Tumor Invasive Border Index ( <scp>TIBI</scp> ) in colorectal cancer: linking infiltrative morphology to molecular insights

Tumor border configuration influences colorectal cancer (CRC) prognosis, yet its molecular determinants remain unclear and existing assessment criteria have faced challenges with reproducibility. We introduce the Tumor Invasive Border Index (TIBI), a novel and reproducible method that quantifies the proportion of tumor stroma and adipose tissue within a hotspot at the deepest point of invasion. TIBI was evaluated in two CRC cohorts (n = 1,100 and n = 776) and analyzed in relation to tumor and patient features. Molecular correlates of an infiltrative growth pattern were explored in The Cancer Genome Atlas (TCGA) CRC cohorts (n = 350), with key features validated independently. High TIBI, indicating an infiltrative border, was associated with advanced disease, tumor budding, lymphovascular invasion, and an immune microenvironment characterized by lower M1-like macrophage and granulocyte densities. High TIBI independently predicted higher CRC-specific mortality, with multivariable hazard ratios of 1.52 (95% CI 1.07-2.17) in cohort 1 and 2.45 (95% CI 1.37-4.37) in cohort 2. Molecular analysis revealed associations with mismatch repair proficiency, TP53 and KRAS mutations, MYC signaling downregulation, and epithelial-mesenchymal transition upregulation. L1CAM and DSG3 were among the genes showing high expression in infiltrative tumors. As experimental validation, we identified a CRC cell line with high expression of L1CAM and DSG3 and demonstrated that silencing them reduced invasion in vitro. A TIBI-associated gene signature also predicted infiltrative growth and adverse outcome in the TCGA gastric cancer cohort. These findings highlight molecular characteristics of tumor border configuration and establish TIBI as a clinically relevant tumor biomarker. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.