Optimization of an automated tumor-infiltrating lymphocyte algorithm for improved prognostication in primary melanoma

Tumor-infiltrating lymphocytes (TIL) have potential prognostic value in melanoma and have been considered for inclusion in the American Joint Committee on Cancer (AJCC) staging criteria. However, inter-observer discordance continues to prevent the adoption of TIL into clinical practice. Computational image analysis offers a solution to this obstacle, representing a methodological approach for reproducibly counting TIL. We sought to evaluate the ability of a TIL-quantifying machine learning algorithm to predict survival in primary melanoma. Digitized hematoxylin and eosin (H&E) slides from prospectively-enrolled patients in the NYU melanoma database were scored for % TIL using machine learning and manually graded by pathologists using Clark’s model. We evaluated the association of % TIL with recurrence-free survival (RFS) and overall survival (OS) using Cox proportional hazards modeling and concordance indices. Discordance between algorithmic and manual TIL quantification was assessed with McNemar’s test and visually by an attending dermatopathologist. 453 primary melanoma patients were scored using machine learning. Automated % TIL scoring significantly differentiated survival using an estimated cutoff of 16.6% TIL (Log Rank P<0.001 for RFS; P=0.002 for OS). % TIL was associated with significantly longer RFS (adjusted HR = 0.92 [0.84–1.00] per 10% increase in % TIL) and OS (adjusted HR = 0.90 [0.83–0.99] per 10% increase in % TIL). In comparison, a subset of the cohort (n=240) was graded for TIL by melanoma pathologists. However, TIL did not associate with RFS between groups (P>0.05) when categorized as brisk, non-brisk, or absent. A standardized and automated % TIL scoring algorithm can improve the prognostic impact of TIL. Incorporation of quantitative TIL scoring into the AJCC staging criteria should be considered.