Morphology Predicts Grade, Transcriptomics Predicts Nodal Status: Task-Dependent Modality Contributions in Multimodal Prostate Cancer Classification

Abstract

Multimodal studies of prostate cancer typically report aggregate fusion gains from histology and transcriptomics but rarely characterize when each modality is informative. We asked whether morphology and transcriptomics contribute differently to distinct clinical endpoints, using Gleason grading and nodal status prediction. On 401 TCGA-PRAD patients with matched whole-slide images, bulk RNA sequencing, and clinical data, we evaluated 45 morphological configurations, seven RNA configurations, and six fusion strategies across four grading formulations, T-stage, and N-stage. To avoid per-task model selection, morphology used a single fixed configuration (gated ABMIL on UNI features). Contribution estimates used repeated stratified five-fold cross-validation, with a locked conformal-prediction protocol and gene set enrichment analysis. The two endpoints showed opposite modality dependence. For Gleason grade, the fixed morphological model exceeded the best RNA configuration across all 45 configurations (five-class macro-F1: 0.445 versus 0.398). For nodal status, no morphological configuration exceeded AUROC 0.62, whereas transcriptomics reached 0.68 (permutation p = 0.037); a direct interaction test confirmed the reversal (bootstrap 95% CI excluding zero). Fusion gains were modest and task-dependent; enrichment analysis linked the nodal signal to loss of smooth muscle programs, consistent with established dedifferentiation biology. The informative modality is task-dependent: morphology predicts grade, transcriptomics predicts nodal status.