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Background
For many years, these epithelial polyps of the stomach were thought to be benign tumors. Although most are sporadic, they may be associated with familial adenomatous polyposis (FAP). FAP-associated polyps occur at earlier ages (including children) and are more frequently multiple. Dysplastic changes may occur in these patients although the overall risk of malignancy is not appreciably increased.
OUTLINE
EPIDEMIOLOGY CHARACTERIZATION SYNONYMS Elster's polyps INCIDENCE Common Incidence of fundic gland polyps in patients without familial adenomatous polyposis.
Kinoshita Y, Tojo M, Yano T, Kitajima N, Itoh T, Nishiyama K, Inatome T, Fukuzaki H, Watanabe M, Chiba T.
Department of Internal Medicine, Miki City Hospital, Hyogo, Japan.
Gastrointest Endosc 1993 Mar-Apr;39(2):161-3 Abstract quote
The incidence of fundic gland polyps was evaluated using a high-resolution videoendoscope.
In 1388 upper gastrointestinal endoscopic studies, 26 cases of fundic gland polyps (1.9% of the studied cases) were found. None of these patients had evidence of familial adenomatous polyposis. Fifteen of these patients (58%) had a solitary polyp in the gastric body, most of which were small sessile polyps of less than 2 mm in diameter.
The results of this study indicated that a small solitary fundic gland polyp is not a rare gastric lesion and that little relationship exists between these solitary fundic gland polyps and familial adenomatous polyposis.
Fundic gland polyps: prevalence and clinicopathologic features.
Marcial MA, Villafana M, Hernandez-Denton J, Colon-Pagan JR.
Division of Surgical Pathology, Universidad Central del Caribe, Bayamon, Puerto Rico
Am J Gastroenterol 1993 Oct;88(10):1711-3 Abstract quote
We evaluated prospectively all gastroscopic examinations performed at two institutions for a period of 24 months with the aim of studying fundic gland polyps in our patient population.
Forty-four patients with fundic gland polyps of the stomach were identified among 5554 patients who underwent endoscopy, for a prevalence of 0.8% in our patient population. Twelve additional patients with fundic gland polyps were identified through our surgical pathology referral practice.
The patients' ages ranged from 27 to 82 yr, with an average age of 53 +/- 13 yr. The vast majority of the patients were female, with a female-to-male ratio of approximately 5:1. The polyps averaged 2.3 +/- 1.2 mm in size. An average of four polyps per patient were seen, with a range of one to 11.
DISEASE ASSOCIATIONS CHARACTERIZATION FAMILIAL ADENOMATOUS POLYPOSIS Dysplasia and dysregulation of proliferation in foveolar and surface epithelia of fundic gland polyps from patients with familial adenomatous polyposis.
Wu TT, Kornacki S, Rashid A, Yardley JH, Hamilton SR.
Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Am J Surg Pathol 1998 Mar;22(3):293-8 Abstract quote
Fundic gland polyps (FGPs) of the stomach are regarded as hamartomatous or hyperplastic/functional polyps that occur sporadically but at increased frequency in patients with familial adenomatous polyposis syndrome (FAP).There is controversy about the histopathology of FGPs, including occurrence of dysplasia.
We, therefore, studied dysplasia in 270 sporadic FGPs from 216 patients and 49 FGPs from 24 patients with FAP. We evaluated dysregulation of epithelial proliferation manifested by loss of the normal inverse topographic distribution of Ki-67 proliferation marker and the cyclin-dependent kinase inhibitor p21(WAF1/CIP1) using immunohistochemistry in 27 sporadic FGPs and in 22 FGPs from patients with FAP. Dysplasia in foveolar and surface epithelia occurred in 12 of 49 (25%) FGPs in patients with FAP but in only 3 of 270 (1%) of sporadic FGPs (p < 0.000001). Fourteen of 49 (29%) of FGPs from patients with FAP were indefinite for dysplasia, as contrasted with 8 of 270 (3%) sporadic FGPs (p < 0.00001). The normal inverse topographic distribution of Ki-67 and p21(WAF1/CIP1) was maintained in 20 of 22 (91%) of FGPs negative for dysplasia but was lost in all (8 of 8) FGPs with dysplasia and in 11 of 19 (58%) FGPs that were indefinite for dysplasia (p = 0.00001).
The results indicate that dysplasia can occur in foveolar and surface epithelia of FGPs, especially in patients with FAP, and often is preceded by dysregulation of epithelial proliferation when the morphologic abnormalities are indefinite for dysplasia.
Dysplastic changes in gastric fundic gland polyps of patients with familial adenomatous polyposis.
Bertoni G, Sassatelli R, Nigrisoli E, Pennazio M, Tansini P, Arrigoni A, Rossini FP, Ponz de Leon M, Bedogni G.
Digestive Endoscopy Service, S. Maria Nuova Hospital, Reggio Emilia.
Ital J Gastroenterol Hepatol 1999 Apr;31(3):192-7 Abstract quote
BACKGROUND: Fundic gland polyps are the most common gastric lesion in patients with familial adenomatous polyposis and are traditionally considered a condition with no malignancy potential. However, some reports have recently questioned this view.
AIMS: To prospectively evaluate their prevalence and the associated dysplastic/malignant changes in a series of affected patients.
PATIENTS AND METHODS: Thirty-seven affected patients were carefully investigated by upper endoscopy over a three-year period. Multiple (at least 10) complete excisions of any representative polyp of the body-fundus were performed and a thorough pathological search for microscopic adenomatous/dysplastic changes carried out.
RESULTS: Of 37 patients, 19 (51.3%) showed gastric fundic gland polyposis and 18 of them gave consent for polypectomies. Overall, 425 endoscopic polypectomies were performed, with a mean of 23.6 +/- 14.6 per patient. At pathology, all excised polyps of the body-fundus were found to be fundic glandular. Microscopic adenomatous changes within such polyps were identified in 8 (44.4%) patients. All the adenomatous foci revealed mild dysplasia with no case of severe atypia or carcinoma. Patients with microadenomas showed a significantly higher total number of gastric polyps compared with those without microadenomas (p < 0.03). No other differences between the two groups were observed. Two further patients presented microadenomas in apparently normal antral mucosa and one also showed a 6 mm antral adenoma with mild dysplasia. Finally, the search for Helicobacter pylori was always negative.
CONCLUSIONS: Patients with familial adenomatous polyposis and gastric fundic gland polyps have a high prevalence of microscopic adenomatous foci within such lesions; nevertheless, these foci seem not to be associated with signs of severe atypia or carcinoma. Moreover, microadenomas are ubiquitous throughout the stomach, as well as in the rest of the gut, and their natural history is still undefined. Thus, their malignancy potential remains uncertain. More extensive follow-up is warranted to better investigate the long-term biological behaviour of these lesions but, at present, our data do not support the need for a change in the usual intervals of upper endoscopy surveillance in familial polyposis patients with or without gastric fundic glands polyps.
Fundic gland polyps in familial adenomatous polyposis: neoplasms with frequent somatic adenomatous polyposis coli gene alterations.
Abraham SC, Nobukawa B, Giardiello FM, Hamilton SR, Wu TT.
Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205-2196, USA.
Am J Pathol 2000 Sep;157(3):747-54 Abstract quote
Fundic gland polyps (FGPs) are the most common gastric polyps in patients with familial adenomatous polyposis (FAP). FGPs have traditionally been regarded as nonneoplastic, possibly hamartomatous lesions, but the pathogenesis of FGPs in both FAP and sporadic patients remains unclear. FGPs in FAP can show foveolar dysplasia, and rarely invasive gastric adenocarcinoma has been reported in patients with FAP and fundic gland polyposis.
Using direct gene sequencing and allelic loss assays at 5q, we analyzed somatic adenomatous polyposis coli (APC) gene alterations in 41 FAP-associated FGPs (20 with foveolar dysplasia, six indefinite for dysplasia, and 15 nondysplastic) and 13 sporadic FGPs. The foveolar epithelium and dilated fundic glands of the polyps were separately microdissected and analyzed in 25 of 41 FAP-associated FGPs and 13 of 13 sporadic FGPs. Somatic APC gene alterations were identified frequently (21 of 41 cases, 51%) in FAP-associated FGPs. Both the foveolar epithelium and the dilated fundic gland epithelium comprising the FGPs were shown to carry the same somatic APC gene alteration in 24 (96%) of 25 cases. Furthermore, there was no difference in the frequency of somatic APC gene alterations between FGPs with foveolar dysplasia (10 of 20, 50%), indefinite for dysplasia (four of six, 67%), and nondysplastic (seven of 15, 47%) in FAP patients (P: = 0.697). In contrast, FGPs from non-FAP patients showed infrequent (one of 13, 8%) APC gene alterations (P: = 0.008).
These results show that FGPs in FAP patients are pathogenetically distinct from sporadic FGPs. Somatic, second-hit APC gene alterations, which precede morphological dysplasia in many FAP-associated FGPs, indicate that FGPs arising in the setting of FAP are neoplastic lesions.
PATHOGENESIS CHARACTERIZATION METHYLATION PATTERNS
- Frequent CpG island methylation in sporadic and syndromic gastric fundic gland polyps.
Abraham SC, Park SJ, Cruz-Correa M, Houlihan PS, Half EE, Lynch PM, Wu TT.
Department of Pathology, Mayo Clinic, Rochester, MN.
Am J Clin Pathol. 2004 Nov;122(5):740-6. Abstract quote
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.PROTON PUMP THERAPY Fundic gland polyps developing during omeprazole therapy.
el-Zimaity HM, Jackson FW, Graham DY.
Baylor College of Medicine, VAMC, Houston, Texas, USA.
Am J Gastroenterol 1997 Oct;92(10):1858-60 Abstract quote
OBJECTIVE: Side effects of omeprazole therapy include reversible hypergastrinemia, entero chromaffin-like hyperplasia, and possibly acceleration of atrophic gastritis in the gastric corpus in patients with Helicobacter pylori infection. The objective of this report is to describe six cases of fundic gland polyps that developed while omeprazole was being used for Barrett's esophagus.
METHODS: Three women and three men developed fundic gland polyps after 1-5 yr of omeprazole therapy, 20 mg/day. In the index case, fundal polyps developed after 2 yr of continuous omeprazole therapy. Omeprazole was stopped, but because of poor clinical efficacy with H2-blockers, it was reinstated.
RESULTS: After 4 yr of therapy, multiple large fundal polyps were present. Histology of all lesions revealed characteristic fundal gland polyps with multiple cystic dilations. None of the patients had H. pylori infection. Serum gastrin was normal in four and slightly increased in two.
CONCLUSION: These cases support the possible causal relation between the use of omeprazole and the development of fundic gland polyps in patients without H. pylori gastritis.
Proton pump inhibitor-associated gastric polyps: a retrospective analysis of their frequency, and endoscopic, histologic, and ultrastructural characteristics.
Choudhry U, Boyce HW Jr, Coppola D.
Center for Swallowing Disorders, Division of Digestive Diseases, University of South Florida College of Medicine, Tampa 33612-9497, USA.
Am J Clin Pathol 1998 Nov;110(5):615-21 Abstract quote
Since 1992 there have been reports of proton pump inhibitors being associated with fundic gland-type gastric polyps. Endoscopic and histologic characteristics and natural history of these polyps have not been clearly defined.
We performed a retrospective study of patients on long-term treatment with proton pump inhibitors who developed gastric polyps. Gastric polyps developed in 17 (10 males and 7 females, 7.3%) of the 231 patients who underwent 2 or more upper endoscopies for complicated gastroesophageal reflux disease and who were receiving long-term treatment with proton pump inhibitors.
The mean interval of proton pump inhibitor use after which an endoscopy revealed gastric polyps was 32.5 months. In 1 patient, discontinuation of treatment resulted in disappearance of the polyps within 3 months. The polyps recurred 4 months after the treatment was restarted. Endoscopy established that typical polyps were generally small (<1 cm), sessile, multiple, and whitish pink with a mottled partially translucent surface. The polyps were most often present in the proximal/midgastric body. Of the 15 polyps removed endoscopically, 9 were of the fundic gland type, 4 were of the hyperplastic type, and 2 were of the inflammatory type. Eight of 9 polyps with typical endoscopic appearance were of the fundic gland type. None of the polyps contained dysplasia or carcinoma.
Long-term use of proton pump inhibitors may be associated with the presence of small gastric fundic gland polyps and hyperplastic polyps. A prospective study is required to establish their incidence, natural history, and clinical significance.
Fundic gland polyps are not induced by proton pump inhibitor therapy.
Vieth M, Stolte M.
Institute of Pathology, Bayreuth Clinic, Germany.
Am J Clin Pathol 2001 Nov;116(5):716-20 Abstract quote
It is still unclear whether proton pump inhibitors (PPIs) could cause fundic gland polyps (FGPs) in patients without Helicobacter pylori infection. The frequency of FGPs in patients during PPI therapy has not been compared, however with a control group of patients who did not have H. pylori infection and were not undergoing PPI treatment.
In a retrospective 12-month study, the frequency of FGPs in 2,251 patients without H. pylori infection receiving PPI therapy (duration of treatment at least 4 weeks) was compared with a control group of 28,096 patients who did not have H. pylori infection and were not receiving PPI therapy. FGPs were identified with an identical frequency in both groups (5.0% in the control and 5.2% in the PPI group).
No significant differences were present between the groups with respect to the presence of gastritis or age or sex. Our study shows that a causal pathogenetic relationship between PPI therapy and FGPs is unlikely.
TUBERIN
Altered cellular distribution of tuberin and glucocorticoid receptor in sporadic fundic gland polyps.Wei J, Chiriboga L, Yee H, Mizuguchi M, Li E, Sidhu GS, West AB.
Department of Pathology, New York University School of Medicine (JW, LC, HY, EL, BW), New York, New York.
Mod Pathol 2002 Aug;15(8):862-9 Abstract quote Gastric fundic gland polyps (FGPs) are considered hamartomas, and various gastrointestinal hamartomas are associated with tuberous sclerosis complex (TSC). The aim of this study was to investigate a possible link between TSC proteins (hamartin and tuberin) and sporadic FGPs.
We examined 33 sporadic FGPs and 26 biopsies of normal fundic mucosa by immunohistochemistry. Nuclear immunoreactivity for tuberin was dramatically reduced or lost in most sporadic FGPs, and tuberin unexpectedly accumulated in the cytoplasm in oxyntic glands. About 18% (6/33) of FGPs were immunopositive in an average of 1.7% of oxyntic cell nuclei, compared with 77% (20/26) of controls in an average of 24.4% of oxyntic cell nuclei (P <.01). No change in hamartin was noted. We further examined the tuberin-associated proteins glucocorticoid receptor (GCR) and p27. Nuclear immunoreactivity for GCR was lost in most sporadic FGPs, but p27 distribution was normal.
Sporadic FGPs had a low frequency of staining for Ki-67 except for some cells from cystic components, which is consistent with their slow growth. Our results are consistent with the hypothesis that tuberin may play an important role in pathogenesis of sporadic FGPs.
First, an altered cellular localization of tuberin may lead to the deregulation of cell proliferation by interrupting its interaction with hamartin. Second, altered cellular localization of tuberin may preclude its negative regulation of gene transcription mediated by GCR.
GROSS APPEARANCE/
CLINICAL VARIANTSCHARACTERIZATION GENERAL
Pol J Pathol. 2005;56(3):131-7. Abstract quote
BACKGROUND: Fundic gland polyps have been described either in association with genetic polyposis syndromes of the colon, or in a sporadic form. In the first case they are diagnosed during family screening in asymptomatic subjects, while sporadic FGP patients often complain of upper gastrointestinal symptoms. So far, no great attention has been paid to the clinical presentation of these patients, so we undertook a clinico-pathologic study to further delineate: the clinical presentation at 1st examination; the associated gastrointestinal conditions; a possible role of omeprazole; Helicobacter pylori (H. pylori) colonization, the presence of intestinal metaplasia and dysplasia.
METHODS: We followed-up for a 9-year period with endoscopies a case series of 70 patients with sporadic FGPs, recording endoscopic data, symptoms, associated gastrointestinal conditions, previous therapies, histopathological findings.
RESULTS: The prevalence of the present series was 0.36%. The patient prevalence and number of polyps by age classes rose in women (maximum value in perimenopausal age), while was constant in males. We observed a frequent association between FGPs and esophageal conditions (34%), namely hiatus hernia-reflux esophagitis, significantly higher than in our endoscopic population (15%). Five patients had an isolated colonic adenoma. Only one patient had received long term omeprazole therapy. H. pylori was negative in all 70 FGPs, and in 15 samples of antral mucosa. No metaplastic or dysplastic lesions were seen.
CONCLUSION: Sporadic FGP patients frequently complain of epigastric pain, burning, dyspepsia, probably related to the frequently associated esophageal pathology, namely reflux esophagitis-hiatus hernia (34%). Prevalence of FGPs and polyps number are linked to female sex (maximum rise for both values in perimenopausal age). No link with omeprazole therapy was seen. FGPs patients appear to be protected from H. pylori colonization and ultimately from the development of intestinal metaplasia-dysplasia-gastric cancer. Nonetheless, they are apparently more prone to colonic adenomas. So, every sporadic FGP patient should undergo colonic surveillance.Gastric Polyps: Classification and Meaning
Susan C. Abraham, MD
From the Division of Gastrointestinal/Liver Pathology, Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD.
Pathol Case Rev 2002;7:2-11 Abstract quote
Gastric polyps encompass a wide variety of lesions that most commonly arise from the gastric epithelium. This review focuses on the histologic features, significance, and differential diagnosis of the two most common epithelial polyps: hyperplastic polyps and fundic gland polyps.
Hyperplastic polyps are characterized by prominent foveolar hyperplasia, tortuosity, and edema and inflammation of the intervening lamina propria. They are associated with abnormalities of the background gastric mucosa, particularly chronic atrophic gastritis of autoimmune or environmental type. Although they uncommonly undergo neoplastic progression (dysplasia or adenocarcinoma), they denote an increased risk of neoplasia in the surrounding abnormal gastric mucosa. Hyperplastic polyps overlap in their histologic appearance with hamartomas (e.g., juvenile polyps, Peutz-Jeghers polyps, Cowden’s disease) and with more generalized hyperplastic or inflammatory conditions (e.g., Menetrier’s disease).
Fundic gland polyps can be sporadic or associated with familial adenomatous polyposis (FAP). FAP-associated polyps occur at earlier ages (including children) and are more frequently multiple. Both sporadic and FAP-associated fundic gland polyps are characterized by ectatic glands lined by attenuated parietal cells, chief cells, and mucus neck cells. The surface epithelium is dysplastic in 25% of FAP-associated fundic gland polyps but only rarely in sporadic polyps. Despite this, the risk of gastric adenocarcinoma does not appear to be significantly increased among Western patients with FAP.
VARIANTS SPORADIC FUNDIC GLAND POLYPOSIS
Sporadic fundic gland polyposis: a clinical, histological, and molecular analysis.Torbenson M, Lee JH, Cruz-Correa M, Ravich W, Rastgar K, Abraham SC, Wu TT.
Department of Pathology (MT, SCA), and Department of Medicine, Division of Gastroenterology (MC-C, WR), The Johns Hopkins Hospital, Baltimore, Maryland.
Mod Pathol 2002 Jul;15(7):718-23 Abstract quote Sporadic fundic gland polyposis (SFGP) is defined as multiple fundic gland polyps in patients without familial adenomatous polyposis syndrome (FAP). Although little is known about the genetic changes in SFGP, mutations in the Wnt signaling pathway have been recently linked to fundic gland polyps in other settings: sporadic polyps are linked to activating beta-catenin mutations, whereas FAP-associated fundic gland polyps are caused by second somatic hits in the adenomatous polyposis coli gene. The relationship between SFGP, single sporadic fundic gland polyps, and FAP-associated polyps remains unclear, and SFGP remain poorly characterized at the clinical, histological, and molecular levels.
A retrospective study was undertaken of eight patients with SFGP who had >/=10 polyps with at least five endoscopic biopsy specimens available for study. One additional patient with attenuated FAP who underwent partial gastrectomy was included as a control. The medical records and biopsy specimens were reviewed. Mutations of the beta-catenin gene were evaluated in each fundic gland as well as in control nonpolypoid tissue by direct sequencing of a mutational hot spot in exon 3 of the beta-catenin gene, which encodes the GSK-3beta phosphorylation sites, and a HinfI endonuclease digestion assay. The four men and four women in the study were an average of 57 years of age at biopsy. All patients were on acid-suppression therapy, 5/8 with proton-pump inhibitors (PPI) and 3/8 with Zantac. Sixty-two polyps were studied, and all were <10 mm, with most between 2 and 7 mm. The polyps were histologically identical to single sporadic fundic gland polyps. No dysplasia was seen. Forty-seven of 62 polyps (76%) had detectable beta-catenin mutations. Mutations were found in all eight of the patients. All were point mutations in codons 32, 33, 34, and 37 and are either phosphorylation sites or immediately adjacent to phosphorylation sites, findings identical to that seen in single sporadic fundic gland polyps. Each polyp had a single mutation, and each patient had more than one unique mutation (median = 4), indicating a multifocal origin for the polyps. No mutations were found in nonpolypoid control tissue and in polyps from the attenuated FAP patient. The patients with SFGP in this series were all between 40 and 70 years of age and had histories of acid-suppressive therapy.
The fundic gland polyps were histologically and genetically identical to single sporadic fundic gland polyps and demonstrated frequent somatic activating mutations in exon 3 of the beta-catenin gene.
HISTOLOGICAL TYPES CHARACTERIZATION GENERAL The histopathology of fundic gland polyps of the stomach.
Lee RG, Burt RW.
Am J Clin Pathol 1986 Oct;86(4):498-503 Abstract quote
To assess the histopathologic features of fundic gland polyps (FGP) of the stomach, 83 specimens from 25 patients were examined.
In nine patients, FGP were associated with an inherited adenomatous polyposis syndrome; the other 16 patients had nonsyndromic FGP. FGP were microscopically characterized by the presence of fundic glands with variably disordered architecture, a feature not previously emphasized.
Disordered architecture, found in 80 of 83 specimens (96%), comprised a spectrum of abnormalities, ranging from prominent glandular and cellular budding, found in 51 biopsies (61%), to irregular tortuous glands, noted in 61 biopsies (75%), to microcysts lined by fundic epithelium, seen in 72 biopsies (87%). The continuous range of these changes suggested that FGP arise through progressive formation and unfolding of secondary glandular buds, to result in cystic dilatation.
No differences were found between syndromic and nonsyndromic FGP with respect to histologic features or mucin histochemistry, including presence of O-acylated sialomucins.
VARIANTS DYSPLASIA Dysplasia and dysregulation of proliferation in foveolar and surface epithelia of fundic gland polyps from patients with familial adenomatous polyposis.
Wu TT, Kornacki S, Rashid A, Yardley JH, Hamilton SR.
Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Am J Surg Pathol 1998 Mar;22(3):293-8 Abstract quote
Fundic gland polyps (FGPs) of the stomach are regarded as hamartomatous or hyperplastic/functional polyps that occur sporadically but at increased frequency in patients with familial adenomatous polyposis syndrome (FAP).There is controversy about the histopathology of FGPs, including occurrence of dysplasia.
We, therefore, studied dysplasia in 270 sporadic FGPs from 216 patients and 49 FGPs from 24 patients with FAP. We evaluated dysregulation of epithelial proliferation manifested by loss of the normal inverse topographic distribution of Ki-67 proliferation marker and the cyclin-dependent kinase inhibitor p21(WAF1/CIP1) using immunohistochemistry in 27 sporadic FGPs and in 22 FGPs from patients with FAP. Dysplasia in foveolar and surface epithelia occurred in 12 of 49 (25%) FGPs in patients with FAP but in only 3 of 270 (1%) of sporadic FGPs (p < 0.000001). Fourteen of 49 (29%) of FGPs from patients with FAP were indefinite for dysplasia, as contrasted with 8 of 270 (3%) sporadic FGPs (p < 0.00001). The normal inverse topographic distribution of Ki-67 and p21(WAF1/CIP1) was maintained in 20 of 22 (91%) of FGPs negative for dysplasia but was lost in all (8 of 8) FGPs with dysplasia and in 11 of 19 (58%) FGPs that were indefinite for dysplasia (p = 0.00001).
The results indicate that dysplasia can occur in foveolar and surface epithelia of FGPs, especially in patients with FAP, and often is preceded by dysregulation of epithelial proliferation when the morphologic abnormalities are indefinite for dysplasia.
SPECIAL STAINS/
IMMUNOPEROXIDASE/
OTHERCHARACTERIZATION
Immunohistochemical evaluation of adenomatous polyposis coli, beta-catenin, c-Myc, cyclin D1, p53, and retinoblastoma protein expression in syndromic and sporadic fundic gland polyps.
Hassan A, Yerian LM, Kuan SF, Xiao SY, Hart J, Wang HL.Hum Pathol 2004;35:328-334 Abstract quote
Syndromic and sporadic fundic gland polyps are morphologically indistinguishable but may arise via different pathogenetic mechanisms involving mutations of the adenomatous polyposis coli (APC) and its downstream target beta-catenin genes. Although a higher frequency of dysplasia has been reported in syndromic forms, the risk of developing invasive carcinoma is exceedingly low.
The current study was designed to investigate whether syndromic and sporadic fundic gland polyps differ in protein expression of a number of genes that are thought to be important in the control of neoplastic transformation.
A total of 262 fundic gland polyps, including 155 syndromic polyps obtained from 35 patients with familial adenomatous polyposis or Gardner's syndrome and 107 sporadic polyps randomly selected from 45 patients with gastroesophageal reflux disease or Barrett's esophagus, were included in this study.
Immunohistochemical evaluation showed that loss of immunoreactivity to the antibody against the carboxyl terminus of the APC protein, presumably resulting from APC gene mutations, was more frequent in syndromic than in sporadic cases (40% versus 6.7%, P < 0.001). However, immunostaining failed to show aberrant nuclear localization of beta-catenin, a protein regulated by APC, in any of the polyps, irrespective of syndromic or sporadic types. Instead, positive membranous staining for beta-catenin was observed in all the cases. In addition, the expression characteristics of 2 other proteins, c-Myc and cyclin D1, whose genes have been reported to be transcriptionally regulated by the APC/beta-catenin pathway, were similar in these two types of polyps. Furthermore, all cases, including those harboring dysplasia, showed negative nuclear staining for p53 and positive nuclear staining for retinoblastoma (RB).
Taken together, these data show a lack of dysregulation in the APC/beta-catenin signaling pathway and in the expression of p53 and RB in fundic gland polyps despite a high frequency of somatic mutations of the APC and beta-catenin genes reported in these polyps.
These findings may explain at least in part why fundic gland polyps show a negligible malignant potential even in the presence of dysplasia.Sporadic fundic gland polyps: an immunohistochemical study of their antigenic profile.
Declich P, Isimbaidi G, Sironi M, Galli C, Ferrara A, Caruso S, Baldacci MP, Stioui S, Privitera O, Boccazzi G, Federici S.
Department of Pathology, Legnano General Hospital, Italy.
Pathol Res Pract 1996 Aug;192(8):808-15 Abstract quote
Fundic Gland Polyps (FGPs) are small sessile (2-5 mm), usually multiple polyps arising in the gastric, acid-secreting mucosa of disputed histogenesis. They have been described in a sporadic form, prevalently in middle aged females, or associated with familial adenomatosis coli-Gardner's syndrome.
We performed an immunohistochemical study on 24 sporadic FGPs, using monoclonal antibodies (MAbs) against differentiation markers, class II MHC antigens (HLA-DR), oncofetal and proliferation antigens, aimed to characterize the antigenic profile of the polyps. A preliminary cytogenetic study on five polyps was also done, using an in situ culture method after collagenase treatment. Cytokeratins 8-18 (CAM 5.2 MAb) and 20 (IT-Ks 20.8 MAb), Epithelial Membrane Antigen (EMA) and Chromogranin A were normally expressed by FGPs. FGPs did not express HLA II DR. FGPs did not react with an anti-CEA MAb (F6), but they were frequently positive (22/24, 91.6%) with B72.3 MAb (reacting with the cancer-associated mucin epitope sialyl-Tn). The PC10 MAb (against PCNA or cyclin) showed enhanced expression in the deep glandular-cystic compartment of FGPs; the PCNA index of FGPs was significantly higher than in normal fundic mucosa. The cytogenetic study on the 5 cases analysed, revealed a normal karyotype.
We have demonstrated that FGPs express in the paranuclear zone the sialyl-Tn epitope, a side-chain sugar normally masqued in adult gastric mucins, thus revealing an alteration in mucin synthesis; FGPs' higher proliferation index as compared with normal fundic mucosa supports the hypothesis of their hyperproliferative nature.
Gastric fundic gland polyps: a morphological study including mucin histochemistry, stereometry, and MIB-1 immunohistochemistry.
Odze RD, Marcial MA, Antonioli D.
Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
Hum Pathol 1996 Sep;27(9):896-903 Abstract quote
Fundic gland polyps are benign lesions, composed of a disorderly arrangement of normal gastric corpus cell types, that occur in a large proportion of patients with familial adenomatous polyposis (FAP) but also develop sporadically in non-FAP patients as well.
In this study, the authors evaluated and compared the endoscopic, histological, mucin histochemical, and microscopic stereologic features of 77 fundic gland polyps (FGPs) (15 FAP; 62 non-FAP) to determine if FAP-associated and sporadic lesions are histologically distinct. The authors also analyzed the distribution of mitotically active cells and smooth muscle cells in these lesions using MIB-1 and smooth muscle alpha-actin immunohistochemistry in an effort to determine the pathogenesis of these lesions.
The results show that, compared with non-FAP cases, FAP patients with FGPs have a lower male-to-female ratio, a younger mean age at diagnosis, and a higher proportion of cases with multiple polyps. However, no differences were detected between FAP and non-FAP-associated FGPs with respect to any endoscopic, morphological, mucin histochemical, or stereometric features. Eighty-six percent of FGPs showed an increase in smooth muscle content, often in a pericystic distribution. MIB-1-positive proliferative cells were observed not only in the foveolar stem cell region, as expected, but also in the epithelium lining the microcysts and in the gland buds located directly adjacent to the microcysts.
The authors conclude that FAP and non-FAP-associated FGPs are histologically identical, and propose that proliferation and subsequent differentiation of aberrantly located proliferative cells in these lesions may explain the histogenesis of FGPs.
PROGNOSIS AND TREATMENT CHARACTERIZATION PROGNOSTIC FACTORS GENERAL Natural history of fundic gland polyposis in patients with familial adenomatosis coli/Gardner's syndrome.
Iida M, Yao T, Itoh H, Watanabe H, Kohrogi N, Shigematsu A, Iwashita A, Fujishima M.
Gastroenterology 1985 Nov;89(5):1021-5 Abstract quote
In order to study the natural history of fundic gland polyposis, 23 patients with familial adenomatosis coli/Gardner's syndrome were examined over a follow-up period ranging from 17 mo to 13 yr (average 6 yr).
Examinations included gastric radiography and endoscopy with biopsy. Fundic gland polyps were found in 10 individuals. The size and number of polyps varied considerably. During the follow-up period, there was an increase in number or size of polyps, or both, in 5 patients (aged 8-27 yr), a decrease or disappearance in 2 patients (aged 36 and 41 yr), an initial decrease or disappearance followed by a late-occurring increase in 2 patients (aged 28 and 35 yr), In addition, malignant or adenomatous changes of fundic gland polyps were not observed in any patient.
Therefore, fundic gland polyposis in patients with familial adenomatosis coli/Gardner's syndrome may appear as early as 8 yr of age. In some patients there is a gradual increase in number and size of polyps, whereas in others, polyp proliferation ceases and polyps may even decrease in number and size.
Our findings indicate that the fundic gland polyposis does not require prophylactic surgery and that careful periodic follow-up should suffice.
Histologic types and surveillance of gastric polyps: a seven year clinico-pathological study.
Papa A, Cammarota G, Tursi A, Montalto M, Cuoco L, Certo M, Fedeli G, Gasbarrini G.
Department of Internal Medicine, Catholic University of Rome, Italy.
Hepatogastroenterology 1998 Mar-Apr;45(20):579-82 Abstract quote
BACKGROUND/AIMS: This is a seven-year prospective study based on all gastroscopic examinations of our patient population in order to study gastric polyps.
METHODOLOGY: One hundred and twenty-one polyps, removed from 96 patients were analysed. All polyps, after endoscopic polypectomy, were classified according to their histotype. The follow-up was carried out in 49 patients for a mean time of 40 months.
RESULTS: Polypoid lesions were more frequent in females (57.3%) and they were preferentially located in antrum (60.3%). Hyperplastic and inflammatory polyps were 55.4% and 28.9%, respectively, while adenomatous lesions were 9.9%. Four fundic gland polyps, 1 carcinoid, 1 type I early gastric cancer and 1 pancreatic heterotopia were also found. During the follow-up no malignant lesion was encountered. On the other hand 25 benign polyps were found in 19 patients.
CONCLUSIONS: Our experience confirms that there is a close relationship between the size of the polyps and the neoplastic change. In fact, in our series all polyps were smaller than 2 cm and only one malignancy was found (an early gastric cancer). None of adenomatous polyps was associated with gastric adenocarcinoma. Our data also indicates that when a polypectomy is carried out for small polyps (smaller than 2 cm.) a strict follow-up is necessary for the neoplastic polyps only.
MALIGNANCY Gastric adenocarcinoma and dysplasia in fundic gland polyps of a patient with attenuated adenomatous polyposis coli.
Zwick A, Munir M, Ryan CK, Gian J, Burt RW, Leppert M, Spirio L, Chey WY.
William B. and Shella Konar Center for Digestive and Liver Diseases, University of Rochester Medical Center, New York, USA.
Gastroenterology 1997 Aug;113(2):659-63 Abstract quote
Gastric adenocarcinoma has been previously recognized as a potential complication of familial adenomatous polyposis coli (APC) and attenuated forms of APC (AAPC). This tumor has only been reported to originate from adenomatous polyps of the gastric mucosa in these clinical conditions. There have been no previous case reports of gastric adenocarcinoma arising from the more commonly found fundic gland polyps associated with AAPC or APC.
We report the first definitive case of gastric adenocarcinoma arising from a hyperplastic polyp of the fundis of a patient with AAPC.
Gastric adenocarcinoma associated with fundic gland polyps in a patient with attenuated familial adenomatous polyposis.
Hofgartner WT, Thorp M, Ramus MW, Delorefice G, Chey WY, Ryan CK, Takahashi GW, Lobitz JR.
Department of Medicine, Providence St. Vincent Medical Center, Portland, Oregon, USA.
Am J Gastroenterol 1999 Aug;94(8):2275-81 Abstract quote
Familial adenomatous polyposis (FAP) is a rare autosomal dominant precancerous condition of the colon caused by mutations in the adenomatous polyposis coli (APC) tumor suppressor gene.
FAP is characterized by the appearance of innumerable adenomatous polyps throughout the large bowel. Fundic gland polyps are the most common gastric lesion in FAP. It is generally believed that fundic gland polyps have little or no potential for malignant transformation in the population at large, and only a few case reports describe the development of high grade dysplasia or gastric adenocarcinoma associated with diffuse fundic gland polyposis in patients with FAP. We report the second case of gastric adenocarcinoma intimately associated with fundic gland polyposis in a family with an attenuated form of FAP. The patient had undergone routine screening per current guidelines because of his known mutation in the APC gene.
This suggests that malignant transformation of fundic gland polyps in patients with FAP occur more frequently than previously believed. Current screening recommendations may not be sufficient for patients with FAP or its attenuated forms.
TREATMENT Simple excision Henry JB. Clinical Diagnosis and Management by Laboratory Methods. Twentieth Edition. WB Saunders. 2001.
Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.
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