DuXplore: A Dual-Hierarchical Deep Learning Model for Prognostic Prediction of Hepatocellular Carcinoma in Digital Pathology

<b>Background</b>: Spatial heterogeneity in tumor tissue has been linked to patient prognosis. To exploit both structural and semantic cues in whole slide images (WSIs), we propose Dual eXplanatory Framework (DuXplore), a dual-branch deep learning framework that integrates tissue architecture and cellular morphology for hepatocellular carcinoma (HCC) prognosis. <b>Method</b>: At the macroscopic level, DuXplore constructs a multi-channel tissue organization probability map (MTOP) to represent the spatial layout of eight tissue categories within the WSIs. At the microscopic level, a feature-guided Fused Structure Tensor (FST) based on tissue composition is employed to extract representative cell morphology patches. Accordingly, MTOP representations are modeled by Macro-Net, while FST-guided patches are modeled by Micro-Net. Each branch produces a 32-dimensional prognostic embedding, which are fused and passed through a multi-layer perceptron with a Cox proportional hazards head to generate patient-level risk predictions. To further elucidate the distinct contributions of the two branches, we conducted model-agnostic interpretability analyses, including occlusion sensitivity mapping (OSM) on MTOP and nuclear morphometrics from CellProfiler on high- versus low-risk tiles. <b>Result</b>: DuXplore achieves promising performance with C-indices of 0.764 on the public Cancer Genome Atlas (TCGA) dataset and 0.713 on the Eastern Hepatobiliary HCC (EHBH) cohort from our clinical center, along with significant patient risk stratification (log-rank <i>p</i> < 0.001). OSM highlighted necrosis and central fibrosis as high-risk and marginal fibrosis as protective; these patterns were corroborated by multivariable Cox using reproducible structural parameters (N-ratio, FIB-center, FIB-edge). Micro-level analysis revealed that higher nuclear staining intensity, increased texture irregularity (GLCM features), and greater morphological heterogeneity characterize high-risk tiles, aligning with pathological understanding. <b>Conclusions</b>: DuXplore advances prognostic modeling by coupling structure-aware micro-sampling with macro architectural encoding, delivering robust, generalizable survival prediction and biologically plausible explanations. While validated on HCC WSIs, broader multi-center, multi-omics studies are warranted to refine sampling scales and enhance clinical translation.