Foundation models are increasingly developed in computational pathology (CPath) given their promise in facilitating many downstream tasks. While recent studies have evaluated task performance across models, less is known about the structure and variability of their learned representations. Here, we systematically analyze the representational spaces of six CPath foundation models using techniques popularized in computational neuroscience. The models analyzed span vision-language contrastive learning (CONCH, PLIP, KEEP) and self-distillation (UNI (v2), Virchow (v2), Prov-GigaPath) approaches. Through representational similarity analysis using H&E image patches from TCGA, we find that UNI2 and Virchow2 have the most distinct representational structures, whereas Prov-Gigapath has the highest average similarity across models. Having the same training paradigm (vision-only vs. vision-language) did not guarantee higher representational similarity. The representations of all models showed a high slide-dependence, but relatively low disease-dependence. Stain normalization decreased slide-dependence for all models by a range of 5.5% (CONCH) to 20.5% (PLIP). In terms of intrinsic dimensionality, vision-language models demonstrated relatively compact representations, compared to the more distributed representations of vision-only models. These findings highlight opportunities to improve robustness to slide-specific features, inform model ensembling strategies, and provide insights into how training paradigms shape model representations. Our framework is extendable across medical imaging domains, where probing the internal representations of foundation models can support their effective development and deployment.

Foundation models in digital pathology use massive datasets to learn useful compact feature representations of complex histology images. However, there is limited transparency into what drives the correlation between dataset size and performance, raising the question of whether simply adding more data to increase performance is always necessary. In this study, we propose a prototype-guided diffusion model to generate high-fidelity synthetic pathology data at scale, enabling large-scale self-supervised learning and reducing reliance on real patient samples while preserving downstream performance. Using guidance from histological prototypes during sampling, our approach ensures biologically and diagnostically meaningful variations in the generated data. We demonstrate that self-supervised features trained on our synthetic dataset achieve competitive performance despite using ~60x-760x less data than models trained on large real-world datasets. Notably, models trained using our synthetic data showed statistically comparable or better performance across multiple evaluation metrics and tasks, even when compared to models trained on orders of magnitude larger datasets. Our hybrid approach, combining synthetic and real data, further enhanced performance, achieving top results in several evaluations. These findings underscore the potential of generative AI to create compelling training data for digital pathology, significantly reducing the reliance on extensive clinical datasets and highlighting the efficiency of our approach.

Whole slide pathology image classification presents challenges due to gigapixel image sizes and limited annotation labels, hindering model generalization. This paper introduces a prompt learning method to adapt large vision-language models for few-shot pathology classification. We first extend the Prov-GigaPath vision foundation model, pre-trained on 1.3 billion pathology image tiles, into a vision-language model by adding adaptors and aligning it with medical text encoders via contrastive learning on 923K image-text pairs. The model is then used to extract visual features and text embeddings from few-shot annotations and fine-tunes with learnable prompt embeddings. Unlike prior methods that combine prompts with frozen features using prefix embeddings or self-attention, we propose multi-granular attention that compares interactions between learnable prompts with individual image patches and groups of them. This approach improves the model's ability to capture both fine-grained details and broader context, enhancing its recognition of complex patterns across sub-regions. To further improve accuracy, we leverage (unbalanced) optimal transport-based visual-text distance to secure model robustness by mitigating perturbations that might occur during the data augmentation process. Empirical experiments on lung, kidney, and breast pathology modalities validate the effectiveness of our approach; thereby, we surpass several of the latest competitors and consistently improve performance across diverse architectures, including CLIP, PLIP, and Prov-GigaPath integrated PLIP. We release our implementations and pre-trained models at this MGPATH.