Habitat-aware radiomics and adaptive 2.5D deep learning predict treatment response and long-term survival in ESCC...

Current radiomic approaches inadequately resolve spatial intratumoral heterogeneity (ITH) in esophageal squamous cell carcinoma (ESCC), limiting neoadjuvant chemoimmunotherapy (NACI) response prediction. We propose an interpretable multimodal framework to: (1) quantitatively map intra-/peritumoral heterogeneity via voxel-wise habitat radiomics; (2) model cross-sectional tumor biology using 2.5D deep learning; and (3) establish mechanism-driven biomarkers via SHAP interpretability to identify resistance-linked subregions.

This dual-center retrospective study analyzed 269 treatment-naïve ESCC patients with baseline PET/CT (training: n = 144; validation: n = 62; test: n = 63). Habitat radiomics delineated tumor subregions via K-means clustering (Calinski-Harabasz-optimized) on PET/CT, extracting 1,834 radiomic features per modality. A multi-stage pipeline (univariate filtering, mRMR, LASSO regression) selected 32 discriminative features. The 2.5D model aggregated ± 4 peri-tumoral slices, fusing PET/CT via MixUp channels using a fine-tuned ResNet50 (ImageNet-pretrained), with multi-instance learning (MIL) translating slice-level features to patient-level predictions. Habitat features, MIL signatures, and clinical variables were integrated via five-classifier ensemble (ExtraTrees/SVM/RandomForest) and Crossformer architecture (SMOTE-balanced). Validation included AUC, sensitivity, specificity, calibration curves, decision curve analysis (DCA), survival metrics (C-index, Kaplan-Meier), and interpretability (SHAP, Grad-CAM).

Habitat radiomics achieved superior validation AUC (0.865, 95% CI: 0.778-0.953), outperforming conventional radiomics (ΔAUC + 3.6%, P < 0.01) and clinical models (ΔAUC + 6.4%, P < 0.001). SHAP identified the invasive front (H2) as dominant predictor (40% of top features), with wavelet_LHH_firstorder_Entropy showing highest impact (SHAP = + 0.42). The 2.5D MIL model demonstrated strong generalizability (validation AUC: 0.861). The combined model achieved state-of-the-art test performance (AUC = 0.824, sensitivity = 0.875) with superior calibration (Hosmer-Lemeshow P > 0.800), effective survival stratification (test C-index: 0.809), and 23-41% net benefit improvement in DCA.

Integrating habitat radiomics and 2.5D deep learning enables interpretable dual diagnostic-prognostic stratification in ESCC, advancing precision oncology by decoding spatial heterogeneity.