Survivin and hedgehog protein expression in serrated colorectal polyps: an immunohistochemical study

Abstract

Sessile serrated adenomas and traditional serrated adenomas are pathogenetically related to inhibition of apoptosis. Survivin and hedgehog proteins, including sonic hedgehog, patched, and smoothened, inhibit apoptosis, with hedgehog proteins forming a signal transduction cascade implicated in digestive cancers. This study compares survivin and hedgehog protein expression in serrated polyps and tubulovillous adenomas. Biopsies of sessile serrated adenomas (48) and traditional serrated adenomas (10) diagnosed during 2005 were retrieved from our files. Biopsies of normal mucosa (10), hyperplastic polyps (14), and tubulovillous adenomas (22) were used for comparison. Immunohistochemistry for survivin, sonic hedgehog, patched, and smoothened was graded as high or low grade. chi(2) tests were used to evaluate correlation between polyp type and survivin and hedgehog expression. Traditional serrated adenomas were also compared to sessile serrated adenomas with foci of cytological dysplasia (11 cases) with respect to MLH1 and p53 expression. Sessile serrated adenomas showed high-grade nuclear and cytoplasmic expression of survivin at the bottom of crypts more frequently than tubulovillous adenomas (60% versus 18%, P = .001 [nuclear]; 54% versus 18%, P = .005 [cytoplasm]), the latter showing a top-heavy pattern of staining. Survivin expression in hyperplastic polyps was similar to sessile serrated adenomas, being bottom-heavy, whereas traditional serrated adenomas showed diffuse staining throughout crypts. Although traditional serrated adenomas showed high-grade expression of sonic hedgehog more frequently than tubulovillous adenomas (90% versus 18%; P < .001), sonic hedgehog, patched, and smoothened expression was low grade among normal mucosa, hyperplastic polyps, and sessile serrated adenomas. All cytological dysplasias showed increased p53 expression within dysplastic foci, and MLH1 was also lost within dysplastic foci in 4 cases; traditional serrated adenomas showed intact MLH1 expression and minimal p53 expression throughout. Survivin expression is localized to the bottom of crypts in sessile serrated adenomas and hyperplastic polyps, whereas tubulovillous adenomas show top-heavy expression. Traditional serrated adenomas express survivin throughout crypts, suggesting intersection between the serrated and conventional adenoma-cancer pathways. Sonic hedgehog up-regulation is characteristic of traditional serrated adenomas, distinguishing this entity from other colorectal polyps.