Preoperative CT Habitat Analysis for Predicting WHO/ISUP Grade in Clear Cell Renal Cell Carcinoma: A Multicenter Study

Purpose To develop and validate a preoperative contrast-enhanced CT–based approach that leverages intratumoral spatial heterogeneity to predict WHO/ISUP grading and prognosis in clear cell renal cell carcinoma (ccRCC). Methods This multicenter retrospective study included 704 patients with pathologically confirmed ccRCC (483 low-grade and 221 high-grade). Patients from SYUCC (n = 308) were randomly split into training and internal validation sets at an 8:2 ratio. Two independent external validation cohorts were used, including GZFPH (n = 106) and two public datasets, KiTS19 (n = 142) and TCGA-KIRC (n = 148). We constructed three models: a conventional whole-tumor radiomics model, an intratumoral habitat model capturing spatial heterogeneity, and a Combined model using score-level fusion of radiomic and habitat scores. Prognostic value was assessed in KiTS19 and TCGA using Kaplan–Meier analysis with log-rank tests based on (i) ground-truth WHO/ISUP grade and (ii) model-derived risk groups. Biological interpretability was explored using differential expression and pathway enrichment analyses, GSVA-based pathway activity mapping to habitat subregions, and immune profiling (IPS and MCPcounter). Results The Combined model achieved consistent performance across cohorts, with AUCs of 0.860 (95% CI: 0.813–0.907) in SYUCC, 0.830 (0.813–0.907) in GZFPH, 0.829 (0.756–0.901) in KiTS19, and 0.750 (0.664–0.830) in TCGA. Although AUC differences between the Combined and Habitat models were not statistically significant, the Combined model showed higher accuracy across all cohorts. Model-derived risk stratification significantly separated overall survival in both KiTS19 (p = 0.017) and TCGA (p = 0.0032). Transcriptomic analyses indicated coherent biological axes involving immune effector and proliferation programs versus differentiation and EMT/TGF-β–related states, with GSVA revealing directionally distinct pathway associations for habitat subregions (S1 vs S3). Immune analyses further supported risk-group differences in antigen presentation and effector immunity components and in inferred immune cell infiltration. Conclusion Intratumoral spatial heterogeneity on preoperative contrast-enhanced CT enables robust prediction of WHO/ISUP grade and prognostic stratification in ccRCC.