HFed-MIL: Patch Gradient-Based Attention Distillation Federated Learning for Heterogeneous Multi-Site Ovarian Cancer Whole-Slide Image Analysis

Ovarian cancer remains a significant global health concern, and its diagnosis heavily relies on whole-slide images (WSIs). Due to their gigapixel spatial resolution, WSIs must be split into patches and are usually modeled via multi-instance learning (MIL). Although previous studies have achieved remarkable performance comparable to that of humans, in clinical practice WSIs are distributed across multiple hospitals with strict privacy restrictions, necessitating secure, efficient, and effective federated MIL. Moreover, heterogeneous data distributions across hospitals lead to model heterogeneity, requiring a framework flexible to both data and model variations. This paper introduces HFed-MIL, a heterogeneous federated MIL framework that leverages gradient-based attention distillation to tackle these challenges. Specifically, we extend the intuition of Grad-CAM to the patch level and propose Patch-CAM,which computes gradient-based attention scores for each patch embedding, enabling structural knowledge distillation without explicit attention modules while minimizing privacy leakage. Beyond conventional logit distillation, we designed a dual-level objective that enforces both class-level and structural-level consistency, preventing the vanishing effect of naive averaging and enhancing the discriminative power and interpretability of the global model. Importantly, Patch-CAM scores provide a balanced solution between privacy, efficiency, and heterogeneity: they contain sufficient information for effective distillation (with minimal membership inference risk, MIA AUC ≈ 0.6) while significantly reducing communication cost (0.32 MB per round), making HFed-MIL practical for real-world federated pathology. Extensive experiments on multiple cancer subtypes and cross-domain datasets (Camelyon16, BreakHis) demonstrate that HFed-MIL achieves state-of-the-art performance with enhanced robustness under heterogeneity conditions. Moreover, the global attention visualizations yield sharper and clinically meaningful heatmaps, offering pathologists transparent insights into model decisions. By jointly balancing privacy, efficiency, and interpretability, HFed-MIL improves the practicality and trustworthiness of deep learning for ovarian cancer WSI analysis, thereby increasing its clinical significance.