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

TL;DR

EAGLE-Net enhances foundation models in computational pathology by integrating structure-preserving and attention-guided mechanisms, improving prediction accuracy, interpretability, and biological relevance in tumor microenvironment analysis.

Contribution

The paper introduces EAGLE-Net, a novel MIL architecture that incorporates multi-scale spatial encoding and neighborhood-aware loss for better tissue structure modeling.

Findings

Up to 3% higher classification accuracy across cancer types.

Achieved top concordance indices in 6 of 7 cancer types.

Produced biologically coherent attention maps aligned with expert annotations.

Abstract

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 relevant 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 present 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 survival 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 smooth, 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