Dysplasia in Fundic Gland Polyps is Associated with Nuclear b-Catenin Expression and Relatively High Cell Turnover Rates M. Jalving, J. J. Koornstra, W. Boersma-van Ek, S. de Jong, A. Karrenbeld, H. Hollema, E. G. E. de Vries & J. H. Kleibeuker Dept. of Gastroenterology and Hepatology, Medical Oncology and Pathology, University Hospital Groningen, Groningen, The Netherlands Jalving M, Koornstra JJ, Boersma-van Ek W, de Jong S, Karrenbeld A, Hollema H, de Vries EGE, Kleibeuker JH. Dysplasia in fundic gland polyps is associated with nuclear b-catenin expression and relatively high cell turnover rates. Scand J Gastroenterol 2003;38:916–922. 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 b-catenin gene mutations. Dysplasia in sporadic FGPs, found less often than in syndromic FGPs, was recently associated with APC rather than b-catenin mutations. These data suggest different functional consequences of APC and b-catenin mutations. To investigate this hypothesis, we examined proliferative activity, degree of apoptosis, b-catenin expression and p53 expression in syndromic and sporadic FGPs. Methods: Syndromic FGPs (n = 9) from familial adenomatous polyposis (FAP) patients and sporadic FGPs (n = 18) were studied. Proliferative activity, apoptotic cell death and expression of b- 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, b-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 b-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 b-catenin gene mutations have different functional consequences in FGPs. The association of dysplasia with relatively high cell turnover rates and nuclear expression of b-catenin indicates activation of the Wnt-APC-b-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. Key words: Apoptosis; b-catenin; dysplasia; familial adenomatous polyposis; fundic gland polyps; proliferation; p53 J. H. Kleibeuker, M.D., Ph.D., Dept. of Gastroenterology and Hepatology, University Hospital, P.O. Box 30.001, NL-9700 RB Groningen, The Netherlands (fax. 31 50 361 9306, e-mail. j.h.kleibeuker@ int.azg.nl) F undic gland polyps (FGPs) are the most common gastric polyps (1, 2). They are characterized histo- logically by distorted glandular architecture consis- ting of microcysts, often lined with fundic type epithelial cells (chief and parietal cells) but occasionally with foveolar type mucous cells (Fig. 1) (3). FGPs occur in both sporadic and syndromic form. The syndromic form is associated with familial adenomatous polyposis (FAP) and attenuated FAP (AFAP) (4). Fundic gland polyps are found in up to 1.9% of the general population (5–7), in up to 84% of FAP patients (6– 13) and in 93% of AFAP patients (4). Histologically, sporadic and syndromic FGPs are identical (3, 14). FGPs have always been regarded as benign lesions, but there have been case reports of FGPs harbouring severe dysplasia or even gastric adenocarcinoma, particularly when associated with FAP (15–17) or AFAP (18–21). Low-grade dysplasia has been observed in up to 53% of syndromic FGPs and in up to 2.3% of sporadic FGPs (3, 9, 13, 14, 22–24). FAP is caused by a germline mutation in the APC gene causing hundreds to thousands of adenomatous polyps in the colon. AFAP typically presents 10–15 years later than FAP and is associated with fewer adenomas. It is caused by germline mutations in the 5' or 3' end of the APC gene (4). Activation of the Wnt-APC-b-catenin pathway is thought to be involved in the pathogenesis of both syndromic and sporadic FGPs (24). In FAP, a germline APC mutation and subsequent somatic mutation of the second allele causes activation of this pathway (25). There is a high frequency of somatic mutations of the second APC allele in syndromic FGPs but not in sporadic FGPs (23, 26). In sporadic FGPs, a ORIGINAL ARTICLE  2003 Taylor & Francis DOI 10.1080/00365520310005433 Scand J Gastroenterol Downloaded from informahealthcare.com by University of Groningen on 04/08/15 For personal use only.