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.