Are all colorectal mucinous adenocarcinomas arising via the serrated neoplasia pathway?

Colorectal mucinous adenocarcinomas (MAC) and serrated adenocarcinomas (SAC) demonstrate considerable overlap in morphological and molecular features, suggesting a spectrum rather than two distinct tumor types. This study investigates 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 revision and mismatch repair evaluation was performed on all cases. Next generation sequencing was performed on 396 cases. On 260 microsatellite stable (MSS) cases, we performed multiplex nested methylation specific (MSP) PCR.
The majority of tumors 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 (CIMP) high. Tumors were divided into six molecular subcategories BRAF/MSS (9.8%), BRAF/MSI (24.7%), KRAS/MSS (38.6%), KRAS/MSI (4.3%), double wildtype/MSS (16.7%), and double wildtype/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 MAC-SAC. MAC-SAC developed in older patients, were more right-sided, showed less perineural invasion, and less nodal metastases, when compared to MAC-nos. Survival analysis showed no significant difference between MAC-SAC and MAC-nos.
We have confirmed that a large majority of colorectal MAC have similar characteristics as SAC.