Chloe Puget Chloe Puget Jonathan Ganz Jonathan Ganz Christof A. Bertram Christof A. Bertram Thomas Conrad Thomas Conrad Malte Baeblich Malte Baeblich Anne Voss Anne Voss Katharina Landmann Katharina Landmann Alexander F. H. Haake Alexander F. H. Haake Andreas Spree Andreas Spree Svenja Hartung Svenja Hartung Leonore Aeschlimann Leonore Aeschlimann Sara Soto Sara Soto Simone de Brot Simone de Brot Martina Dettwiler Martina Dettwiler Heike Aupperle-Lellbach Heike Aupperle-Lellbach Pompei Bolfa Pompei Bolfa Alexander Bartel Alexander Bartel Matti Kiupel Matti Kiupel Katharina Breininger Katharina Breininger Marc Aubreville Marc Aubreville Robert Klopfleisch Robert Klopfleisch Sage Publications Inc 2025 Canine cutaneous mast cell tumors (ccMCTs) are frequent neoplasms with variable biological behaviors. Internal tandem duplication mutations in c-KIT exon 11 (c-KIT-11-ITD) are associated with poor prognosis but predict therapeutic response to tyrosine kinase inhibitors. In a previous work, deep learning algorithms managed to predict the presence of c-KIT-11-ITD on digitalized hematoxylin and eosin-stained histological slides (whole-slide images, WSIs) in up to 87% of cases, suggesting the existence of morphological features characterizing ccMCTs carrying c-KIT-11-ITD. This 3-stage blinded study aimed to identify morphological features indicative of c-KIT-11-ITD and to evaluate the ability of human observers to learn this task. 17 untrained pathologists first classified 8 WSIs and 200 image patches (highly relevant for algorithmic classification) of ccMCTs as either positive or negative for c-KIT-11-ITD. Second, they self-trained to recognize c-KIT-11-ITD by looking at the same WSIs and patches correctly sorted. Third, pathologists classified 15 new WSIs and 200 new patches according to c-KIT-11-ITD status. In addition, participants reported microscopic features they considered relevant for their decision. Without training, participants correctly classified the c-KIT-11-ITD status of 63%–88% of WSIs and 43%–55% of patches. With self-training, 25%–38% of WSIs and 55%–56% of patches were correctly classified. High cellular pleomorphism, anisokaryosis, and sparse cytoplasmic granulation were commonly suggested as features associated with c-KIT-11-ITD-positive ccMCTs, none of which showed reliable predictivity in a follow-up study. The results indicate that transfer of algorithmic skills to the human observer is difficult. A c-KIT-11-ITD-specific morphological feature remains to be extracted from the artificial intelligence model. Online Version of Record before inclusion in an issue PDFDocument eng 2025-11-28T08:50:40.899920Z 2025 c-KIT Digital Pathology Deep Learning Dog Genotype Prediction Mast Cell Tumor Morphological Feature Performance Study 1951617 b application/pdf http://creativecommons.org/licenses/by-nc/4.0/