Automated histopathological measurements of the tumor micro-environment predict distant metastasis after stage I/II Melanoma: discovery and validation in the population-based Dutch Early-Stage Melanoma (D-ESMEL) study

Abstract: Background: More than half of metastatic melanomas arise from patients initially diagnosed with early-stage melanoma. Objective biomarkers are needed to better identify high-risk patients. Objective: To evaluate the prognostic value of multiple histopathological characteristics in predicting distant metastasis risk, in early-stage melanoma. Methods: Using data from discovery set (n=442) and a population-based validation cohort (n=306, sampled from 5,815 patients) of the Dutch Early-Stage Melanoma (D-ESMEL) study, we investigated 14 histopathological characteristics of melanoma and their tumor micro-environment (TME) in an unprecedented integration, by expert pathologist scoring and automated quantitative measurements derived from a validated automated segmentation. Results: Increased immune infiltrates (40% in cases vs. 50% in controls) were associated with lower risk of metastasis. Automated immune cell density was predictive in both the discovery set and the validation cohort, outperforming the manual pathological tumor infiltrating lymphocytes. The remaining histopathological features, including mitotic activity, did not retain independent value after controlling for current staging variables. Limitations: TME evaluation in standard Hematoxylin-Eosin slides. Conclusion: TME reaction is an important determinant of melanoma progression. The automated quantification of immune cell density appears to be a biomarker for distant metastasis risk. Further investigation into specific immune cell subtypes is required to facilitate clinical integration.