Copyright ©2008 The WJG Press and Baishideng. All rights reserved.
World J Gastroenterol. Mar 7, 2008; 14(9): 1318-1320
Published online Mar 7, 2008. doi: 10.3748/wjg.14.1318
Proton pump inhibitors and an emerging epidemic of gastric fundic gland polyposis
Hugh James Freeman
Hugh James Freeman, Department of Medicine (Gastroenterology), University of British Columbia, Vancouver V6T 1W5, Canada
Author contributions: Freeman HJ contributed all to this paper.
Correspondence to: Dr. Hugh James Freeman, MD, FRCPC, FACP, Department of Medicine Gastroenterology, University of British Columbia, 2211 Wesbrook Mall, Vancouver V6T 1W5, Canada.
Telephone: +1-604-8227216
Fax: +1-604-8227236
Received: November 10, 2007
Revised: January 10, 2008
Published online: March 7, 2008


Fundic gland polyps are now commonly recognized during endoscopy. These polyps are benign, often multiple and usually detected in the gastric body and fundus. In the past, these polyps were sometimes associated with familial adenomatous polyposis. In recent years, it has become evident that increasing numbers of these polyps are being detected during endoscopic studies, particularly in patients treated with proton pump inhibitors for prolonged periods. In some, dysplastic changes in these polyps have also been reported. Recent studies have suggested that there may be no increase in risk of colon cancer with long-term proton pump inhibitor therapy. While temporarily reassuring, ongoing vigilance, particularly in those genetically predisposed to colon cancer, is still warranted.

Key Words: Gastric polyps, Fundic gland polyposis, Gastric dysplasia, Gastric cancer, Colon polyps, Familial polyposis coli, Adenomatous polyposis coli gene mutation

Citation: Freeman HJ. Proton pump inhibitors and an emerging epidemic of gastric fundic gland polyposis. World J Gastroenterol 2008; 14(9): 1318-1320

Gastric polyps and tumors have been classified into mucosal, lymphoid, mesenchymal and stromal types[1]. Both neoplastic (adenoma, carcinoma, carcinoids) and non-neoplastic mucosal types occur. Most neoplastic epithelial polyps are asymptomatic and, usually, occur in the gastric antrum. Occasionally, these polyps bleed or present with an iron deficiency anemia. Rarely, gastric adenomas, particularly if large and pedunculated, cause symptoms from intermittent gastric outlet obstruction due to duodenal prolapse. Carcinoma may also complicate such adenomas. But, even these complex malignant polyps have been amenable to endoscopic resection[2].


One of the most common types of gastric polyps, generally classified as non-neoplastic, is the sporadic fundic gland polyp. Usually, these are confined to the gastric body and fundus and rarely cause symptoms. Fundic gland polyps are typically detected during investigation for abdominal pain, dyspepsia or chronic reflux. Historically, it has been estimated that these polyps occur in up to 2% of all endoscopic studies. Although quite characteristic, they were only first described as a distinct pathological type in 1977[3]. Previously, these were reported to occur most often in females and were thought to be derived from the parietal cell- and chief cell-bearing region of the gastric mucosa[1]. Cystic dilation of pits deep in the mucous neck cells was observed with mucous cells, chief cells and parietal cells lining these mucosal cysts. Inflammatory changes in these polyps is usually minimal or absent. It has been reported that these polyps may resolve spontaneously[4].


Gastric polyps also occur in the majority of patients with FAP, screened with endoscopy[57]. FAP results from inherited germline mutations in the adenomatous polyposis coli (APC) gene, coupled with second somatic mutations. This leads to inactivation of both copies of the APC tumor suppressor gene[89]. Importantly, the most common gastric lesion in FAP is the syndromic fundic gland polyp, histologically similar to sporadic fundic gland polyps. Gastric and duodenal adenomas also occur in FAP, but are much less common. Fundic gland polyps are most often not associated with FAP and have little or no potential for malignant transformation[510]. However, high-grade dysplasia and gastric adenocarcinoma have both been associated with fundic gland polyps in FAP[71115]. As a result, colonoscopic surveillance has been suggested to determine if FAP or an attenuated form of FAP is present when fundic gland polyps are first detected[16]. Evidence strongly supporting this approach is not available. As fundic gland polyps are being increasingly recognized during endoscopic evaluations, added colonoscopic studies might be best reserved for those with concomitant gastric or duodenal adenomas.


Since both sporadic and syndromic FAP-associated fundic gland polyps have similar histological appearances, genetic markers have been explored to determine if there are additional similarities or differences. Distinct disruptions in the Wnt signaling pathway with activating beta-catenin mutations occur with sporadic polyps, while FAP-associated polyps showed second, somatic mutations of the APC gene[17]. With chronic acid suppression therapy, multiple fundic gland polyps develop that are also histologically and genetically identical to single sporadic polyps[18]. In these, beta-catenin mutations were detected in most polyps. In addition, distinct mutations in different polyps from the same individual indicated a multifocal origin for the polyps[18]. Separate studies on fundic gland polyps in the absence of FAP have also failed to show APC gene deletions[19]. Interestingly, a very low prevalence of H pylori infection was also noted with these polyps[19]. In contrast, APC gene mutations were found in FAP with both syndromic fundic gland polyps and high grade dysplasia in gastric epithelium[20]. While these studies have served to elucidate molecular changes in sporadic and syndromic (FAP) gastric fundic gland polyps, more information is needed to determine if these markers could be used cost-effectively to predict risk in fundic gland polyps for eventual development of gastric cancer.


Omeprazole was first introduced for clinical use as a proton pump inhibitor in 1988. Since then, worldwide sales figures for proton pump inhibitors have dramatically risen with estimated sales now totaling over $10 billion and rising. Over 720 million prescriptions for proton pump inhibitors have been written worldwide, largely for long-term use, while large randomized clinical trials have confirmed the high efficacy and safety profile of long-term treatment[21]. In addition, however, substantial physiological changes occur with chronic acid suppression therapy. Increased levels of circulating gastrin occur. This hormone stimulates increased cell proliferation. Chronic ECL cell stimulation also results as reflected by increased levels of chromogranin A, an endocrine cell product[22]. In recent years, gastric fundic gland polyps have become increasingly detected in patients on long-term proton pump inhibitor therapy[2326]. These fundic gland polyps are often multiple in this setting and localized in the gastric body and fundus. No definite sex predilection has been defined. They appear to have similar histologic and genetic features to those developing without proton pump inhibitor use. Recent studies have defined a relationship between the length of drug use, especially after 12 mo, and increased polyp risk[26]. In addition, most patients with fundic gland polyps on proton pump inhibitors are H pylori-negative[26], consistent with a previous report of fundic gland polyp regression following acquisition of H pylori[27]. Of concern, multiple fundic gland polyps have also been noted in some children on long-term omeprazole therapy[2829]. Moreover, in a pediatric FAP population on proton pump inhibitors for more than 6 mo, dysplasia was reported in fundic gland polyps[29]. These studies imply that with increasing use of long-term proton pump inhibitors, an epidemic of fundic gland polyposis will be defined. Studies are needed to determine if further follow-up of patients on long-term therapy with proton pump inhibitors and fundic gland polyps is warranted. In spite of an early record of safety with long-term use, there remain concerns regarding the potential risk of cancer with long-term exposure, not only in those with FAP, but also in those genetically predisposed to cancer. This concern is reflected in the recently published studies on colon cancer risk with long-term proton pump inhibitor exposure. In these studies, no increased risk was shown[3031]. While temporarily reassuring, ongoing vigilance will be required before the final chapter is written.


Peer reviewer: Volker F Eckardt, Chief, MD, Professor, Department of Gastroenterology, Deutsche Klinik für Diagnostik, Aukammallee 33, 65191 Wiesbaden, Germany

1.  Lewin KJ, Riddell RH, Weinstein WM.  Gastrointestinal Pathology and Its Clinical Implications. New York, Tokyo: Igaku-Shoin; 1992;610.  [PubMed]  [DOI]
2.  Freeman HJ. Endoscopic excision of a prolapsing malignant polyp which caused intermittent gastric outlet obstruction. World J Gastroenterol. 2005;11:5245-5247.  [PubMed]  [DOI]
3.  Elster K, Eidt H, Ottenjann R, Rosch W, Seifert E. Drusenkor-perzysten, eine polypoide Lasion der Magenschleimhaut. Deutsch Med Wochenschr. 1977;102:183-187.  [PubMed]  [DOI]
4.  Iida M, Yao T, Watanabe H, Imamura K, Fuyuno S, Omae T. Spontaneous disappearance of fundic gland polyposis: report of three cases. Gastroenterology. 1980;79:725-728.  [PubMed]  [DOI]
5.  Sarre RG, Frost AG, Jagelman DG, Petras RE, Sivak MV, McGannon E. Gastric and duodenal polyps in familial adenomatous polyposis: a prospective study of the nature and prevalence of upper gastrointestinal polyps. Gut. 1987;28:306-314.  [PubMed]  [DOI]
6.  Watanabe H, Enjoji M, Yao T, Ohsato K. Gastric lesions in familial adenomatosis coli: their incidence and histologic analysis. Hum Pathol. 1978;9:269-283.  [PubMed]  [DOI]
7.  Domizio P, Talbot IC, Spigelman AD, Williams CB, Phillips RK. Upper gastrointestinal pathology in familial adenomatous polyposis: results from a prospective study of 102 patients. J Clin Pathol. 1990;43:738-743.  [PubMed]  [DOI]
8.  Toyooka M, Konishi M, Kikuchi-Yanoshita R, Iwama T, Miyaki M. Somatic mutations of the adenomatous polyposis coli gene in gastroduodenal tumors from patients with familial adenomatous polyposis. Cancer Res. 1995;55:3165-3170.  [PubMed]  [DOI]
9.  Abraham SC, Nobukawa B, Giardiello FM, Hamilton SR, Wu TT. Fundic gland polyps in familial adenomatous polyposis: neoplasms with frequent somatic adenomatous polyposis coli gene alterations. Am J Pathol. 2000;157:747-754.  [PubMed]  [DOI]
10.  Odze RD, Marcial MA, Antonioli D. Gastric fundic gland polyps: a morphological study including mucin histochemistry, stereometry, and MIB-1 immunohistochemistry. Hum Pathol. 1996;27:896-903.  [PubMed]  [DOI]
11.  Coffey RJ Jr, Knight CD Jr, van Heerden JA, Weiland LH. Gastric adenocarcinoma complicating Gardner's syndrome in a North American woman. Gastroenterology. 1985;88:1263-1266.  [PubMed]  [DOI]
12.  Goodman AJ, Dundas SA, Scholefield JH, Johnson BF. Gastric carcinoma and familial adenomatous polyposis (FAP). Int J Colorectal Dis. 1988;3:201-203.  [PubMed]  [DOI]
13.  Odze RD, Quinn PS, Terrault NA, Vivona AA, Ward MA, Cohen Z, Gallinger S. Advanced gastroduodenal polyposis with ras mutations in a patient with familial adenomatous polyposis. Hum Pathol. 1993;24:442-448.  [PubMed]  [DOI]
14.  Zwick A, Munir M, Ryan CK, Gian J, Burt RW, Leppert M, Spirio L, Chey WY. Gastric adenocarcinoma and dysplasia in fundic gland polyps of a patient with attenuated adenomatous polyposis coli. Gastroenterology. 1997;113:659-663.  [PubMed]  [DOI]
15.  Hofgartner WT, Thorp M, Ramus MW, Delorefice G, Chey WY, Ryan CK, Takahashi GW, Lobitz JR. Gastric adenocarcinoma associated with fundic gland polyps in a patient with attenuated familial adenomatous polyposis. Am J Gastroenterol. 1999;94:2275-2281.  [PubMed]  [DOI]
16.  Declich P, Tavani E, Ferrara A, Caruso S, Bellone S. Sporadic fundic gland polyps: clinico-pathologic features and associated diseases. Pol J Pathol. 2005;56:131-137.  [PubMed]  [DOI]
17.  Declich P, Isimbaldi G, Sironi M, Galli C, Ferrara A, Caruso S, Baldacci MP, Stioui S, Privitera O, Boccazzi G. Sporadic fundic gland polyps: an immunohistochemical study of their antigenic profile. Pathol Res Pract. 1996;192:808-815.  [PubMed]  [DOI]
18.  Torbenson M, Lee JH, Cruz-Correa M, Ravich W, Rastgar K, Abraham SC, Wu TT. Sporadic fundic gland polyposis: a clinical, histological, and molecular analysis. Mod Pathol. 2002;15:718-723.  [PubMed]  [DOI]
19.  Shand AG, Taylor AC, Banerjee M, Lessels A, Coia J, Clark C, Haites N, Ghosh S. Gastric fundic gland polyps in south-east Scotland: absence of adenomatous polyposis coli gene mutations and a strikingly low prevalence of Helicobacter pylori infection. J Gastroenterol Hepatol. 2002;17:1161-1164.  [PubMed]  [DOI]
20.  Sekine S, Shimoda T, Nimura S, Nakanishi Y, Akasu T, Katai H, Gotoda T, Shibata T, Sakamoto M, Hirohashi S. 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.  [PubMed]  [DOI]
21.  Raghunath AS, O'Morain C, McLoughlin RC. Review article: the long-term use of proton-pump inhibitors. Aliment Pharmacol Ther. 2005;22 Suppl 1:55-63.  [PubMed]  [DOI]
22.  Fossmark R, Jianu CS, Martinsen TC, Qvigstad G, Syversen U, Waldum HL. Serum gastrin and chromogranin A levels in patients with fundic gland polyps caused by long-term proton-pump inhibition. Scand J Gastroenterol43(1):20-24.  [PubMed]  [DOI]
23.  Graham JR. Gastric polyposis: onset during long-term therapy with omeprazole. Med J Aust. 1992;157:287-288.  [PubMed]  [DOI]
24.  el-Zimaity HM, Jackson FW, Graham DY. Fundic gland polyps developing during omeprazole therapy. Am J Gastroenterol. 1997;92:1858-1860.  [PubMed]  [DOI]
25.  Choudhry U, Boyce HW Jr, Coppola D. Proton pump inhibitor-associated gastric polyps: a retrospective analysis of their frequency, and endoscopic, histologic, and ultrastructural characteristics. Am J Clin Pathol. 1998;110:615-621.  [PubMed]  [DOI]
26.  Jalving M, Koornstra JJ, Wesseling J, Boezen HM, DE Jong S, Kleibeuker JH. Increased risk of fundic gland polyps during long-term proton pump inhibitor therapy. Aliment Pharmacol Ther. 2006;24:1341-1348.  [PubMed]  [DOI]
27.  Watanabe N, Seno H, Nakajima T, Yazumi S, Miyamoto S, Matsumoto S, Itoh T, Kawanami C, Okazaki K, Chiba T. Regression of fundic gland polyps following acquisition of Helicobacter pylori. Gut. 2002;51:742-745.  [PubMed]  [DOI]
28.  Pashankar DS, Israel DM. Gastric polyps and nodules in children receiving long-term omeprazole therapy. J Pediatr Gastroenterol Nutr. 2002;35:658-662.  [PubMed]  [DOI]
29.  Attard TM, Yardley JH, Cuffari C. Gastric polyps in pediatrics: an 18-year hospital-based analysis. Am J Gastroenterol. 2002;97:298-301.  [PubMed]  [DOI]
30.  Robertson DJ, Larsson H, Friis S, Pedersen L, Baron JA, Sorensen HT. Proton pump inhibitor use and risk of colorectal cancer: a population-based, case-control study. Gastroenterology. 2007;133:755-760.  [PubMed]  [DOI]
31.  Yang YX, Hennessy S, Propert K, Hwang WT, Sedarat A, Lewis JD. Chronic proton pump inhibitor therapy and the risk of colorectal cancer. Gastroenterology. 2007;133:748-754.  [PubMed]  [DOI]