Prognostic Significance of Immune and Stromal Components in Colorectal Cancer: Practical Tools for Routine Pathologic Assessment

Context.— In colorectal cancer (CRC), the tumor microenvironment includes cancer-associated fibroblasts and a variety of immune cells, which are increasingly recognized for their prognostic significance. Objective.— To evaluate the tumor microenvironment in CRC using methodologies applicable in routine pathologic practice. Design.— A comprehensive evaluation of the local immune response and tumor to stroma ratio (TSR) was performed in 930 CRC cases by thoroughly reviewing the whole hematoxylin-eosin (H&E) slides. Local immune responses were assessed using peritumoral inflammatory infiltration (Klintrup-Mäkinen and modified Klintrup-Mäkinen methods), intratumoral stromal tumor-infiltrating lymphocytes (TILs; International TILs Working Group system and deep stromal TIL system), and Crohn-like lymphoid reaction (CLR). Results.— In the multivariate analysis, age (>68 years), stage III–IV, microsatellite stability, signet ring cell/undifferentiated carcinoma, extramural venous invasion, high TSR (>50%), and CLR were independent prognostic factors for disease-specific survival. Excluding microsatellite stability, these factors also served as significant prognostic indicators for progression-free survival. Among the 4 methods for measuring local immune response, evaluating the proportion of TILs within the deepest intratumoral stroma was an independent predictor of progression-free survival. Conclusions.— We suggest that evaluating CLR, TSR, and stromal TILs on hematoxylin-eosin–stained slides represent a practical and straightforward approach with significant prognostic value.