Advertisement
Surgical Pathology Clinics

Gastric Epithelial Polyps

When to Ponder, When to Panic
Open AccessPublished:July 11, 2020DOI:https://doi.org/10.1016/j.path.2020.05.004

      Keywords

      Key points
      • Gastric epithelial polyps comprise a wide spectrum of lesions with different cause, histology, malignant potential, and sometimes associations with tumor predisposition syndromes.
      • Most gastric polyps are sporadic with no malignant potential, but clinical correlation is necessary, and pathologists should be familiar with the morphologic characteristics of gastric polyps as an indication for a search for an underlying genetic syndrome, such as familial adenomatous polyposis, Peutz-Jeghers syndrome, or juvenile polyposis syndrome.
      • In the presence of a gastric polyp, preferably biopsies of background mucosa are taken of at least the antrum and corpus. Evaluation of the background nonpolypoid mucosa is essential in reaching a diagnosis that can characterize the condition in which the polyp developed and may have therapeutic consequences.

      Overview

      Gastric polyps comprise a wide spectrum of lesions arising from different cell or epithelial compartments in the stomach and with different causes, histology, malignant potential, and association with different tumor predisposition syndromes. Gastric polyps can be defined as lesions projecting above the plane of the surrounding gastric mucosa.
      • Park D.Y.
      • Lauwers G.Y.
      Gastric polyps: classification and management.
      In about 1% to 6% of gastroscopies, polyps are found in the stomach.
      • Castro R.
      • Pimentel-Nunes P.
      • Dinis-Ribeiro M.
      Evaluation and management of gastric epithelial polyps.
      ,
      • Carmack S.W.
      • Genta R.M.
      • Graham D.Y.
      • et al.
      Management of gastric polyps: a pathology-based guide for gastroenterologists.
      Most polyps are of epithelial origin and asymptomatic.
      • Castro R.
      • Pimentel-Nunes P.
      • Dinis-Ribeiro M.
      Evaluation and management of gastric epithelial polyps.
      Less frequently found subepithelial lesions presenting as gastric polyps include neuroendocrine tumors, pancreatic heterotopia, mesenchymal polyps (eg, inflammatory fibroid polyp, gastrointestinal stromal tumor, leiomyoma, schwannoma, inflammatory myofibroblastic tumor) as well as lymphomas.
      • Carmack S.W.
      • Genta R.M.
      • Schuler C.M.
      • et al.
      The current spectrum of gastric polyps: a 1-year national study of over 120,000 patients.
      Large geographic differences have been observed in the occurrence of gastric polyps, mainly caused by differences in Helicobacter pylori (H pylori) infection rate.
      • Brosens L.A.A.
      • Wood L.D.
      • Offerhaus G.J.
      • et al.
      Pathology and genetics of syndromic gastric polyps.
      In areas with high rates of H pylori infection, hyperplastic polyps (HPs), with or without dysplasia, are most prevalent. In contrast, fundic gland polyps (FGPs) are the most frequently encountered type of polyps in areas with a low prevalence of H pylori infection as well as high use of proton-pump inhibitory therapy, for example, western countries.
      • Carmack S.W.
      • Genta R.M.
      • Graham D.Y.
      • et al.
      Management of gastric polyps: a pathology-based guide for gastroenterologists.
      ,
      • Carmack S.W.
      • Genta R.M.
      • Schuler C.M.
      • et al.
      The current spectrum of gastric polyps: a 1-year national study of over 120,000 patients.
      Gastric polyps often arise in association with an inflammatory background or a polyposis syndrome. Careful attention to the background mucosa and awareness of syndromic gastric polyps are therefore important for correct interpretation and diagnosis of gastric polyps.
      Gastric polyps can be classified based on their cell or epithelial compartment of origin (Table 1). The stomach consists of the following anatomic regions: cardia, fundus, body, antrum, and pylorus. These areas have variable histologic appearances, which reflect differences in physiologic functions. Gastric pits or foveolae, lined by mucus-secreting foveolar cells, comprise the whole luminal surface of the stomach. Underneath these pits, the mucous neck cells as well as deep gastric glands are located, of which the cellular composition is region-dependent. The glands in the fundus and body consist of parietal cells, chief cells, and enterochromaffin-like cells. In the cardia, antrum, and pylorus, mainly mucus cells with clear cytoplasm line the deep glands with a small mixture of neuroendocrine cells. In the transitional zones, small numbers of parietal and chief cells are present. Familiarity with these histologic features will aid in gastric polyp recognition and diagnosis.
      Table 1Overview of gastric epithelial polyps classified by cell or epithelial compartment of origin
      OriginNonneoplasticNeoplastic
      Foveolar layerHyperplastic polypFoveolar-type adenomaIntestinal-type adenoma
      CharacteristicsPolyp consisting of dilated, branched, and elongated glands in edematous stroma

      Background of chronic gastritis
      Polyp with atypical foveolar cells (at least low-grade dysplasia)

      No background of inflammation, atrophy, or metaplasia

      Expression of MUC5AC; usually no expression of MUC2
      Polyp with intestinal-type columnar epithelium containing absorptive cells, goblet cells, endocrine cells, and/or Paneth cells with at least low-grade dysplasia

      Background of intestinal metaplasia and/or inflammation or atrophy. Variable expression of MUC2; no or slight expression of MUC5AC and MUC6
      Of noteHistopathologically indistinguishable from hamartomatous polyp/hamartomatous polyposis syndrome

      Reasonable risk of malignancy (background)
      Association with FAP

      Low risk of malignant transformation
      Association with FAP (although rare)

      Relatively high risk of malignant transformation
      Glandular layerFundic gland polypPyloric gland adenomaOxyntic gland adenoma
      CharacteristicsPolyp consisting of dilated glands with parietal and chief cells and some mucous cellsPolyp with atypical pyloric-type glands (at least low-grade dysplasia)

      No background of inflammation, atrophy, or metaplasia

      Expression of MUC6; usually no expression of MUC2
      Polyp with atypical oxyntic glands, consisting of chief cells or combination of chief and parietal cells (at least low-grade dysplasia)

      In general, no background of inflammation, atrophy, or metaplasia
      Of noteSporadic (association with PPI therapy) or in the context of FAP

      Low risk of malignant transformation
      Association with several polyposis/tumor predisposition syndromes

      Relatively high risk of malignant transformation
      Low risk of malignant transformation

      Fundic gland polyp

      Introduction

      FGPs are the most common type of gastric polyp, comprising almost 80% of all gastric polyps, and seem to be more common in areas with low H pylori infection rates.
      • Carmack S.W.
      • Genta R.M.
      • Graham D.Y.
      • et al.
      Management of gastric polyps: a pathology-based guide for gastroenterologists.
      ,
      • Carmack S.W.
      • Genta R.M.
      • Schuler C.M.
      • et al.
      The current spectrum of gastric polyps: a 1-year national study of over 120,000 patients.
      Sporadic FGPs are strongly related to the use of proton-pump inhibitors (PPIs). Long-term use leads especially to increased risk of developing FGPs. PPI therapy gives acid suppression, which elevates serum gastrin, a growth factor for oxyntic mucosa and a downstream target of Wnt signaling. Patients on PPI therapy have hyperplasia and protrusions of parietal cells in their gastric biopsy, which is thought to be an initial step in the development of an FGP. After this, there is development of small and subsequently larger fundic gland cysts. The glands dilate because of increased intraglandular pressure, probably because of the parietal cell hyperplasia that gives increased outflow resistance.
      In younger patients with multiple FGPs (>20), that is, fundic gland polyposis, or FGPs with dysplasia, an underlying familial adenomatous polyposis (FAP) syndrome (owing to a germline mutation in the Adenomatous Polyposis Coli [APC] gene) or MUTYH polyposis should be considered, and colonoscopy is advised, in particular if there are also duodenal adenomas.

      Gross Features

      FGPs are typically less than 5 mm and have a smooth surface. Sporadic FGPs are usually solitary or few in number (Fig. 1). However, FGPs can be numerous in patients using PPIs and in patients with familial polyposis syndrome (Fig. 2).
      • Brosens L.A.A.
      • Wood L.D.
      • Offerhaus G.J.
      • et al.
      Pathology and genetics of syndromic gastric polyps.
      ,
      • Vogt S.
      • Jones N.
      • Christian D.
      • et al.
      Expanded extracolonic tumor spectrum in MUTYH-associated polyposis.
      Figure thumbnail gr1
      Fig. 1Sporadic FGP: gross features. Several sporadic FGPs in the cardiac region of the stomach.
      Figure thumbnail gr2
      Fig. 2FAP-associated FGP: gross features. Numerous FGPs and foveolar adenomas throughout the stomach of a patient with FAP syndrome.

      Microscopic Features

      FGPs are characterized by cystically dilated oxyntic glands mainly lined by parietal and chief cells and variable numbers of mucous neck cells (Fig. 3). The overlying foveolar surface is usually normal. Surface erosion can be present with resulting reactive changes of the foveolar epithelium, which may be misinterpreted as dysplasia. Sporadic single FGPs rarely show dysplasia; however, in some FGPs, dysplasia of the overlying foveolar epithelium is observed. Dysplasia in FGPs is of foveolar type, characterized by low columnar cells resembling foveolar cells with round to oval nuclei (Fig. 4). The cytoplasm contains a MUC5AC-positive mucin cap. The surrounding mucosa of FGPs is normal or shows signs of PPI use. There is no background of atrophy or intestinal metaplasia.
      Figure thumbnail gr3a
      Fig. 3FGP: microscopic features. (A) Low-power view of an FGP, consisting of cystically dilated glands lined by parietal and chief cells and variable numbers of mucous neck cells. (B) High-power view of the same polyp. The polyp is lined by nondysplastic foveolar epithelium at the surface.
      Figure thumbnail gr3b
      Fig. 3FGP: microscopic features. (A) Low-power view of an FGP, consisting of cystically dilated glands lined by parietal and chief cells and variable numbers of mucous neck cells. (B) High-power view of the same polyp. The polyp is lined by nondysplastic foveolar epithelium at the surface.
      Figure thumbnail gr4a
      Fig. 4FGP with high-grade dysplasia. (A) This FGP from a patient with FAP shows a focus of high-grade dysplasia of the overlying foveolar epithelium, characterized by columnar cells showing severe nuclear atypia with round to oval, vesicular nuclei with prominent nucleoli and loss of polarity as well as some architectural atypia with crowding and branching of glands. (B) The dysplastic cells show p53 overexpression.
      Figure thumbnail gr4b
      Fig. 4FGP with high-grade dysplasia. (A) This FGP from a patient with FAP shows a focus of high-grade dysplasia of the overlying foveolar epithelium, characterized by columnar cells showing severe nuclear atypia with round to oval, vesicular nuclei with prominent nucleoli and loss of polarity as well as some architectural atypia with crowding and branching of glands. (B) The dysplastic cells show p53 overexpression.

      (Differential) Diagnosis

      In general, FGPs are straightforward to diagnose both endoscopically and microscopically. Some FGPs can be difficult to differentiate from pyloric or oxyntic gland adenomas (OGAs), depending on the degree of cystic changes and pyloric or oxyntic differentiation, respectively. GNAS mutations are often present in pyloric gland adenomas (PGAs) and absent in FGPs, and this may be used to differentiate between PGA and FGP.
      • Hackeng W.M.
      • Montgomery E.A.
      • Giardiello F.M.
      • et al.
      Morphology and genetics of pyloric gland adenomas in familial adenomatous polyposis.
      Very large FGPs can pose a differential diagnosis with HPs. The key difference between FGPs and HPs is that the cystically dilated glands in FGPs are lined by a mixture of cell types, including parietal and foveolar cells, whereas in HPs, the glands are lined by hyperplastic foveolar epithelium. FGPs with dysplasia can be difficult to distinguish from foveolar-type adenomas with low-grade dysplasia, but this is of little clinical significance because both lesions carry a low risk of neoplastic progression.
      • Wood L.D.
      • Salaria S.N.
      • Cruise M.W.
      • et al.
      Upper GI tract lesions in familial adenomatous polyposis (FAP).

      Prognosis, When to Ponder, When to Panic

      FGPs are generally regarded as nonneoplastic lesions, either hamartomatous or hyperplastic/functional in nature, because they are retention cysts caused by corpus gland secretion impairment. However, the frequent finding of mutations in the Wnt pathway (APC and CTNNB1 genes) indicates that FGPs are neoplastic growths as well. Most (60%–90%) sporadic FGPs without dysplasia have somatic CTNNB1 mutations.
      • Abraham S.C.
      • Park S.J.
      • Mugartegui L.
      • et al.
      Sporadic fundic gland polyps with epithelial dysplasia: evidence for preferential targeting for mutations in the adenomatous polyposis coli gene.
      ,
      • Sekine S.
      • Shibata T.
      • Yamauchi Y.
      • et al.
      Beta-catenin mutations in sporadic fundic gland polyps.
      Dysplastic sporadic FGPs may have a somatic APC mutation without CTNNB1 (β-catenin) mutation.
      • Abraham S.C.
      • Park S.J.
      • Mugartegui L.
      • et al.
      Sporadic fundic gland polyps with epithelial dysplasia: evidence for preferential targeting for mutations in the adenomatous polyposis coli gene.
      In contrast, FGPs in FAP show somatic second-hit inactivation of the APC gene that precedes dysplasia, but lacks CTNNB1 mutations.
      • Abraham S.C.
      • Nobukawa B.
      • Giardiello F.M.
      • et al.
      Fundic gland polyps in familial adenomatous polyposis.
      The type of second-hit APC mutation may play a role in the chance of progression to high-grade dysplasia in FAP-associated FGPs.
      • Sekine S.
      • Shimoda T.
      • Nimura S.
      • et al.
      High-grade dysplasia associated with fundic gland polyposis in a familial adenomatous polyposis patient, with special reference to APC mutation profiles.
      Dysplasia in sporadic FGPs is extremely rare and has an indolent nature.
      • Straub S.F.
      • Drage M.G.
      • Gonzalez R.S.
      Comparison of dysplastic fundic gland polyps in patients with and without familial adenomatous polyposis.
      • Levy M.D.
      • Bhattacharya B.
      Sporadic fundic gland polyps with low-grade dysplasia: a large case series evaluating pathologic and immunohistochemical findings and clinical behavior.
      • Abraham S.C.
      Fundic gland polyps: common and occasionally problematic lesions.
      • Burt R.W.
      Gastric fundic gland polyps.
      • Torbenson M.
      • Lee J.-H.
      • Cruz-Correa M.
      • et al.
      Sporadic fundic gland polyposis: a clinical, histological, and molecular analysis.
      In general, sporadic FGPs do not progress to cancer and tend to regress when PPI therapy is stopped. Presence of FGPs is inversely correlated with H pylori infection, active gastritis, and gastric neoplasia.
      • Genta R.M.
      • Schuler C.M.
      • Robiou C.I.
      • et al.
      No association between gastric fundic gland polyps and gastrointestinal neoplasia in a study of over 100,000 patients.
      FAP is an autosomal-dominant polyposis syndrome caused by a germline mutation in the APC gene. It is characterized by hundreds to thousands of adenomatous polyps (≥100) throughout the colorectum and inevitable development of colorectal cancer if left untreated by colectomy. In addition, FAP patients develop several benign and malignant extracolonic lesions. In the stomach, most patients with FAP have multiple FGPs (polyposis). Low-grade dysplasia is often seen in FGPs in FAP, but the risk of malignant progression is low.
      • Brosens L.A.A.
      • Wood L.D.
      • Offerhaus G.J.
      • et al.
      Pathology and genetics of syndromic gastric polyps.
      ,
      • Brosens L.A.A.
      • Offerhaus G.J.A.
      • Giardiello F.M.
      Hereditary colorectal cancer: genetics and screening.
      Based on older literature, western FAP patients are considered not to carry an increased risk of gastric cancer compared with the general population,
      • Offerhaus G.J.
      • Giardiello F.M.
      • Krush A.J.
      • et al.
      The risk of upper gastrointestinal cancer in familial adenomatous polyposis.
      whereas a 3 to 4 times increased risk of gastric cancer was reported in FAP patients from South Korea and Japan.
      • Park J.-G.
      • Park K.J.
      • Ahn Y.-O.
      • et al.
      Risk of gastric cancer among Korean familial adenomatous polyposis patients.
      ,
      • Iwama T.
      • Mishima Y.
      • Utsunomiya J.
      The impact of familial adenomatous polyposis on the tumorigenesis and mortality at the several organs. Its rational treatment.
      The increased risk of gastric cancer in Asian populations likely results from higher prevalence of H pylori infection and associated atrophic gastritis and intestinal metaplasia in these populations.
      However, several recent reports of FAP patients with gastric cancer suggest an increased incidence of gastric cancer in western patients.
      • Walton S.-J.
      • Frayling I.M.
      • Clark S.K.
      • et al.
      Gastric tumours in FAP.
      ,
      • Mankaney G.
      • Leone P.
      • Cruise M.
      • et al.
      Gastric cancer in FAP: a concerning rise in incidence.
      Interestingly, these gastric cancers are almost exclusively located in the proximal stomach and are associated with extensive carpeting fundic gland polyposis, and a large size (>20 mm) of polyps and dysplasia.
      • Leone P.J.
      • Mankaney G.
      • Sarvapelli S.
      • et al.
      Endoscopic and histologic features associated with gastric cancer in familial adenomatous polyposis.
      One study reported an association between gastric cancer and desmoid tumors in FAP patients, suggesting a genotype-phenotype correlation for gastric cancer.
      • Walton S.-J.
      • Frayling I.M.
      • Clark S.K.
      • et al.
      Gastric tumours in FAP.
      In addition, gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) is characterized by carpeting proximal fundic gland polyposis of the stomach with antral sparing, increased risk of gastric cancer, and no or a small number of duodenal and colorectal adenomas. Because it is caused by a point mutation in exon 1B of APC, it is now considered a variant of FAP with a unique gastric phenotype, further supporting that gastric cancer risk may depend on the genotype.
      • Worthley D.L.
      • Phillips K.D.
      • Wayte N.
      • et al.
      Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS): a new autosomal dominant syndrome.
      • Li J.
      • Woods S.L.
      • Healey S.
      • et al.
      Point mutations in exon 1B of APC reveal gastric adenocarcinoma and proximal polyposis of the stomach as a familial adenomatous polyposis variant.
      • van der Post R.S.
      • Carneiro F.
      Emerging concepts in gastric neoplasia: heritable gastric cancers and polyposis disorders.
      GAPPS patients with gastric cancer more often have gastric adenomas, FGPs, and PGAs with high-grade dysplasia.
      • Leone P.J.
      • Mankaney G.
      • Sarvapelli S.
      • et al.
      Endoscopic and histologic features associated with gastric cancer in familial adenomatous polyposis.
      Thus, although low-grade gastric foveolar-type dysplasia is not very alarming in FAP patients, extensive proximal gastric polyposis and possibly also the presence of PGAs (see later discussion) may be markers of an increased risk of proximal gastric cancer in FAP. In addition, it remains important to detect FAP patients with H pylori infection, gastric atrophy, and intestinal-type adenomas because these patients seem to be at increased risk for distal intestinal-type adenocarcinomas.
      • Leggett B.
      FAP: another indication to treat H pylori.
      • Cystically dilated oxyntic glands lined by parietal and chief cells
      • Lined by nondysplastic foveolar epithelium
      • Rarely foveolar-type dysplasia (mainly in FAP)
      • Pyloric or oxyntic gland adenomas
      • Large FGPs can be difficult to distinguish from HPs
      • FGPs with dysplasia versus foveolar-type adenomas
      • !
        Multiple FGPs (fundic gland polyposis) are associated with FAP and GAPPS.

      Hyperplastic polyp/inflammatory polyp/hamartomatous polyp

      Introduction

      Gastric HPs are among the most common epithelial polyps of the stomach; incidences vary among populations and range between 15% and 75% of all gastric polyps.
      • Abraham S.C.
      • Singh V.K.
      • Yardley J.H.
      • et al.
      Hyperplastic polyps of the stomach: associations with histologic patterns of gastritis and gastric atrophy.
      HPs are localized, nonneoplastic mucosal expansions consisting of elongated, tortuous, and cystically dilated foveolae supported by an edematous lamina propria with distended vessels. In contrast to colonic HPs, which are neoplastic polyps, gastric HPs are reactive lesions resulting from reparative and regenerative responses to mucosal injury. First, there is an ongoing healing and reparative response in the form of foveolar hyperplasia after mucosal injury and erosion. This hyperplastic reaction can end or persist and progress with the formation of an HP. Mostly the initial inflammation is caused by H pylori or autoimmune gastritis, although any agent causing chronic gastritis or mucosal erosion may lead to the formation of an HP. In addition, mucosal prolapse can result in HPs.
      • Gonzalez-Obeso E.
      • Fujita H.
      • Deshpande V.
      • et al.
      Gastric hyperplastic polyps: a heterogeneous clinicopathologic group including a distinct subset best categorized as mucosal prolapse polyp.
      HPs can be multiple, which is the case in 20% of patients.
      • Abraham S.C.
      • Singh V.K.
      • Yardley J.H.
      • et al.
      Hyperplastic polyps of the stomach: associations with histologic patterns of gastritis and gastric atrophy.
      Gastric “inflammatory polyp” is a commonly used misnomer for an HP and should not be used in the stomach to avoid confusion with an inflammatory fibroid polyp. Hamartoma defines an overgrowth of normal tissue elements in their own native location. Hamartomatous gastric polyps are rare in the stomach and are, from a histopathological point of view, indistinguishable from HPs because they share the same morphology. Hamartomatous gastric polyps occur in the context of Peutz-Jeghers syndrome (PJS), juvenile polyposis syndrome (JPS), and Cowden (PTEN hamartoma tumor) syndrome.
      • Lam-Himlin D.
      • Park J.Y.
      • Cornish T.C.
      • et al.
      Morphologic characterization of syndromic gastric polyps.

      Gross Features

      HPs are mostly small, generally less than 2 cm, although sizes of up to 12 cm are reported. The polyps are usually solitary, smooth or lobulated, and can be sessile or pedunculated. There is often surface erosion. HPs cannot reliably be distinguished from small adenomas endoscopically. HPs are most common in the antrum (60%), but may arise throughout the stomach, including the cardia and gastroesophageal area.
      • Abraham S.C.
      • Singh V.K.
      • Yardley J.H.
      • et al.
      Hyperplastic polyps of the stomach: associations with histologic patterns of gastritis and gastric atrophy.
      ,
      • Abraham S.C.
      • Singh V.K.
      • Yardley J.H.
      • et al.
      Hyperplastic polyps of the esophagus and esophagogastric junction: histologic and clinicopathologic findings.

      Microscopic Features

      HPs have a polypoid form and show elongated, branching, and cystically dilated foveolar glands (Fig. 5). The foveolar cells have a hyperplastic appearance with abundant mucinous cytoplasm. The glands may contain prominent globoid cells. There is crowding of foveolar cells, and glands may be tortuous or have a corkscrew appearance. The lamina propria can be edematous and moderately to heavily infiltrated by immune cells. In other cases, the lamina propria is more fibrotic with or without chronic inflammatory infiltrate. The surface of the polyp can be eroded and have a regenerative appearance with nuclear enlargement and depletion of cytoplasmic mucin.
      • Abraham S.C.
      • Singh V.K.
      • Yardley J.H.
      • et al.
      Hyperplastic polyps of the stomach: associations with histologic patterns of gastritis and gastric atrophy.
      Small lesions may be best addressed as polypoid foveolar hyperplasia.
      • Gonzalez-Obeso E.
      • Fujita H.
      • Deshpande V.
      • et al.
      Gastric hyperplastic polyps: a heterogeneous clinicopathologic group including a distinct subset best categorized as mucosal prolapse polyp.
      Figure thumbnail gr5a
      Fig. 5HP. (A) Low-power view of an HP, showing elongated, branching, and cystically dilated foveolar glands with abundant mucinous cytoplasm. The lamina propria is edematous and infiltrated by immune cells. (B) High-power view of the same polyp.
      Figure thumbnail gr5b
      Fig. 5HP. (A) Low-power view of an HP, showing elongated, branching, and cystically dilated foveolar glands with abundant mucinous cytoplasm. The lamina propria is edematous and infiltrated by immune cells. (B) High-power view of the same polyp.

      (Differential) Diagnosis

      HPs have an overlapping morphology with polyps arising in juvenile polyposis, Peutz-Jeghers (PJ) polyposis, and Cowden/PTEN hamartoma tumor syndrome (see Overview).
      • Lam-Himlin D.
      • Park J.Y.
      • Cornish T.C.
      • et al.
      Morphologic characterization of syndromic gastric polyps.
      Many of the hamartomatous syndrome polyps lack specific histology, and to distinguish them from each other and from sporadic HPs based on only histology is unreliable. Therefore, one should think of the possibility of an underlying hamartomatous polyposis syndrome in the case of multiple gastric hyperplastic-type polyps but at the same time be cautious to establish a diagnosis of a polyposis syndrome based on gastric polyp pathologic condition alone.
      • Brosens L.A.A.
      • Wood L.D.
      • Offerhaus G.J.
      • et al.
      Pathology and genetics of syndromic gastric polyps.
      ,
      • Lam-Himlin D.
      • Park J.Y.
      • Cornish T.C.
      • et al.
      Morphologic characterization of syndromic gastric polyps.
      The syndromes in which they can occur are now briefly discussed.
      PJS is an autosomal-dominant inherited disorder caused by a germline mutation in LKB1 (STK11). Intestinal PJ polyps have characteristic features with an arborizing pattern of smooth muscle proliferating between mucosal epithelial components.
      • Tse J.Y.
      • Wu S.
      • Shinagare S.A.
      • et al.
      Peutz-Jeghers syndrome: a critical look at colonic Peutz-Jeghers polyps.
      However, this is less pronounced in gastric PJ polyps (Fig. 6). Thus, in gastric polyps, there are mostly only foveolar hyperplastic features without the characteristic arborizing smooth muscle fibers. Therefore, clinical correlation and information on previous gastrointestinal polyps are necessary.
      • Shaco-Levy R.
      • Jasperson K.W.
      • Martin K.
      • et al.
      Morphologic characterization of hamartomatous gastrointestinal polyps in Cowden syndrome, Peutz-Jeghers syndrome, and juvenile polyposis syndrome.
      A classic clinical feature of PJS is perioral hyperpigmentation, and patients also are at high risk of developing malignancies in the gastrointestinal tract, pancreas, lung, breast, and gynecologic tract.
      • Giardiello F.M.
      • Brensinger J.D.
      • Tersmette A.C.
      • et al.
      Very high risk of cancer in familial Peutz-Jeghers syndrome.
      Diagnostic criteria for PJS are as follows: (1) 3 or more morphologically defined PJ polyps; (2) a personal diagnosis in combination with a family history of PJ polyps; and (3) characteristic mucocutaneous hyperpigmentation with a personal or family history of PJ polyps. Gastric cancer risk is increased with a cumulative lifetime risk of 29% from age 15 to 64 years.
      • Giardiello F.M.
      • Brensinger J.D.
      • Tersmette A.C.
      • et al.
      Very high risk of cancer in familial Peutz-Jeghers syndrome.
      Interestingly, polyps in PJS are likely not the obligate precursor lesion in PJS, but an epiphenomenon owing to mucosal prolapse. In this regard, it interesting to note that mucosal prolapse also plays a role in the pathogenesis of a subset of sporadic gastric HPs.
      • Gonzalez-Obeso E.
      • Fujita H.
      • Deshpande V.
      • et al.
      Gastric hyperplastic polyps: a heterogeneous clinicopathologic group including a distinct subset best categorized as mucosal prolapse polyp.
      Dysplasia is rare in gastric PJ polyps.
      • Brosens L.A.A.
      • Wood L.D.
      • Offerhaus G.J.
      • et al.
      Pathology and genetics of syndromic gastric polyps.
      ,
      • Jansen M.
      • de Leng WWJ
      • Baas A.F.
      • et al.
      Mucosal prolapse in the pathogenesis of Peutz-Jeghers polyposis.
      Figure thumbnail gr6
      Fig. 6PJ polyp (hamartomatous polyp). A PJ hamartomatous polyp showing an arborizing pattern of smooth muscle proliferation between the epithelial components. This characteristic arborization pattern is often less pronounced in gastric polyps compared with intestinal PJ polyps. Therefore, these polyps generally cannot be reliably distinguished from gastric HPs based on histopathological characteristics.
      JPS is caused by germline mutation in SMAD4 or BMPR1A and characterized by a few to multiple juvenile polyps throughout the gastrointestinal tract. Because germline mutations are only found in 50% to 60% of JPS patients, the diagnosis is made when a patient fulfills any of the following criteria: (1) 3 or more colorectal juvenile polyps; (2) juvenile polyps throughout the gastrointestinal tract; or (3) any number of juvenile polyps in combination with a family history of juvenile polyposis.
      • Syngal S.
      • Brand R.E.
      • Church J.M.
      • et al.
      ACG clinical guideline: genetic testing and management of hereditary gastrointestinal cancer syndromes.
      ,

      Lokuhetty D, White VA, Watanabe R, et al, WHO Classification of tumors 5th edition Digestive system. IARC 2019;76-80.

      Gastric juvenile polyposis may be quite extensive, in particular, in patients with SMAD4 germline mutations, and can simulate Ménétrier disease. Polyps are described being more “stroma-rich” with elongated filiform projections, smooth outer surfaces, and prominent stroma with edema and mixed inflammation (Fig. 7).
      • Gonzalez R.S.
      • Adsay V.
      • Graham R.P.
      • et al.
      Massive gastric juvenile-type polyposis: a clinicopathological analysis of 22 cases.
      On the other hand, “epithelium-rich” juvenile gastric polyps have little stromal edema, but tightly packed glands and surface epithelium with hyperplasia.
      • Gonzalez R.S.
      • Adsay V.
      • Graham R.P.
      • et al.
      Massive gastric juvenile-type polyposis: a clinicopathological analysis of 22 cases.
      Immunohistochemistry for SMAD4 can be used because polyps from carriers of a SMAD4 germline mutation can show decreased or absent staining compared with normal epithelium.
      • Brosens L.A.A.
      • Wood L.D.
      • Offerhaus G.J.
      • et al.
      Pathology and genetics of syndromic gastric polyps.
      ,
      • Gonzalez R.S.
      • Adsay V.
      • Graham R.P.
      • et al.
      Massive gastric juvenile-type polyposis: a clinicopathological analysis of 22 cases.
      ,
      • Langeveld D.
      • van Hattem W.A.
      • de Leng WWJ
      • et al.
      SMAD4 immunohistochemistry reflects genetic status in juvenile polyposis syndrome.
      Massive gastric polyposis, associated with SMAD4 germline mutation, is often impossible to control endoscopically, and partial or complete gastrectomy is often necessary.
      • Syngal S.
      • Brand R.E.
      • Church J.M.
      • et al.
      ACG clinical guideline: genetic testing and management of hereditary gastrointestinal cancer syndromes.
      High-grade dysplasia and gastric cancer can develop in juvenile polyposis patients. Estimates of gastric cancer risk vary between 10% and 30%.
      • Brosens L.A.A.
      • Wood L.D.
      • Offerhaus G.J.
      • et al.
      Pathology and genetics of syndromic gastric polyps.
      ,
      • Syngal S.
      • Brand R.E.
      • Church J.M.
      • et al.
      ACG clinical guideline: genetic testing and management of hereditary gastrointestinal cancer syndromes.
      ,
      • Gonzalez R.S.
      • Adsay V.
      • Graham R.P.
      • et al.
      Massive gastric juvenile-type polyposis: a clinicopathological analysis of 22 cases.
      Figure thumbnail gr7a
      Fig. 7Juvenile polyp (hamartomatous polyp). (A) Hamartomatous polyp in the context of JPS (juvenile polyp). Juvenile polyps are described as being more “stroma-rich” with smooth outer surfaces and prominent edematous and inflamed stroma. However, these polyps generally cannot be reliably distinguished from gastric HPs based on morphologic characteristics, although SMAD4 immunohistochemistry may be of help because juvenile polyps show decreased or absent staining compared with normal epithelium and (sporadic) HPs (B).
      Figure thumbnail gr7b
      Fig. 7Juvenile polyp (hamartomatous polyp). (A) Hamartomatous polyp in the context of JPS (juvenile polyp). Juvenile polyps are described as being more “stroma-rich” with smooth outer surfaces and prominent edematous and inflamed stroma. However, these polyps generally cannot be reliably distinguished from gastric HPs based on morphologic characteristics, although SMAD4 immunohistochemistry may be of help because juvenile polyps show decreased or absent staining compared with normal epithelium and (sporadic) HPs (B).
      Phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome comprises a heterogeneous group of disorders, including Cowden (most cases), Bannayan-Riley-Ruvalcaba, and Proteus syndromes, all of which result from various germline mutations in PTEN. Clinical features of Cowden syndrome include mental retardation, macrocephaly, mucocutaneous lesions (facial trichilemmoma, acral keratoses, papillomatous papules), esophageal glycogenic acanthosis, thyroid lesions, fibrocystic disease, breast cancer, and a spectrum of gastrointestinal polyps, including hamartomatous polyps, adenomas, lipomas, and ganglioneuromas.
      • Shaco-Levy R.
      • Jasperson K.W.
      • Martin K.
      • et al.
      Gastrointestinal polyposis in Cowden syndrome.
      ,
      • Pilarski R.
      • Burt R.
      • Kohlman W.
      • et al.
      Cowden syndrome and the PTEN hamartoma tumor syndrome: systematic review and revised diagnostic criteria.
      The World Health Organization (WHO) defined diagnostic criteria based on the International Cowden Consortium, which is based on the presence of one or more of the mentioned diseases that can occur in Cowden syndrome. Gastric Cowden syndrome polyps are multiple and small and simulate sporadic HPs.
      • Coriat R.
      • Mozer M.
      • Caux F.
      • et al.
      Endoscopic findings in Cowden syndrome.
      ,
      • Levi Z.
      • Baris H.N.
      • Kedar I.
      • et al.
      Upper and lower gastrointestinal findings in PTEN mutation–positive Cowden syndrome patients participating in an active surveillance program.
      Probably there is an increased gastric cancer risk, but no definite estimates are available.
      • Pilarski R.
      • Burt R.
      • Kohlman W.
      • et al.
      Cowden syndrome and the PTEN hamartoma tumor syndrome: systematic review and revised diagnostic criteria.
      • Coriat R.
      • Mozer M.
      • Caux F.
      • et al.
      Endoscopic findings in Cowden syndrome.
      • Levi Z.
      • Baris H.N.
      • Kedar I.
      • et al.
      Upper and lower gastrointestinal findings in PTEN mutation–positive Cowden syndrome patients participating in an active surveillance program.
      Biopsies in patients with Ménétrier disease show hyperplastic foveolar epithelium, which on biopsies may be impossible to differentiate from HPs. The clinical and endoscopic information and biopsies of surrounding mucosa are especially needed to distinguish HPs from the protein-losing gastropathy in Ménétrier disease. This condition typically involves the oxyntic area (fundus and body) of the stomach, whereas HPs are more commonly situated in the antrum. In Ménétrier disease, there is diffusely oxyntic glandular atrophy and prominent foveolar hyperplasia.
      • Wolfsen H.C.
      • Carpenter H.A.
      • Talley N.J.
      Menetrier’s disease: a form of hypertrophic gastropathy or gastritis?.

      Prognosis, When to Ponder, When to Panic

      Gastric HPs were thought to be generally benign and banal polyps, but most HPs arise in a background of mucosal disease with a strong association with chronic gastritis with atrophy and intestinal metaplasia, which are the main risk factors of gastric cancer. Intestinal metaplasia can be observed in around 15% of HPs, dysplasia in less than 5%, and cancer in less than 1%.
      • Abraham S.C.
      • Singh V.K.
      • Yardley J.H.
      • et al.
      Hyperplastic polyps of the stomach: associations with histologic patterns of gastritis and gastric atrophy.
      There should be a thorough search and sampling for dysplasia in large polyps, because especially in polyps with a diameter greater than 2 cm, the risk of malignancy increases. Patients with HPs are at increased risk of gastric cancer, because of background of chronic (atrophic) gastritis in which HPs arise. Preferably, HPs are removed endoscopically in order to determine their nature and prove that the lesions are benign. Because HPs are important markers for an abnormal gastric mucosal background and are not isolated preneoplastic lesions, endoscopic evaluation with biopsies of the background mucosa is necessary to look for concomitant conditions like H pylori inflammation, intestinal metaplasia, atrophy, dysplasia, and malignancy.
      • Goddard A.F.
      • Badreldin R.
      • Pritchard D.M.
      • et al.
      British Society of Gastroenterology
      The management of gastric polyps.
      • Elongated, branching, and dilated foveolar glands with a hyperplastic appearance with abundant mucinous cytoplasm
      • Edematous stroma and chronic (active) inflammation
      • Syndromic hamartomatous polyps
      • Ménétrier disease
      • !
        The histology of gastric hamartomatous polyps arising in the context of PJS, JPS, and Cowden syndrome is not specific, and reliable distinction between syndromic hamartomatous polyps and HPs is impossible.
      • !
        An underlying hamartomatous polyposis syndrome should be considered in the case of multiple gastric hyperplastic-type polyps. Clinical correlation is pivotal because these syndromes have typical clinical characteristics and a family history.
      • !
        Sporadic HPs are associated with H pylori chronic gastritis. Therefore, biopsies of the background mucosa are necessary to look for intestinal metaplasia, dysplasia, and malignancy.

      Gastric foveolar-type adenoma

      Introduction

      Gastric foveolar-type adenomas are epithelial polyps consisting of neoplastic foveolar epithelium.

      Lokuhetty D, White VA, Watanabe R, et al, WHO Classification of tumors 5th edition Digestive system. IARC 2019;76-80.

      Foveolar-type adenomas are rare and show an equal sex distribution.
      • Wood L.D.
      • Salaria S.N.
      • Cruise M.W.
      • et al.
      Upper GI tract lesions in familial adenomatous polyposis (FAP).
      ,
      • Abraham S.C.
      • Montgomery E.A.
      • Singh V.K.
      • et al.
      Gastric adenomas.
      ,
      • Chen Z.-M.
      • Scudiere J.R.
      • Abraham S.C.
      • et al.
      Pyloric gland adenoma: an entity distinct from gastric foveolar type adenoma.
      The mean age of diagnosis is 44 years.
      • Abraham S.C.
      • Montgomery E.A.
      • Singh V.K.
      • et al.
      Gastric adenomas.
      ,
      • Chen Z.-M.
      • Scudiere J.R.
      • Abraham S.C.
      • et al.
      Pyloric gland adenoma: an entity distinct from gastric foveolar type adenoma.
      These adenomas can occur sporadically, but there is also an association with FAP and GAPPS.
      • Wood L.D.
      • Salaria S.N.
      • Cruise M.W.
      • et al.
      Upper GI tract lesions in familial adenomatous polyposis (FAP).

      Gross Features

      Gastric foveolar-type adenomas are typically solitary lesions, usually less than 1 cm in diameter, and occur more frequently in the body and fundus than in the antral region.

      Lokuhetty D, White VA, Watanabe R, et al, WHO Classification of tumors 5th edition Digestive system. IARC 2019;76-80.

      ,
      • Abraham S.C.
      • Montgomery E.A.
      • Singh V.K.
      • et al.
      Gastric adenomas.
      ,
      • Chen Z.-M.
      • Scudiere J.R.
      • Abraham S.C.
      • et al.
      Pyloric gland adenoma: an entity distinct from gastric foveolar type adenoma.
      In patients with FAP or GAPPS, these polyps usually coexist with multiple FGPs (see above).
      • Wood L.D.
      • Salaria S.N.
      • Cruise M.W.
      • et al.
      Upper GI tract lesions in familial adenomatous polyposis (FAP).

      Microscopic Features

      Gastric foveolar-type adenomas are composed of gastric epithelial mucin cells with a pink or pale apical mucin cap and show at least low-grade dysplasia (Fig. 8).
      • Brosens L.A.A.
      • Wood L.D.
      • Offerhaus G.J.
      • et al.
      Pathology and genetics of syndromic gastric polyps.
      ,
      • Abraham S.C.
      • Montgomery E.A.
      • Singh V.K.
      • et al.
      Gastric adenomas.
      ,
      • Chen Z.-M.
      • Scudiere J.R.
      • Abraham S.C.
      • et al.
      Pyloric gland adenoma: an entity distinct from gastric foveolar type adenoma.
      These polyps can be distinguished from the background mucosa by an abrupt transition from normal to atypical foveolar cells with hyperchromatic, crowded, and slightly disorganized nuclei, extending to the epithelial surface. Immunohistochemical expression for MUC5AC (gastric mucin marker) can confirm gastric differentiation, whereas expression of MUC6 (pyloric mucin marker), MUC2, and CDX2 (intestinal markers) are generally absent in these lesions.
      • Abraham S.C.
      • Montgomery E.A.
      • Singh V.K.
      • et al.
      Gastric adenomas.
      ,
      • Chen Z.-M.
      • Scudiere J.R.
      • Abraham S.C.
      • et al.
      Pyloric gland adenoma: an entity distinct from gastric foveolar type adenoma.
      Foveolar-type adenomas typically occur in normal gastric mucosa without metaplasia, atrophy, or inflammation.
      • Brosens L.A.A.
      • Wood L.D.
      • Offerhaus G.J.
      • et al.
      Pathology and genetics of syndromic gastric polyps.
      ,
      • Abraham S.C.
      • Montgomery E.A.
      • Singh V.K.
      • et al.
      Gastric adenomas.
      ,
      • Chen Z.-M.
      • Scudiere J.R.
      • Abraham S.C.
      • et al.
      Pyloric gland adenoma: an entity distinct from gastric foveolar type adenoma.
      Moreover, they rarely show high-grade dysplasia (characterized by severe nuclear atypia, loss of polarity, and/or architectural atypia) (Fig. 9) or carcinoma (Fig. 10).
      • Brosens L.A.A.
      • Wood L.D.
      • Offerhaus G.J.
      • et al.
      Pathology and genetics of syndromic gastric polyps.
      ,
      • Abraham S.C.
      • Montgomery E.A.
      • Singh V.K.
      • et al.
      Gastric adenomas.
      ,
      • Chen Z.-M.
      • Scudiere J.R.
      • Abraham S.C.
      • et al.
      Pyloric gland adenoma: an entity distinct from gastric foveolar type adenoma.
      Figure thumbnail gr8
      Fig. 8Foveolar-type adenoma with low-grade dysplasia. High-power view of a foveolar-type adenoma with low-grade dysplasia, showing atypical foveolar cells at the surface with hyperchromatic, crowded, and slightly disorganized nuclei.
      Figure thumbnail gr9
      Fig. 9Foveolar-type adenoma with high-grade dysplasia. High-power view of a foveolar-type adenoma with high-grade dysplasia, showing foveolar cells at the surface with more severe nuclear atypia as compared with , with round to oval, hyperchromatic nuclei with prominent nucleoli, loss of polarity, high nuclear-to-cytoplasmic ratio, and some architectural atypia with crowding and branching of glands. This case was from a patient with FAP syndrome.
      Figure thumbnail gr10a
      Fig. 10Foveolar-type adenoma with invasive carcinoma. (A) This foveolar-type adenoma shows intramucosal and superficial submucosal invasion with atypical back-to-back glands. (B) The neoplastic and invasive glands can be easily detected in this p53 staining, as they show p53 overexpression.
      Figure thumbnail gr10b
      Fig. 10Foveolar-type adenoma with invasive carcinoma. (A) This foveolar-type adenoma shows intramucosal and superficial submucosal invasion with atypical back-to-back glands. (B) The neoplastic and invasive glands can be easily detected in this p53 staining, as they show p53 overexpression.

      (Differential) Diagnosis

      Differential diagnostic considerations include other types of gastric adenomas (intestinal-type adenomas and PGAs). The cytoplasmic feature of the foveolar cells as described above helps to distinguish foveolar-type adenomas from the other types, although distinction may become more challenging in high-grade dysplasia. Intestinal-type adenomas show at least focal goblet cell or Paneth cell differentiation. Gastric foveolar-type adenomas rarely show high-grade dysplasia or carcinoma, whereas this is more common in intestinal-type adenomas. Moreover, the background mucosa of intestinal-type adenomas typically shows inflammation, atrophy, and/or intestinal metaplasia, whereas the background mucosa of foveolar-type adenomas is normal.
      • Abraham S.C.
      • Montgomery E.A.
      • Singh V.K.
      • et al.
      Gastric adenomas.
      No statistically significant differences in genetic mutations have been found between foveolar-type and intestinal-type adenomas.
      • Abraham S.C.
      • Park S.J.
      • Lee J.-H.
      • et al.
      Genetic alterations in gastric adenomas of intestinal and foveolar phenotypes.
      Foveolar-type adenomas in the context of FAP show biallelic APC inactivation, whereas sporadic variants infrequently harbor APC or KRAS mutations.

      Lokuhetty D, White VA, Watanabe R, et al, WHO Classification of tumors 5th edition Digestive system. IARC 2019;76-80.

      PGAs are characterized by an apical neutral mucin cap, show expression for MUC6 rather than MUC5AC, and harbor GNAS mutations not found in gastric foveolar-type and intestinal-type adenomas (see later discussion).
      • Matsubara A.
      • Sekine S.
      • Kushima R.
      • et al.
      Frequent GNAS and KRAS mutations in pyloric gland adenoma of the stomach and duodenum.
      ,
      • Hashimoto T.
      • Ogawa R.
      • Matsubara A.
      • et al.
      Familial adenomatous polyposis-associated and sporadic pyloric gland adenomas of the upper gastrointestinal tract share common genetic features.

      Prognosis, When to Ponder, When to Panic

      For foveolar-type adenomas, the rate of progression to high-grade dysplasia or cancer is exceedingly low (irrespective of sporadic or familial setting).
      • Wood L.D.
      • Salaria S.N.
      • Cruise M.W.
      • et al.
      Upper GI tract lesions in familial adenomatous polyposis (FAP).
      ,
      • Abraham S.C.
      • Montgomery E.A.
      • Singh V.K.
      • et al.
      Gastric adenomas.
      A genetic background of FAP syndrome can be found in 68% of foveolar-type adenomas.
      • Wood L.D.
      • Salaria S.N.
      • Cruise M.W.
      • et al.
      Upper GI tract lesions in familial adenomatous polyposis (FAP).
      Foveolar-type adenomas are the most frequent type of gastric adenomas in western FAP patients (85%). It should be noted, however, that distinguishing a gastric foveolar-type adenoma and an FGP with low-grade dysplasia can be difficult, but this is of little clinical significance because both lesions harbor a low risk of malignant transformation.
      • Wood L.D.
      • Salaria S.N.
      • Cruise M.W.
      • et al.
      Upper GI tract lesions in familial adenomatous polyposis (FAP).
      Similar to sporadic cases, the background mucosa of FAP patients with a foveolar-type adenoma is typically normal. Western FAP patients likely do not carry an increased risk of gastric cancer, although recently several cases of gastric cancer were reported in western patients with FAP and GAPPS
      • Walton S.-J.
      • Frayling I.M.
      • Clark S.K.
      • et al.
      Gastric tumours in FAP.
      ,
      • Mankaney G.
      • Leone P.
      • Cruise M.
      • et al.
      Gastric cancer in FAP: a concerning rise in incidence.
      ,
      • de Boer W.B.
      • Ee H.
      • Kumarasinghe M.P.
      Neoplastic lesions of gastric adenocarcinoma and proximal polyposis syndrome (GAPPS) are gastric phenotype.
      (see also above, Prognosis of fundic gland polyps).
      • Lesion composed of foveolar cells with a clear or pale apical mucin cap
      • Per definition, at least low-grade dysplasia
      • Immunohistochemistry: expression of MUC5AC; negative for MUC2, CDX2, and MUC6
      • In general, normal background gastric mucosa
      • Intestinal-type adenoma (at least focal presence of goblet cells and/or Paneth cells, expression of MUC2, background gastric mucosa with inflammation, atrophy, and intestinal metaplasia)
      • Pyloric gland adenoma (pyloric-type glands, expression of MUC6)
      • FGP with dysplasia (cystically dilated glands lined by parietal and chief cells)
      • Reactive atypia (more gradual gradient in atypia, background of inflammation/erosion)
      • !
        Association with FAP and GAPPS (low risk of malignant transformation)

      Gastric intestinal-type adenoma

      Introduction

      Gastric intestinal-type adenomas are localized polypoid lesions composed of dysplastic intestinalized epithelium and are the most frequent type of all gastric adenomas.

      Lokuhetty D, White VA, Watanabe R, et al, WHO Classification of tumors 5th edition Digestive system. IARC 2019;76-80.

      They occur more commonly in men than women (ratio 3:1), and usually in patients 60 to 80 years of age.
      • Abraham S.C.
      • Montgomery E.A.
      • Singh V.K.
      • et al.
      Gastric adenomas.
      Risk factors for developing this type of adenoma are any cause of gastric intestinal metaplasia (eg, H pylori infection, autoimmune atrophic gastritis).

      Lokuhetty D, White VA, Watanabe R, et al, WHO Classification of tumors 5th edition Digestive system. IARC 2019;76-80.

      Gross Features

      Gastric intestinal-type adenomas are usually single, well-circumscribed, sessile or pedunculated lesions, measuring less than 2 cm3. They are mostly found in the antral and pyloric region (about 60%) where intestinal metaplasia is most prevalent.
      • Abraham S.C.
      • Park S.J.
      • Lee J.-H.
      • et al.
      Genetic alterations in gastric adenomas of intestinal and foveolar phenotypes.

      Microscopic Features

      Gastric intestinal-type adenomas show an intestinal-type columnar epithelium containing absorptive cells, goblet cells, endocrine cells, and/or Paneth cells (although they may be sparse) and show by definition at least low-grade dysplasia (Fig. 11). These lesions show columnar cells with hyperchromatic, elongated nuclei with pseudostratification and crowding, extending to the surface, similar to tubular adenomas in the colon and rectum. There is increased mitotic activity. Often, a distinct brush border is present that confirms intestinal differentiation in the dysplastic epithelium. Because of an abrupt transition from the background mucosa with striking hyperchromasia, these lesions can usually be easily detected at low power, although reactive epithelial changes in surrounding mucosa can cause diagnostic challenges. Architectural complexity (cribriform, branching, budding, or crowding glands) as well as severe cytologic atypia (rounded nuclei with loss of polarity, clumped chromatin, and prominent nucleoli) are features of high-grade dysplasia. Almost all intestinal-type adenomas occur in background gastric mucosa with H pylori infection (42%), background gastritis and atrophy (environmental atrophic metaplastic gastritis [52%], autoimmune metaplastic atrophic gastritis [19%]), and/or intestinal metaplasia.
      • Brosens L.A.A.
      • Wood L.D.
      • Offerhaus G.J.
      • et al.
      Pathology and genetics of syndromic gastric polyps.
      ,
      • Abraham S.C.
      • Montgomery E.A.
      • Singh V.K.
      • et al.
      Gastric adenomas.
      Intestinal-type adenomas show variable expression of intestinal markers MUC2 and CD10. There is no or slight expression for gastric mucins MUC5AC and MUC6.
      Figure thumbnail gr11
      Fig. 11Intestinal-type adenoma. High-power view of an intestinal-type adenoma with low-grade dysplasia, showing columnar cells with hyperchromatic, elongated nuclei and pseudostratification, extending to the surface. Several goblet cells and Paneth cells can be seen.

      (Differential) Diagnosis

      Differential diagnostic considerations include other types of gastric adenomas (foveolar-type adenomas and PGAs; see Differential diagnosis section of Gastric foveolar-type adenomas). Another diagnostic difficulty can be caused by reactive epithelial changes due to inflammation or erosion, which is frequently present in chronic gastritis. In contrast to intestinal-type adenomas, reactive atypia is characterized by a gradual gradient in atypia from the background mucosa with slight hyperchromatic nuclei and no nuclear crowding.

      Prognosis, When to Ponder, When to Panic

      It is important to realize that intestinal-type adenomas have a reasonable risk of malignant transformation. Approximately 40% of lesions show high-grade dysplasia, and approximately 25% progress to adenocarcinoma.
      • Abraham S.C.
      • Montgomery E.A.
      • Singh V.K.
      • et al.
      Gastric adenomas.
      ,
      • Abraham S.C.
      • Park S.J.
      • Lee J.-H.
      • et al.
      Genetic alterations in gastric adenomas of intestinal and foveolar phenotypes.
      Therefore, complete (endoscopic) excision is important, and the lesions should be processed entirely for microscopic examination to identify potential areas of high-grade dysplasia or carcinoma. Moreover, these adenomas are also associated with separate foci of intestinal metaplasia (97%), flat dysplasia (6%), and adenocarcinoma (16%) elsewhere in the stomach.
      • Abraham S.C.
      • Montgomery E.A.
      • Singh V.K.
      • et al.
      Gastric adenomas.
      Therefore, biopsies of the background mucosa are crucial.
      Intestinal-type adenomas are very rare in western FAP patients (1%–2% of gastric adenomas in FAP) but more common in Asian FAP patients, probably related to differences in prevalence of H pylori infection and atrophic gastritis.
      • Wood L.D.
      • Salaria S.N.
      • Cruise M.W.
      • et al.
      Upper GI tract lesions in familial adenomatous polyposis (FAP).
      ,
      • Nakamura S.
      • Matsumoto T.
      • Kobori Y.
      • et al.
      Impact of Helicobacter Pylori Infection and Mucosal Atrophy on Gastric Lesions in Patients With Familial Adenomatous Polyposis.
      FAP patients with intestinal-type adenomas with additional H pylori infection and gastric atrophy especially seem to have an increased risk of developing intestinal-type gastric adenocarcinoma.
      • Leggett B.
      FAP: another indication to treat H pylori.
      ,
      • Nakamura S.
      • Matsumoto T.
      • Kobori Y.
      • et al.
      Impact of Helicobacter Pylori Infection and Mucosal Atrophy on Gastric Lesions in Patients With Familial Adenomatous Polyposis.
      • Localized lesion composed of dysplastic intestinalized epithelium with at least focal presence of goblet cells and/or Paneth cells
      • Per definition, at least low-grade dysplasia
      • Immunohistochemistry: expression of MUC2; negative for MUC5AC and MUC6
      • Background gastric mucosa often shows inflammation, atrophy, and/or intestinal metaplasia
      • Foveolar-type adenomas (foveolar-type cells with pale or clear mucin cap, no goblet cells or Paneth cells)
      • Pyloric gland adenoma (pyloric-type glands, positive for MUC6)
      • Reactive atypia (more gradual gradient in atypia)
      • !
        Reasonable risk of malignant transformation (high-grade dysplasia or carcinoma in same lesion, or presence of synchronous lesions with high-grade dysplasia or carcinoma)
      • !
        Association with FAP syndrome, especially in non-western populations
      • !
        FAP patients with intestinal-type adenoma together with H pylori infection and gastric atrophy are especially at risk for developing gastric adenocarcinoma

      Gastric glandular adenomas: pyloric gland adenoma and oxyntic gland adenoma

      Introduction

      PGA and OGA are rare polyps. They are the most recently recognized gastric epithelial polyps, characterized by closely packed pyloric or oxyntic glands, respectively. Of these polyps, PGAs are the more common. Sporadic PGAs are found in patients with conditions resulting in pyloric metaplasia, such as autoimmune atrophic gastritis or chronic H pylori gastritis. More than 30% of PGAs arise in a background of autoimmune atrophic gastritis.
      • Chen Z.-M.
      • Scudiere J.R.
      • Abraham S.C.
      • et al.
      Pyloric gland adenoma: an entity distinct from gastric foveolar type adenoma.
      ,
      • Vieth M.
      • Kushima R.
      • Borchard F.
      • et al.
      Pyloric gland adenoma: a clinico-pathological analysis of 90 cases.
      Nevertheless, PGAs remain a rare finding, even in patients with autoimmune atrophic gastritis, and most polyps in patients with autoimmune atrophic gastritis are HPs (80%), oxyntic mucosa pseudopolyps (10%), or intestinal adenomas (10%).
      • Park J.Y.
      • Cornish T.C.
      • Lam-Himlin D.
      • et al.
      Gastric lesions in patients with autoimmune metaplastic atrophic gastritis (AMAG) in a tertiary care setting.
      Of note, PGAs were recently also described in FAP patients, where they arise in nonatrophic background mucosa.
      • Wood L.D.
      • Salaria S.N.
      • Cruise M.W.
      • et al.
      Upper GI tract lesions in familial adenomatous polyposis (FAP).
      PGAs have also been reported in Lynch syndrome, McCune-Albright syndrome, and JPS.
      • Lee S.E.
      • Kang S.Y.
      • Cho J.
      • et al.
      Pyloric gland adenoma in Lynch syndrome.
      • Ma C.
      • Giardiello F.M.
      • Montgomery E.A.
      Upper tract juvenile polyps in juvenile polyposis patients: dysplasia and malignancy are associated with foveolar, intestinal, and pyloric differentiation.
      • Wood L.D.
      • Noë M.
      • Hackeng W.
      • et al.
      Patients with McCune-Albright syndrome have a broad spectrum of abnormalities in the gastrointestinal tract and pancreas.
      Various terms have been used in the literature for gastric neoplasms with oxyntic gland differentiation. Most such lesions are best addressed as OGA, whereas rare cases with atypia and submucosal invasion may be better addressed as gastric adenocarcinoma of fundic gland type (GA-FG).
      • Ushiku T.
      • Kunita A.
      • Kuroda R.
      • et al.
      Oxyntic gland neoplasm of the stomach: expanding the spectrum and proposal of terminology.
      Neoplasms with oxyntic gland differentiation are exceedingly rare, and most cases have been reported in Japanese literature. Gastric glandular adenoma has been suggested as an appropriate unifying diagnostic term for polyps arising from the glandular compartment, as opposed to gastric foveolar and intestinal type adenomas.
      • Hackeng W.M.
      • Montgomery E.A.
      • Giardiello F.M.
      • et al.
      Morphology and genetics of pyloric gland adenomas in familial adenomatous polyposis.

      Gross Features

      Most PGAs form polypoid lesions or masses varying from a few millimeters to 10 cm, with an average of 2 cm. OGAs tend to be smaller in size (usually <1 cm), whereas GA-FG are larger (1.5–4 cm).

      Microscopic Features

      Histologically, PGA is characterized by densely packed cuboidal to low columnar epithelium resembling pyloric gland cells (Fig. 12). Immunohistochemically, PGAs are positive for both MUC6 (strong) and MUC5AC (slight or partially). PGAs typically lack expression of intestinal markers MUC2 and CDX2, although MUC2 is sometimes positive in areas with transition to intestinal metaplasia.
      • Vieth M.
      • Kushima R.
      • Mukaisho K.
      • et al.
      Immunohistochemical analysis of pyloric gland adenomas using a series of Mucin 2, Mucin 5AC, Mucin 6, CD10, Ki67 and p53.
      High-grade dysplasia has been reported in about half of PGAs and is characterized by disturbed architecture and loss of nuclear polarity. Ki-67 immunohistochemistry can be helpful to identify high-grade dysplasia in PGAs (Fig. 13). Activating GNAS mutations are relatively specific for PGA because it is found in most PGAs but not in gastric foveolar-type or intestinal-type adenomas or FGPs.
      • Hackeng W.M.
      • Montgomery E.A.
      • Giardiello F.M.
      • et al.
      Morphology and genetics of pyloric gland adenomas in familial adenomatous polyposis.
      ,
      • Matsubara A.
      • Sekine S.
      • Kushima R.
      • et al.
      Frequent GNAS and KRAS mutations in pyloric gland adenoma of the stomach and duodenum.
      ,
      • Hashimoto T.
      • Ogawa R.
      • Matsubara A.
      • et al.
      Familial adenomatous polyposis-associated and sporadic pyloric gland adenomas of the upper gastrointestinal tract share common genetic features.
      Figure thumbnail gr12a
      Fig. 12PGA. (A) Low-power view of a PGA showing densely packed, sometimes cystically dilated, monotonous pyloric-type glands. (B) High-power view of the same polyp showing cells with ground-glass cytoplasm. PGAs show strong expression of MUC6 (not shown).
      Figure thumbnail gr12b
      Fig. 12PGA. (A) Low-power view of a PGA showing densely packed, sometimes cystically dilated, monotonous pyloric-type glands. (B) High-power view of the same polyp showing cells with ground-glass cytoplasm. PGAs show strong expression of MUC6 (not shown).
      Figure thumbnail gr13a
      Fig. 13High-grade dysplasia in a PGA. (A) High-grade dysplasia in a PGA characterized by complex architecture and loss of nuclear polarity. (B) High-power view showing loss of nuclear polarity and mitotic activity. (C) Increased Ki-67 immunolabeling in high-grade dysplasia in a PGA. Note Ki-67 negativity in the low-grade glands at the bottom.
      Figure thumbnail gr13b
      Fig. 13High-grade dysplasia in a PGA. (A) High-grade dysplasia in a PGA characterized by complex architecture and loss of nuclear polarity. (B) High-power view showing loss of nuclear polarity and mitotic activity. (C) Increased Ki-67 immunolabeling in high-grade dysplasia in a PGA. Note Ki-67 negativity in the low-grade glands at the bottom.
      Figure thumbnail gr13c
      Fig. 13High-grade dysplasia in a PGA. (A) High-grade dysplasia in a PGA characterized by complex architecture and loss of nuclear polarity. (B) High-power view showing loss of nuclear polarity and mitotic activity. (C) Increased Ki-67 immunolabeling in high-grade dysplasia in a PGA. Note Ki-67 negativity in the low-grade glands at the bottom.
      Gastric neoplasms with oxyntic gland differentiation are characterized by closely packed oxyntic gland with either a monotonous proliferation of chief cells or an admixture of chief cells and parietal cells resembling fundic glands (Fig. 14).
      • Ushiku T.
      • Kunita A.
      • Kuroda R.
      • et al.
      Oxyntic gland neoplasm of the stomach: expanding the spectrum and proposal of terminology.
      ,
      • Singhi A.D.
      • Lazenby A.J.
      • Montgomery E.A.
      Gastric adenocarcinoma with chief cell differentiation.
      Most of these tumors have only very mild atypia and are restricted to the mucosa. These lesions are benign and best addressed as OGA. Some of these lesions show superficial submucosal involvement (<0,1 cm). Larger lesions (>1.5 cm) can show more aggressive histologic features with deeper submucosal invasion, atypical cellular differentiation (ie, mucus neck or foveolar differentiation), and mild to moderate nuclear atypia and may be best addressed as GA-FG.
      • Ushiku T.
      • Kunita A.
      • Kuroda R.
      • et al.
      Oxyntic gland neoplasm of the stomach: expanding the spectrum and proposal of terminology.
      In contrast to PGA, OGAs arise in oxyntic mucosa without atrophy or pyloric metaplasia.
      • Ushiku T.
      • Kunita A.
      • Kuroda R.
      • et al.
      Oxyntic gland neoplasm of the stomach: expanding the spectrum and proposal of terminology.
      Figure thumbnail gr14
      Fig. 14OGA. High-power view of an OGA showing densely packed oxyntic glands with a monotonous proliferation of parietal and chief cells.

      (Differential) Diagnosis

      The differential diagnosis is mainly with other gastric glandular polyps, such as FGP. In contrast to GA-FG, dysplastic changes in FGP are only present in the superficial foveolar layer, whereas the glandular part of the lesion lacks atypia and architectural complexity. Depending on the background mucosa, distinction between PGA and OGA can be challenging.
      • Hackeng W.M.
      • Montgomery E.A.
      • Giardiello F.M.
      • et al.
      Morphology and genetics of pyloric gland adenomas in familial adenomatous polyposis.
      There is a morphologic continuum between OGA and GA-FG, if these are indeed considered as separate entities.
      • Benedict M.A.
      • Lauwers G.Y.
      • Jain D.
      Gastric adenocarcinoma of the fundic gland type: update and literature review.

      Prognosis, When to Ponder, When to Panic

      Up to half of PGAs harbor high-grade dysplasia, but submucosal invasion is rare (<10%).
      • Chen Z.-M.
      • Scudiere J.R.
      • Abraham S.C.
      • et al.
      Pyloric gland adenoma: an entity distinct from gastric foveolar type adenoma.
      ,
      • Choi W.-T.
      • Brown I.
      • Ushiku T.
      • et al.
      Gastric pyloric gland adenoma: a multicentre clinicopathological study of 67 cases.
      Therefore, radical local excision is indicated. After radical resection, recurrence rate is low (<10%).
      • Choi W.-T.
      • Brown I.
      • Ushiku T.
      • et al.
      Gastric pyloric gland adenoma: a multicentre clinicopathological study of 67 cases.
      Although submucosal invasion is commonly found in OGA, these lesions have a very low malignant potential. Lymphovascular invasion has only been found in lesions fulfilling criteria of GA-FG. Even in those cases with invasion, lymph node metastasis is extremely rare, and complete (endoscopic) resection of GA-FG seems adequate treatment.
      • Ushiku T.
      • Kunita A.
      • Kuroda R.
      • et al.
      Oxyntic gland neoplasm of the stomach: expanding the spectrum and proposal of terminology.
      ,
      • Benedict M.A.
      • Lauwers G.Y.
      • Jain D.
      Gastric adenocarcinoma of the fundic gland type: update and literature review.
      ,
      • Gannon B.R.
      • Riddell R.H.
      Gastric polyps with intramucosal carcinoma.
      In contrast to sporadic cases, PGAs in FAP patients develop in nonatrophic mucosa and show variable presence of parietal cells, making differentiation from OGA sometimes very difficult or even impossible. Based on these observations and the common GNAS mutations in OGA and PGA, it has been hypothesized that PGA and OGA are likely the same lesions within a spectrum with subtle histologic differences depending on the background mucosa in which they arise.
      • Hackeng W.M.
      • Montgomery E.A.
      • Giardiello F.M.
      • et al.
      Morphology and genetics of pyloric gland adenomas in familial adenomatous polyposis.
      • Pyloric gland adenoma: densely packed pyloric-type glands
      • OGA: closely packed oxyntic glands (can be chief cell-predominant or an admixture of chief cells and parietal cells)
      • FGPs
      • Distinction between PGA and OGA can be difficult and may depend on type of background mucosa (eg, atrophic mucosa with pseudopyloric metaplasia or nonatrophic oxyntic mucosa)
      • OGA versus GA-FG is a histologic continuum

      How to recognize early invasion in gastric polyps (intramucosal carcinoma)

      Introduction

      Most gastric polyps, such as adenomas, HPs, FGPs, and PGAs, are sporadic with no significant malignant potential; however, it is important to search for areas of high-grade dysplasia and infiltrative growth. Early gastric cancer, defined as carcinoma confined to the mucosa or submucosa, may be encountered in endoscopically benign-appearing polyps.
      • Gannon B.R.
      • Riddell R.H.
      Gastric polyps with intramucosal carcinoma.
      Especially in the Japanese population, there is experience with the risks that intramucosal cancers exhibit. Patients with well-differentiated early gastric cancer limited to the mucosa or the upper submucosa (SM1, up to a depth of 500 μm) and without lymphovascular invasion generally have a very low risk of lymph node metastases.
      • Gannon B.R.
      • Riddell R.H.
      Gastric polyps with intramucosal carcinoma.
      ,
      • Ishikawa S.
      • Togashi A.
      • Inoue M.
      • et al.
      Indications for EMR/ESD in cases of early gastric cancer: relationship between histological type, depth of wall invasion, and lymph node metastasis.
      Therefore, surgery is not necessary in most early gastric cancers, and these may be treated effectively with endoscopic resection or endoscopic polypectomy.

      Microscopic Features

      Polyps with low-grade dysplasia are characterized by mild to moderate nuclear atypia and crowding of nuclei with mild pseudostratification. There is no complex architecture. Features of high-grade dysplasia are cribriform architecture, marked glandular crowding, full-thickness nuclear stratification, and severe nuclear atypia. Intramucosal carcinomas are defined by invasion into the lamina propria. It is difficult to distinguish nuclear features of intramucosal carcinomas from high-grade dysplasia. Features in favor of carcinoma are syncytial growth pattern, effacement of normal architecture with back-to-back glands, and single cells infiltrating the lamina propria (see Fig. 10). Often there are cystic glands. Desmoplastic stroma is often lacking or difficult to detect in intramucosal cancer. Intramucosal cancer should be classified and graded. Classification is preferably according to the WHO classification scheme.

      Lokuhetty D, White VA, Watanabe R, et al, WHO Classification of tumors 5th edition Digestive system. IARC 2019;76-80.

      Grading applies only to tubular and papillary gastric cancers. A tumor can be designated as poorly differentiated if there are marked architecturally distorted glands and single cells are present. Tumors with signet ring cells or diffuse growth are classified as poorly cohesive cancers; these gastric cancers often have a higher stage with consequently a poor prognosis. Therefore, limited endoscopic resection is often inferior for the treatment of these tumors, especially in a western population. Assessing the extent of invasion into the mucosa and/or submucosa is essential to determine whether the patient requires a (partial) gastrectomy.
      • Gannon B.R.
      • Riddell R.H.
      Gastric polyps with intramucosal carcinoma.
      As for all gastric polyps, the nonneoplastic surrounding epithelium should be assessed for features predisposing to neoplasia, such as intestinal metaplasia, atrophic mucosa, and H pylori infection.

      Concluding remarks

      In this review, the authors provide an overview of different types of gastric epithelial polyps, based on their cell or epithelial compartment of origin. Most gastric polyps are sporadic with no malignant potential, but clinical correlation is necessary, and pathologists should be familiar with the morphologic characteristics of gastric polyps as an indication for a search for an underlying genetic syndrome, such as FAP, PJS, or JPS. Moreover, in the presence of a gastric polyp, preferably biopsies of background mucosa are taken of at least the antrum and corpus. Evaluation of the background nonpolypoid mucosa is essential in reaching a diagnosis that can characterize the condition in which the polyp developed, which may have therapeutic consequences.

      Acknowledgments

      The authors thank Folkert Morsink for his help with the figures.

      Disclosure

      The authors have nothing to disclose.

      References

        • Park D.Y.
        • Lauwers G.Y.
        Gastric polyps: classification and management.
        Arch Pathol Lab Med. 2008; 132: 633-640
        • Castro R.
        • Pimentel-Nunes P.
        • Dinis-Ribeiro M.
        Evaluation and management of gastric epithelial polyps.
        Best Pract Res Clin Gastroenterol. 2017; 31: 381-387
        • Carmack S.W.
        • Genta R.M.
        • Graham D.Y.
        • et al.
        Management of gastric polyps: a pathology-based guide for gastroenterologists.
        Nat Rev Gastroenterol Hepatol. 2009; 6: 331-341
        • Carmack S.W.
        • Genta R.M.
        • Schuler C.M.
        • et al.
        The current spectrum of gastric polyps: a 1-year national study of over 120,000 patients.
        Am J Gastroenterol. 2009; 104: 1524-1532
        • Brosens L.A.A.
        • Wood L.D.
        • Offerhaus G.J.
        • et al.
        Pathology and genetics of syndromic gastric polyps.
        Int J Surg Pathol. 2016; 24: 185-199
        • Vogt S.
        • Jones N.
        • Christian D.
        • et al.
        Expanded extracolonic tumor spectrum in MUTYH-associated polyposis.
        Gastroenterology. 2009; 137: 1976-1985.e1-10
        • Hackeng W.M.
        • Montgomery E.A.
        • Giardiello F.M.
        • et al.
        Morphology and genetics of pyloric gland adenomas in familial adenomatous polyposis.
        Histopathology. 2017; 70: 549-557
        • Wood L.D.
        • Salaria S.N.
        • Cruise M.W.
        • et al.
        Upper GI tract lesions in familial adenomatous polyposis (FAP).
        Am J Surg Pathol. 2014; 38: 389-393
        • Abraham S.C.
        • Park S.J.
        • Mugartegui L.
        • et al.
        Sporadic fundic gland polyps with epithelial dysplasia: evidence for preferential targeting for mutations in the adenomatous polyposis coli gene.
        Am J Pathol. 2002; 161: 1735-1742
        • Sekine S.
        • Shibata T.
        • Yamauchi Y.
        • et al.
        Beta-catenin mutations in sporadic fundic gland polyps.
        Virchows Arch. 2002; 440: 381-386
        • Abraham S.C.
        • Nobukawa B.
        • Giardiello F.M.
        • et al.
        Fundic gland polyps in familial adenomatous polyposis.
        Am J Pathol. 2000; 157: 747-754
        • Sekine S.
        • Shimoda T.
        • Nimura S.
        • et al.
        High-grade dysplasia associated with fundic gland polyposis in a familial adenomatous polyposis patient, with special reference to APC mutation profiles.
        Mod Pathol. 2004; 17: 1421-1426
        • Straub S.F.
        • Drage M.G.
        • Gonzalez R.S.
        Comparison of dysplastic fundic gland polyps in patients with and without familial adenomatous polyposis.
        Histopathology. 2018; 72: 1172-1179
        • Levy M.D.
        • Bhattacharya B.
        Sporadic fundic gland polyps with low-grade dysplasia: a large case series evaluating pathologic and immunohistochemical findings and clinical behavior.
        Am J Clin Pathol. 2015; 144: 592-600
        • Abraham S.C.
        Fundic gland polyps: common and occasionally problematic lesions.
        Gastroenterol Hepatol (N Y). 2010; 6: 48-51
        • Burt R.W.
        Gastric fundic gland polyps.
        Gastroenterology. 2003; 125: 1462-1469
        • Torbenson M.
        • Lee J.-H.
        • Cruz-Correa M.
        • et al.
        Sporadic fundic gland polyposis: a clinical, histological, and molecular analysis.
        Mod Pathol. 2002; 15: 718-723
        • Genta R.M.
        • Schuler C.M.
        • Robiou C.I.
        • et al.
        No association between gastric fundic gland polyps and gastrointestinal neoplasia in a study of over 100,000 patients.
        Clin Gastroenterol Hepatol. 2009; 7: 849-854
        • Brosens L.A.A.
        • Offerhaus G.J.A.
        • Giardiello F.M.
        Hereditary colorectal cancer: genetics and screening.
        Surg Clin North Am. 2015; 95: 1067-1080
        • Offerhaus G.J.
        • Giardiello F.M.
        • Krush A.J.
        • et al.
        The risk of upper gastrointestinal cancer in familial adenomatous polyposis.
        Gastroenterology. 1992; 102: 1980-1982
        • Park J.-G.
        • Park K.J.
        • Ahn Y.-O.
        • et al.
        Risk of gastric cancer among Korean familial adenomatous polyposis patients.
        Dis Colon Rectum. 1992; 35: 996-998
        • Iwama T.
        • Mishima Y.
        • Utsunomiya J.
        The impact of familial adenomatous polyposis on the tumorigenesis and mortality at the several organs. Its rational treatment.
        Ann Surg. 1993; 217: 101-108
        • Walton S.-J.
        • Frayling I.M.
        • Clark S.K.
        • et al.
        Gastric tumours in FAP.
        Fam Cancer. 2017; 16: 363-369
        • Mankaney G.
        • Leone P.
        • Cruise M.
        • et al.
        Gastric cancer in FAP: a concerning rise in incidence.
        Fam Cancer. 2017; 16: 371-376
        • Leone P.J.
        • Mankaney G.
        • Sarvapelli S.
        • et al.
        Endoscopic and histologic features associated with gastric cancer in familial adenomatous polyposis.
        Gastrointest Endosc. 2019; 89: 961-968
        • Worthley D.L.
        • Phillips K.D.
        • Wayte N.
        • et al.
        Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS): a new autosomal dominant syndrome.
        Gut. 2012; 61: 774-779
        • Li J.
        • Woods S.L.
        • Healey S.
        • et al.
        Point mutations in exon 1B of APC reveal gastric adenocarcinoma and proximal polyposis of the stomach as a familial adenomatous polyposis variant.
        Am J Hum Genet. 2016; 98: 830-842
        • van der Post R.S.
        • Carneiro F.
        Emerging concepts in gastric neoplasia: heritable gastric cancers and polyposis disorders.
        Surg Pathol Clin. 2017; 10: 931-945
        • Leggett B.
        FAP: another indication to treat H pylori.
        Gut. 2002; 51: 463-464
        • Abraham S.C.
        • Singh V.K.
        • Yardley J.H.
        • et al.
        Hyperplastic polyps of the stomach: associations with histologic patterns of gastritis and gastric atrophy.
        Am J Surg Pathol. 2001; 25: 500-507
        • Gonzalez-Obeso E.
        • Fujita H.
        • Deshpande V.
        • et al.
        Gastric hyperplastic polyps: a heterogeneous clinicopathologic group including a distinct subset best categorized as mucosal prolapse polyp.
        Am J Surg Pathol. 2011; 35: 670-677
        • Lam-Himlin D.
        • Park J.Y.
        • Cornish T.C.
        • et al.
        Morphologic characterization of syndromic gastric polyps.
        Am J Surg Pathol. 2010; 34: 1656-1662
        • Abraham S.C.
        • Singh V.K.
        • Yardley J.H.
        • et al.
        Hyperplastic polyps of the esophagus and esophagogastric junction: histologic and clinicopathologic findings.
        Am J Surg Pathol. 2001; 25: 1180-1187
        • Tse J.Y.
        • Wu S.
        • Shinagare S.A.
        • et al.
        Peutz-Jeghers syndrome: a critical look at colonic Peutz-Jeghers polyps.
        Mod Pathol. 2013; 26: 1235-1240
        • Shaco-Levy R.
        • Jasperson K.W.
        • Martin K.
        • et al.
        Morphologic characterization of hamartomatous gastrointestinal polyps in Cowden syndrome, Peutz-Jeghers syndrome, and juvenile polyposis syndrome.
        Hum Pathol. 2016; 49: 39-48
        • Giardiello F.M.
        • Brensinger J.D.
        • Tersmette A.C.
        • et al.
        Very high risk of cancer in familial Peutz-Jeghers syndrome.
        Gastroenterology. 2000; 119: 1447-1453
        • Jansen M.
        • de Leng WWJ
        • Baas A.F.
        • et al.
        Mucosal prolapse in the pathogenesis of Peutz-Jeghers polyposis.
        Gut. 2006; 55: 1-5
        • Syngal S.
        • Brand R.E.
        • Church J.M.
        • et al.
        ACG clinical guideline: genetic testing and management of hereditary gastrointestinal cancer syndromes.
        Am J Gastroenterol. 2015; 110 ([quiz: 263]): 223-262
      1. Lokuhetty D, White VA, Watanabe R, et al, WHO Classification of tumors 5th edition Digestive system. IARC 2019;76-80.

        • Gonzalez R.S.
        • Adsay V.
        • Graham R.P.
        • et al.
        Massive gastric juvenile-type polyposis: a clinicopathological analysis of 22 cases.
        Histopathology. 2017; 70: 918-928
        • Langeveld D.
        • van Hattem W.A.
        • de Leng WWJ
        • et al.
        SMAD4 immunohistochemistry reflects genetic status in juvenile polyposis syndrome.
        Clin Cancer Res. 2010; 16: 4126-4134
        • Shaco-Levy R.
        • Jasperson K.W.
        • Martin K.
        • et al.
        Gastrointestinal polyposis in Cowden syndrome.
        J Clin Gastroenterol. 2017; 51: e60-e67
        • Pilarski R.
        • Burt R.
        • Kohlman W.
        • et al.
        Cowden syndrome and the PTEN hamartoma tumor syndrome: systematic review and revised diagnostic criteria.
        J Natl Cancer Inst. 2013; 105: 1607-1616
        • Coriat R.
        • Mozer M.
        • Caux F.
        • et al.
        Endoscopic findings in Cowden syndrome.
        Endoscopy. 2011; 43: 723-726
        • Levi Z.
        • Baris H.N.
        • Kedar I.
        • et al.
        Upper and lower gastrointestinal findings in PTEN mutation–positive Cowden syndrome patients participating in an active surveillance program.
        Clin Transl Gastroenterol. 2011; 2: e5
        • Wolfsen H.C.
        • Carpenter H.A.
        • Talley N.J.
        Menetrier’s disease: a form of hypertrophic gastropathy or gastritis?.
        Gastroenterology. 1993; 104: 1310-1319
        • Goddard A.F.
        • Badreldin R.
        • Pritchard D.M.
        • et al.
        • British Society of Gastroenterology
        The management of gastric polyps.
        Gut. 2010; 59: 1270-1276
        • Abraham S.C.
        • Montgomery E.A.
        • Singh V.K.
        • et al.
        Gastric adenomas.
        Am J Surg Pathol. 2002; 26: 1276-1285
        • Chen Z.-M.
        • Scudiere J.R.
        • Abraham S.C.
        • et al.
        Pyloric gland adenoma: an entity distinct from gastric foveolar type adenoma.
        Am J Surg Pathol. 2009; 33: 186-193
        • Abraham S.C.
        • Park S.J.
        • Lee J.-H.
        • et al.
        Genetic alterations in gastric adenomas of intestinal and foveolar phenotypes.
        Mod Pathol. 2003; 16: 786-795
        • Matsubara A.
        • Sekine S.
        • Kushima R.
        • et al.
        Frequent GNAS and KRAS mutations in pyloric gland adenoma of the stomach and duodenum.
        J Pathol. 2013; 229: 579-587
        • Hashimoto T.
        • Ogawa R.
        • Matsubara A.
        • et al.
        Familial adenomatous polyposis-associated and sporadic pyloric gland adenomas of the upper gastrointestinal tract share common genetic features.
        Histopathology. 2015; 67: 689-698
        • de Boer W.B.
        • Ee H.
        • Kumarasinghe M.P.
        Neoplastic lesions of gastric adenocarcinoma and proximal polyposis syndrome (GAPPS) are gastric phenotype.
        Am J Surg Pathol. 2017; 42: 1
        • Nakamura S.
        • Matsumoto T.
        • Kobori Y.
        • et al.
        Impact of Helicobacter Pylori Infection and Mucosal Atrophy on Gastric Lesions in Patients With Familial Adenomatous Polyposis.
        Gut. 2002; 51: 485-489https://doi.org/10.1136/gut.51.4.485
        • Vieth M.
        • Kushima R.
        • Borchard F.
        • et al.
        Pyloric gland adenoma: a clinico-pathological analysis of 90 cases.
        Virchows Arch. 2003; 442: 317-321
        • Park J.Y.
        • Cornish T.C.
        • Lam-Himlin D.
        • et al.
        Gastric lesions in patients with autoimmune metaplastic atrophic gastritis (AMAG) in a tertiary care setting.
        Am J Surg Pathol. 2010; 34: 1591-1598
        • Lee S.E.
        • Kang S.Y.
        • Cho J.
        • et al.
        Pyloric gland adenoma in Lynch syndrome.
        Am J Surg Pathol. 2014; 38: 784-792
        • Ma C.
        • Giardiello F.M.
        • Montgomery E.A.
        Upper tract juvenile polyps in juvenile polyposis patients: dysplasia and malignancy are associated with foveolar, intestinal, and pyloric differentiation.
        Am J Surg Pathol. 2014; 38: 1618-1626
        • Wood L.D.
        • Noë M.
        • Hackeng W.
        • et al.
        Patients with McCune-Albright syndrome have a broad spectrum of abnormalities in the gastrointestinal tract and pancreas.
        Virchows Arch. 2017; 470: 391-400
        • Ushiku T.
        • Kunita A.
        • Kuroda R.
        • et al.
        Oxyntic gland neoplasm of the stomach: expanding the spectrum and proposal of terminology.
        Mod Pathol. 2019; https://doi.org/10.1038/s41379-019-0338-1
        • Vieth M.
        • Kushima R.
        • Mukaisho K.
        • et al.
        Immunohistochemical analysis of pyloric gland adenomas using a series of Mucin 2, Mucin 5AC, Mucin 6, CD10, Ki67 and p53.
        Virchows Arch. 2010; 457: 529-536
        • Singhi A.D.
        • Lazenby A.J.
        • Montgomery E.A.
        Gastric adenocarcinoma with chief cell differentiation.
        Am J Surg Pathol. 2012; 36: 1030-1035
        • Benedict M.A.
        • Lauwers G.Y.
        • Jain D.
        Gastric adenocarcinoma of the fundic gland type: update and literature review.
        Am J Clin Pathol. 2018; 149: 461-473
        • Choi W.-T.
        • Brown I.
        • Ushiku T.
        • et al.
        Gastric pyloric gland adenoma: a multicentre clinicopathological study of 67 cases.
        Histopathology. 2018; 72: 1007-1014
        • Gannon B.R.
        • Riddell R.H.
        Gastric polyps with intramucosal carcinoma.
        Pathol Case Rev. 2008; 13: 199-202
        • Ishikawa S.
        • Togashi A.
        • Inoue M.
        • et al.
        Indications for EMR/ESD in cases of early gastric cancer: relationship between histological type, depth of wall invasion, and lymph node metastasis.
        Gastric Cancer. 2007; 10: 35-38