Serrated colorectal polyps often show DNA hypermethylation and/or BRAF mutations and have been implicated in the "serrated neoplastic pathway." Although similar lesions occur in the appendix, they have never been systematically investigated. We evaluated a study group of 56 serrated polyps, a control group of 17 mucinous cystadenomas, and 4 adenocarcinomas with adjacent serrated polyps of the appendix to better understand their pathogenesis. The study cases were classified as nondysplastic or dysplastic serrated polyps and evaluated for MLH-1, MSH-2, MGMT, beta-catenin, p53, and Ki-67 expression, BRAF and KRAS mutations, and microsatellite instability. Serrated polyps usually occurred in older adults with no sex predilection. Most (59%) lacked dysplasia, but all showed similar molecular features, regardless of the degree of dysplasia present. Decreased MLH-1 (50%, P<0.001) and/or MGMT (59%, P<0.001) expression and BRAF (29%, P=0.007) mutations were significantly more common in serrated polyps, but BRAF mutations were detected in a minority of the extracted DNA in 15/16 cases. Of the 28 cases with decreased MLH-1 expression, none showed high-frequency microsatellite instability. Loss of MLH-1 (25%) or MGMT (50%) expression and BRAF or KRAS mutations (50%) were inconsistently present in adenocarcinomas and were not identified in combination in any cases. We conclude that molecular features of the "serrated neoplastic pathway" are present with similar frequencies among dysplastic and nondysplastic serrated appendiceal polyps and are not highly prevalent in adjacent carcinomas. These features, including BRAF mutations, may be more closely related to a serrated morphology in appendiceal polyps rather than biologically important changes.

Sessile serrated polyps (SSPs) have been implicated in the pathogenesis of proximal colonic carcinomas, but they lack well-defined diagnostic criteria and their features overlap considerably with those of microvesicular hyperplastic polyps (MVHPs). We have noted that morphologic features of SSPs are often present in small, distally located MVHPs, suggesting that these polyps represent points on a continuum, rather than distinct entities. We evaluated the molecular features of diminutive (<1 cm) nondysplastic serrated polyps that met at least 4 of the 7 "SSP-like" morphologic criteria, but occurred throughout the colorectum, and compared them with SSPs and MVHPs. Fifty nondysplastic serrated polyps (6 SSPs, 31 study polyps, and 13 MVHPs) were evaluated for Ki-67, O6-methylguanine methyltransferase, MUC2, and MUC5AC expression, and also their BRAF and KRAS mutational status. The study polyps and SSPs were similar; 52% and 50% expressed MUC5AC, and 87% and 100% harbored BRAF mutations, respectively, compared with 15% and 46% of MVHPs (P < or = 0.05, all comparisons). O6-methylguanine methyltransferase expression in the study polyps (29%) was intermediate between that of SSPs (83%, P=0.02) and MVHPs (15%, P=0.04). We conclude that the pathologic and molecular features of diminutive, distally located nondysplastic serrated polyps are often indistinguishable from proximally located SSPs, although convincing evidence linking the former to appreciable colorectal cancer risk is entirely lacking. Thus, we propose that, at present, the term "sessile serrated polyp" be restricted to large (> or = 1 cm), proximally located polyps with a presumed biologic risk, until prospective data regarding the natural history of small, distal lesions are available.