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Updated: Jun 30, 2026

Enhancing Tumor Content through Tumor Macrodissection
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Dissecting and directing pathology foundation models.

Chanwoo Kim, Jakub Kaczmarzyk, Deepika Savant

    Biorxiv : the Preprint Server for Biology
    |June 29, 2026
    PubMed
    Summary
    This summary is machine-generated.

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    PICASSO makes foundation models (FMs) in digital pathology interpretable by decomposing image embeddings into visual concepts. This framework enhances trustworthiness, enables discovery of new biomarkers, and facilitates controlled manipulation of models for research.

    Area of Science:

    • Computational Pathology
    • Artificial Intelligence in Medicine
    • Digital Pathology

    Background:

    • Foundation models (FMs) are crucial in digital pathology, encoding histology images into embeddings for diagnostics and outcome prediction.
    • The 'black box' nature of these embeddings limits clinical trust and scientific discovery potential.
    • Existing FM embeddings lack transparency, hindering their full clinical translation and utility.

    Purpose of the Study:

    • To introduce PICASSO (Pathology Image Concept Atlas built via SparSe dictiOnary learning), a framework for interpretable and controllable pathology FMs.
    • To decompose FM embeddings into human-interpretable visual concepts.
    • To enable auditing, discovery, and controlled manipulation of pathology FM representations.

    Main Methods:

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    Last Updated: Jun 30, 2026

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  • Developed PICASSO, a framework utilizing sparse autoencoder for decomposing FM embeddings into visual concepts.
  • Trained PICASSO on over 120 million tissue patches across 32 cancer types to create a pan-cancer atlas of histomorphological concepts.
  • Integrated PICASSO-derived concepts with spatial transcriptomics and explored concept manipulation for counterfactual analysis.
  • Main Results:

    • PICASSO successfully decomposes FM embeddings into interpretable concepts, creating the first pan-cancer atlas of histomorphological concepts.
    • Demonstrated PICASSO's utility in auditing clinical models, discovering novel biomarkers (e.g., hobnailing morphology for EGFR mutations), and linking morphology to gene expression.
    • Showcased PICASSO's ability to mitigate technical artifacts and enable controlled manipulation of embeddings for therapeutic analysis, such as survival outcome prediction.

    Conclusions:

    • PICASSO provides a principled framework to transform opaque pathology FMs into interpretable platforms for mechanistic insight and discovery.
    • The framework enhances trustworthiness and utility of FMs in digital pathology for both clinical validation and scientific exploration.
    • PICASSO facilitates the discovery of new biological insights and enables precise control over FM representations for advanced research applications.