Expression of gastric pyloric mucin, MUC6, in colorectal serrated polyps

Abstract

Serrated polyps of the colorectal mucosa represent a heterogeneous and controversial taxonomic category with variation in histopathological, molecular, and immunohistochemical characteristics and with an incomplete understanding of pathogenesis. A previous study reported that the expression of gastric pyloric-type mucin, MUC6, characterized sessile serrated adenomas. We therefore evaluated the expression of MUC6 in serrated polyps identified among 2502 participants in a Phase III chemoprevention trial within the Arizona Cancer Center Colorectal Cancer Prevention Trials Program and characterized the associated histopathological features and location. We carried out immunohistochemistry for MUC6 on 146 serrated lesions and 87 conventional tubular adenomas, and assessed the percentage of cells with expression and the grade of staining intensity. In all 92 hyperplastic polyps, 43 sessile serrated adenomas, and 11 traditional serrated adenomas were included. Polyps ranged in size from 1-150 mm. The association of MUC6 staining with serrated polyp category was evaluated using classification and regression tree (CART) analysis and two-sided Fisher's exact test. A total of 53% of sessile serrated adenomas (n=23), 17% of hyperplastic polyps (n=16), and 18% of traditional serrated adenomas (n=2), but none of 87 tubular adenomas, expressed MUC6. Expression was limited to the lower crypts in all serrated polyps. The extent of positive staining ranged from 2-100% of crypt cells and was independent of the histopathological type. MUC6 expression had relatively high specificity for sessile serrated adenoma (82%) but low sensitivity (54%). In CART analysis, proximal location was found to be the best partitioning factor for MUC6, followed by classification as sessile serrated adenoma. We conclude that MUC6 expression is strongly associated with proximal location of serrated polyps, but only has modest utility as a tissue biomarker for sessile serrated adenoma.

Figure 1

a. and b. : Sessile Serrated Adenoma, H&E, Proximal Colon, 20X: a. Section of proximal colon stained with hematoxylin and eosin showing some features of sessile serrated adenoma including dilatation of the base of the crypts, crypts extending parallel to the muscularis mucosae, serration at the base of the crypts, and eosinophilic change of the surface epithelium. b. Section of proximal colon sessile serrated adenoma in Figure 1a. with MUC6 immunostaining of the basal crypts. c. and d. : Hyperplastic Polyp, H&E, Distal Colon, 20X: c. Section of distal colon stained with hematoxylin and eosin showing features of hyperplastic polyp including serration in the upper half to one third of the crypts with normal proliferation including a proliferation zone at the base of the crypts that is symmetric, and crypts that remain narrow and lined with proliferative cells. d. Section of distal colon hyperplastic polyp in Figure 1c. with MUC6 immunostaining of the basal crypts.

Figure 2. Classification and Regression Tree Analysis

CART model of basal MUC6 staining and patient clinical characteristics. The model indicates that a polyp staining positive for MUC6 was explained by an interaction between proximal location and sessile serrated adenoma category. When sidedness was proximal, the proportion of MUC6-positive specimens was 56.0% compared to 16.1% in specimens from the distal colon. When histology was included, 94.1% of specimens that were MUC6-positive in the proximal colon were sessile serrated adenomas compared to only 29.2% of proximal specimens that were hyperplastic polyps or traditional serrated adenomas. In the distal specimens, the corresponding frequencies were 26.9% and 13.9% No further splits were found to significantly improve the homogeneity of the subgroup outcomes for MUC6 staining. Abbreviation Key: HP- hyperplastic polyp, SSA- sessile serrated adenoma, TSA- traditional serrated adenoma