Epithelial Polyps and Neoplasms of the Stomach

Clinical Features

Fundic gland polyps occur in two common settings, sporadic and syndromic. In the sporadic setting, the polyps are most commonly detected in the fourth to sixth decade of life. However, in syndromic cases, the polyps occur in younger individuals in the second or third decade. They can be seen even in children and show an equal sex distribution. Patients are mostly asymptomatic or may present with mild abdominal pain, dyspepsia, or reflux.

The increased prevalence noted over the past 2 decades is attributed to the decreasing Helicobacter pylori infection and widespread use of PPIs. In fact, FGPs have an inverse correlation with H. pylori infection and atrophy. Long-term PPI use is associated with a fourfold risk of developing FGPs. Moreover, complete regression of some FGPs has been shown on cessation of the PPI therapy.

Fundic gland polyps are present in 0.8% to 1.9% of all patients undergoing gastroscopy. Among the syndromic conditions, they are most commonly found in patients with familial adenomatous polyposis (FAP) followed by gastric adenocarcinoma and proximal polyposis of stomach (GAPPS) and rarely in those with MUTYH -associated polyposis (MAP). FGP is diagnosed in 26% to 84% of patients with FAP.

Pathologic Features

Gross Findings

Fundic gland polyps are present exclusively in the body or fundus. In the syndromic setting, these polyps often carpet the oxyntic mucosa. They are soft, sessile, and hemispherical, with a smooth and translucent appearance ( Fig. 4.1 ). FGPs are small, ranging from 1 to 7 mm in size. Because of their small size, these polyps are often hidden by gastric rugal folds and become visible when the stomach is fully distended. They are usually identical in color to the surrounding gastric mucosa. The nonpolypoid gastric mucosa is typically normal.

Microscopic Findings

Fundic gland polyps consist of proliferation of oxyntic glands with cystic dilation. The proliferating glands are formed predominantly by parietal cells, but chief cells and mucous neck cells may also be present ( Fig. 4.2 ). The morphology of FGPs is slightly different according to the etiologic background of the polyp. PPI therapy–induced lesions are characterized by the presence of more prominent parietal cell hyperplasia, increased diameter of dilated oxyntic glands, and elongation of surface foveolar epithelium. FAP-associated lesions tend to show smaller microcysts lined by pure fundic epithelium with limited parietal cell and surface foveolar hyperplasia. FGPs in patients with GAPPS tend to be generally large, but the microcysts are smaller than PPI-related lesions and are lined by a mixture of fundic and foveolar type cells. The characteristic inverted foveolar epithelium in this setting is designated as hyperproliferative aberrant pits . The lamina propria lacks inflammation and is mildly edematous. There may be slight hyperplasia of the surface foveolar epithelium with shallow to absent pits.

In 25% to 46% of FGPs in FAP and fewer than 1% of sporadic FGPs, low-grade epithelial dysplasia characterized by nuclear hyperchromasia, enlargement, mild pseudostratification, and loss of mucin ( Fig. 4.3 ) may be present. The dysplasia in FGPs is usually of the foveolar type. High-grade dysplasia or adenocarcinoma are uncommon in patients with FAP. In contrast, low- and high-grade dysplasia as well as adenocarcinoma can be seen in patients with GAPPS.

Molecular Studies

Studies have revealed molecular abnormalities in FGPs, suggesting they are neoplastic lesions. FGPs associated with FAP and even sporadic FGPs with dysplasia harbor somatic APC gene alterations in 50% of cases. Sporadic FGPs show activating β-catenin mutations in up to 90% of cases. In the setting of MAP, the changes are driven by biallelic mutations in MUTYH . Recently, point mutations in the YY1 binding site of the APC promoter 1B were reported in several patients with GAPPS.

Differential Diagnosis

Biopsies of oxyntic mucosa from patients on PPI therapy can show hypertrophic parietal cells with apical cytoplasmic protrusions and dilated glands. The low-acid environment created by the H+/K+-ATPase inhibiting action of the PPIs causes gastrin stimulation, which in turn has a trophic effect on parietal cells, resulting in dilated intracytoplasmic canaliculi caused by the inspissated hydrogen ion. FGPs, on the other hand, show fundic gland cysts with flattened oxyntic lining. Compensatory hyperplastic parietal cells in remnant oxyntic mucosal islands of patients with autoimmune gastritis may mimic hyperplastic features reminiscent to the effect of PPI therapy. This phenomenon can lead to the development of endoscopic pseudopolyposis when the remnant nonatrophic mucosal patches appear polypoid between the depressed atrophic areas.

Oxyntic gland adenomas (OGAs) are also composed of proliferating fundic or oxyntic gland but display unmistakable neoplastic features, including an irregular tubular growth pattern and usually mild but obvious cytologic atypia. Hyperplastic polyps are also common polypoid lesions involving the stomach but are composed entirely of mucous neck cells. Parietal cells and chief cells are not part of the polyp lining epithelium in hyperplastic polyps

Prognosis and Therapy

Sporadic- and FAP-associated low-grade dysplastic FGPs have a low progression rate to high-grade dysplasia or adenocarcinoma. Conversely, GAPPS-associated FGPs have a higher risk of progression. The diagnosis of FGPs virtually never requires surgical resection, but endoscopic mucosal resection may be considered in large dysplastic FGPs. Upper endoscopic surveillance in patients with FAP is warranted to monitor the 300-fold risk for duodenal adenocarcinoma, but the question whether dysplastic FGPs deserve follow-up surveillance remains controversial.

Clinical Features

Hyperplastic polyps have a prevalence rate of approximately 1% to 2% at endoscopic examination in the adult population and represent about 20% of all gastric polyps. The prevalence of hyperplastic polyps has significantly decreased over the past 20 years because of the declining rate of H. pylori infection.

Hyperplastic polyps are antral predominant (60%). They are usually single but can be multiple in 20% of cases. The term hyperplastic polyposis is used to denote greater than 50 hyperplastic polyps in the stomach. A slight female predominance may be seen (male-to-female ratio, 1 to 2.4), and adults in the sixth and seventh decades of life are commonly affected. Hyperplastic polyps are the most common polyps in pediatric patients, accounting for 42% of gastric polyps in children.

Most (especially small) polyps are incidental findings during endoscopy performed for other reasons. Symptoms sometimes associated with large hyperplastic polyps include bleeding, abdominal pain, anemia, nausea, and vomiting. Large pedunculated polyps in the pyloric region may produce gastric outlet obstruction. Gastric hyperplastic polyps are frequently associated with abnormalities in the surrounding nonpolypoid mucosa in up to 85% of cases. These changes include H. pylori gastritis (25%), chemical gastropathy (21%), autoimmune gastritis (12%), intestinal metaplasia (37%), dysplasia (2%), and synchronous or metachronous carcinoma (6%). Other common etiological associations include partial gastrectomies for ulcers, postlaser therapy for gastric antral vascular ectasia, and cytomegalovirus gastritis. An increased prevalence of hyperplastic polyps has also been reported in the transplant setting.

Finally, a rare family pedigree with hyperplastic polyposis and increased incidence of poorly cohesive gastric carcinoma has been reported and associated with KRAS point mutation at codon 12. In recent studies on small cohorts, no pathogenic mutations were detected in small hyperplastic polyps without dysplasia; however, TP53 gene mutations were the most common alteration in hyperplastic polyps with dysplasia. Large hyperplastic polyps may show loss of MGMT expression or APC , CTNNB1 (beta-catenin), KRAS , or BRAF mutations.

Pathologic Features

Gross Findings

Most hyperplastic polyps are smaller than 1 cm, but they can sometimes grow up to 12 cm in size and be mistaken for a carcinoma. They are usually broad based or sessile but can also be pedunculated. The polyps have a smooth, lobulated, and glistening surface, often containing areas of erosion ( Fig. 4.4 ).

Microscopic Findings

The polyps are composed of hyperplastic, elongated, and tortuous gastric foveolae ( Fig. 4.5 ) with outpouchings, papillary infoldings, or cystic dilation. The foveolar cells may become hypertrophic and reminiscent of goblet cells because of accumulation of abundant cytoplasmic mucin. Scattered single hyperplastic foveolar cells created by the damage and disintegration of such foveolar epithelium should not be mistaken for signet ring cells. The stroma is edematous, causing separation of glands, and contains variable numbers of inflammatory cells such as lymphocytes, plasma cells, eosinophils, and even lymphoid aggregates. A subset of larger polyps contain prominent vessels and wisps of smooth muscle bundles extending from muscularis mucosae into the lamina propria of the polyp, a phenomenon most likely caused by mucosal prolapse. Areas with erosion may show regenerative changes with depleted mucin, hyperchromatic nuclei, and visible nucleoli that should not be mistaken for dysplasia.

Hyperplastic polyps may contain foci of intestinal metaplasia (16%), dysplasia (4%), and rarely malignant transformation (0.6%). Dysplastic foci are characterized by lack of surface maturation, pseudostratified epithelium with enlarged hyperchromatic nuclei, and increased mitotic figures. High-grade dysplasia is characterized by loss of polarity, marked cytologic atypia, and architectural abnormalities such as cribriform glands. Size appears to be the biggest risk factor with most lesions harboring dysplasia or carcinoma measuring 2 cm or more.

Clinical Features

This rare entity is similar to mucosal prolapse lesions elsewhere in the GI tract, such as solitary rectal ulcer, colitis cystica profunda, and prolapse at colostomy and ileostomy sites. Gastritis cystica polyposa presents near gastroenterostomy stomal sites 3 to 40 years after surgery, typically in men in their 70 s who have history of Billroth I and II procedures. Clinically, the patients are frequently suspected of having stump carcinoma or an adenoma. Computed tomography examination can demonstrate multiple exophytic masses around gastric stomal or anastomotic sites. Anastomotic site changes, including mechanical or ischemic injury, mucosal prolapse, and bile reflux, are thought to play a role in the pathogenesis. Unlike the benign rectal mucosal prolapse lesions, gastritis cystica polyposa can be associated with dysplasia and gastric stump carcinoma.

Gross Findings

Gastritis cystica polyposa presents as single or multiple, soft, sessile 1- to 3-cm polyps or confluent, circumferential masses around gastric stomal or anastomotic sites. The mucosa overlying the polyp is usually smooth and resembles the surrounding gastric mucosa or may be red. Cut sections show thickened gastric wall containing numerous cystic structures.

Microscopic Findings

Histologic features include foveolar hyperplasia, regenerative surface epithelial changes, and cystically dilated pyloric-type glands in the mucosa, the submucosa, and even the muscularis propria ( Fig. 4.6 ). Depending on the location of the cystic glands, these lesions can also be termed gastritis cystica superficialis or gastritis cystica profunda . The lamina propria and submucosa contain increased chronic inflammation, fibrosis, and scarring and often display thickened and splayed muscle bundles. Biopsy of the gastric remnant shows reduced oxyntic glands owing to the lack of gastrin caused by antrectomy, lamina propria edema, and chronic inflammation. There may be intestinal metaplasia or dysplasia.

Differential Diagnosis

The presence of epithelial elements deep in the submucosa or even muscularis propria in gastritis cystica profunda can be mistaken for invasive adenocarcinoma. Unlike in carcinomas, these cystic glands lack pleomorphism and desmoplastic stroma and are often surrounded by lamina propria or smooth muscle bundles.

Clinical Features

Pancreatic heterotopia is an uncommon lesion, detected in 0.5% to 13% of autopsies, the majority of which are seen in the stomach (30%) followed by the duodenum, jejunum, and Meckel’s diverticulum. Less common sites include the lungs, gallbladder, mediastinum, mesentery, esophagus, bile ducts, and umbilical cord. It can affect adult and pediatric patients, and the average age is 45 years with a slight male predominance. Most patients are not symptomatic, but abdominal pain, epigastric discomfort, nausea, vomiting, and bleeding can develop. Large prepyloric lesions may present with gastric outlet obstruction. Rarely, the heterotopic tissue may develop pancreatitis, pancreatic cysts, neuroendocrine (islet cell) tumor, or even ductal adenocarcinoma.

Pathologic Features

Microscopic Findings

The heterotopic pancreas ( Fig. 4.7 ) may contain varying proportions of acinar, ductal, and islet cell components and can be divided into four types: type I, total heterotopia (all cell types, most common variant); type II, canalicular heterotopia (ducts only); type III, exocrine heterotopia (acinar cells only); and type IV, endocrine heterotopia (islets only, rare).

Because the usually submucosal location, superficial biopsies may not be diagnostic. Thus, deeper biopsies or endoscopic removal are important for a definite diagnosis.

Pancreatic Heterotopia—Pathologic Features

Gross Findings

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  Usually solitary, antral or prepyloric, dome-shaped polypoid nodules

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  Covered by smooth normal or ulcerated mucosa with a central umbilication

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  Cut sections show a well-demarcated tan-yellow and often lobulated intramural mass, resembling normal pancreatic parenchyma

Microscopic Findings

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  The heterotopic tissue contains admixture of pancreatic acini, ducts, and islets in varying proportions

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  Superficial biopsies may not be diagnostic because of the submucosal location, thus necessitating deeper sampling

Immunohistochemical Features

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  Most cases are easily diagnosed based on the hematoxylin and eosin stain

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  Endocrine or islet cell stain with chromogranin A and synaptophysin

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  Pancreas exocrine markers mark the acinar cells

Differential Diagnosis

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  Invasive well-differentiated adenocarcinoma

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  Gastritis cystica profunda

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  Neuroendocrine tumor

Differential Diagnosis

The submucosal location of the lesion brings about an endoscopic differential of GI stromal tumors, lipomas, and leiomyomas, which is easily resolved on histologic examination. Invasive adenocarcinoma is an important microscopic differential diagnosis considering that most pancreatic heterotopias arise in deep submucosa or muscularis and can be misinterpreted, especially during frozen sections. The key to the correct diagnosis is the lobulated arrangement of acinar and duct structure (like in normal pancreas) and the lack of malignant cytoarchitectural features and desmoplasia. Gastritis cystica profunda occurs in stomal or anastomotic sites and consists of surface foveolar hyperplasia with prominent features of mucosal prolapse, cystically dilated mucous glands located in the submucosa and muscularis propria. The finding of acinar and islet tissue in pancreatic heterotopias is especially helpful in excluding this possibility. Pure endocrine heterotopia (the rarest among the pancreatic heterotopias) may present a diagnostic challenge with neuroendocrine tumors (NETs). Endocrine heterotopias present as microscopic nests scattered in the submucosa and muscularis and are not associated with any stromal response. NETs present as mass lesions with the tumor cells arranged as trabeculae, tubules, and rosettes.