PURPOSE: Necrosis quantification in the neoadjuvant setting using pathology slide review is the most important validated prognostic marker in conventional osteosarcoma. Herein, we explored three deep-learning strategies on histology samples to predict outcome for osteosarcoma in the neoadjuvant setting. EXPERIMENTAL DESIGN: Our study relies on a training cohort from New York University (NYU; New York, NY) and an external cohort from Charles University (Prague, Czechia). We trained and validated the performance of a supervised approach that integrates neural network predictions of necrosis/tumor content and compared predicted overall survival (OS) using Kaplan-Meier curves. Furthermore, we explored morphology-based supervised and self-supervised approaches to determine whether intrinsic histomorphologic features could serve as a potential marker for OS in the neoadjuvant setting. RESULTS: Excellent correlation between the trained network and pathologists was obtained for the quantification of necrosis content (R2 = 0.899; r = 0.949; P < 0.0001). OS prediction cutoffs were consistent between pathologists and the neural network (22% and 30% of necrosis, respectively). The morphology-based supervised approach predicted OS; P = 0.0028, HR = 2.43 (1.10-5.38). The self-supervised approach corroborated the findings with clusters enriched in necrosis, fibroblastic stroma, and osteoblastic morphology associating with better OS [log-2 hazard ratio (lg2 HR); -2.366; -1.164; -1.175; 95% confidence interval, (-2.996 to -0.514)]. Viable/partially viable tumor and fat necrosis were associated with worse OS [lg2 HR; 1.287; 0.822; 0.828; 95% confidence interval, (0.38-1.974)]. CONCLUSIONS: Neural networks can be used to automatically estimate the necrosis to tumor ratio, a quantitative metric predictive of survival. Furthermore, we identified alternate histomorphologic biomarkers specific to the necrotic and tumor regions, which could serve as predictors.

Applied Bioinformatics Laboratories New York University School of Medicine New York New York

Cancer Research UK Scotland Institute Glasgow Scotland

Department of Pathology and Molecular Medicine 2nd Faculty of Medicine Charles University and Motol University Hospital Prague Czech Republic

Department of Pathology NYU Langone Grossman School of Medicine New York New York

Division of Precision Medicine Department of Medicine New York University School of Medicine New York New York

Ronald O Perelman Department of Dermatology NYU Langone Grossman School of Medicine New York New York

School of Cancer Sciences University of Glasgow Glasgow Scotland

School of Computing Science University of Glasgow Glasgow Scotland

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