Fundic Gland Polyps in Familial Adenomatous Polyposis

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. 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. Fundic gland polyps (FGPs) are the most common gastric polyps in both familial adenomatous polyposis (FAP) and sporadic patients.1Stolte M Sticht T Eidt S Ebert D Finkenzeller G Frequency, location, and age and sex distribution of various types of gastric polyp.Endoscopy. 1994; 26: 659-665Crossref PubMed Scopus (206) Google Scholar FGPs are reported to occur in 12.5 to 84% of patients with FAP,2Watanabe H Enjoji M Yao T Ohsato K Gastric lesions in familial adenomatous coli.Hum Pathol. 1978; 9: 269-283Abstract Full Text PDF PubMed Scopus (170) Google Scholar, 3Spigelman AD Williams CB Talbot IC Domizio P Phillips RKS Upper gastrointestinal cancer in patients with familial adenomatous polyposis.Lancet. 1989; 2: 783-785Abstract PubMed Scopus (654) Google Scholar, 4Church JM McGannon E Hull-Boiner S Sivak MV Van Stolk R Jagelman DG Fazio VW Oakley JR Lavery IC Milsom JW Gastroduodenal polyps in patients with familial adenomatous polyposis.Dis Colon Rectum. 1992; 35: 1170-1173Crossref PubMed Scopus (155) Google Scholar, 5Tonelli F Nardi F Bechi P Taddei G Gozzo P Romagnoli P Extracolonic polyps in familial polyposis coli and Gardner's syndrome.Dis Colon Rectum. 1985; 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27: 896-903Abstract Full Text PDF PubMed Scopus (55) Google Scholar Histopathologically, FGPs are characterized by cystically dilated and irregularly budded fundic glands in a background of otherwise normal gastric mucosa.18Lee RG Burt RW The histopathology of fundic gland polyps of the stomach.Am J Clin Pathol. 1986; 86: 498-503Crossref PubMed Scopus (65) Google Scholar, 19Sipponen P Laxen F Seppala K Cystic ‘hamartomatous' gastric polyps: a disorder of oxyntic glands.Histopathology. 1983; 7: 729-737Crossref PubMed Scopus (35) Google Scholar The pathogenesis of FGPs remains uncertain. FGPs have generally been regarded as nonneoplastic lesions, either hamartomatous or hyperplastic/functional in nature.16Iida M Yao T Itoh H Watanabe H Kohrogi N Shigelmatsu A Iwashita A Fujishima M Natural history of fundic gland polyposis in patients with familial adenomatosis coli/Gardner's syndrome.Gastroenterology. 1985; 89: 1021-1025Abstract Full Text PDF PubMed Scopus (68) Google Scholar, 19Sipponen P Laxen F Seppala K Cystic ‘hamartomatous' gastric polyps: a disorder of oxyntic glands.Histopathology. 1983; 7: 729-737Crossref PubMed Scopus (35) Google Scholar, 20Odze R Gastric fundic gland polyps: are they preneoplastic lesions?.Gastroenterology. 1998; 114: 422-423Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar Although some studies have reported no differences in the histology between sporadic FGPs and FGPs in patients with FAP,18Lee RG Burt RW The histopathology of fundic gland polyps of the stomach.Am J Clin Pathol. 1986; 86: 498-503Crossref PubMed Scopus (65) Google Scholar, 19Sipponen P Laxen F Seppala K Cystic ‘hamartomatous' gastric polyps: a disorder of oxyntic glands.Histopathology. 1983; 7: 729-737Crossref PubMed Scopus (35) Google Scholar, 20Odze R Gastric fundic gland polyps: are they preneoplastic lesions?.Gastroenterology. 1998; 114: 422-423Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar others have disputed this. In contrast to sporadic FGPs, FGPs in patients with FAP frequently show foveolar dysplasia,8Domizio P Talbot IC Spigelman AD Williams CB Phillips RKS Upper gastrointestinal pathology in familial adenomatous polyposis: results from a prospective study of 102 patients.J Clin Pathol. 1990; 43: 738-743Crossref PubMed Scopus (146) Google Scholar, 21Wu TT Kornacki S Rashid A Yardley JH Hamilton SR Dysplasia and dysregulation of proliferation in foveolar and surface epithelia of fundic gland polyps from patients with familial adenomatous polyposis.Am J Surg Pathol. 1998; 22: 293-298Crossref PubMed Scopus (137) Google Scholar, 22Bertoni G Sassatelli R Nigrisoli E Pennazio M Tansini P Arrigoni A Rossini FP Ponz de Leon M Bedogni G Dysplastic changes in gastric fundic gland polyps of patients with familial adenomatous polyposis.Ital J Gastroenterol Hepatol. 1999; 31: 192-197PubMed Google Scholar, 23Zwick A Munir M Ryan CK Gian J Burt RW Leppert M Spiro L Chey WY Gastric adenocarcinoma and dysplasia in fundic gland polyps of a patient with attenuated adenomatous polyposis coli.Gastroenterology. 1997; 113: 659-663Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar including a 25% prevalence of low-grade dysplasia in FAP-associated FGPs.21Wu TT Kornacki S Rashid A Yardley JH Hamilton SR Dysplasia and dysregulation of proliferation in foveolar and surface epithelia of fundic gland polyps from patients with familial adenomatous polyposis.Am J Surg Pathol. 1998; 22: 293-298Crossref PubMed Scopus (137) Google Scholar In addition, neoplastic progression of FGPs in FAP patients has occasionally been reported, including the development of a large dysplastic gastric polyp with an activating codon 12 K-ras gene mutation in one patient24Odze 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: 442-448Abstract Full Text PDF PubMed Scopus (36) Google Scholar and three cases of infiltrating gastric adenocarcinoma23Zwick A Munir M Ryan CK Gian J Burt RW Leppert M Spiro L Chey WY Gastric adenocarcinoma and dysplasia in fundic gland polyps of a patient with attenuated adenomatous polyposis coli.Gastroenterology. 1997; 113: 659-663Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar, 25Coffey RJ Knight CD Van Heerden JA Weiland LH Gastric adenocarcinoma complicating Gardner's syndrome in a North American woman.Gastroenterology. 1985; 88: Scopus Google Scholar, M G Chey WY Ryan CK JR Gastric adenocarcinoma with fundic gland polyps in a patient with attenuated familial adenomatous polyposis.Am J Gastroenterol. 1999; PubMed Google Scholar arising in with fundic gland polyposis. The pathogenesis of lesions in the upper and gastrointestinal tract in FAP patients has been from 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, M M R M T K M H Y M Y T Y T M of somatic mutation of the adenomatous polyposis coli gene in 1994; Google Scholar, M M R T M Somatic mutations of the adenomatous polyposis coli gene in gastroduodenal from patients with familial adenomatous Google Scholar of the and in patients with FAP can be to have of the adenomatous polyposis coli (APC) gene These a somatic alteration of one of the APC gene either mutation or allelic with an APC gene mutation in the Although the of the APC are there that has a in in from the to in the P JH The adenomatous polyposis coli to in 1996; PubMed Scopus Google Scholar The pathogenesis of foveolar dysplasia in FGPs from FAP patients has been study identified somatic mutations of the APC gene in three of FAP-associated FGPs, that at some FGPs the APC in the M M R T M Somatic mutations of the adenomatous polyposis coli gene in gastroduodenal from patients with familial adenomatous Google Scholar the of the FGPs, the of foveolar dysplasia, were reported in that the pathogenesis of FGPs, we somatic APC gene alterations in dysplastic and nondysplastic FGPs from FAP patients and in sporadic FGPs. somatic alterations in with gastrointestinal to foveolar dysplasia in FGPs, we K-ras gene mutations in dysplastic and nondysplastic FAP-associated FGPs. The study of patients with FAP or attenuated FAP upper gastrointestinal with gastric at The between and APC gene mutations in from The shown in A of 41 FGPs from patients was FGPs were three of and to TT Kornacki S Rashid A Yardley JH Hamilton SR Dysplasia and dysregulation of proliferation in foveolar and surface epithelia of fundic gland polyps from patients with familial adenomatous polyposis.Am J Surg Pathol. 1998; 22: 293-298Crossref PubMed Scopus (137) Google Scholar no dysplasia of the foveolar epithelium changes indefinite for dysplasia and foveolar dysplasia (20 with low-grade dysplasia and one with gastric from patients were in the 13 sporadic FGPs from 13 patients without FAP were and Somatic APC in FAP of gastric APC patients clinical for FAP or attenuated Somatic APC alterations either allelic loss or mutation by direct of somatic mutation shown by codon of APC gene patients were for allelic loss at one or more fundic gland low-grade foveolar indefinite for foveolar in a patients clinical for FAP or attenuated Somatic APC alterations either allelic loss or mutation by direct of somatic mutation shown by codon of APC gene patients were for allelic loss at one or more fundic gland low-grade foveolar indefinite for foveolar of for was from the 41 FAP-associated FGPs, of the dilated fundic glands of the polyp and the foveolar epithelium was in 25 cases. In cases, the foveolar epithelium be microdissected of of the dilated glands by in cases the dilated glands be microdissected of of the foveolar and in one both the foveolar and epithelium of the polyp were In 13 sporadic FGPs, foveolar epithelium and glands were microdissected and analyzed was as and of from J Pathol. 1997; Google Scholar was from nonneoplastic gastric or duodenal of and for to and for to were to the mutation of the APC gene for gastroduodenal M M R T M Somatic mutations of the adenomatous polyposis coli gene in gastroduodenal from patients with familial adenomatous Google Scholar, K S Y A K Y T of the adenomatous polyposis coli gene in the mutation of and J 1994; PubMed Scopus (68) Google Scholar was in a and of both and with for for and for were and were with with the same for were with mutations were in both the and of was by assays of three and as TT Watanabe T R M AA Hamilton SR alterations in and of the and J Pathol. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar assays were in with for for and for in a of both and and of in The was with was to be there was or at a in the of a as with nonneoplastic in at one of the K-ras gene was in FAP-associated FGPs and 13 sporadic FGPs. of and was to a in of K-ras 12 and was in a and of both and with for for and for were and were with the an was to differences in of somatic APC gene alterations or allelic between FAP-associated and sporadic FGPs. The was to somatic APC gene alteration FAP-associated FGPs which were and for foveolar A P of was A frequency of somatic APC alterations gene mutation by direct sequencing or allelic loss at was in FGPs from FAP of FAP patients with FGPs an somatic APC gene alteration in at one of 41 FGPs from patients with FAP somatic APC gene Somatic APC alterations were in three of six FAP-associated gastric a to that in FAP-associated FGPs. Somatic APC gene mutations were of of A a tract to in 13 FGPs, and mutation at codon in FGPs and one was in an six FGPs and for somatic APC gene mutation or allelic were to occur in the same patients from polyps were analyzed showed either or APC gene mutations in of the APC gene alterations in FGPs and gastric in were no differences between somatic APC alteration FGPs with dysplasia, indefinite for dysplasia, and no we somatic APC gene alterations in of 15 nondysplastic FGPs, of six FGPs indefinite for dysplasia, and of dysplastic FGPs (P = and was for alterations in the foveolar epithelium and the dilated fundic glands of the FGPs. the 25 FGPs in which the foveolar epithelium and fundic glands were microdissected and analyzed 24 (96%) of 25 showed in APC gene In the one a somatic APC gene mutation of A in to was in the foveolar epithelium but in the glands of an with low-grade dysplasia possibly to by or nonneoplastic fundic of normal from FAP patient no somatic APC mutation in APC gene mutations in FAP-associated FGPs. sequencing of a mutation at codon in both the foveolar epithelium and the epithelium of the dilated fundic glands from an as indefinite for dysplasia A a tract in both the foveolar epithelium and the dilated fundic glands from an with low-grade dysplasia mutations are in the loss in FAP-associated FGPs. of with the and in both the foveolar epithelium and dilated fundic glands from an with low-grade dysplasia but in an with dysplasia or in the from the same of Somatic APC in and APC gene of loss FGPs were more to show somatic APC alterations mutation by direct sequencing or than were sporadic FGPs (P = for was no difference in the frequency of APC gene alterations identified in FAP-associated FGPs that were or for foveolar dysplasia (P = for was no difference in the frequency of APC gene alterations identified in FAP-associated FGPs that were or for foveolar dysplasia (P = was no difference in the frequency of APC gene alterations identified in FAP-associated FGPs that were or for foveolar dysplasia (P = FGPs were more to show somatic APC alterations mutation by direct sequencing or than were sporadic FGPs (P = FAP-associated FGPs were more to show somatic APC alterations mutation by direct sequencing or than were sporadic FGPs (P = was no difference in the frequency of APC gene alterations identified in FAP-associated FGPs that were or for foveolar dysplasia (P = in a were to the APC mutation in from one a to In sequencing of the and in equal whereas three FGPs which at showed a in the of the that the allelic were of the APC gene mutations were identified in the same 13 sporadic FGPs, and was in one sporadic In allelic loss was identified with both the and was in the foveolar epithelium but in the dilated fundic glands of the The frequency of somatic APC alterations in FAP-associated FGPs was than in sporadic FGPs P = A K-ras gene mutation was in one of FAP-associated FGPs, an low-grade foveolar dysplasia with a mutation in codon 12 K-ras gene mutations were in of the sporadic FGPs. that FAP-associated FGPs are and distinct from sporadic FGPs, both the and of foveolar dysplasia in FAP-associated but sporadic FGPs. study that FGPs in patients with FAP have a pathogenesis that distinct from sporadic FGPs. FAP-associated FGPs in with somatic APC gene alterations, whereas APC alterations are identified in sporadic FGPs. results are in with and of M M R T M Somatic mutations of the adenomatous polyposis coli gene in gastroduodenal from patients with familial adenomatous Google Scholar somatic APC mutations in three of FAP-associated FGPs. The of the somatic APC mutations that we identified sequencing A mutation in to to a for gastroduodenal in of FAP-associated FGPs and of gastric by M M R T M Somatic mutations of the adenomatous polyposis coli gene in gastroduodenal from patients with familial adenomatous Google Scholar results contrast with which have regarded both FAP-associated and sporadic FGPs as or hamartomatous lesions with have reported no differences between the or mucin of FAP-associated and sporadic FGPs, that in both FGPs from the and of RD Marcial MA Antonioli D Gastric fundic gland polyps: a morphologic study including mucin histochemistry, stereometry, and MIB-1 immunohistochemistry.Hum Pathol. 1996; 27: 896-903Abstract Full Text PDF PubMed Scopus (55) Google Scholar, RG Burt RW The histopathology of fundic gland polyps of the stomach.Am J Clin Pathol. 1986; 86: 498-503Crossref PubMed Scopus (65) Google Scholar P G M A S S G S fundic gland polyps: an study of 1996; PubMed Scopus Google Scholar have that FGPs are polyps in FGPs than in normal fundic These have to the by some that dysplastic changes in the foveolar epithelium FAP-associated FGPs are the of gastric which at an increased frequency in with FGPs of increased proliferation and increased of to R Gastric fundic gland polyps: are they preneoplastic lesions?.Gastroenterology. 1998; 114: 422-423Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar of the that FGPs in patients with FAP in the pathogenesis of FAP-associated FGPs, to second-hit APC gene alterations, distinct from that of sporadic FGPs. the same somatic APC gene alterations are in both the dilated fundic glands comprising the and the foveolar there no difference in the of somatic APC gene alterations in and nondysplastic FAP-associated FGPs. These indicate that somatic APC alterations are to the of FAP-associated FGPs and are to or foveolar The of somatic APC gene alterations that FGPs arising in the setting of FAP are neoplastic lesions. FGPs in FAP patients show a pathogenesis to that of adenomatous polyps of the and which have been to from second-hit APC gene alterations the APC from 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, M M R M T K M H Y M Y T Y T M of somatic mutation of the adenomatous polyposis coli gene in 1994; Google Scholar of and for somatic APC alterations in FAP-associated FGPs and gastric are an of the frequency of second-hit APC we the mutation for gastroduodenal polyps in M M R T M Somatic mutations of the adenomatous polyposis coli gene in gastroduodenal from patients with familial adenomatous Google Scholar Although was in the of cases to that the somatic APC gene alterations the than in one we were to the to by sequencing of In three FGPs that allelic loss at showed a in the of the sequencing allelic the APC indicate that gastric polyps from the same patient are one for somatic APC gene either mutation or allelic H M A S J J K S R P D K Phillips R Talbot The of somatic mutation at APC in familial adenomatous polyposis by the of the a to 1999; PubMed Scopus Google Scholar have reported that the of the APC mutation the nature of the second-hit APC with some FAP patients allelic loss in and others of a in the of a of gastric The in study an the of the APC gene in gastric FAP-associated FGPs are the polyps in the gastrointestinal tract shown to APC without an adenomatous in a the APC gene the of FGPs than be by that FGPs in FAP patients are to the of foveolar dysplasia to in the of FAP-associated FGPs show foveolar TT Kornacki S Rashid A Yardley JH Hamilton SR Dysplasia and dysregulation of proliferation in foveolar and surface epithelia of fundic gland polyps from patients with familial adenomatous polyposis.Am J Surg Pathol. 1998; 22: 293-298Crossref PubMed Scopus (137) Google Scholar In the results of study indicate that somatic APC to the or of foveolar we no difference in the of somatic APC alterations in FAP-associated FGPs with and without foveolar that alterations for the of foveolar dysplasia and to neoplastic progression in a of FGPs. In activating K-ras gene mutations to a as we were to a K-ras gene mutation in one FAP-associated with low-grade foveolar dysplasia to be The of FGPs in gastric in patients with FAP remains unclear. In and FAP has been with an increased of gastric H Enjoji M Yao T Ohsato K Gastric lesions in familial adenomatous coli.Hum Pathol. 1978; 9: 269-283Abstract Full Text PDF PubMed Scopus (170) Google Scholar, J T T Y T T E N Gastric of familial polyposis PubMed Scopus (116) Google Scholar, of gastric cancer familial adenomatous polyposis of three Colon Rectum. 1992; 35: PubMed Scopus Google Scholar In patients with FAP, to be but from that of the in the study reported by Hamilton SR The of upper gastrointestinal cancer in familial adenomatous 1992; Google Scholar progression of FGPs in patients with FAP has been including of a large fundic gland polyp with dysplasia and K-ras gene and infiltrating arising in with fundic gland A Munir M Ryan CK Gian J Burt RW Leppert M Spiro L Chey WY Gastric adenocarcinoma and dysplasia in fundic gland polyps of a patient with attenuated adenomatous polyposis coli.Gastroenterology. 1997; 113: 659-663Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar, 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: 442-448Abstract Full Text PDF PubMed Scopus (36) Google Scholar, 25Coffey RJ Knight CD Van Heerden JA Weiland LH Gastric adenocarcinoma complicating Gardner's syndrome in a North American woman.Gastroenterology. 1985; 88: Scopus Google Scholar, M G Chey WY Ryan CK JR Gastric adenocarcinoma with fundic gland polyps in a patient with attenuated familial adenomatous polyposis.Am J Gastroenterol. 1999; PubMed Google Scholar the of more of the of progression in patients with FAP and fundic gland that FAP-associated FGPs are neoplastic to the of neoplastic polyps of the upper gastrointestinal tract in patients with FAP, the of fundic gland polyposis and for and of