Artificial intelligence predicts <i>c-KIT</i> exon 11 genotype by phenotype in canine cutaneous mast cell tumors: Can human observers learn it?

Canine cutaneous mast cell tumors (ccMCTs) are frequent neoplasms with variable biological behaviors. Internal tandem duplication mutations in <i>c-KIT</i> exon 11 (<i>c-KIT</i>-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 <i>c-KIT</i>-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 <i>c-KIT</i>-11-ITD. This 3-stage blinded study aimed to identify morphological features indicative of <i>c-KIT</i>-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 <i>c-KIT</i>-11-ITD. Second, they self-trained to recognize <i>c-KIT</i>-11-ITD by looking at the same WSIs and patches correctly sorted. Third, pathologists classified 15 new WSIs and 200 new patches according to <i>c-KIT</i>-11-ITD status. In addition, participants reported microscopic features they considered relevant for their decision. Without training, participants correctly classified the <i>c-KIT</i>-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 <i>c-KIT</i>-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 <i>c-KIT</i>-11-ITD-specific morphological feature remains to be extracted from the artificial intelligence model.