma.

Both intestinal and pancreaticobiliary mass-forming lesions of the ampulla are often associated with adjacent invasive adenocarcinoma (~80%). Although most adenocarcinomas of the ampulla arise from adenomas, nonpolypoid (or flat) dysplastic lesions of the ampulla also occur. These dysplastic lesions are almost always associated with an adjacent invasive adenocarcinoma. Some of these lesions have a micropapillary architecture lined by dysplastic cuboidal to columnar cells.

The evaluation of biopsy or resection specimens of ampullary and peraampullary adenomas may be difficult for several reasons. Ampullary ducts and glands are in close proximity to bundles of smooth muscle, and when dysplastic epithelium extends into these structures, a mistaken diagnosis of invasive adenocarcinoma may be rendered ( Fig. 21.18 ). The lobular architecture and lack of desmoplasia can be helpful in distinguishing this finding from invasive adenocarcinoma. As with their colonic counterparts, misplacement of the dysplastic epithelium into the submucosa may occur as a consequence of mechanical injury or prolapse in these adenomas. The presence of lamina propria around these dysplastic glands and the presence of hemosiderin deposits and acellular mucin pools are helpful features to differentiate epithelial misplacement from invasive adenocarcinoma. Finally, because many patients with ampullary lesions have obstructive jaundice, biliary stents are often placed. Stents cause inflammatory epithelial injury and erosions of the ampullary epithelium with concomitant reactive and regenerative epithelial changes, as well as inflammation of the underlying stroma ( Fig. 21.19 ). This constellation of findings may mimic dysplasia or even invasive cancer. Therefore, it is imperative to know the patient’s status regarding stenting of the common bile duct to evaluate the specimen properly and avoid the pitfall of overdiagnosing neoplasia. The presence of active inflammation and foveolar metaplasia should make one cautious in interpreting the epithelial changes as dysplastic.

Ampullary adenoma involving peraampullary glands. A, Adenomatous epithelium extends into the underlying peraampullary glands, which are embedded in smooth muscle. B, At higher power, there is an admixture of adenomatous glands and non-neoplastic peraampullary glands associated with a rim of lamina propria.

Regenerative epithelial changes secondary to biliary stenting. In this example, the lamina propria is expanded and inflamed with prominent capillaries suggestive of previous injury. The epithelium demonstrates mucin loss and areas of pseudostratification. However, the nuclei are not markedly enlarged and hyperchromatic. Furthermore, the ratios of nucleus to cytoplasm are not increased.

Immunohistochemical and Molecular Features

Sporadic peraampullary and ampullary adenomas harbor mutations in the APC gene (discussed in the next section) in approximately two thirds of cases, although loss of heterozygosity at chromosome 5q is infrequent. Almost half demonstrate KRAS mutations, but TP53 mutations are usually lacking, particularly in the absence of high-grade dysplasia. Mutations in BRAF are only rarely seen in ampullary and peraampullary adenomas. Therefore, the molecular features of sporadic ampullary adenomas are similar to those of colonic adenomas and small intestinal adenomas associated with FAP.

Clinical and Endoscopic Features

FAP is an autosomal dominant inherited disease occurring in 1 to 2 of 100,000 persons. Fortunately, FAP is relatively easy to diagnose clinically, because most affected patients have strong family histories and commonly have 100 to 1000 colonic polyps (classic FAP is defined as the presence of >100 colonic adenomas). An attenuated form of FAP has been described that manifests with significantly fewer colonic polyps, often more than 15 but always less than 100. Small intestinal adenomas occur in approximately 90% of FAP patients ( Fig. 21.20 ). Typically, they are more prominent in the duodenum and ampulla. The incidence of small bowel or ampullary carcinoma was estimated to be 4.5% among those patients enrolled in a screening program.

Duodenojejunal resection specimen from a patient with familial adenomatous polyposis syndrome. Numerous small polyps and exaggerated mucosal folds are present throughout the specimen. In addition, several larger, irregular polyps are seen.

In 1987, the gene responsible for FAP was localized to chromosome 5q21, and in 1991 it was identified as the adenomatous polyposis coli gene ( APC ). The APC gene contains 15 transcribed exons encoding a 312-kDa tumor suppressor. Mutations in APC constitute the initial step in the development of colorectal carcinoma in FAP patients. APC is involved in a wide variety of cellular functions, including cell adhesion, migration, chromosome segregation, and signal transduction. One of the most important roles of APC is to regulate the activity of β-catenin, a protein involved in the Wnt signaling pathway and cellular adhesion. In conjunction with other proteins, APC is essential in inducing the phosphorylation and subsequent degradation of β-catenin. Loss of APC function through mutation leads to accumulation of β-catenin, which subsequently translocates to the nucleus, leading to transcription of many proto-oncogenes such as MYC . Because APC also regulates the microtubule spindle apparatus, mutations predispose to aneuploidy and further neoplastic transformation. More than 700 mutations in APC have been identified in FAP patients. Interestingly, the location of the mutation has striking effects on the phenotype of FAP. Particularly those occurring in the central portion of the APC gene (codons 279-1309) correlate with increased numbers of duodenal polyps as well as the size of the adenomas.

Risk of Malignancy

In the early 1990s, Spigelman developed a classification scheme based on the number and size of adenomas, their architectural features, and the degree of dysplasia, in an attempt at risk stratification of FAP patients ( Table 21.3 ). Originally, the dysplasia was classified as mild, moderate, or severe; however, more recent studies have modified the original Spigelman classification to reflect the division of dysplasia into high-grade and low-grade. The risk of progression to duodenal or ampullary adenocarcinoma is likely strongly correlated to the Spigelman stage at initial endoscopy. In a study of 114 patients with FAP, 6 duodenal or ampullary carcinomas were identified. In five cases, the original Spigelman stage was III (one case) or IV (four cases). Only 17% of patients progressed to a higher Spigelman stage during the surveillance program. A more recent study demonstrated a much higher rate of progression in Spigelman stage (40%); however, no patient developed adenocarcinoma. Given that the Spigelman stage depends on villousity and degree of dysplasia, it is possible that interobserver variability among pathologists could account for these differences. Currently, endoscopic mucosal resection or prophylactic pancreaticoduodenectomy is considered for patients with advanced Spigelman stage.

Table 21.3

Modified Spigelman Score *

Factor	1 Point	2 Points	3 Points
Polyp number	1-4	5-20	>20
Polyp size, mm	1-4	5-10	>10
Architecture	Tubular	Tubulovillous	Villous
Dysplasia	Low-grade	—	High-grade

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