Cyclooxygenase-2 overexpression is common in serrated and non-serrated colorectal adenoma, but uncommon in hyperplastic polyp and sessile serrated polyp/adenoma

Background: Cyclooxygenase-2 (COX-2, PTGS2) plays an important role in colorectal carcinogenesis. COX-2 overexpression in colorectal cancer is inversely associated with microsatellite instability (MSI) and the CpG island methylator phenotype (CIMP). Evidence suggests that MSI/CIMP+ colorectal cancer may arise through the serrated tumorigenic pathway through various forms of serrated neoplasias. Therefore, we hypothesized that COX-2 may play a less important role in the serrated pathway. Methods: By immunohistochemistry, we assessed COX-2 expression in 24 hyperplastic polyps, 7 sessile serrated polyp/adenomas (SSA), 5 mixed polyps with SSA and adenoma, 27 traditional serrated adenomas, 515 non-serrated adenomas (tubular adenoma, tubulovillous adenoma and villous adenoma), 33 adenomas with intramucosal carcinomas, 96 adenocarcinomas with serration (corkscrew gland) and 111 adenocarcinomas without serration. Results: Strong (2+) COX-2 overexpression was more common in non-serrated adenomas (28%=143/515) than in hyperplastic polyps (4.2%=1/24, p=0.008) and serrated polyps (7 SSAs and 5 mixed polyps) (0%=0/12, p=0.04). Furthermore, any (1+/2+) COX-2 overexpression was more frequent in non-serrated adenomas (60%=307/515) than in hyperplastic polyps (13%=3/24, p < 0.0001) and serrated polyps ( SSAs and mixed polyps) (25%=3/12, p=0.03). Traditional serrated adenomas and non-serrated adenomas showed similar frequencies of COX-2 overexpression. Regardless of serration, COX-2 overexpression was frequent (similar to 85%) in colorectal adenocarcinomas. Tumor location was not significantly correlated with COX-2 overexpression, although there was a trend towards higher frequencies of COX-2 overexpression in distal tumors (than proximal tumors) among hyperplastic polyps, SSAs, mixed polyps, traditional serrated adenomas and adenocarcinomas. Conclusion: COX-2 overexpression is infrequent in hyperplastic polyp, SSA and mixed polyp with SSA and adenoma, compared to non-serrated and serrated adenoma. COX-2 overexpression becomes more frequent as tumors progress to higher grade neoplasias. Our observations suggest that COX-2 may play a less significant role in the serrated pathway of tumorigenesis; however, COX-2 may still play a role in later stage of the serrated pathway.