Predictive value of a mesenchymal phenotype grading system combining tumor budding and FRMD6 expression for disease-free survival in colorectal carcinomas.

Background/objectives: The mesenchymal phenotype in solid epithelial tumors contributes to aggressive outcomes. This study examined histological indicators of tumor mesenchymal phenotypes, including the Glasgow Microenvironment Score (GMS), tumor budding (TB) grades and Ferm Containing Domain 6 (FRMD6) expression in colorectal carcinomas (CRC) and correlated these with disease-free survival (DFS).

Methods: Total 101 CRC cases were included. Peri-tumoral inflammation was classified as low (none/mild) and high (band/dense cup-like) infiltration. Tumor stromal percentage was assessed as low (≤ 50% intra-tumor stroma) and high (> 50% fibrosis) based on intra-tumoral fibrosis. TB at the invasive border was categorized as low (0-9/0.785 mm²) and high (≥ 10/0.785 mm²). FRMD6 expression was graded as low and high according to the median H score. All these parameters were correlated with DFS.

Results: The mean DFS in this cohort was 19.7 months. While the GMS grades did not correlate with DFS at 36 months (p 0.71) and 48 months (p 0.79), TB and FRMD6 grades separately were significantly correlated with DFS at 36 months (TB p 0.001 and FRMD6 p 0.004) and 48 months (TB p 0.002 and FRMD6 p 0.008). When combined, the mesenchymal classification using GMS + TB + FRMD6 did not show correlation with DFS at 36 months (p 0.09) and 48 months (p 0.49). However, mesenchymal phenotyping combining TB + FRMD6 showed a significant correlation with DFS both at 36 months (p < 0.001) and 48 months (p < 0.001) in multivariate analysis. In this cohort, CRCs with low-GMS, low-TB and low-TB + GMS grades were found to be mostly mismatch repair (MMR) deficient (GMS p 0.007, TB p 0.03 and GMS + TB p 0.009).

Conclusion: Mesenchymal tumor phenotyping combining TB and FRMD6 expression correlates well with DFS in CRCs.