Organizations: Tsinghua Shenzhen International Graduate School, Tsinghua University · University of Washington · City University of Hong Kong (Dongguan) · Medical Optical Technology R&D Center, Research Institute of Tsinghua · Jinfeng Laboratory
Abstract
Multiple instance learning (MIL) has become the main paradigm for whole-slide image (WSI) analysis in computational pathology. However, existing MIL aggregators are still typically trained from scratch for each downstream task, relying on limited slide-level labels to learn both aggregation mechanisms and downstream discriminative representations simultaneously. As a result, they often suffer from unstable optimization, overfitting, and limited transferability. Similar to pretrained ResNet and Vision Transformer models in natural image learning, MIL also requires reusable pretrained initialization. However, high-quality slide-level pretraining data remain scarce, and MIL models are usually lightweight and weakly supervised, making large-scale pretraining difficult in practice. To address this challenge, we propose a distillation-based pretraining framework for MIL, which leverages two slide-level foundation models, TITAN and CARE, as teachers to transfer their representational knowledge into a diverse set of MIL architectures. To effectively balance supervision from different teachers, we further introduce an angular dispersion normalized distillation loss. The distilled weights are then used as initialization for downstream adaptation. We conduct systematic evaluations on 15 benchmark datasets under both linear probing and full-parameter fine-tuning, and further validate its advantages in few-shot scenarios. Experimental results show that pretraining generally improves MIL aggregators over from scratch training, especially in linear-probing and few-shot settings, while maintaining the computational efficiency of lightweight MIL models. Code is available at https://github.com/fu0201/MIL_Pretrained.
Multiple instance learning (MIL) has become a standard paradigm for whole slide image (WSI) analysis in digital pathology, as it enables slide-level prediction without dense annotations. Existing MIL methods typically rely on exhaustive extraction and encoding of high-resolution patches. However, this practice suffers from two critical limitations in real-world clinical settings: it struggles to capture global visual cues at lower magnifications, and incurs substantial computational overhead due to the massive number of high-resolution patches per slide. To address these limitations, we propose an efficient low-resolution multiple instance learning (LRMIL) framework that transfers high-resolution knowledge to low-resolution representations. LRMIL adopts a two-stage distillation strategy. First, patch-level cross-resolution distillation aligns low-resolution patch embeddings with high-resolution representations. Second, slide-level knowledge distillation trains a low-resolution student MIL model under both slide-level supervision and teacher guidance. At inference time, LRMIL operates exclusively on low-resolution patches, substantially reducing data preprocessing and computational cost. Extensive experiments on multiple WSI benchmarks demonstrate that LRMIL consistently outperforms state-of-the-art MIL methods while achieving more efficient inference. These results highlight LRMIL as a practical and scalable solution for WSI analysis in clinical pathology.
Multiple instance learning (MIL) is the standard approach for whole-slide image (WSI) classification and survival prediction, where attention-based models ag gregate patch features into slide-level predictions. These models treat attention weights as evidence for their predictions, but attention is optimized for classi fication, not for identifying which patches actually support the diagnosis. This conflation leads to three failures: selected patches are insufficient (keeping them alone drops Macro-F1 by 0.078), unnecessary (removing them barely changes the prediction), and unrecoverable (continuous attention scores disagree with discrete patch subsets used at inference). The central premise is that evidence quality should be optimized directly through explicit criteria- Sufficiency, Necessity, and Recov erability (S/N/R)- rather than inherited as a byproduct of classification. GCE-MIL is a backbone-agnostic wrapper implemented through three injection modes and three evidence components: a grounding mechanism that aligns selection with domain-specific concepts, noisy-OR coverage that acts as a differentiable proxy for interventional evidence search, and threshold-plus-repair recovery that converts continuous selectors into discrete subsets through marginal-guided repair. Across 9 backbones and 9 datasets (81 configurations), GCE-MIL improves average Macro-F1 by 0.024 and C-index by 0.014, reduces the continuous-discrete gap by 4-7, and increases complement degradation by 2-4. With optional tile prefiltering after discrete recovery, inference runs up to 5 faster while retaining 0.989 full-bag utility.
Foundation models are reshaping computational pathology, yet their capabilities remain shaped by pretraining objectives, data sources, and spatial scales, fragmenting complementary expertise across separate backbones. Here we present ALICE, a unified foundation model trained through multi-stage agglomerative distillation that sequentially distills eight vision-only, vision-language, and slide-level teacher models into dedicated modules of a single backbone. ALICE is pretrained on 24,985,184 tile-level pathology images and 155,604 high-resolution images, and evaluated across 21 task scenarios, 96 downstream tasks, and 48 data sources, spanning region-of-interest tissue analysis, vision-language multimodal evaluation, and whole-slide clinical assessment. In all three evaluation settings, ALICE achieved the best average rank among task-matched pathology foundation models. These results demonstrate that agglomerative distillation can consolidate complementary capabilities from specialized models into a unified backbone for broad computational pathology applications. The model is available at https://github.com/WonderLandxD/ALICE.