Clinical Features and Pathogenesis

Numerous synonyms, including inflammatory polyp, regenerative polyp, and hyperplasiogenous polyp, have been used to describe hyperplastic polyps. The diversity of names is not surprising given the prevalence and pathologic diversity of these lesions. Hyperplastic polyps account for approximately 75% of all gastric polyps.

Hyperplastic polyps are detected most often in older patients, with a peak incidence occurring in the sixth and seventh decades of life, and they are diagnosed equally in both genders. Because they most often appear in the context of chronic gastritis, hyperplastic polyps are associated with clinical symptoms and signs similar to those in patients with chronic gastritis. In many cases, patients are asymptomatic. Rarely, large lesions can cause obstructive symptoms if located near the pylorus or gastroesophageal junction. Helicobacter pylori infection is common.

More than 85% of hyperplastic polyps occur in a background of chronic gastritis, and this observation has led some to conclude that the lesions develop as a consequence of an exaggerated mucosal response to tissue injury and inflammation. It is thought that gastritis initiates the process of injury and that the mucosal healing response results in a stepwise progression through phases of foveolar hyperplasia and polypoid foveolar hyperplasia to the formation of a hyperplastic polyp.

Conditions associated with the development of hyperplastic polyps include H. pylori gastritis, chronic non– H. pylori gastritis, chemical or reactive gastritis (including gastritis caused by bile reflux), and gastritis related to Billroth II gastrectomy. The H. pylori CagA protein may have a more direct role, because expression of CagA in the gastric mucosa of transgenic mice produces hyperplastic polyps. The tendency of hyperplastic polyps to occur more proximally in the stomach in the setting of autoimmune gastritis (which involves the corpus of the stomach) than in other types of gastritis supports the hypothesis that hyperplastic polyps develop as a consequence of chronic mucosal injury.

In one study, 33% of hyperplastic polyps of the gastroesophageal junction were related to Barrett’s esophagus, and they presumably developed in the context of reflux. In other instances, a hyperplastic polyp may be the first biopsy finding that leads to a diagnosis of Barrett’s esophagus. One study suggests that many so-called hyperplastic polyps (as many as 49%) instead represent foveolar hyperplasia resulting from a lack of significant stromal edema or inflammatory changes, cyst formation, muscle hyperplasia, or large-sized vessels. In that study, 51% of originally diagnosed hyperplastic polyps were reclassified as mucosal prolapse polyps. They occurred more commonly in the antral or prepyloric region of the stomach and showed thickened and hyperplastic-appearing bands of muscle extending toward the surface of the polyp and thick-walled blood vessels, both of which are characteristic of prolapse-type polyps in other areas of the GI tract.

Pathologic Features

Almost 50% of hyperplastic polyps are less than 0.5 cm in greatest dimension at the time of diagnosis; most are smaller than 1 cm. However, lesions may rarely grow to as large as 12 cm. Large polyps can easily be misdiagnosed clinically and pathologically as carcinomas. All hyperplastic polyps should be exhaustively sampled and the entire polyp submitted for histologic evaluation.

Hyperplastic polyps occur most commonly in the antrum, but they can be found anywhere in the stomach. They may develop as solitary lesions but frequently occur as multiple polyps, particularly in patients with atrophic gastritis. In some studies, fundic gland polyps have been associated with as much as a 7% incidence of hyperplastic polyps. These data may reflect a link between hyperplastic polyps and gastritis, the frequent use of proton pump inhibitors in chronic gastritis, and an association between proton pump inhibitors and fundic gland polyps.

Grossly, hyperplastic polyps are typically ovoid and contain a smooth surface contour, although villiform or pedunculated polyps may develop ( Fig. 20.1, A ). Surface erosion is often seen. Rarely, patients may have more than 50 polyps, in which case a diagnosis of gastric hyperplastic polyposis should be considered, although specific diagnostic criteria for this syndrome have not been well established. In this situation, pathologists should obtain further clinical and endoscopic information to rule out another type of polyposis disorder, such as juvenile polyposis, Peutz-Jeghers syndrome, or familial adenomatous polyposis (FAP).

Gastric hyperplastic polyps. A, This typical sessile hyperplastic polyp is covered by normal-appearing mucosa. B, The polyp is composed of elongated, tortuous, and hyperplastic foveolar epithelium with cystic changes. C, The surface epithelium is hyperplastic and can include dystrophic goblet cells, which may give a false appearance of signet ring cell carcinoma in situ. D, A minor amount of muscularis hyperplasia can be seen in the lamina propria, particularly surrounding cystically dilated glands. E, Focal ulceration can occur in hyperplastic polyps. F, Proliferating capillaries, which can give the impression of a vascular lesion, can accumulate beneath ulcerated sites. G, A marked pseudosarcomatous proliferation of reactive fibroblasts and endothelial cells can be seen in the granulation tissue.

Microscopically, hyperplastic polyps are characterized by architecturally distorted, irregular, cystically dilated, and elongated foveolar epithelium (see Fig. 20.1, B ). Intestinal metaplasia (i.e., goblet cells) may be identified, particularly in polyps located at the gastroesophageal junction and associated with Barrett’s esophagus. Crowding of cells and infolding of the epithelium often impart a corkscrew appearance. Foveolar cells typically have abundant mucinous cytoplasm, but they may be mucin depleted focally and contain slightly enlarged and hyperchromatic nuclei with prominent nucleoli, which are considered to be regenerative features. Mitotic activity may be brisk in areas of active inflammation and surface ulceration.

Pseudogoblet or globoid mucinous cells, which are frequently seen, are cells that contain apically located nuclei and basally oriented mucous vacuoles (see Fig. 20.1, C ). These cells were considered to be dysplastic before they were recognized as a reactive change. Therefore, previously used term globoid dysplasia has been discarded in favor of the more descriptive term dystrophic goblet cell . Intestinal metaplasia is identified in less than 25% of hyperplastic polyps and, paradoxically, is more often seen in the surrounding nonpolypoid mucosa than in the polyp itself. The lamina propria of hyperplastic polyps is typically edematous and congested, with various degrees of acute and chronic inflammation and smooth muscle consistent with prolapse (see Fig. 20.1, D ). The inflammatory infiltrate is usually most prominent in the superficial aspects of the polyp and is often associated with surface erosions (see Fig. 20.1, E ). In rare cases, granulation tissue associated with ulcerations (see Fig. 20.1, F ) may show marked atypical pseudosarcomatous changes in reactive stromal fibroblasts and endothelial cells (see Fig. 20.1, G ).

Nodular lymphoid aggregates, with or without germinal centers, may be seen in gastric hyperplastic polyps. Most well-developed hyperplastic polyps also contain thick or thin, wispy bundles of smooth muscle that extend upward from the muscularis mucosae toward the polyp surface and have large, thick-walled blood vessels at the base of the polyp, which may indicate prolapse as a pathogenic factor. These polyps tend to occur in the antral or prepyloric region of the stomach. As noted above, H. pylori infection is common, and organisms are found in as many as 76% of hyperplastic polyps.

Differential Diagnosis

The differential diagnosis of gastric hyperplastic polyps includes polypoid gastritis, polypoid foveolar hyperplasia, gastritis cystica polyposa or profunda, fundic gland polyps, polyps associated with Ménétrier disease, Cronkhite-Canada syndrome, juvenile polyposis, and Peutz-Jeghers polyposis. Features helpful in determining the correct diagnosis are summarized in Table 20.1 . Polyps in patients with polypoid gastritis and polypoid foveolar hyperplasia are typically smaller than hyperplastic polyps, and they lack cystically dilated, irregular, and tortuous foveolar epithelium. The lamina propria of polypoid foveolar hyperplasia contains less inflammation and lacks smooth muscle hyperplasia.

Gastritis cystica polyposa or profunda is closely related to hyperplastic polyps in its pathogenesis and morphologic appearance (see Gastritis Cystica Polyposa or Profunda ). The surface and intraluminal portions of these lesions may be identical. However, unlike hyperplastic polyps, gastritis cystica polyposa is characterized by cystically dilated, distorted, and irregularly shaped glands or acellular mucin pools located in the muscularis mucosae or the submucosa. Polyps related to gastritis cystica polyposa often develop adjacent to anastamotic sites in patients who have had a partial gastrectomy.

In contrast to hyperplastic polyps, fundic gland polyps show surface and foveolar hypoplasia and contain cystically dilated glands lined predominantly by parietal and chief cells. Occasional cysts may contain mucous cells. Fundic gland polyps do not normally contain prominent inflammation, ulceration, or marked regenerative changes typical of hyperplastic polyps.

Polyps associated with Ménétrier disease, Cronkhite-Canada syndrome, and juvenile polyps are histologically similar to hyperplastic polyps. Appropriate clinical and endoscopic information is essential to establish a correct diagnosis.

Examination of Peutz-Jeghers polyps of the stomach may reveal a characteristic arborizing pattern of smooth muscle that is more extensive than that of hyperplastic polyps. Peutz-Jeghers polyps also lack significant stromal inflammation and are usually not associated with underlying chronic gastritis. However, other features of Peutz-Jeghers polyps are similar to those of hyperplastic polyps.

Natural History and Treatment

The natural history of hyperplastic polyps is poorly understood, but some data suggest that as many as 67% remain stable, 27% may enlarge, and 5% shrink with time. Recurrent polyps develop in as many as 50% of patients after endoscopic resection. Conversely, regression of hyperplastic polyps has been documented in as many as 71% of patients with H. pylori infection after eradication of the bacteria. Because of the risk of dysplasia in larger polyps, resection is recommended for all polyps greater than 1.5 cm in the largest dimension.

Polypoid Foveolar Hyperplasia

Polypoid foveolar hyperplasia is regarded as a precursor of hyperplastic polyps. Similar to hyperplastic polyps, polypoid foveolar hyperplasia is a regenerative lesion associated with chronic gastritis and with other types of acute and chronic mucosal injury. For example, polypoid foveolar hyperplasia often develops at the mucosal edges of surface erosions, ulcers, and carcinomas or adjacent to gastrojejunostomy stomas. It may also be associated with the use of nonsteroidal antiinflammatory drugs, bile reflux, alcohol use, or cytomegalovirus infection. Polypoid foveolar hyperplasia may remain stable in size, regress, or grow. The proportion of these lesions that ultimately progress to hyperplastic polyps is unknown.

Grossly, polypoid foveolar hyperplasia usually appears as a sessile lesion that is 1 to 2 mm in diameter. Lesions may be single or multiple and are most often found in the antrum. Microscopically, polypoid foveolar hyperplasia is characterized by simple hyperplasia of the gastric foveolar epithelium without cystic change or significant distortion. The foveolar epithelium is increased in length, and luminal serration imparts a corkscrew-like pattern ( Fig. 20.4 ). The foveolae are typically crowded and tightly packed, containing little intervening stroma. The epithelium is often mucin depleted and reactive in appearance, with mitotic figures, enlarged nuclei, and prominent nucleoli. Various degrees of intestinal metaplasia may be seen. Examination of the lamina propria may reveal a mild lymphoplasmacytic infiltrate, but smooth muscle proliferation is typically absent unless there is associated bile reflux.

Polypoid foveolar hyperplasia. A, In contrast to hyperplastic polyps, polypoid foveolar hyperplasia shows elongated, hyperplastic, and tortuous foveolar epithelium without significant cystic change or increased inflammation in the lamina propria. B, The villiform surface that predominates in this case of foveolar hyperplasia can be mistaken for Ménétrier disease (see Fig. 20.7, A and B ). Clinical correlation is essential for avoiding this error. C, Corkscrew architecture and mucin depletion are typical of foveolar hyperplasia. In this patient, polypoid foveolar hyperplasia is associated with chronic bile reflux. D, Nuclear hyperchromasia is common in hyperplastic foveolar epithelium.

Gastric Foveolar Polyps

Gastric foveolar polyps were originally described by Goldman and Appelman in 1972. It is unclear whether they represent regenerative lesions, a subtype of hyperplastic polyp, or a hamartomatous proliferation. Some lesions resemble pyloric gland adenomas. A foveolar polyp is not universally accepted as a separate polyp type, perhaps because foveolar hyperplasia occurs so frequently in other reactive lesions.

Foveolar polyps are found primarily in the antrum and are usually smaller than 2 cm in diameter. However, some can reach sizes of as great as 8 cm. They are composed of densely packed foveolar mucinous epithelium that forms an arborizing network. Intestinal metaplasia is observed in approximately 33% of cases. Inflammation is conspicuously absent. Of the eight patients originally described, one had coexisting gastric carcinoma and a second had colonic carcinoma. Other rare reports of dysplasia do exist, but foveolar polyps are not thought to be associated with an increased risk of malignancy. Foveolar polyps can be differentiated from hyperplastic polyps and polypoid foveolar hyperplasia by the absence of an inflammatory infiltrate and cystic change.

Gastritis Cystica Polyposa or Profunda

Gastritis cystica polyposa or profunda is defined as a hyperplastic polyp that contains foci of misplaced foveolar or glandular epithelium, or both, in the muscularis mucosae or in deeper portions of the submucosa, muscularis propria, or serosa. The lesion is referred to as polyposa when an intraluminal polyp is identified and as profunda when the bulk of the lesion is located in the wall of the stomach; both forms may result in gastric bleeding.

Although these lesions may develop in surgically naive stomachs, they more often occur in patients with partial gastrectomy-induced chronic bile reflux or surgical or endoscopic manipulation. Gastritis cystica polyposa can be referred to as stromal polypoid hypertrophic gastritis when it occurs in a postoperative gastric remnant. Because of the association with chronic gastritis and partial gastrectomy, it is presumed that gastritis cystica polyposa or profunda is caused by an exuberant reactive proliferation with trauma-induced entrapment of epithelium in deep portions of the gastric wall. However, the reasons for the development of epithelial cysts in deeper portions of the gastric wall are not clear. Some have suggested that local ischemia and mucosal prolapse are critical to the development of submucosal or mural cysts.

Pathologically, polyps of gastritis cystica polyposa or profunda are usually located on the gastric side of gastroenteric anastomoses. Rarely, they develop on a background of chronic gastritis and are grossly indistinguishable from hyperplastic polyps. Lesions may reach as great as 3 cm in diameter and are often associated with enlarged rugal folds. The characteristic histologic feature is entrapped epithelium or glands in or beneath the muscularis mucosae of the polyp ( Fig. 20.5 ). The epithelium may be mucinous or glandular, is often cystic, and is usually surrounded by a rim of lamina propria–like stroma. The cysts are usually entrapped in dense, disorganized bundles of smooth muscle that extend downward from the muscularis mucosae. Marked hyperplasia, reactive changes, and mucin depletion impart an atrophic appearance to the epithelium. An associated inflammatory infiltrate, composed of neutrophils and mononuclear cells, may be found in the lamina propria. Superficial erosion and intestinal metaplasia may also occur. Dysplasia and cancer rarely develop in association with gastritis cystica polyposa or profunda, and it is unclear whether the frequency of occurrence is equal to or greater than that of ordinary hyperplastic polyps.

Gastritis cystica polyposa or profunda. A, The submucosa is replaced by multiple cysts in this case of gastritis cystica profunda. B, The mucosa displays features of hyperplastic polyps but also shows a proliferation of cystic glands within the muscularis mucosae and submucosa. C, At high power, the misplaced glands show a lobular configuration and are composed of cells with basally located nuclei. A thin rim of lamina propria surrounds the glands. D, In places, the deep glands can mimic invasive adenocarcinoma. The absence of cytologic atypia and lack of desmoplasia are helpful in making this distinction (see Fig. 20.6, B ).

It is sometimes difficult to distinguish misplaced epithelium in gastritis cystica polyposa or profunda from a well-differentiated invasive adenocarcinoma ( Fig. 20.6 ). Features such as desmoplasia, cytologic pleomorphism, irregularity in the size and shape of the glands, atypical mitoses, and lack of a lamina propria rim surrounding the epithelium favor a diagnosis of adenocarcinoma ( Table 20.3 ).

Well-differentiated adenocarcinoma associated with chronic gastritis. A, In contrast to misplaced glands in gastritis cystica polyposa or profunda, carcinomatous glands are highly irregular in size and shape, have jagged edges, and are arranged in a haphazard nonlobular fashion. B, At high power, malignant glands show cytologic atypia, loss of polarity, and hyperchromasia. Most importantly, in place of a rim of lamina propria, invasive glands are surrounded by desmoplasia.

Clinical Features

Ménétrier disease is a rare disorder characterized by diffuse hyperplasia of the foveolar epithelium of the body and fundus combined with hypoproteinemia resulting from protein-losing enteropathy. Other symptoms include weight loss, diarrhea, and peripheral edema. In rare (mostly pediatric) cases, the antrum may be involved. In adults, onset typically occurs between 30 and 60 years of age, with a male-to-female ratio of 3 to 1.

Although the clinical and pathologic features of Ménétrier disease in children are similar to those in adults, many children have a history of recent respiratory infection, peripheral blood eosinophilia, and cytomegalovirus infection. The disease is usually self-limited in children, lasting only several weeks. In contrast, adult Ménétrier disease is unlikely to regress.

Pathogenesis

Ménétrier disease is a form of hyperplastic gastropathy that in many cases is driven by excessive secretion of transforming growth factor-α (TGF-α). In children, some cases are associated with cytomegalovirus or other types of infections. In these cases, spontaneous and treatment-associated remissions may occur. Although H. pylori infection and various other conditions have been associated with Ménétrier disease in adults, antibiotics, acid suppression, octreotide, and anticholinergic agents have had therapeutic benefit in rare adult patients. In contrast, inhibition of TGF-α signaling has been effective in some cases.

Pathologic Features

On endoscopic examination, Ménétrier disease is characterized by diffuse, irregular enlargement of the gastric rugae. However, some areas may appear polypoid. Enlarged rugae typically involve the body and fundus, but they may also involve the antrum, particularly in children. Histologically, the most characteristic feature of Ménétrier disease is foveolar (mucous cell) hyperplasia ( Fig. 20.7 ). The foveolae are elongated and have a corkscrew appearance. Cystic dilation is also common. Hyperplastic mucous cells are typically fully differentiated without regenerative features or mucin depletion. Inflammation is usually only modest, and ulceration is not normally identified. Intestinal metaplasia is usually absent. Some cases show marked intraepithelial lymphocytosis. Diffuse or patchy glandular atrophy and hypoplasia of parietal and chief cells are also characteristic features of Ménétrier disease.

Ménétrier disease. A, At low power, a biopsy from Ménétrier disease may look histologically similar to a hyperplastic polyp because it is composed of irregular, tortuous, cystically dilated, and elongated foveolar epithelium. B, A biopsy from a patient with Ménétrier disease may look histologically similar to the surface of a hyperplastic polyp or foveolar hyperplasia. C, In areas, the mucosa can be replaced by epithelial cysts. The absence of submucosal involvement can differentiate Ménétrier disease from gastritis cystica polyposa or profunda. D, In some cases of Ménétrier disease, a marked degree of intraepithelial lymphocytosis simulates lymphocytic gastritis. E, Although not commonly identified, a cytomegalovirus infection should be considered in pediatric cases of Ménétrier disease.

A diagnosis of Ménétrier disease may be difficult to establish on analysis of mucosal biopsies alone because some of the histologic features mimic hyperplastic polyps. Clinical information is essential to establish a correct diagnosis. Ménétrier disease must be distinguished from other causes of enlarged gastric rugae, such as robust chronic gastritis, Zollinger-Ellison syndrome, and infiltration by tumor cells, such as lymphoma. Most of these other entities are easily distinguished histologically. For example, chronic gastritis shows abundant inflammation in the lamina propria without marked foveolar hyperplasia. The absence of foveolar hyperplasia and the presence of parietal cell hyperplasia in Zollinger-Ellison syndrome help to distinguish this lesion from Ménétrier disease. Lymphoma and other infiltrating tumors may mimic Ménétrier disease grossly, but biopsies are typically diagnostic.

Treatment

In the past, the treatment of Ménétrier disease was mainly supportive and provided in the form of serum albumin and nutritional supplementation. In severe cases, gastrectomy was and often still is necessary. However, studies have shown remarkable efficacy of treatment with a monoclonal antibody against the epidermal growth factor receptor, which is also a TGF-α receptor. These successes have been replicated in many patients. These outcomes validate the pivotal role of TGF-α in the pathogenesis of Ménétrier disease and demonstrate the potential of this mechanistic approach of targeted biologic therapy.

Clinical Features and Pathogenesis

Fundic gland polyps may be sporadic or familial. They were originally reported as a manifestation of FAP. These polyps are now recognized as one of the most common types of gastric polyps. The apparent increase in incidence may reflect the widespread and increasing use of proton pump inhibitors, which have been strongly implicated in sporadic fundic gland polyp pathogenesis. In one series, fundic gland polyps were more common than hyperplastic polyps and represented the most common type of gastric polyp (77% of all gastric polyps).

Detection of fundic gland polyps in children should always prompt consideration of FAP. In addition, up to half of fundic gland polyps are associated with symptoms of gastroesophageal reflux. Fundic gland polyps occur more often in women, with an average age of 50 to 60 years at diagnosis. Fundic gland polyps may also develop in patients with Zollinger-Ellison syndrome. As many as 90% of patients with FAP have fundic gland polyps within the oxyntic mucosa.

The contrasting natural histories and biologic features of sporadic and FAP-associated fundic gland polyps are discussed later. In molecular terms, FAP-associated polyps usually have adenomatous polyposis coli (APC) gene mutations and less frequently demonstrate mutations in the gene for β-catenin (CTNNB1) , another component of the APC signaling pathway ( Table 20.4 ). Conversely, sporadic fundic gland polyps are associated with activating CTNNB1 mutations in more than 90% of cases but show APC gene mutations in less than 10% of cases. Tumor suppressor gene methylation occurs more commonly in sporadic than FAP-associated fundic gland polyps, but the presence or absence of tumor suppressor gene methylation is not specifically associated with the development of dysplasia in these lesions. Although it remains controversial whether H. pylori can induce fundic gland polyp regression, it is true that H. pylori infection is uncommon in patients with fundic gland polyps.

Pathologic Features

Fundic gland polyps are smooth, sessile, well-circumscribed lesions that occur exclusively in gastric oxyntic mucosa. They may be single or multiple, particularly in FAP patients. When multiple in patients with FAP, the term fundic gland polyposis may be used. One study of FAP-associated fundic gland polyps found an average of four polyps per patient, with a range of 1 to 11. Fundic gland polyps are most often smaller than 1.0 cm in diameter, but lesions as large as 2 to 3 cm have been reported.

Histologically, fundic gland polyps are composed of cystically dilated and architecturally irregular fundic glands ( Fig. 20.10 ). Fundic glands, which often assume a microcystic configuration or show prominent budding, are lined by flattened parietal and chief cells and occasional mucinous foveolar cells. Inflammation is typically absent or minimal. The surface and foveolar epithelium in fundic gland polyps are atrophic.

Fundic gland polyps. A, Endoscopic view shows an unusual case of a patient with numerous fundic gland polyps. The patient was not known to have familial adenomatous polyposis and did not have colonic polyps. B and C, Microscopic views show that in contrast to hyperplastic polyps, fundic gland polyps have atrophic foveolar epithelium and a marked increase in the number of oxyntic glands, some with irregular budding, and microcystic changes. At high power ( C ), the microcysts are lined by parietal and chief cells, endocrine cells, and variable numbers of mucinous columnar cells. The degree of inflammation in the lamina propria is typically minimal. D and E, Parietal cell hyperplasia and cysts lined exclusively by parietal cells ( E ) are not typical of fundic gland polyps. The differential diagnosis in this case included Zollinger-Ellison syndrome.

Natural History and Treatment

Sporadic fundic gland polyps are considered benign lesions with almost no malignant potential. Dysplasia occurs in less than 1% of these lesions. In contrast, dysplasia may be present in as many as 48% of FAP-associated fundic gland polyps. When present, dysplasia is usually low-grade. High-grade dysplasia has been reported only in a single sporadic fundic gland polyp, but the prevalence of high-grade dysplasia in FAP-associated lesions ranges from 0% to 12.5%. Similar to dysplasia in adenomas and hyperplastic polyps, analysis of dysplasia in fundic gland polyps usually reveals intestinal-type differentiation characterized by elongated hyperchromatic nuclei, an increased nucleus-to-cytoplasm ratio, and nuclear pseudostratification that extends to the surface of the polyp ( Fig. 20.11 ).

Dysplasia arising in a fundic gland polyp associated with familial adenomatous polyposis (FAP). A, Hyperchromasia of the surface epithelium is apparent at low power. The presence of dysplasia is almost pathognomonic for a syndromic (FAP-associated) fundic gland polyp. B, The dysplastic epithelium shows a proliferation of cells containing hyperchromatic, pencil-shaped nuclei with clumped chromatin, pseudostratification, and increased mitoses. Dysplastic epithelium may be seen in the glandular or surface compartment of the polyps.

When hyperchromaticity and nuclear enlargement are limited to the proliferative zones of the polyp, particularly in the setting of active inflammation, regenerative atypia should be considered. The risk of malignant transformation is rare, and the few cases of adenocarcinoma have all been reported for FAP patients.

All dysplastic fundic gland polyps should be completely resected. Although formal surveillance guidelines have not been established, the data suggest that surveillance of FAP patients for dysplastic fundic gland polyps should be considered on an individual basis. Surveillance for duodenal adenomas, particularly periampullary lesions, and less common gastric adenomas may also be performed.

Clinical Features and Pathogenesis

Peutz-Jeghers syndrome is an autosomal dominant syndrome characterized by the presence of mucocutaneous pigmentation and multiple GI hamartomatous polyps. The disease occurs equally in men and women. Patients usually are diagnosed in the second or third decade of life and have abdominal pain, GI bleeding, or less commonly, obstruction.

Hamartomatous polyps in Peutz-Jeghers syndrome may occur in any portion of the GI tract, but they are most common in the small intestine. Gastric lesions occur in 25% to 50% of patients. Because of their small size, gastric Peutz-Jeghers polyps are usually asymptomatic. Morphologically identical polyps can occur in McCune-Albright syndrome, which is caused by somatic activating mutations in the GNAS gene.

Most cases of Peutz-Jeghers syndrome are caused by a germline mutation of the serine-threonine kinase STK11/LKB1 tumor suppressor gene. The function of this gene product is not entirely understood, but it is an important component of adenosine monophosphate (AMP) kinase/mTOR and transforming growth factor-β (TGF-β) signal transduction pathways. Tuberous sclerosis genes TSC1 and TSC2 are also downstream effectors of STK11/LKB1 . Some of these signaling events may take place in mesenchymal rather than in epithelial, cells, which is consistent with reports of wnt5a signaling defects in Peutz-Jeghers syndrome.

Dysplasia and carcinoma are rare in gastric polyps, with an estimated incidence of 2% to 3%. However, they may develop at a young age. For example, in one series of Peutz-Jeghers syndrome patients with gastric cancer, carcinoma developed at a mean patient age of 27 years.

Lkb1 -knockout mice develop GI hamartomatous polyposis similar to that in Peutz-Jeghers syndrome. These mice represent a unique opportunity to investigate new therapeutic agents, such as specific kinase inhibitors. For example, some studies of Lkb1 heterozygous mice and patients with Peutz-Jeghers syndrome suggests that cyclooxygenase-2 inhibition may ultimately prove beneficial in chemoprevention of polyposis.

Pathologic Features

Peutz-Jeghers polyps may be sessile, but they are more commonly pedunculated and are usually less than 1 cm in the largest dimension. Rarely, larger lesions may develop. The gross appearance is similar to Peutz-Jeghers polyps in other portions of the GI tract, and they often have a velvety papillary or villiform surface. They occur most commonly in the antrum but may develop in any part of the stomach.

Microscopically, gastric Peutz-Jeghers polyps have a complex, arborizing architecture. Irregular bundles of smooth muscle extend from the muscularis mucosae into the lamina propria of the papillary projections and extend to the polyp surface ( Fig. 20.12 ). Marked surface and foveolar hyperplasia with cystic change is often identified. Glandular atrophy is common, and a mild degree of lamina propria edema, congestion, and inflammation may also be apparent. The morphologic features are essentially similar to those of gastric hyperplastic polyps, with the exception that hamartomatous polyps often have a more fully developed and prominent smooth muscle component. However, gastric Peutz-Jeghers polyps are defective in glandular differentiation. For polyps occurring in oxyntic mucosa, this can be recognized by a paucity of parietal cells.

Gastric Peutz-Jeghers polyp. A, The low-power appearance of a Peutz-Jeghers polyp is similar to that of a hyperplastic polyp. It is composed of an irregular and architecturally distorted proliferation of foveolar epithelium with increased inflammation in the lamina propria. The cyst surrounded by arc-shaped glands in the center of the field is typical, although not diagnostic, of Peutz-Jeghers–associated polyps B, This Peutz-Jeghers polyp shows more prominent infiltration of the muscularis.

Although gastric Peutz-Jeghers polyps are usually clinically silent, they can lead to intussusception. There are also rare examples of patients who have vomited large polyps, presumably as a result of autoamputation. Dysplasia can occur in Peutz-Jeghers polyps ( Fig. 20.13 ), but this is uncommon in gastric lesions. There is no consensus on appropriate surveillance or follow-up of gastric Peutz-Jeghers polyps with or without dysplasia, although general guidelines have been proposed.

Dysplasia in Peutz-Jeghers polyps. A, Note the villiform architecture, smooth muscle infiltration, and irregularly shaped glands in this hamartomatous polyp. Even at low power, the absence of epithelial surface maturation is apparent. B and C, Higher-power views show nuclear elongation, stratification, and hyperchromasia in superficial and deep foveolar cells.

Clinical Features and Pathogenesis

Sporadic gastric juvenile polyps are rare. They may occur as part of generalized juvenile polyposis coli or as part of the rare gastric subtype of this syndrome. Gastric juvenile polyps occur in 15% to 25% of patients with generalized juvenile polyposis coli. Between 20% and 50% of patients with gastric juvenile polyps have a positive family history for juvenile polyposis coli, an autosomal dominant condition characterized by a genetic dysregulation of the TGF-β pathway. The mutation most commonly identified involves the SMAD4/DPC4 gene, which encodes a cytoplasmic intermediate in TGF-β signaling. However, this mutation occurs in only a minority of cases. Possible gene candidates include PTEN , which is mutated in Cowden syndrome.

Pathologic Features

The gross and microscopic features of gastric juvenile polyps resemble those of gastric hyperplastic polyps ( Fig. 20.14 ). In some instances, juvenile polyps may show a less pronounced degree of muscularis hyperplasia and a more prominently inflamed lamina propria than hyperplastic polyps. However, because of significant overlap, this feature particularly is not helpful. The essential features of juvenile polyps include surface and foveolar hyperplasia, cystic change, edema and inflammation of the lamina propria, smooth muscle hyperplasia, and some degree of intestinal metaplasia. The polyps may range from a few millimeters to several centimeters in diameter. Based on histology alone, it is not possible to reliably distinguish an isolated gastric juvenile polyp from a hyperplastic polyp, and knowledge of the clinical context, including the family history, is essential in establishing a correct diagnosis.

Gastric juvenile polyposis. A, Similar to hyperplastic polyps and Peutz-Jeghers polyps, juvenile polyps are composed of irregular, dilated, and villiform structures. This polyp occurred in a patient with juvenile polyposis coli. B, Notice the lobular organization of epithelial structures in this hamartomatous polyp. C, Epithelial foveolar hyperplasia is typical. D, The lamina propria is expanded by inflammation. E, Low-grade dysplasia ( left ) arises in a gastric juvenile polyp.

Dysplasia and carcinoma occur with increased frequency among patients with generalized juvenile polyposis coli (see Fig. 20.14, E ). Dysplasia in juvenile polyps appears histologically similar to that in hyperplastic polyps and is mostly of the intestinal type. It is characterized by mucin-depleted surface and foveolar epithelium; hyperchromatic, elongated nuclei with clumped chromatin; an increased nucleus-to-cytoplasm ratio; a loss of polarity; and pseudostratification. Lack of surface maturation is typical of dysplasia. With increasing degrees of dysplasia, the nuclei become larger and show a greater degree of overlapping and loss of polarity, and the glands may take on a back-to-back or cribriform growth pattern.

Clinical Features

Cronkhite-Canada syndrome is a rare, nonhereditary generalized polyposis disorder. L. W. Cronkhite and W.  J. Canada described the first two cases in 1955. The disease involves the stomach, small intestine, and colorectum but spares the esophagus. Unlike most syndromic polyposis disorders, Cronkhite-Canada syndrome typically appears in middle adulthood, with a mean age of onset at 59 years. Europeans and Asians are affected most often, and it occurs equally in men and women.

In addition to numerous GI polyps, patients with this disorder have alopecia, nail atrophy, skin hyperpigmentation, and vitiligo. Common GI complaints include diarrhea, weight loss, abdominal pain, anorexia, weakness, and hematochezia. The efficacy of corticosteroids for induction of remission and azathioprine for maintenance in some patients and positive immunoglobulin G4 (IgG4) staining of as many as 50% of Cronkhite-Canada syndrome polyps but not on other tissues have led some authorities to propose an autoimmune basis for this disorder. However, the cause of Cronkhite-Canada syndrome remains unknown.

Cronkhite-Canada syndrome is associated with a mortality rate of approximately 50%; most deaths are related to anemia and chronic wasting. Optimal therapy has not been established, but treatment options include nutritional support, antibiotics, corticosteroids, anabolic steroids, histamine receptor antagonists, and surgery, depending on the particular circumstances of the patient. Controlled therapeutic trials have not been reported. Up to 20% of patients with Cronkhite-Canada syndrome develop adenocarcinoma, which may occur in any portion of the GI tract, including the stomach. Although cancers may develop in polyps or nonpolypoid mucosa, the malignant potential of the polyps themselves remains largely unknown.

Pathologic Features

Advanced cases of Cronkhite-Canada syndrome show diffuse, irregular enlargement of the gastric rugae throughout the fundus and antrum. Numerous small to medium-sized polyps that typically measure between 0.5 and 1.5 cm in diameter may be superimposed on enlarged rugae ( Fig. 20.15, A ). The endoscopic appearance is similar to that of Ménétrier disease, except that the entire stomach is involved. Individual polyps may appear as elongated, papillary or villiform lesions or, alternatively, as clusters of sessile nodules, which can help in the diagnosis of Cronkhite-Canada syndrome.

Cronkhite-Canada syndrome. A, In the resected stomach of a patient with Cronkhite-Canada syndrome, the fundus and the antrum show a carpet-like proliferation of small polyps and enlarged rugae. B, The polypoid and the interpolypoid mucosa show elongated, tortuous, and cystically dilated foveolar epithelium and edema and hemorrhage in the lamina propria. In contrast to hyperplastic polyps, Cronkhite-Canada syndrome–associated polyps typically do not show prominent inflammation or muscularis hyperplasia.

Microscopically, changes in the stomach involve the interpolypoid and polypoid mucosa (see Fig. 20.15, B ). As in Ménétrier disease, marked surface and foveolar hyperplasia with cystic change and atrophy of the glands are characteristic features. The lamina propria is often edematous and shows a mild to moderate degree of inflammation, but intestinal metaplasia is uncommon. The surrounding nonpolypoid mucosa shows alternating areas of atrophy and foveolar hyperplasia with microcystic changes. Unfortunately, a single biopsy from a Cronkhite-Canada syndrome–associated polyp may appear histologically identical to a juvenile polyp, hyperplastic polyp, or Ménétrier disease. However, knowledge of other clinical features of this disorder, particularly when combined with diffuse enlargement of gastric rugae and multiple polyps in all areas of the stomach, is helpful in establishing a correct diagnosis.

Clinical Features

Ectopic rests of pancreatic tissue may develop in several parts of the upper GI tract when fragments of pancreas separate during embryonic rotation of the foregut. Foci of ectopic or heterotopic pancreatic tissue are most commonly found in the stomach, but they may also occur in the small intestine and colon. Between 0.1% and 4% of all gastric polyps have been reported to represent pancreatic heterotopia. Men and women are affected equally, and the average age at diagnosis is 45 years. However, pediatric patients also may be affected.

Heterotopic pancreatic tissue is susceptible to many of the same inflammatory disorders that affect the native pancreas, including acute and chronic pancreatitis and cancer. Although pancreatic adenocarcinoma in ectopic pancreas is extremely uncommon, patients with adenocarcinoma of the pancreas and ectopic pancreas usually have pancreatic intraepithelial neoplasia within the focus of the ectopic pancreas. Some cases may have elevated serum pancreatic enzyme levels.

Pathologic Features

Pancreatic heterotopia most commonly occurs in the prepyloric and antral regions of the stomach, but it may rarely occur in the corpus. The lesions usually are less than 3 cm in diameter. Grossly, they consist of small submucosal nodules that protrude through the mucosa, often forming a central dimple or surface erosion, which represents a draining pancreatic duct. This finding offers an endoscopic clue to the diagnosis. Alternatively, pancreatic heterotopia can form a submucosal mass that can easily be mistaken for a well-differentiated neuroendocrine (carcinoid) tumor, well-differentiated tubular adenocarcinoma, or gastrointestinal stromal tumor (GIST). Ulceration and bleeding are common. Gastric heterotopic pancreas is frequently asymptomatic. Clinical symptoms are related to the location and size of the lesion and to the presence or absence of ulceration and bleeding.

Microscopically, heterotopic pancreatic tissue may be composed of any one or combination of the three normal components of pancreatic parenchyma (i.e., ducts, acini, and islets). Exocrine (acinar tissue), endocrine (islet cells), and epithelial (ducts) elements in combination with pancreatic stroma may be found in various proportions. Some have proposed a classification in which type I pancreatic heterotopia includes acini, ducts, and islets; type II has only two of these elements, and type III has only one element. Histologically, each component of a heterotopic pancreas is similar to that which occurs in the normal pancreas ( Fig. 20.16 ). Morphologically similar lesions develop in knockout mice that lack Hes1, a basic helix-loop-helix transcription factor required for differentiation of secretory, endocrine, and Paneth cell lineages in the small intestine.

Pancreatic heterotopia. A, The low-power appearance suggests a nodule of pancreas within the submucosa. B, Pancreatic heterotopia can include ducts, acinar glands, and islets. C, This adenomyoma is composed only of ducts and smooth muscle.

Acini within heterotopic pancreatic tissue typically drain into ducts lined by tall columnar epithelium. However, squamous metaplasia is occasionally identified. Thick, disorganized bundles of hyperplastic smooth muscle are often admixed with acini and ducts. When only smooth muscle and ducts are present, the lesion may be referred to as an adenomyoma . Endocrine elements, representing islets of Langerhans, are found in less than 50% of cases. Acute and chronic inflammation and necrosis, resembling acute and chronic pancreatitis of the native pancreas, may be seen. Gastric mucosa overlying the heterotopic pancreas often shows reactive changes, including foveolar hyperplasia, and has various degrees of edema, congestion, and inflammation.

Differential Diagnosis

The differential diagnosis of pancreatic heterotopia includes well-differentiated adenocarcinoma, gastritis cystica polyposa or profunda, and pancreatic acinar metaplasia. Pancreatic acinar metaplasia is far more common than pancreatic heterotopia and does not contain ducts, stroma, smooth muscle, or endocrine cells. Distinguishing well-differentiated adenocarcinoma, gastritis cystica polyposa or profunda, and heterotopic pancreatic tissue, particularly heterotopic foci associated with pancreatic intraepithelial neoplasia, may be difficult if pancreatic acini and endocrine cells are not readily identifiable. However, most examples of pancreatic heterotopia lack architectural and cytologic atypia, atypical mitoses, and other features of malignancy that are common in well-differentiated carcinomas. In contrast to carcinoma, the ducts in pancreatic heterotopia normally grow in an organoid or lobular growth pattern. The duct profiles are smooth rather than irregular or jagged. The smooth muscle hyperplasia often associated with pancreatic heterotopia contrasts sharply with the desmoplasia often associated with invasive carcinoma.

Gastritis cystica polyposa or profunda may resemble pancreatic heterotopia, but the former is associated with mucosal hyperplastic changes, inflammation, and erosions. The submucosal epithelium of gastritis cystica polyposa or profunda is composed of mucinous columnar epithelium with or without gastric glands, which contrasts with the pancreatic duct–type epithelium that is characteristic of pancreatic heterotopia.

Clinical Features

Pancreatic acinar metaplasia may occur in children or adults. It is identified in as many as 25% of gastric biopsies from adults. The mean age at which pancreatic acinar metaplasia is detected is 55 years, although patients of all ages may be affected. There is no gender preference.

Pancreatic acinar metaplasia occurs most often in antral and cardiac (i.e., gastroesophageal junction) mucosa, typically on a background of little or no inflammation and often without glandular atrophy or intestinal metaplasia. However, pancreatic acinar metaplasia in the corpus should prompt consideration of autoimmune gastritis. Pancreatic acinar metaplasia has been associated with H. pylori infection, chronic gastritis, gastroesophageal reflux (when located near the gastroesophageal junction), and gastric adenocarcinoma. These associations do not necessarily hold true for pancreatic acinar metaplasia located above the gastroesophageal junction.

Although the cause of pancreatic acinar metaplasia is unknown, it has been suggested that it represents a congenital rest, particularly for lesions that occur at the gastroesophageal junction. It may also be a type of metaplasia that develops in chronic gastritis.

Pathologic Features

Pancreatic acinar–like cells are characterized by fine acidophilic granules in the apical cytoplasm and prominent basophilia of the basal portion of the cells. The cells are usually arranged in small nests or lobules, often in continuity with the surrounding gastric glands ( Fig. 20.17 ). Alternatively, lobules of pancreatic acinar cells may be separated from the surrounding gastric mucosa by connective tissue and smooth muscle.

Only gold members can continue reading. Log In or Register to continue

Share this:

• Click to share on Twitter (Opens in new window)
• Click to share on Facebook (Opens in new window)

Related posts:

Systemic Illnesses Involving the Gastrointestinal Tract Polyps of the Esophagus Epithelial Neoplasms of the Stomach Polyps of the Small Intestine Molecular Pathogenesis and Diagnostics of Hepatocellular Tumors Toxin- and Drug-Induced Disorders of the Liver

Stay updated, free articles. Join our Telegram channel

Join