The Tumor Microenvironment Score and Its Subsite-Specific Relevance in Colon Cancer

Colon cancer is a major global malignancy with significant mortality. Right-sided (RCC) and left-sided colon cancers (LCC) exhibit distinct clinicopathological characteristics. Tumor microenvironment score (TMS) combines Klintrup-Mäkinen grade, tumor stroma percentage, and tumor budding, classifying cases into 4 groups (TMS 0-3). Evaluation of TMS is an integrative method for prognostic classification; however, further validation is needed, and differences between RCC and LCC remain unclear. A discovery cohort (n=940) and a validation cohort (n=613) were retrospectively included. TMS was evaluated from hematoxylin-eosin-stained slides. Five-year disease-specific survival (DSS) was analyzed using life-table methods and Cox regression. Associations with clinicopathological variables were assessed. In both the discovery and validation cohorts, higher TMS was associated with worse 5-year DSS in univariable analyses for both RCC and LCC. In multivariable analysis, high TMS (TMS3 vs. TMS0) remained independently associated with survival in the discovery cohort (RCC-HR: 2.47, 95% CI: 1.36-4.46, P=0.003; LCC-HR: 3.08, 95% CI: 1.46-6.45, P=0.003). In the validation cohort, the prognostic impact of TMS was more pronounced in RCC (HR: 4.35, 95% CI: 2.32-8.14, P<0.001) than in LCC (HR: 2.21, 95% CI: 0.81-6.03, P=0.12). TMS also appeared to provide improved prognostic stratification compared with the Glasgow microenvironment score (combination of Klintrup-Mäkinen grade and tumor stroma percentage). In conclusion, TMS serves as an integrative histopathological marker with potential to improve prognostic stratification in colon cancer, particularly in right-sided tumors.