Rethinking mucinous colorectal adenocarcinoma classification: evidence from histopathology and RAS mutations

Mucinous adenocarcinoma (MAC) is a distinct and aggressive subtype of colorectal cancer (CRC), traditionally defined by > 50% mucinous component. However, evidence suggests tumors with lower mucin content may behave similarly. This study investigated clinicopathological and molecular differences between mucinous and non-mucinous CRC, and evaluated the prognostic relevance of the current mucin threshold.

We retrospectively analyzed 1716 CRC cases (2017-2021) from the Institut Pasteur de Tunis. Tumors were classified as NMAC (0-5% mucin), ACMC1 (5-50%), or MAC (> 50%). .RAS mutation status was determined using Lightmix (TibMolBiol). Clinical, histological, and metastatic features comparison across groups and survival analysis were assessed using SPSS v26.

Tumors with any mucinous component (5-100%) were significantly associated with right-sided location (p < 0.001), signet-ring cells (p < 0.001), synchronous peritoneal metastasis (p = 0.002-0.02), and KRAS mutations (p = 0.031) versus NMAC. Importantly, ACMC1 (5-50%) shared aggressive features with MAC, including lymphovascular invasion (p = 0.027) and distinct metastatic patterns.

Our findings debate the WHO 50% mucin threshold, showing that tumors with 5-50% mucin exhibit comparable aggressiveness to classical MAC. Integrating molecular profiling with histology may improve risk stratification and guide tailored therapeutic strategies for mucinous CRC, regardless of mucin proportion.