Sporadic Fundic Gland Polyp with High-Grade Dysplasia in a Helicobacter pylori-Negative Non-atrophic Stomach.

Fundic Gland Polyps Lack DNA Content Abnormality Characteristic of Other Adenomatous Precursor Lesions in the Gastrointestinal Tract

Sporadic Fundic Gland Polyps with Epithelial Dysplasia: Evidence for Preferential Targeting for Mutations in the Adenomatous Polyposis Coli Gene

Fundic gland polyps: not so trivial entity and worth evaluation

We studied methylation of 2 tumor suppressor genes (p14, p16) and 4 MINT (methylated in tumor) clones (MINT1, MINT2, MINT25, MINT31) among 51 fundic gland polyps (FGPs) and 27 normal gastric body biopsy samples using bisulfite treatment of genomic DNA followed by methylation-specific polymerase chain reaction. Thirty-two FGPs were syndromic polyps from 14 patients with familial adenomatous polyposis (FAP); 19 were sporadic FGPs from 15 patients without FAP. Significantly higher mean methylation indices were found between FGPs and normal gastric mucosa (P = .012). FGPs arising in a background of proton pump inhibitor (PPI) effect had significantly higher mean methylation indices than those that did not (P = .023). Perhaps because sporadic FGPs were more likely to be associated with PPI effect than were FAP-associated FGPs, they also demonstrated higher mean methylation indices than syndromic polyps (P = .024). Among FAP-associated FGPs, there was no statistical difference in methylation indices between polyps that were dysplastic, indefinite for dysplasia, or nondysplastic (P = .87). Epigenetic alterations involving methylation of CpG islands might have a role in the development of some FGPs, particularly those with a PPI effect. They do not account for the presence or absence of a dysplastic phenotype in FGPs.

Fundic Gland Polyp Dysplasia Is Common in Familial Adenomatous Polyposis

<h3>Introduction</h3> Literature indicates the rate of dysplasia in Fundic Gland Polyps (FGP) is 1% in non-familial adenomatous polyposis syndrome (FAP) patients.^{1 2} The 2019 British Society Guideline (BSG) advise sampling any stomach polyps (SP) and to perform polypectomy for polyps ≥1cm.^{3 4} We aimed to assess the rate of dysplasia in sporadic FGP and its association with proton pump inhibitors (PPI). <h3>Methods</h3> A retrospective &amp; prospective cohort study of patients with SP diagnosed between 2015 - 2021 in a single tertiary referral centre. We captured detail on patient demographics, referral indication, endoscopy findings, biopsy results, &amp; PPI usage. FGP’s in patients with FAP were excluded. <h3>Results</h3> 181 patients with SP of whom 103 (57%) were sporadic FGP (mean age 70.71 ± 12.56; Female to male ratio 1:31). Of these, 5/181 (4.8%) had dysplasia (4 low grade dysplasia (LGD); 1 high grade dysplasia (HGD)). Only 58% of sporadic FGPs were biopsied. In the 78 (43%) non-FGPs; (mean age 70.44 ± 13.05; Female to male ratio 1.48), 6 (7.7%) had LGD and 1 (1.3%) had cancer. Indications for referral were melaena/haematemesis 50(27%), anaemia 43(24%), dysphagia 16(9%) and dyspepsia 14(8%). Most of the patients (176/181) were on PPI before the index endoscopy. Lansoprazole was the most common PPI 110(62.5%), followed by Omeprazole 51(29%) and Esomeprazole 15(8.5%). The duration of PPI prescription was between 4-229 months. Patients who developed LGD in FGP were on PPI for at least 9 years. One patient with HGD in FGP was on PPI for 19 years. None of the FGP patients had cancer secondary to polyps, in contrast to one patient with adenocarcinoma in non-FGP. <h3>Conclusion</h3> Our study showed the rate of dysplasia to be higher than previously published. The risk of dysplasia development may be associated with prolonged PPI usage (&gt;8 years) in our cohort. Our practice is not yet in line with BSG guidelines due to service implications of this recommendation of sampling all polyps. Primary care should review and stop PPI where necessarily given its association with FGP.^{6 7} <h3>References</h3> Levy MD. Sporadic FGP with LGD: A Large Case Series Evaluating Pathologic and Immunohistochemical Findings and Clinical Behavior. <i>Am J Clin Pathol</i>. 2015 Oct;144(4). Gastric FGP. R W BURT. <i>GASTROENTEROLOGY</i> 2003; 125. Goddard AF. The management of gastric polyps. <i>Gut</i>. 2010 Sep;59(9). Banks M. Diagnosis&amp; management of patients at risk of gastric adenocarcinoma. <i>Gut</i>. 2019 Sep;68(9). Islam RS. Gastric polyps: a review of clinical, endoscopic, and histopathologic features and management decisions. Gastroenterol Hepatol (N Y). 2013 Oct;9(10). Tran-Duy A. Use of PPI and Risks of FGP and Gastric Cancer: Systematic Review and Meta-analysis. Clin Gastro Hepatol. 2016 Dec;14(12). Martin FC. Systematic review with meta-analysis: FGP and PPI. Aliment Pharma Ther. 2016 Nov;44(9).

The incidence of fundic gland polyps (FGPs) is increasing rapidly and has surpassed hyperplastic polyps to become the most common epithelial gastric polyps in Western countries and China.1, 2 They are usually multiple, small (1-5 mm), transparent, and sessile; the background gastric mucosa is typically normal.3 FGPs are more prevalent among females and are often located in the gastric fundus and body. There are two types of FGPs: sporadic and syndromic (in association with familial adenomatosis polyposis). Although different in their genetic and molecular backgrounds, sporadic and syndromic FGPs are histologically and histochemically indistinguishable. Syndromic FGPs occur in the presence of inherited germline mutation in the adenomatous polyposis coli (APC) gene plus the acquisition of a somatic mutation, leading to complete inactivation of the APC tumor suppressor gene.4 Familial adenomatosis polyposis should be excluded by colonoscopy if FGPs are numerous, large (>1 cm), or dysplasic.3 For sporadic FGPs, up to 23% are associated with proton pump inhibitor (PPI) use.5, 6 A recent review with meta-analysis indicated that long-term use of PPIs (≥12 months) increased the risk of FGPs (pooled odds ratio [confidence interval]: 3.81 [2.78-5.24] for the fixed effects model and 2.88 [0.97-8.55] for the random effects model).7 The risk was even higher if the exposure duration was more than 48 months (pooled odds ratio: 4.02). There is no or inverse association with Helicobacter pylori infection.1, 3 FGPs rarely harbor dysplastic lesions. A study in the USA of 35 372 FGPs found that only 0.3% had low-grade dysplasia.5 Moreover, even syndromic FGPs rarely progress to cancer.8 Once epithelial gastric polyps are found at initial endoscopy, it is important to sample polyps and/or normal-appearing gastric mucosa to establish histological diagnosis and to define who needs surveillance. Biopsies from the background antrum and corpus mucosa could rule out atrophic gastritis, intestinal metaplasia, dysplasia, and H. pylori infection. All these information is important for the management of other epithelial gastric polyps, including hyperplastic polyp, adenoma, and type 1 or 2 gastric neuroendocrine tumors.3 Once sporadic FGPs are diagnosed, routine endoscopic surveillance is not recommended in the absence of dysplasia. There is still no consensus on the indication of endoscopy resection of sporadic FGPs. However, many experts suggest the removal of FGPs larger than 10 mm.3 Few studies have considered risk factors other than age, gender, PPIs, and H. pylori infection for sporadic FGPs. A recent one-center, endoscopy-based retrospective study in Taiwan indicated the incidence of FGPs increased from 0.6% in 2010 to 1.3% in 2015.9 The controls were age- and gender-matched subjects who received upper endoscopy during the similar period with the cases. The authors found the presence of liver cirrhosis, gastric ulcer, duodenal ulcer (adjusted odds ratio: 0.18, 0.28, and 0.35, respectively, all P < 0.001), but not reflux esophagitis, were inversely associated with FGP risk. FGPs are commonly seen in patients with relatively healthy gastric mucosa. This is an interesting finding that implies causative factors to gastric mucosa, including cirrhosis and peptic ulcers, which could reduce the formation of FGPs, probably through the facilitation of glandular outflow. However, more than 30% of H. pylori status was missing, and the information of PPI exposure was less than adequate in this study. Future studies are necessary to support this finding and the proposed mechanism behind it. The author declares no conflict of interest.

A fundic gland polyp (FGP) is a common gastric polyp. Intraepithelial neoplasia in FGPs, referred to as FGP with dysplasia, is often seen in patients with familial adenomatous polyposis (FAP). In sporadic FGPs, low-grade dysplasia (LGD) is rare, and high-grade dysplasia (HGD) or carcinoma arising from sporadic FGPs is extremely rare. Because of this rarity, the prognosis and appropriate management of these lesions have not been clarified. In the present case, a sporadic FGP with LGD did not develop into invasive carcinoma, but contained foci of HGD 14 years after diagnosis. The biopsy specimen of the polyp taken at the first esophagogastroduodenoscopy 15 years earlier was diagnosed as FGP without dysplasia. At the second histological examination, LGD was found. Because the polyp increased in size during proton pump inhibitor therapy for 14 years, endoscopic mucosal resection was performed. The pathological diagnosis of the resected specimen was FGP with HGD mixed in LGD, with no invasive carcinoma. Dysplasia in FGPs might have less malignant potential regardless of dysplasia or size.

Background: Fundic gland polyps (FGPs) occur in both syndromic and sporadic form. Syndromic FGPs arise through mutations in the adenomatous polyposis coli (APC) gene, whereas sporadic FGPs are caused by $ -catenin gene mutations. Dysplasia in sporadic FGPs, found less often than in syndromic FGPs, was recently associated with APC rather than $ -catenin mutations. These data suggest different functional consequences of APC and $ -catenin mutations. To investigate this hypothesis, we examined proliferative activity, degree of apoptosis, # -catenin expression and p53 expression in syndromic and sporadic FGPs. Methods: Syndromic FGPs ( n r = r 9) from familial adenomatous polyposis (FAP) patients and sporadic FGPs ( n r = r 18) were studied. Proliferative activity, apoptotic cell death and expression of # -catenin and p53 were examined by immunohistochemistry. In FGPs containing dysplasia, areas with and without dysplasia were compared. Results: Syndromic and sporadic FGPs without dysplasia exhibited similar proliferative activity, degree of apoptosis, # -catenin and p53 expression. Dysplasia was observed more often in syndromic (4/9) than in sporadic FGPs (1/18). Within FGPs containing dysplasia, dysplastic areas showed abnormal nuclear # -catenin staining in 3/5 cases and higher rates of cell proliferation and apoptosis than non-dysplastic areas. Overexpression of p53 was not observed. Conclusion: The finding of similar rates of proliferation and apoptosis in syndromic and sporadic FGPs does not support the hypothesis that APC and $ -catenin gene mutations have different functional consequences in FGPs. The association of dysplasia with relatively high cell turnover rates and nuclear expression of $ - catenin indicates activation of the Wnt-APC- # -catenin pathway in dysplasia. The finding of dysplasia in some but not all syndromic FGPs suggests the involvement of other genes in addition to the APC gene in the development of dysplasia in FGPs.

Sporadic Fundic Gland Polyps: Common Gastric Polyps Arising Through Activating Mutations in the β-Catenin Gene

We read with great interest the paper by Lam and Lau,1 which recently appeared on your journal. In their paper, the authors report about two patients with a large number (52 and 147, respectively) of fundic gland polyps (FGPs) without any known association with previous therapies or genetic familial syndromes, which they aptly named “idiopathic” (literally “without known cause”) multidinous FGPs. FGPs are small sessile polyps (2–3 mm), usually multiple, of the acid-secreting gastric mucosa. They are characterized by shortened gastric pits and cystic dilations, both superficial and deep, bordered by columnar mucous, chief, and parietal cells. They are almost always negative for Helicobacter pylori colonization.2 Although they show the same histology, they have been described as sporadic,3 associated with familial adenomatous polyposis (FAP),4 attenuated FAP,5 Zollinger–Ellison syndrome,6-8 MUTYH-associated polyposis,9 gastric adenocarcinoma and proximal polyposis of the stomach (GAAPS),10, 11 and absorptive hypercalciuria12 (Fig. 1). Although recently Kővári et al.13 described subtle differences between sporadic, FAP-associated, and GAAPS-associated FGPs, so far the only difference between the histology of fundic polyps has been in the frequency of dysplasia, which is rare in sporadic FGPs (1%), frequent in FAP-associated polyps (30–50%), and almost universal in GAAPS-associated polyps. Lam and Lau1 were clearly faced with a management dilemma—how to treat such unusual patients. They never received a long-term treatment with proton pump inhibitors (if such a treatment promotes polyps at all), nor had a positive family history for genetic syndromes with a known risk for FGP development. In absence of clear guidelines for such a situation, the authors decided to endoscopically remove all polyps and to submit them to histologic examination. Quite surprisingly, not a single polyp showed dysplasia. Given such results, we would suggest to Lam and Lau to submit their polyps to molecular biology examination, in a search for possible new mechanisms driving such an exceptional multidinous polyposis.

Altered Cellular Distribution of Tuberin and Glucocorticoid Receptor in Sporadic Fundic Gland Polyps

Sporadic fundic gland polyps (FGPs) are the most frequent gastric polyps. These FGPs develop almost exclusively in a normal corpus mucosa without Helicobacter pylori infection. This means that they represent an absolutely benign disease (no ulcers, almost no gastric carcinoma and mucosa associated lymphoid tissue (MALT) lymphoma). Most probably there exists a statistically accumulated coincidence rate of sporadic FGPs with colorectal epithelial neoplasias, so it is recommended to consider preventive colonoscopy. In familial adenomatous polyposis (FAP), FGPs are present in up to 80-93% of patients. In such patients, low-grade dysplasia and/or foveolar microadenomas may be present in 44-54% of cases. To date, only three case reports on early gastric carcinoma have been published. In this issue, to the best of our knowledge the first case of a high-grade dysplasia (intraepithelial neoplasia) in a sporadic FGP is reported. Recently, it has been shown that beta-catenin mutations might have led to FGP. Therefore, in the future, patients showing nuclear beta-catenin expression must undergo examination to discover whether this expression may lead to neoplasia. According to the data available at present, such a constellation must be regarded as an extremely rare event.

Most patients with familial adenomatous polyposis (FAP) develop gastric fundic gland polyps, with many displaying low-grade dysplasia. This study evaluates the natural history and morphological phenotype of dysplasia in FAP-associated fundic gland polyps. Patients with FAP and dysplastic fundic gland polyps (n = 24) were identified. Twenty-two of 24 FAP-associated dysplastic fundic gland polyps showed a gastric phenotype and two had mixed phenotype. During a mean 6.1-year follow-up (range 0.8-12.6 years) and 5.7 endoscopies (range 2-22), one patient (4%) was diagnosed with a fundic gland polyp with high-grade dysplasia, while 23 patients (96%) in this cohort had either no dysplasia or persistent low-grade dysplasia. Contemporary patients with sporadic fundic gland polyps with low-grade dyplasia had similar morphology and outcomes to the FAP-associated fundic gland polyp cohort. Dysplasia in fundic gland polyps (FAP-associated and sporadic) was associated less frequently with intestinal phenotype, high-grade dysplasia and the finding of concurrent or subsequent carcinoma compared to contemporary patients with sporadic gastric dysplasia not occurring in fundic gland polyps. This cohort of patients with FAP-associated dysplastic fundic gland polyps rarely developed high-grade dysplasia and gastric adenocarcinoma was absent.

We retrospectively studied the clinical and histologic features of pediatric fundic gland polyps (FGPs) in 16 patients. FGPs had an endoscopic prevalence of 0.25% in 8527 pediatric gastric biopsies. Five patients had familial adenomatous polyposis (FAP). The median age of onset was 17.7 years in FAP and 17.3 years in sporadic patients. All syndromic patients were asymptomatic and FGPs were identified during surveillance for existing or concurrent colon polyps. They did not take antacids. In comparison, all 11 sporadic FGPs were identified during evaluation of symptomatic patients who had taken antacids (median duration 21 months). Syndromic FGPs can be multiple at single endoscopy and were more likely to recur, while sporadic FGPs were often single. None of the sporadic patients had recurrence of FGPs or a subsequent diagnosis of FAP during a median follow-up of 20.5 months. The dilated fundic glands were lined by parietal and chief cells only in a majority (22/41, 53.7%) of syndromic FGPs, while additional tall mucinous lining cells were found in all sporadic FGPs. Syndromic FGPs did not have parietal cell hypertrophy in the background oxyntic mucosa. Nuclear immunopositivity for beta-catenin was essentially absent in all the FGPs. In conclusion, FGPs were rare in pediatric patients. In syndromic patients, FGPs are asymptomatic and did not precede colon polyps. Prolonged antacid intake seems to be associated with development of sporadic FGPs. Cellular components of dilated fundic glands and background parietal cell hypertrophy can be useful features to eliminate concern for syndromic polyposis.