Do all colorectal mucinous adenocarcinomas arise via the serrated neoplasia pathway?

Colorectal mucinous adenocarcinomas (MACs) and serrated adenocarcinomas (SACs) demonstrate considerable overlap in morphological and molecular features, suggesting a spectrum rather than two distinct tumour types. This study investigates the presence of serrated morphological features, precursors, and molecular features in a large cohort of MAC. The study includes 698 MAC collected via the Dutch nationwide pathology databank. Histological review and mismatch repair evaluation were performed on all cases. Next generation sequencing was performed on 396 cases. Multiplex nested methylation-specific PCR (MSP) was performed on 260 microsatellite stable (MSS) cases. The majority of tumours were right-sided (62.6%). Precursor lesions were identified in 9.6% of cases, 88% of which were serrated. Serrated morphology was present in 71% of MAC. Of all cases, 33.8% were microsatellite unstable (MSI). Half of the evaluated cases were CpG island methylator phenotype high. Tumours were divided into six molecular subcategories BRAF/MSS (9.8%), BRAF/MSI (24.7%), KRAS/MSS (38.6%), KRAS/MSI (4.3%), double wild-type/MSS (16.7%), and double wild-type/MSI (5.8%). Based on the presence of a serrated precursor, and/or serrated morphology, and/or a serrated molecular profile, 83.1% of MAC in our cohort could be classified as serrated-MAC. Serrated-MAC developed in older patients, was more often right-sided, showed less perineural invasion, and fewer nodal metastases, when compared to MAC-NOS. Survival analysis showed no significant difference between serrated-MAC and MAC-NOS. We have confirmed that a large majority of colorectal MAC have similar characteristics to SAC.