The Next Layer: Augmenting Foundation Models with Structure-Preserving and Attention-Guided Learning for Local Patches to Global Context Awareness in Computational Pathology

Foundation models have recently emerged as powerful feature extractors in computational pathology, yet they typically omit mechanisms for leveraging the global spatial structure of tissues and the local contextual relationships among diagnostically relevan t regions -- key elements for understanding the tumor microenvironment. Multiple instance learning (MIL) remains an essential next step following foundation model, designing a framework to aggregate patch - level features into slide - level predictions. We presen t EAGLE - Net, a structure - preserving, attention - guided MIL architecture designed to augment prediction and interpretability. EAGLE - Net integrates multi - scale absolute spatial encoding to capture global tissue architecture, a top - K neighborhood - aware loss to focus attention on local microenvironments, and background suppression loss to minimize false positives. We benchmarked EAGLE - Net on large pan - cancer datasets, including three cancer types for classification (10,260 slides) and seven cancer types for surv ival prediction (4,172 slides), using three distinct histology foundation backbones (REMEDIES, Uni - V1, Uni2 - h). Across tasks, EAGLE - Net achieved up to 3% higher classification accuracy and the top concordance indices in 6 of 7 cancer types, producing smoot h, biologically coherent attention maps that aligned with expert annotations and highlighted invasive fronts, necrosis, and immune infiltration. These results position EAGLE - Net as a generalizable, interpretable framework that complements foundation models, enabling improved biomarker discovery, prognostic modeling, and clinical decision support.