Polyps of the Stomach

Clinical Features and Pathogenesis

Gastric hyperplastic polyps represent an exophytic inflammatory proliferation of foveolar epithelium. Numerous synonyms, including inflammatory, regenerative, and hyperplasiogenous polyp, have been used to describe these lesions. The prevalence of hyperplastic polyps is predominantly related to the rate of Helicobacter pylori infection and to the geographic locale. Although these lesions once accounted for up to 75% of all gastric polyps, ^, in North America, gastric hyperplastic polyps now represent less than 20% of these lesions.

Hyperplastic polyps are detected most often in older individuals, with a peak incidence in the sixth and seventh decades of life and with a slight female predominance. ^, Because they most often appear in the context of chronic gastritis, hyperplastic polyps are usually associated with clinical symptoms related to the underlying chronic gastritis. However, in most cases, patients are asymptomatic. Rarely, large lesions can cause obstructive symptoms if located near the pylorus or the gastroesophageal junction. Anemia and upper GI bleeding may occur if the polyp is eroded. As noted earlier, associated H. pylori infection, and to a lesser degree autoimmune gastritis, is common.

More than 85% of hyperplastic polyps occur in patients with chronic gastritis, ^{, ,} and this has led to the hypothesis that these lesions develop as a consequence of an exaggerated mucosal response to tissue injury and inflammation. ^{, ,} It is believed that inflammation 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, eventually, the formation of a hyperplastic polyp.

Conditions associated with the development of hyperplastic polyps include H. pylori gastritis, chronic non– H. pylori gastritis including autoimmune gastritis, chemical or reactive gastropathy (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 patients with autoimmune gastritis compared with 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 these presumably developed in the context of reflux.

Finally, another study showed that up to 49% of lesions diagnosed as a hyperplastic polyps presented without a characteristic stromal edema or inflammatory changes, but with cystic glands, thickened and hyperplastic smooth muscle wisps extending toward the mucosal surface, and thick-walled blood vessels—all features similar to anorectal prolapse lesions. These polypoid lesions have been reclassified as mucosal prolapse polyps. Notably, these polyps also occurred more commonly in the antrum, or prepyloric region of the stomach, an area of heightened peristalsis.

Rarely, patients may have more than 50 polyps, in which case a diagnosis of gastric hyperplastic polyposis may be considered. However, the specific diagnostic criteria for this syndrome are not well established. To date, some 10 cases of hyperplastic polyposis have been reported with and without familiar clustering. Although the pathogenetic background has not been elucidated, an autosomal dominant inheritance pattern was noted in a family with nine cases of hyperplastic polyposis and two cases of poorly cohesive (signet ring cell) carcinoma. Of note, chronic gastritis and H. pylori infection was also recognized in most patients. Reported cases with no familiar clustering may represent exuberant sporadic hyperplastic polyps because concurrent H. pylori infection, hypergastrinemia, pernicious anemia, proton pump inhibitor therapy, or gastric antral vascular ectasia was documented in most patients. In patients with multiple polyps, other types of polyposis disorders to consider include juvenile polyposis, Peutz-Jeghers syndrome, Cowden’s syndrome, and Cronkhite-Canada syndrome (see the “Differential Diagnosis” section).

Pathological Features

Most cases measuring less than 0.5 cm in greatest dimension at the time of endoscopic sampling lack the stromal and epithelial diagnostic features of a classic hyperplastic polyp and, as a result, are reclassified as polypoid foveolar hyperplasia (see Differential Diagnosis and Table 20.1 ). At the other end of the spectrum, true hyperplastic polyps may, rarely, grow up to 12 cm in size.

Hyperplastic polyps occur most commonly in the antrum, but they can develop anywhere in the stomach. They are most often solitary lesions; however, about 20% of cases are multiple, particularly in patients with atrophic gastritis.

Endoscopically, hyperplastic polyps are typically ovoid in shape and show a smooth surface contour, although villiform or pedunculated polyps may develop as well ( Fig. 20.2A ). Surface erosion often develops as they grow in size.

Microscopically, hyperplastic polyps are characterized by the presence of architecturally distorted, irregular, cystically dilated, and elongated foveolae ( Fig. 20.2B ,C). Cellular proliferation and infoldings of the epithelium often impart a corkscrew appearance to the epithelium. Foveolar cells typically have abundant mucinous cytoplasm, but they may be mucin depleted and contain enlarged and hyperchromatic nuclei with prominent nucleoli, which are regenerative features. Mitotic activity may be brisk in areas of active inflammation and surface ulceration.

“Pseudogoblet” or “globoid” mucinous cells are common in hyperplastic polyps. These are hypertrophic foveolar cells that contain an abundance of apically located mucous vacuoles that mimic goblet cells ( Fig. 20.2D ). Both pseudogoblet and true goblet cells stain blue with Alcian blue histochemistry, however, pseudogoblet cells tend to cluster and form linear segments entirely composed of globoid cells, while true goblet cells are usually intermingled more randomly with columnar cells. These cells should not be mistaken for true intestinal metaplasia. Intestinal metaplasia (i.e., true goblet cells) is identified in less than 25% of hyperplastic polyps and, paradoxically, is more often seen in the surrounding nonpolypoid mucosa than within the polyp itself. Intestinal metaplasia is identified more frequently in polyps located at the gastroesophageal junction because it is presumed that these are associated with Barrett’s esophagus.

The lamina propria in hyperplastic polyps is typically edematous and congested, and it usually shows a variable degree of acute and chronic inflammation. Most well-developed hyperplastic polyps also contain bundles of smooth muscle that extend upward from the muscularis mucosae toward the polyp surface. As alluded to previously, some polyps demonstrate broader bands of smooth muscle and thick-walled blood vessels at the base of the polyp, which may indicate prolapse as the pathogenic factor ( Fig. 20.2E ,F). The inflammatory infiltrate in typical hyperplastic polyps is usually most prominent in the superficial aspects of the polyp and is often associated with surface erosions. Nodular lymphoid aggregates, either with or without germinal centers, may be present as well. Rarely, granulation tissue associated with ulceration may show marked atypical “pseudosarcomatous” reactive stromal fibroblasts and endothelial cells. As noted earlier, H. pylori infection is common. These organisms are detected in up to 76% of hyperplastic polyps. ^,

Differential Diagnosis

Large polyps may be endoscopically suspicious for a malignant lesion. Furthermore, as they grow in size, they have a tendency to become eroded. Regenerative superficial epithelial changes can be misdiagnosed as a neoplastic process. Thus cautious interpretation of epithelial atypia in the setting of mucosal erosion is advised. Exhaustive sampling of the entire polyp and analysis of multiple levels is often helpful in excluding a true neoplastic transformation.

Another pitfall is the of presence “Pseudogoblet” or “globoid” mucinous cells, as described earlier, which should not be mistaken for signet ring cells if dissociated in an eroded or mechanically damaged polyp.

The differential diagnosis of gastric hyperplastic polyps includes polypoid foveolar hyperplasia; gastritis cystica polyposa or profunda; polyps associated with juvenile polyposis and Peutz-Jeghers syndromes; and polypoid areas in Ménétrier’s disease, Cowden’s syndrome, and Cronkhite-Canada syndrome. Features helpful in determining the correct diagnosis are summarized in Table 20.1 . Polyps in patients with polypoid foveolar hyperplasia and Cronkhite-Canada syndrome are typically smaller in size than hyperplastic polyps and 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 morphology (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 deep to the muscularis mucosae and/or in the submucosa, or even the muscle and serosa in rare circumstances. Polyps related to gastritis cystica polyposa often develop adjacent to anastomotic sites in patients who have had a partial gastrectomy.

Juvenile polyps as well as polypoid areas of gastric mucosa in patients with Ménétrier’s disease and Cronkhite-Canada syndrome are histologically very similar to hyperplastic polyps. As a result, these are diagnostically challenging, particularly when evaluating superficial forceps biopsy specimens. However, having appropriate clinical and endoscopic information (i.e., number of polyps and appearance and histology of the non-polypoid mucosa) is essential to helping pathologists establish a correct diagnosis.

Nevertheless, Peutz-Jeghers polyps of the stomach may reveal the characteristic arborizing smooth muscle in the lumina propria, which is typically much more extensive than that of hyperplastic polyps. Unfortunately, most gastric polyps in Peutz-Jeghers syndrome are devoid of this feature, which is usually more prominent in polyps located in the small bowel. Peutz-Jeghers polyps also normally lack significant stromal inflammation and are usually not associated with chronic gastritis unless the latter is a coincidental, synchronous disorder in the patient as a result of other causes.

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 up to 50% of patients after endoscopic resection. ^, Conversely, regression of hyperplastic polyps has been documented in up to 71% of patients with H. pylori infection after eradication of the bacteria. ^{, ,} Because of the risk of dysplasia in larger polyps (see Dysplasia and Cancer in Hyperplastic Polyps), resection and a thorough examination is highly recommended for all polyps greater than 1.0 cm in size. In such cases, evaluation of the margins is an important feature if the polyp contains dysplasia or cancer.

Furthermore, because hyperplastic polyps commonly arise on a background of chronic atrophic gastritis, evaluation of the surrounding mucosa is helpful to understand the course of the polyp and the etiology of the patient’s gastritis.

Polypoid Foveolar Hyperplasia

Polypoid foveolar hyperplasia is simply 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 currently unknown.

Grossly, polypoid foveolar hyperplasia usually appears as a sessile lesion 1 to 2 mm in size. These polyps may be single or multiple, and they are most often located in the antrum. Microscopically, polypoid foveolar hyperplasia is characterized by simple hyperplasia of the gastric foveolar epithelium, but without cystic change or significant architectural distortion of the epithelium. The foveolar epithelium is increased in length, and the presence of luminal serration imparts a corkscrew-like pattern to the epithelium ( Fig. 20.5 ). The foveolae are typically crowded and tightly packed, containing little intervening stroma. The quality of the epithelium is variable. In some cases, it is mucin depleted and reactive-appearing with mitotic figures, enlarged nuclei, and prominent nucleoli. In others, cytoplasmic mucin is retained and the epithelium appears mature. Various degrees of intestinal metaplasia may be present as well, but this is much less common than in hyperplastic polyps. The lamina propria may contain a mild lymphoplasmacytic infiltrate, but smooth muscle proliferation is typically absent unless there is associated bile reflux.

Gastritis Cystica Polyposa or Profunda

Gastritis cystica polyposa, or profunda, is defined as a polypoid lesion characterized by the presence of misplaced foveolar or glandular epithelium, or both, in the muscularis mucosae or in deeper portions of the gastric wall, such as the submucosa, muscularis propria, or even the serosa. The lesion is referred to as polyposa when an intraluminal polyp is prominent and as profunda when the bulk of the lesion is located in the wall of the stomach; both types may result in gastric bleeding.

Although these lesions may develop rarely within surgically naive stomachs, they occur more often in patients who have had a partial gastrectomy with subsequent chronic bile reflux, or after surgical or endoscopic manipulation. Because of the association of this disease with chronic gastritis and prior gastrectomy, it is presumed that gastritis cystica polyposa/profunda is caused by an exuberant reactive proliferation with trauma- or inflammation/necrosis-induced entrapment of epithelium within the deep portions of the gastric wall. Some authorities have suggested that ischemia and/or mucosal prolapse are critical to the development of this disorder.

Pathologically, polyps associated with gastritis cystica polyposa/profunda are usually located on the gastric side of gastroenteric anastomoses. Rarely, they develop on a background of chronic gastritis. They are grossly indistinguishable from hyperplastic polyps. Polyps may be as large as 3 cm in size and are often associated with enlarged rugal folds. The most characteristic and defining histological feature is the presence of entrapped epithelium and/or glands, either within or beneath the muscularis mucosae of the polyp ( Fig. 20.6A–D ). Because this is a benign reactive lesion, the epithelial components of the polyp are classically surrounded by lamina propria–like stroma, which is presumably carried along with the epithelium during the process of displacement. The epithelium is often cystic. 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 may impart an atrophic appearance to the epithelium, especially when there is associated bile reflux. A mixed neutrophilic and mononuclear infiltrate may be found in the lamina propria in cases with active injury. Superficial erosion and even intestinal metaplasia may be present as well. Dysplasia and even cancer may, extremely rarely, develop in association with gastritis cystica polyposa or profunda. However, it is unclear whether the frequency of occurrence is equal to or greater than that of ordinary hyperplastic polyps.

The principle differential diagnosis is differentiating misplaced epithelium in gastritis cystica polyposa/profunda from a de novo well-differentiated invasive adenocarcinoma, particularly when sampling is limited, such as in biopsies ( Fig. 20.6E,F ). ^, The presence of desmoplasia, cytonuclear pleomorphism, irregularity in the size and shape of the glands, atypical mitoses, and lack of lamina propria surrounding the epithelium in question are all indicative of adenocarcinoma (see Table 20.3 for further details).

Clinical Features

Ménétrier’s disease is a rare disorder characterized by the presence of diffuse hyperplasia of the foveolar epithelium of the body and fundus of the stomach 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 as well. 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 pathological features of Ménétrier’s 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’s disease is very unlikely to regress.

Pathogenesis

Ménétrier’s 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, such as herpes simplex virus and Mycoplasma pneumoniae. ^{, ,} In these cases, spontaneous and treatment-associated remissions may occur. Although H. pylori infection and various other conditions have been associated with Ménétrier’s disease in adults, antibiotics, acid suppression, octreotide, and anticholinergic agents have had only minimal therapeutic benefit in adult patients. In contrast, inhibition of TGF-α signaling has been effective in some cases.

Pathological Features

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

A diagnosis of Ménétrier’s disease may be difficult to establish by evaluation of mucosal biopsies alone because some of the histological features mimic other types of polyps, such as hyperplastic polyps, juvenile polyps, and polyps associated with Cronkhite-Canada syndrome. Clinical information including the endoscopic appearance is essential to help pathologists establish a correct diagnosis. Ménétrier’s disease should also be distinguished from other causes of enlarged gastric rugae, such as robust chronic gastritis, Zollinger-Ellison syndrome, and even infiltration by tumor cells, such as lymphoma or poorly cohesive gastric carcinoma. Fortunately, most of these other entities are usually easy to distinguish histologically. For example, chronic gastritis shows abundant inflammation in the lamina propria in the absence of prominent foveolar hyperplasia. In Zollinger-Ellison syndrome, the absence of foveolar hyperplasia and the presence of massive parietal cell hyperplasia helps distinguish this entity from Ménétrier’s disease. Lymphoma, poorly cohesive gastric carcinoma, and other infiltrating tumors may mimic Ménétrier’s disease grossly, but the biopsies are usually diagnostic.

Treatment

In the past, the treatment of Ménétrier’s 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, recent 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’s disease and demonstrate the potential of targeted biological therapy in this disorder.

Clinical Features and Pathogenesis

Fundic gland polyps may be sporadic or familial. They were originally reported as a manifestation of familial adenomatous polyposis (FAP). These polyps are now recognized as the most common type of gastric polyp. The apparent increase in incidence reflects the widespread and ever-increasing use of proton pump inhibitors and an overall decreased prevalence rate of H. pylori infection, which have been strongly implicated in the genesis of sporadic fundic gland polyp. In many series, fundic gland polyps are more common than hyperplastic polyps and, in fact, represent the most common type of gastric polyp (77% of all gastric polyps). However, in some parts of the world, where H. pylori gastritis remains prevalent, the hyperplastic polyp remains the dominant type of gastric polyp.

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 the time of diagnosis. ^, Fundic gland polyps may also develop in patients with Zollinger-Ellison syndrome. Up to 90% of patients with FAP have fundic gland polyps within oxyntic mucosa. ^{, ,} The same prevalence rate is noted in the recently characterized gastric adenocarcinoma and proximal polyposis syndrome (GAPPS) (see Chapter 25 ). Less frequently, FGPs may also develop in patients with MUTYH-associated polyposis (MAP).

There are quite distinct natural histories and biological features of sporadic versus FAP-associated fundic gland polyps. In molecular terms, sporadic fundic gland polyps are associated with activating CTNNB1 mutations in more than 90% of cases, but they show APC gene mutations in less than 10% of cases. ^{, ,} Conversely, 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 ). ^{, ,} GAPPS and MAP families have point mutations in the promoter 1B of the APC gene and biallelic mutations in the DNA base excision repair gene, MUTYH, respectively. ^, 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. ^{, ,} There is a negative relationship between fundic gland polyps and H. pylori infection. ^{, ,}

Pathological Features

Fundic gland polyps are translucent, smooth, sessile, well-circumscribed lesions that occur exclusively within gastric oxyntic mucosa. They may be single or multiple, the latter of which is common in FAP and in patients with GAPPS. When multiple in patients with FAP, the term fundic gland polyposis is often used. One study of FAP-associated fundic gland polyps found an average of four polyps per patient, with a range of 1 to 11. GAPPS patients typically show over 100 polyps. Fundic gland polyps are usually smaller than 1.0 cm in diameter, but they may grow to 2 or even 3 cm in size on occasion, especially in polyposis syndromes.

Histologically, fundic gland polyps are composed of cystically dilated and architecturally irregular fundic (oxyntic) glands ( Fig. 20.8 ). In this lesion, the fundic glands assume a microcystic configuration and/or show prominent budding, and they are lined by parietal and chief cells, and occasionally mucinous foveolar cells. Parietal cell hyperplasia is common following PPI therapy and to a lesser degree foveolar cell hyperplasia. Fundic gland polyps in GAPPS tend to be larger in size and also may show inverted foveolar hyperplasia (hyperproliferative aberrant pits) ( Fig. 20.8F ). Inflammation is typically absent or minimal. The surface and foveolar epithelium in fundic gland polyps is typically atrophic. Regenerative changes are not uncommon, and this is usually restricted to the deep proliferative zones of the polyp, particularly in cases with active inflammation. This should be differentiated from dysplasia that is typically of foveolar type and develops predominantly in patients with syndromic fundic gland polyps. One of the most useful distinguishing features of dysplasia is the sharp transition of atypical and normal adjacent epithelium, whereas regenerative epithelium usually shows a more continuous, seamless transition. In the majority of dysplastic cases, both architectural and cytological atypia are low grade. Dysplasia is frequently limited to the surface epithelium and the neck region. The overall architecture of the oxyntic glands is maintained. Rare cases classified as high-grade dysplasia usually also show low-grade architecture, and only the features of cytological atypia (i.e., loss of polarity, cuboidal rather than columnar cell shape, high nuclear-to-cytoplasm ratio, prominent nucleoli, and atypical mitoses) warrant the high-grade designation. Marked glandular crowding, cribriforming, excessive branching, and budding are usually absent. The morphology of dysplasia in sporadic and syndromic fundic gland polyps is generally similar. The utility of immunohistochemistry in the differential diagnosis is also limited, as β-catenin nuclear positivity is rare in both types.

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 25% to 46% of FAP-associated fundic gland polyps. ^{, , , , , ,} Dysplasia in fundic gland polyps is usually of the foveolar type ( Fig. 20.9 ). When present, it is usually low grade. High-grade dysplasia has been reported only very rarely in sporadic fundic gland polyps, but the prevalence rate of high-grade dysplasia in FAP-associated lesions ranges from 0% to 12.5% in several series. ^{, , , , ,} The progression rate from low- to high-grade dysplasia or adenocarcinoma is minimal in sporadic cases, and is approximately 4% in FAP-associated polyps, but it is much higher in GAPPS. The few cases of adenocarcinoma that have been reported have all occurred in syndromic patients.

All dysplastic fundic gland polyps should be completely resected. Although formal surveillance guidelines have not yet been established, data suggest that surveillance of FAP patients for dysplastic fundic gland polyps should be performed on an individualized basis. In FAP patients, surveillance for duodenal adenomas, particularly periampullary lesions and less commonly gastric adenomas, should be carefully 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 in women. Patients are usually diagnosed in the second or third decade of life and present with 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. Polyps usually develop in the antrum and pylorus, and the median age of onset is 16 years. ^, Because of their small size, gastric Peutz-Jeghers polyps are usually asymptomatic. Morphologically identical polyps can occur in McCune-Albright’s syndrome, which is caused by somatic activating mutations in the GNAS gene.

Most cases (70%) of Peutz-Jeghers syndrome are caused by a germline mutation of the serine-threonine kinase STK11/LKB1 tumor suppressor gene, which is an important component of adenosine monophosphate (AMP) kinase/mTOR and transforming growth factor-β (TGF-β) signal transduction pathways. Truncating mutations of STK11/LKB1 are associated with an earlier (compared with missense mutations) development of gastric polyps. 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. Notably, secondary somatic “driver” mutations and loss of heterozygosity (LOH) of 17p and 18q have been detected in association with neoplastic transformation.

Dysplasia is rarely detected in gastric polyps; the estimated incidence is 2% to 3%. However, affected patients have a 29% risk of developing gastric cancer. In one series of Peutz-Jeghers syndrome patients with gastric cancer, carcinoma developed in patients with a mean age of 27 years.

Pathological 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 may display complex, arborizing architecture. However, the typical pattern of smooth muscle that extends from the muscularis mucosae up into the lamina propria of the papillary projections and to the polyp surface is much less common in the stomach than in the small bowel or colon ( Fig. 20.10 ). 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 morphological features are essentially similar to those of gastric hyperplastic polyps, with the exception that some, but not all, hamartomatous polyps have a more fully developed smooth muscle component. Gastric Peutz-Jeghers polyps show defective glandular differentiation. For polyps that occur in the fundic mucosa, this can be recognized by a general depletion of parietal cells.

Natural History and Treatment

Although gastric Peutz-Jeghers polyps are usually clinically silent, large lesions 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. 20.11 ), but this is uncommon in gastric lesions. There is no consensus on appropriate surveillance or follow-up of gastric Peutz-Jeghers polyps. ^, Novel therapeutic strategies have included the role of mTOR and COX2 inhibitors as well as metformin. It has been suggested that surveillance be initiated in the first decade of life, and follow-up endoscopy customized (1- to 3-year interval) based on findings of the first examination.