Topologically distinct 2D and 3D intratumoral heterogeneity scores for preoperatively predicting invasiveness in stage I lung adenocarcinoma: A multicenter study

This multicenter study aims to enhance the preoperative prediction of pathological invasiveness in clinical stage I lung adenocarcinoma (LUAD) by developing and validating topologically distinct 2D and 3D intratumoral heterogeneity (ITH) scores derived from chest CT imaging. Patients with histopathologically confirmed LUAD were enrolled from three medical centers. We established a dual-scale computational framework to quantify ITH: the 2D ITH score was derived by integrating local radiomics features with global pixel distribution patterns on the largest cross-sectional slice, while the 3D ITH score captured volumetric heterogeneity using a voxel-based topology-aware approach. Subsequently, six machine learning models integrating clinicoradiologic (CR) features with these heterogeneity scores were developed. Model performance was optimized based on the area under the curve (AUC) across a training set and validated in both an internal test set and an independent external validation set. A total of 1,238 eligible patients were enrolled. Centers 1 and 2 provided 1,053 patients (Training: n=737; Internal Test: n=316), while Center 3 provided 185 patients for external validation. The CatBoost classifier integrating 2D/3D ITH scores with CR features (2DITH-3DITH-CR CatBoost) exhibited superior diagnostic performance, achieving AUCs of 0.867 in the internal test set and 0.881 in the external validation set. The integration of topologically distinct 3D ITH scores significantly improves the preoperative stratification of LUAD invasiveness. The 2DITH-3DITH-CR CatBoost model serves as a robust, non-invasive tool to guide individualized surgical decision-making in clinical practice.