We conducted this study to examine COX-2 expression in various serrated and non-serrated colorectal neoplasias. We have demonstrated that, compared to non-serrated adenomas, COX-2 overexpression is infrequent in hyperplastic polyps, sessile serrated polyps/adenomas (SSAs) and mixed polyps with SSA and adenoma. Traditional serrated adenoma and non-serrated adenoma show similar frequencies of COX-2 overexpression. In addition, COX-2 overexpression appears to become frequent as tumors progress to higher grade neoplasias, which is in agreement with a previous study showing a positive correlation between COX-2 expression and tumor grade in colorectal adenomas .
SSAs have been named in a variety of ways in the literature . Torlakovic and Snover  found that the histopathologic features of polyps of "hyperplastic polyposis" were different from those of small sporadic hyperplastic polyps, and the term "sessile serrated adenoma" was coined to distinguish these distinct lesions from the more pedunculated lesions of traditional serrated adenomas . Similar lesions have been reported under different names, including "serrated adenoma, superficial types"  and "serrated adenoma types 1 and 2" . A recent review by Jass  used the term "sessile serrated polyp" because "this lesion lacks the traditional cytology of colorectal adenoma and in order to avoid confusion with serrated adenoma, it is referred to in this review as sessile serrated polyp". To reconcile this terminology issue, we used the term "sessile serrated polyp/adenoma (SSA)".
A few previous studies have examined COX-2 expressions in sporadic serrated adenomas as well as hyperplastic polyps. Arao et al.  examined COX-2 expression in serrated adenomas and hyperplastic polyps, and found that 71% of serrated adenomas showed moderate to intense positivity, in contrast to 32% of hyperplastic polyps showing weak to moderate positivity. Takeuchi et al.  examined COX-2 expression in serrated adenomas, tubular adenomas and hyperplastic polyps, but not in SSAs. They found that serrated adenomas of the cerebriform pattern showed a similar COX-2 expression score as tubular adenomas, and concluded that serrated adenoma of the cerebriform pattern should be treated similarly as tubular adenoma. There are other studies that have shown infrequent COX-2 overexpression in hyperplastic polyps [2, 31]. However, to our knowledge, no study to date has compared COX-2 expression levels between SSAs, traditional serrated adenomas, non-serrated adenomas and adenocarcinomas.
The serrated pathway of colorectal carcinogenesis has been linked to widespread promoter methylation referred to as the CpG island methylator phenotype (CIMP) [23, 46]. CIMP-high colorectal cancers are inversely correlated with COX-2 overexpression independent of MSI status . Together with our current data on the inverse association between COX-2 and the serrated polyps, these observations support the proposed link between the serrated pathway and CIMP-high in colorectal cancer development.
Our data may have significant clinical implications because of emerging importance of COX-2 as a promising chemopreventive target [10, 18]. Regular aspirin use has been shown to decrease risks of colorectal cancer as well as adenoma [8, 9]. We have recently shown that regular aspirin use decreases a risk of COX-2-overexpressing colorectal cancer, but not a risk of COX-2-negative colorectal cancer . In light of our findings, aspirin, celecoxib, and other non-steroidal anti-inflammatory drugs (NSAIDs) may be less frequently effective against serrated polyps than non-serrated adenomas. However, since COX-2 overexpression also appears to be dependent on tumor progression, it is possible that COX-2 inhibition may still be effective for the prevention of tumor progression in a subset of any types of precursor lesions.