Pathologist-like explainable AI for interpretable Gleason grading in prostate cancer

Gesa Mittmann, Sara Laiouar-Pedari, Hendrik A. Mehrtens, Sarah Haggenmüller, Tabea-Clara Bucher, Tirtha Chanda, Nadine T. Gaisa, Mathias Wagner, Gilbert Georg Klamminger, Tilman T. Rau, Christina Neppl, Eva Maria Compérat, Andreas Gocht, Monika Haemmerle, Niels J. Rupp, Jula Westhoff, Irene Krücken, Maximilian Seidl, Christian M. Schürch, Marcus Bauer, Wiebke Solass, Yu Chun Tam, Florian Weber, Rainer Grobholz, Jaroslaw Augustyniak, Thomas Kalinski, Christian Hörner, Kirsten D. Mertz, Constanze Döring, Andreas Erbersdobler, Gabriele Deubler, Felix Bremmer, Ulrich Sommer, Michael Brodhun, Jon Griffin, Maria Sarah L. Lenon, Kiril Trpkov, Liang Cheng, Fei Chen, Angelique Levi, Guoping Cai, Tri Q. Nguyen, Ali Amin, Alessia Cimadamore, Ahmed Shabaik, Varsha Manucha, Nazeel Ahmad, Nidia Messias, Francesca Sanguedolce, Diana Taheri, Ezra Baraban, Liwei Jia, Rajal B. Shah, Farshid Siadat, Nicole Swarbrick, Kyung Park, Oudai Hassan, Siamak Sakhaie, Michelle R. Downes, Hiroshi Miyamoto, Sean R. Williamson, Tim Holland-Letz, Christoph Wies, Carolin V. Schneider, Jakob Nikolas Kather, Yuri Tolkach and Titus J. Brinker ()
Additional contact information
Gesa Mittmann: German Cancer Research Center (DKFZ)
Sara Laiouar-Pedari: German Cancer Research Center (DKFZ)
Hendrik A. Mehrtens: German Cancer Research Center (DKFZ)
Sarah Haggenmüller: German Cancer Research Center (DKFZ)
Tabea-Clara Bucher: German Cancer Research Center (DKFZ)
Tirtha Chanda: German Cancer Research Center (DKFZ)
Nadine T. Gaisa: RWTH Aachen University
Mathias Wagner: Homburg Saar Campus
Gilbert Georg Klamminger: Homburg Saar Campus
Tilman T. Rau: Heinrich-Heine-University and University Hospital Düsseldorf
Christina Neppl: Heinrich-Heine-University and University Hospital Düsseldorf
Eva Maria Compérat: Medical University of Vienna
Andreas Gocht: University Hospital Schleswig-Holstein
Monika Haemmerle: Martin Luther University Halle-Wittenberg
Niels J. Rupp: University Hospital Zurich
Jula Westhoff: Städtisches Klinikum Karlsruhe
Irene Krücken: Klinikum Bremen Mitte
Maximilian Seidl: Heinrich-Heine-University and University Hospital Düsseldorf
Christian M. Schürch: University Hospital and Comprehensive Cancer Center Tübingen
Marcus Bauer: Martin Luther University Halle-Wittenberg
Wiebke Solass: University Bern
Yu Chun Tam: Ruhr University Bochum
Florian Weber: University of Regensburg
Rainer Grobholz: University of Zurich
Jaroslaw Augustyniak: Laborteam Pathology
Thomas Kalinski: University Hospital Brandenburg an der Havel
Christian Hörner: University of Heidelberg
Kirsten D. Mertz: University Hospital Basel
Constanze Döring: Zweigpraxis Zwickau
Andreas Erbersdobler: University Medicine Rostock
Gabriele Deubler: Kreiskliniken Reutlingen
Felix Bremmer: University Medical Center Goettingen
Ulrich Sommer: University Hospital of Dresden
Michael Brodhun: HELIOS Klinikum Erfurt
Jon Griffin: University of Sheffield
Maria Sarah L. Lenon: University of Santo Tomas Hospital
Kiril Trpkov: Rockyview General Hospital
Liang Cheng: and Brown University Health
Fei Chen: NYU Langone Health
Angelique Levi: Yale University School of Medicine
Guoping Cai: Yale University School of Medicine
Tri Q. Nguyen: University Medical Centre Utrecht
Ali Amin: Warren Alpert Medical School of Brown University
Alessia Cimadamore: University of Udine
Ahmed Shabaik: UC San Diego School of Medicine
Varsha Manucha: University of Mississippi Medical Center
Nazeel Ahmad: Department of Pathology & Cell Biology and James A. Haley Veterans’ Hospital
Nidia Messias: Washington University in St. Louis
Francesca Sanguedolce: University of Foggia
Diana Taheri: Isfahan University of Medical Sciences
Ezra Baraban: Johns Hopkins University
Liwei Jia: University of Texas Southwestern Medical Center
Rajal B. Shah: University of Texas Southwestern Medical Center
Farshid Siadat: Rockyview General Hospital
Nicole Swarbrick: PathWest Laboratory Medicine WA
Kyung Park: NYU Langone Health
Oudai Hassan: Henry Ford Health System
Siamak Sakhaie: Dorevitch Pathology
Michelle R. Downes: Sunnybrook Health Sciences Centre
Hiroshi Miyamoto: University of Rochester Medical Center
Sean R. Williamson: Cleveland Clinic
Tim Holland-Letz: German Cancer Research Center(DKFZ)
Christoph Wies: German Cancer Research Center (DKFZ)
Carolin V. Schneider: RWTH University of Aachen
Jakob Nikolas Kather: TUD Dresden University of Technology
Yuri Tolkach: University Hospital Cologne
Titus J. Brinker: German Cancer Research Center (DKFZ)

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract The aggressiveness of prostate cancer is primarily assessed from histopathological data using the Gleason scoring system. Conventional artificial intelligence (AI) approaches can predict Gleason scores, but often lack explainability, which may limit clinical acceptance. Here, we present an alternative, inherently explainable AI that circumvents the need for post-hoc explainability methods. The model was trained on 1,015 tissue microarray core images, annotated with detailed pattern descriptions by 54 international pathologists following standardized guidelines. It uses pathologist-defined terminology and was trained using soft labels to capture data uncertainty. This approach enables robust Gleason pattern segmentation despite high interobserver variability. The model achieved comparable or superior performance to direct Gleason pattern segmentation (Dice score: $${0.713}_{\pm 0.003}$$ 0.713 ± 0.003 vs. $${0.691}_{\pm 0.010}$$ 0.691 ± 0.010 ) while providing interpretable outputs. We release this dataset to encourage further research on segmentation in medical tasks with high subjectivity and to deepen insights into pathologists’ reasoning.

Date: 2025
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DOI: 10.1038/s41467-025-64712-4

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