A Comprehensive Study of Nondysplastic and Dysplastic Serrated Polyps of the Vermiform Appendix

Abstract

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.

Hyperplastic/Serrated Polyposis in Inflammatory Bowel Disease

“…For each case, nonlesional tissue was manually removed from the tissue slides using surgical blades for each section examined and DNA was extracted from the remaining lesional tissue using the QIAamp DNA MiniKit (Qiagen Sciences, Valencia, CA). Polymerase chain reaction amplifications were performed using the following primers, as previously described 43 :…”

Clinicopathologic and molecular analysis of disseminated appendiceal mucinous neoplasms: identification of factors predicting survival and proposed criteria for a three-tiered assessment of tumor grade

“…Most previous studies have identified KRAS mutation in a high proportion of disseminated low-grade mucinous neoplasms. 4,29 The frequent presence of activating KRAS mutations in disseminated mucinous neoplasms arising from the appendix is not surprising given that KRAS mutations have been identified in between 41 and 100% appendiceal mucinous adenomas 4,29,30 which are the presumed precursor lesion to disseminated neoplasms. Notably, none of the high-grade mucinous adenocarcinomas with signet ring cells (grade G3) composed of a pure (495%) signet ring cell component harbored a KRAS mutation suggesting that the underlying genetic events leading to carcinogenesis are different for grade G3 adenocarcinomas.…”

A mutation spectrum that includes GNAS, KRAS and TP53 may be shared by mucinous neoplasms of the appendix

“…Overexpression of p53 is reported to be rare in appendiceal tumors [4,6], although KRAS mutation and p53 overexpression can be seen in half of pseudomyxoma peritonei (PMP) cases of appendiceal origin [7]. Furthermore, microsatellite instability is rare in appendiceal carcinoma, and hypermethylation is not a mechanism for genetic instability in these tumors [8] although some hyperplastic polyps and sessile serrated adenomas of the appendix show decreased expression of MLH1 and BRAF mutation is more common in serrated polyps [9]. The Wnt signaling pathway that involves ␤-catenin plays a critical role in colorectal carcinogenesis, and approximately 90% of cases of colorectal carcinoma express nuclear ␤-catenin.…”