The impact of next generation sequencing studies on the diagnosis of BAP1 inactivated melanocytic tumors

BAP1 inactivated melanocytic tumors (BIMTs) are recognized for their potential for significant morphologic atypia including nuclear atypia, expansile growth, and mitotic activity, making it difficult to form firm morphologic criteria for malignancy. Next generation sequencing (NGS) is becoming increasingly utilized in melanocytic pathology. We conducted a two-phase survey with 26 dermatopathologists from the International Melanoma Pathology Study Group to assess the impact of NGS on diagnostic accuracy and interobserver agreement in 31 BIMTs. After NGS results, interobserver agreement improved from fair on Survey 1 (κ = 0.348) to moderate on Survey 2 (κ = 0.441). Respondents were 1.7 times more likely to be correct on Survey 2 after NGS results (OR = 1.67, 95% CI [1.16-2.44], p = 0.005). When accounting for case variability and difficulty, respondents were 8.7 times more likely to provide a correct diagnosis for a given case (CMH OR = 8.69, 95% CI [4.89-15.44], p < 0.001). Among the 8 BAP1 inactivated melanomas in this study, 3 transitioned from a majority of votes for benign/intermediate grade BIMT to a majority of votes for melanoma after seeing NGS data. Genomic aberrations exclusive to malignant cases included pathogenic variants in TERT-p, CDKN2A, PTEN, and amplification of MYC. Our study suggests NGS has the potential to improve diagnostic accuracy and interobserver agreement for BAP1 inactivated melanocytic tumors. With the advent of increasingly effective therapies for melanoma, there is value in forming a definitive diagnosis of melanoma when appropriate. Additional studies with greater case numbers and follow-up are needed to further validate these findings.