Agrin in the Muscularis Mucosa Serves as a Biomarker Distinguishing Hyperplastic Polyps from Sessile Serrated Lesions

Purpose: Sessile serrated lesions (SSL) are precursors to colon carcinoma (CRC), and their distinction from other polyps, in particular hyperplastic polyps (HPs), presents significant diagnostic challenges. We evaluated expression patterns in colonic polyps of previously identified CRC-associated extracellular matrix (ECM) proteins to identify markers distinguishing SSLs from other polyps. Experimental Design: Gene-expression analyses of ECM proteins were performed using publicly available data on pre-neoplastic colonic polyps. In parallel, we evaluated by immunohistochemistry the expression of agrin (AGRN) in over 400 colonic polyps, including HP, SSL with and without dysplasia, traditional serrated adenomas (TSA), tubular adenomas (TA) and compared the consistency of standard histological diagnosis of SSLs by experienced gastrointestinal pathologists with that of AGRN immunohistochemistry. Results: Differential gene expression analysis and immunohistochemistry identified AGRN, serine peptidase inhibitor (SERPINE2) and TIMP metallopeptidase inhibitor 1 (TIMP1) elevated in SSLs and HPs but decreased in TAs and absent in normal colon. AGRN-positive basal laminae (BL) were noted in all TA, TSA, HP and SSL in distinguishable patterns, whereas other polyps and normal mucosa were negative. SSL with or without dysplasia consistently showed immunohistochemical staining for AGRN in the muscularis mucosae (MM), which was absent in HP, TSA, TA, and other polyps. In contrast, histological evaluation showed only weak inter-observer agreement (kappa value = 0.493) in distinguishing SSLs. Conclusions: Muscularis-mucosae-based AGRN immunostaining is a novel biomarker to distinguish SSL from HP, TSA and TA with a specificity of 97.1% and sensitivity of 98.9% and can assist in diagnosis of morphologically challenging colonic polyps.