CT-based Intratumoral Heterogeneity Score for Preoperative Prediction of Lymphovascular Invasion and Prognosis in Lung Adenocarcinoma: A Multicenter Validation and Radiogenomic Interpretation.

BACKGROUND: Lymphovascular invasion (LVI) is a key determinant of recurrence and survival in lung adenocarcinoma (LUAD), but preoperative identification remains challenging. We developed and validated a CT-based intratumoral heterogeneity (ITH) score for LVI prediction, prognostic stratification, and exploratory radiogenomic interpretation. METHODS: We retrospectively included 1322 patients from three institutions and one public dataset. The discovery cohort was divided into training (n = 590) and internal validation (n = 253) sets; an independent cohort (n = 362) was used for external validation and prognostic analysis. A Stanford Radiogenomics set (n = 117) was used for exploratory transcriptomic analysis. Multiple machine learning algorithms were trained using the same feature matrix and cohort partitions. RESULTS: Random forest was selected as the final classifier, with AUCs of 0.886 (95% confidence interval [CI] 0.842-0.923) in internal validation and 0.850 (95% CI 0.806-0.892) in external validation. The model showed acceptable calibration and positive net benefit across low-to-intermediate threshold probabilities. High ITH remained associated with worse recurrence-free survival (hazard ratio [HR] 12.92; 95% CI 3.90-42.78; P < 0.001) and overall survival (HR 26.47; 95% CI 3.52-198.76; P = 0.001). Exploratory radiogenomic analysis showed enrichment of hypoxia-, angiogenesis-, epithelial-mesenchymal transition-, and glycolysis-related pathways. CONCLUSIONS: The CT-based ITH score may support preoperative risk stratification for LVI and prognosis in LUAD. Radiogenomic findings suggest potential biological correlates and should be considered hypothesis-generating.