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.^19,20 The cells are cytologically bland with abundant neutral mucin and small, basally located nuclei with minimal to absent mitotic activity.

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.²¹ In the setting of histologic findings indicative of peptic-type duodenal injury, the presence of Brunner gland hyperplasia should be attributed to peptic duodenitis.

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.²²

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.²³ Patients are typically asymptomatic, but larger polyps may manifest as masses and cause obstruction or intussusception.^24,25 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.^24,26 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.²⁷

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).²⁷ 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.²⁸

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.³⁰ 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.^31–33 Symptomatic mural pancreatic heterotopias often mimic a neoplastic process, leading to surgical resection,³¹ 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.³⁴ 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.^34–37

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.^38–40 Jaundice may also be seen late in the disease course as the result of compression of the common bile duct.³⁸ 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.³⁰ 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.³⁹ 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.⁴¹ 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.^39,41 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.³⁰

PJS is an autosomal dominant hamartomatous polyposis syndrome with a prevalence of 1 in 200,000.^45,46 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.^45,47 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.^45,48 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.⁴⁹ 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).^45,50–59 For this reason, patients are enrolled in an endoscopic screening protocol at a very young age.⁴⁵ 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).^{50,57,58,60–62} 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.

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.^48,63–66 STK11 is a tumor suppressor gene that is involved in a wide spectrum of cellular functions, including cellular proliferation, cell polarity, and apoptosis.^67–69 STK11 has been shown to interact with other tumor suppressors, including TP53 and PTEN.⁶⁷

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.⁴²

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.⁷⁰ 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).⁷¹

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.⁷² 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.⁷³ These results argue that the hamartoma-adenoma-carcinoma hypothesis proposed by some authors rarely occurs.⁷⁴ 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.^57,72

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.⁷¹ 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.

Juvenile polyps of the small intestine are rare and occur in two polyposis syndromes: juvenile polyposis syndrome and PTEN hamartoma tumor syndrome.⁷⁵ Juvenile-type polyps can also be seen in Cronkhite-Canada syndrome, an extremely rare, noninherited disorder associated with diffuse GI polyposis.^76,77 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.⁷⁸ The lifetime risk of developing carcinomas of the stomach, small intestine, or pancreas is approximately 10% to 15%.⁷⁹ Prevention of intestinal adenocarcinoma mandates intensive screening, with colonoscopy and upper GI endoscopy every 2 years, beginning at age 15.⁷⁵ 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).^80–85 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 SMAD4.⁸⁶

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.^75,87 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.⁸⁸ 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%.^89,90 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.⁷⁵

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.

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.

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.⁹⁵

Ampullary adenomas typically occur in older adults (mean age, 64 years), and most are sporadic⁹⁶ (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.^97,98

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) classification⁹⁹—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 MUC6.¹⁰⁰ However, there is considerable overlap in the expression of these proteins in these lesions, limiting their clinical utility.

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.

FAP is an autosomal dominant inherited disease occurring in 1 to 2 of 100,000 persons.⁸⁷ 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.¹⁰¹ The incidence of small bowel or ampullary carcinoma was estimated to be 4.5% among those patients enrolled in a screening program.^102,103

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).¹⁰⁴ 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.¹⁰⁵ 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.¹⁰⁶

Pyloric Gland Adenoma

Pyloric gland adenomas are composed of tightly packed glands lined by cuboidal epithelium with an even monolayer of round nuclei with abundant mucinous cytoplasm reminiscent of pyloric-type glands (Fig. 21.21, A).^109,110 These polyps are likely more common in the stomach, but 46% of pyloric gland adenomas occurred in the duodenum in one study.¹⁰⁹ Given their resemblance to Brunner glands, the distinction between pyloric gland adenoma and Brunner gland hamartoma/hyperplasia can be difficult. However, pyloric gland adenomas often do not have overlying intestinalized epithelium when they occur in the duodenum. Furthermore, there is no lobular configuration in these lesions, in contrast to Brunner gland hamartoma/hyperplasia.

By definition, these lesions are neoplastic. However, despite being called adenomas, some are fairly bland without areas of conventional dysplasia. Therefore, nondysplastic pyloric gland adenomas do occur. However, often there are areas of dysplasia (classified as either low-grade or high-grade) (see Fig. 21.21, B). Between 10% and 30% of pyloric gland adenomas are associated with invasive adenocarcinoma.

Hyperplastic Polyp

Recent reports have described small intestinal polyps with morphologic features resembling colonic microvesicular hyperplastic polyps with prominent epithelial serrations and abundant cytoplasm with small mucin droplets (Fig. 21.22).^111,112 In a series of nine polyps, five were found in the second portion of the duodenum. Molecular analysis performed on six of these polyps found a V600E BRAF mutation in two polyps and KRAS mutations in another two polyps.¹¹² These polyps also expressed gastric mucins similar to serrated colorectal polyps. Although these findings are suggestive, additional studies need to be performed to further characterize these lesions.

Gastrin-producing NETs represent the largest group NETs of the duodenum and proximal jejunum, accounting for approximately two thirds of NETs in the upper GI tract.^116,117 Gastrin-producing NETs can be either nonfunctioning or associated with Zollinger-Ellison syndrome (ZES), a syndrome of hypergastrinemia, gastric hypersecretion, and refractory peptic ulcer disease.¹¹⁸ The functional status of the NET is defined by clinical and serologic findings and not by the immunohistochemical expression of peptide hormones. Gastrin-producing NETs develop in the pancreaticoduodenal region (gastrinoma triangle); the primary tumor is found with near-equal frequency in the pancreas and in the duodenum. Rarely, a gastrin-producing NET is identified in a lymph node in the gastrinoma triangle without an apparent duodenal or pancreatic primary tumor, suggesting the possibility of a primary lymph node gastrinoma.¹¹⁹ However, it is likely that so-called primary lymph node gastrinomas represent metastases from microscopic primary tumors that are easily overlooked on routine examination.^120–124

The association of ZES is found in approximately 40% to 50% of duodenal gastrin-producing NETs.^116,117,125 Most ZES NETs are sporadic, and approximately 25% are associated with multiple endocrine neoplasia type 1 (MEN1). Sporadic ZES NETs most commonly occur in the duodenum (60% to 75%) but can also be found in the pancreas.^122,126 In contrast, most MEN1-associated ZES NETs occur in the duodenum rather than the pancreas, and they can frequently be multifocal within the duodenum.¹²⁶

Nonfunctional gastrin-producing NETs typically occur in the duodenal bulb and are localized in the lamina propria and submucosa.¹²⁷ Most nonfunctioning gastrin-producing NETs are clinically indolent, small (<1cm), and asymptomatic; they are often discovered during endoscopy for other reasons or during surgical resections for unrelated causes. Nonfunctioning gastrin-producing NETs of the duodenum have been associated with H. pylori infection of the stomach or long-term PPI therapy.¹²⁷ It is postulated that H. pylori infection and PPI therapy result in G-cell hyperplasia within the duodenum, leading to formation of sporadic nonfunctional gastrin-producing NETs.¹²⁷

Pathologic Features

Gastrin-producing NETs resemble NETs elsewhere in the gastroenteropancreatic system and are composed of uniform cells with lightly eosinophilic cytoplasm arranged in anastomosing cords, trabeculae, and tubules (Fig. 21.23, A and B). Immunohistochemistry often reveals staining with synaptophysin, chromogranin A, and gastrin (see Fig. 21.23, C). Other peptides may be detected in a subset of tumor cells.^116,117 Gastrin-producing NETs infrequently label with CDX2¹²⁸ but may express PAX8 by immunohistochemistry.^129,130 The nontumorous duodenum can demonstrate gastrin cell proliferation in MEN1-associated gastrinomas and in sporadic nonfunctional gastrin-producing NETs associated with H. pylori gastritis and long-term PPI therapy.^127,131 However, sporadic ZES NETs typically do not exhibit proliferative gastrin cell changes in the nontumorous mucosa.¹³¹ Both sporadic and MEN1-associated ZES NETs may be multifocal. However, the pathogenesis varies in these two conditions. Multifocal sporadic ZES NETs from the same patient probably represent metastases, because they frequently demonstrate the same somatic MEN1 gene mutation and similar patterns of X-chromosome inactivation in tumors at different sites within the same patient.¹³² Multifocal ZES NETs in patients with MEN1 syndrome have varied genetic abnormalities and probably represent independent primary tumors.¹³³

Somatostatin-Producing NETs

Clinical Features

Somatostatin-producing NETs have a predilection to affect the ampulla and peraampullary region (Fig. 21.24).^137–139 Somatostatin inhibits secretion of a number of endocrine and exocrine products and diminishes peristaltic contractions of the gallbladder and stomach.¹⁴⁰ The somatostatinoma syndrome—consisting of diabetes mellitus (due to inhibition of insulin secretion), steatorrhea (due to inhibition of pancreatic enzyme secretion), hypohydria or achlorydia, and cholelithiasis (due to suppression of cholecytokinin-pancreozymin release and gallbladder contraction)—is rarely observed in duodenal somatostatin-producing NETs.^141–144 In contrast, somatostatin-producing NETs of the pancreas may produce the somatostatinoma syndrome.^138,145

Because of the preferred ampullary and peraampullary location, somatostatin-producing NETs of the duodenum typically manifest with symptoms and signs related to bile duct obstruction, abdominal pain, or cholelithiasis.^146,147 Somatostatin-producing ampullary/peraampullary NETs have been associated with von Recklinghausen disease (neurofibromatosis type 1, or NF1), although the frequency with which patients with NF1 develop these tumors is not clear.^{144,148–159} Some patients with ampullary somatostatin-producing NETs also have a pheochromocytoma involving one or both adrenal glands.¹⁵⁰

Pathologic Features

Somatostatin-producing ampullary/peraampullary NETs have characteristic morphologic features that help distinguish these tumors from other NETs of the duodenum. Approximately 60% of somatostatin-producing NETs display a characteristic mixed pseudoglandular and trabecular architectural arrangement with polarized cells arranged in pseudoglandular structures; the central lumina frequently contain diastase-resistant proteinaceous secretions (Fig. 21.25, A).^133,150 Psammoma bodies are seen in approximately 60% of sporadic somatostatin-producing ampullary/peraampullary NETs and in almost all NF1-associated somatostatin-producing NETs (see Fig. 21.25, B).^133,136 In contrast, pancreatic somatostatin-producing NETs less frequently exhibit a pseudoglandular architecture (~20%) or psammoma bodies (~40%).¹³³ Somatostatin-producing NETs are strongly positive for somatostatin, chromogranin A, and synaptophysin. A subset of the tumor cells may also express other peptide hormones, including gastrin, calcitonin, and serotonin.^141,160

Natural History

Both sporadic and NF1-associated somatostatin-producing duodenal NETs may metastasize to regional lymph nodes and to the liver.¹³³ The risk of metastasis appears to be related to tumor size. Tumors smaller than 2.0 cm have a low metastatic potential, whereas larger lesions are at increased risk of metastatic disease.¹⁵² Even in the setting of metastatic disease, patients with somatostatin-producing duodenal NETs typically have a protracted clinical course.

Gangliocytic Paraganglioma

Clinical Features

Gangliocytic paragangliomas are rare tumors that have a predilection for the ampulla/peraampullary area. Gangliocytic paragangliomas occur slightly more frequently in men and usually occur in middle age (mean age, 54 years) but have been reported to occur in younger patients.^161–163 These lesions manifest as polypoid submucosal nodules ranging in size from 2 to 4 cm. Many patients present with GI bleeding due to mucosal erosion, but ampullary/peraampullary tumors can cause obstructive jaundice.^162,164,165 Similar to somatostatin-producing NETs, gangliocytic paragangliomas are associated with NF1.^164,166,167

Pathologic Features

Gangliocytic paragangliomas are composed of a variable mixture of (1) nests of uniform polygonal neuroendocrine cells that occasionally form tubules, (2) mature ganglion cells, and (3) spindle cells with schwannian differentiation arranged in broad fascicles or associated with the polygonal cells and ganglion cells (Fig. 21.26).^163,168,169 Psammoma bodies may be identified in the neuroendocrine cell population.¹⁴¹ The neuroendocrine cells typically stain for both chromogranin A and synaptophysin but can also label for the peptide hormones somatostatin, pancreatic polypeptide, vasoactive intestinal peptide (VIP), and gastrin. The spindle cells show tapered ends, contain faintly eosinophilic cytoplasm, and stain intensely for S100 and neurofilament. The ganglion cells may be dispersed singly, or they may form small clusters and stain for synaptophysin.

Natural History

Gangliocytic paragangliomas usually follow a benign course. However, there are reports of gangliocytic paragangliomas with metastasis to regional lymph nodes, particularly large tumors (>2 cm).^170–174 Most frequently, the metastatic tumor in lymph nodes consists of the neuroendocrine component of the tumor, although cases of metastasis containing all three components have been described.¹⁷² To our knowledge, none of the reported cases of metastatic gangliocytic paraganglioma has resulted in patient death. Therefore, a conservative management approach seems appropriate.

In contrast to duodenal NETs, NETs of the distal jejunum and ileum are derived from serotonin-producing enterochromaffin (EC) cells and may secrete serotonin. Therefore, jejunoileal NETs are true carcinoid tumors. These tumors also elicit peritumoral or mesenteric fibrosis that may produce symptoms of recurrent small bowel obstruction, bowel ischemia and infarction, and protracted abdominal pain.¹⁷⁵ The mechanism by which jejunoileal NETs stimulate fibrosis remains poorly understood but may be related to the secretion of serotonin or possibly growth factors by these tumors.¹⁷⁵ A significant percentage (approximately one third) of jejunoileal NETs are associated with second synchronous or metachronous malignancies, most frequently adenocarcinomas of the GI, genitourinary, and gynecologic tracts.^176–179 Gene expression profiling and comparative genomic hybridization analysis of jejunoileal NETs has revealed frequent loss of chromosome 18q with frequent gain of chromosomes 4 and 7 seen in metastases.^180–182 Other genetic analyses have suggested that gain of chromosome 14 predicts poor outcome in ileal NETs.¹⁸³

Pathologic Features

Jejunoileal NETs have a variable gross appearance, ranging from the presence of polypoid tan-yellow submucosal nodules to annular masses or strictures secondary to marked fibrosis characteristic of these lesions (Fig. 21.27). Approximately 25% of tumors manifest as multiple mucosa-based polypoid lesions, with younger patients more frequently presenting with multiple tumors.¹⁸⁴ X-chromosome inactivation analysis of multifocal carcinoid tumors of the small intestine has demonstrated identical X-chromosome inactivation patterns, indicating that multiple tumors represent mucosal metastases in some cases.¹⁸⁵

Jejunoileal NETs are typically composed of rounded nests of uniform tumor cells with lightly eosinophilic cytoplasm (Fig. 21.28). Anastomosing cords, trabeculae, and cribriform and pseudoglandular structures may also be observed. The tumor cells are associated with densely fibrotic stroma that may compress the tumor cells into a single-file and cord-like arrangement. Most tumors demonstrate perineural and lymphovascular invasion. Jejunoileal NETs are typically strongly positive for synaptophysin and chromogranin and usually display diffuse, strong reactivity for CDX2.^{128,186–190} Jejunoileal NETs are negative for PAX8, which may help to localize the primary site of a NET in the setting of metastatic disease to the liver with an unknown primary.^129,130 However, the antibody commonly used for PAX8 may actually recognize another related PAX protein.¹⁹¹

Neuroendocrine carcinomas are defined by the presence of either a high mitotic rate (>20 per 10 HPF) or a high Ki67 index (>20%).¹¹³ Neuroendocrine carcinoma can be further subdivided into small cell and large cell types, comparable to neuroendocrine carcinomas seen in the lung. Within the small intestine, neuroendocrine carcinomas are relatively rare but appear to have a predilection for the ampulla/peraampullary area.^196,197 Neuroendocrine carcinomas appear to occur more frequently in males and in older patients (mean age, 68 years).^196,198

Primary Lymphangiectasia

Primary intestinal lymphangiectasia is a rare condition affecting children and young adults that is characterized by severe edema, thickening of the small bowel wall, protein-losing enteropathy, ascites, and pleural effusion.²⁰² Secondary generalized edema may occur as a result of hypoproteinemia. The pathogenesis of this disorder is unclear. Computed tomographic imaging is most often used in the diagnosis; it reveals diffuse, nodular thickening of the bowel wall with ascites and hypodense streaks in the small bowel due to markedly dilated lymphatics.^203,204 Mucosal biopsies are not specific, revealing only multiple dilated lymphatic spaces, but they are often necessary to confirm the presence of dilated lymphatics. Mesenteric lymphatics are also dilated and thickened; however, surgical resections are not performed for this disorder. The diagnosis requires knowledge of the clinical and radiographic findings.

Secondary Lymphangiectasia

A number of disorders can give rise to dilated lymphatics in the small intestine. Acute inflammatory disorders including infections frequently display dilated lymphatics. In particular, dilated lymphatics are a common histologic finding in Whipple disease, and their presence should prompt a careful evaluation for the characteristic PAS-positive macrophages in the lamina propria. Dilated lymphatics may also be the result of extraluminal compression due to malignancy elsewhere in the GI tract or regional lymph nodes, malrotation, fibrosis, or lymph node obstruction or infiltration by inflammation, tumor (Fig. 21.29), or infection.

Malignant Lymphoma

A detailed discussion of hematopoietic malignancies that may affect the small intestine is presented in Chapter 31. With the exception of enteropathy-associated T-cell lymphoma, most lymphomas of the small intestine are B-cell lymphomas, and specific subtypes demonstrate a predilection to affect different regions of the small intestine. Enteropathy-associated T-cell lymphomas usually develop in the jejunum or distal duodenum, reflecting the disease distribution of celiac disease. Most lymphomas of the ileum are diffuse large B-cell lymphomas. Primary follicular lymphoma of the GI tract has a predilection for the duodenum and is typically low-grade with a favorable prognosis.^217–219

Malignant lymphoid neoplasms can also result in amyloid deposition in any portion of the GI tract including the small bowel (primary amyloidosis). Secondary amyloidosis and inherited amyloidotic disorders can also involve the GI tract.^220,221 The small bowel is most commonly affected. Whereas amyloid deposition within the gut is usually around submucosal vessels, occasionally amyloid deposition can manifest as nodules or polyps (Fig. 21.31, A and B).

Multiple Lymphomatous Polyposis

Lymphomatous polyposis is an unusual form of GI involvement by lymphoma that is characterized by innumerable polypoid excrescences (Fig. 21.32). It can affect any portion of the GI tract but frequently produces large polyps in the ileocecal region. Lymphomatous polyposis usually occurs as a manifestation of mantle cell lymphoma, although other lymphoma types, including follicular lymphoma, diffuse large B-cell lymphoma, marginal zone lymphoma, and T-cell lymphoma, can give rise to lymphomatous polyposis.^222–225