A classification based on tumor-stroma ratio and tumor budding for patients with muscle-invasive bladder cancer

Abstract

Background Tumor-stroma ratio (TSR) and tumor budding (TB) play important roles in muscle-invasive bladder cancer (MIBC). We developed a rating system (TSR-TB type) based on the morphological evaluation of TSR and TB for predicting patient outcome and using individualized care. Research design and methods TSR and TB were assessed in publicly accessible MIBC tumor slides from the TCGA database. MIBC patients were classified as low stromal type or high stromal type based on TSR, and high stromal type was further classified as compartmentalized stromal type or mixed stromal type based on TB. Results TSR-TB type was an independent adverse prognostic factor for OS in MIBC (P<0.001). Low stromal type had a greater prognosis than the other subtypes (P<0.001) and were enriched for FGFR3 mutations (P=0.001), which could be susceptible to targeted therapy. The mixed stromal type was distinguished by increased M2 macrophage penetration (P<0.001), anti-tumor immune activity, DNA repair pathway mutations, and poor survival. GSEA showed that certain cancer-related pathways, such as mitotic spindle, PI3K-AKT-MTOR signaling, and the G2M checkpoint, were hyperactivated in high stromal type (all FDR<0.05). Furthermore, mixed stromal type demonstrated enhanced activation of epithelial mesenchymal transformation (EMT), inflammatory response, KRAS signaling, and angiogenesis (all FDR<0.05). Conclusion TSR and TB-based MIBC classification coincides with patient survival and molecular alterations. The identified subtypes may have important implications for individualized MIBC therapy.