Pathological and Molecular Features of Mucinous Colorectal Adenocarcinoma

Background: Mucinous carcinomas (MC) account for 10-15% of colorectal carcinomas (CRC) and are considered aggressive tumors.They differ from conventional adenocarcinoma for many clinico-pathologic and molecular characteristics with implications on patient management and prognosis. Aim of the study was to compare clinical, pathological and biologic features of MC (mucin >50%) with those of conventional adenocarcinomas (AD) and of adenocarcinomas with <50% of mucin (AD-MC). Design: The study included 1675 patients with CRC surgically resected between 2004 and 2018. Mismatch repair status (MMR) was determined in 1422 cases by immunohistochemical analysis of MLH1, MSH2, MSH6 and PMS2 expression and/or by microsatellite instability analysis using a fluorescent PCR method. Tumors with loss of MMR protein expression and/or MSI-H were classified as MMRdeficient (MMR-D) and tumors with retained MMR proteins expression and/or MSS/MSI-L as MMR-proficient (MMR-P). KRAS exon 2 and BRAF-V600E mutation were investigated by direct DNA sequencing or RT-PCR in 630 cases. Results: Of the 1675 tumors, 1123 (67%) were classified as AD, 352 (21%) as AD-MC and 200 (12%) as MC. Comparing the three groups, MC and AD-MC occurred more frequently in the proximal colon (p<0.001) and more often demonstrated poor differentiation. No other significative differences were found concerning the other clinical and pathological variables examined. MC (37%) and AD-MC (34%) were more frequently MMR-D (p<0.001) than AD (6%). MC (36%) and AD-MC (41%) were also more often BRAF mutated than AD (12%). KRAS mutations were detected at a higher rate in AD and MC with respect to AD-MC (p=0.01). As a whole the proportion of KRASwt/BRAFwt AD (45%) was higher with respect to AD-MC (22%) and MC (18%). The strong association between BRAF mutation and tumor type was also observed in the group of MMR-P carcinomas. Conclusions: MC represent a distinct but heterogeneous group of CRC, characterized by specific molecular features such as MMR deficit and BRAF mutation. Interestingly, AD-MC display a genetic