Expert Histopathologic Evaluation and Molecular Analyses for Ambiguous Cutaneous Melanocytic Tumors

Purpose A subset of cutaneous melanocytic tumors has ambiguous histopathologic features that preclude reliable classification as benign or malignant. We evaluated the diagnostic yield and long-term clinical validity of expert histopathologic evaluation and, when inconclusive, additional molecular analyses in patients with ambiguous primary cutaneous melanocytic tumors. Methods In this prospective cohort study, consecutive patients with primary cutaneous melanocytic tumors deemed ambiguous by referring pathologists were evaluated at a tertiary dermatopathology referral center in the Netherlands from September 2018 through December 2021. Tumors underwent expert histopathologic evaluation, with next-generation sequencing, single-nucleotide polymorphism array, and targeted RNA sequencing when inconclusive. Tumors were classified as nonmelanoma, melanoma, or borderline melanoma. Clinical validity was assessed by melanoma-related events during follow-up. Results Among 258,562 patients with excised melanocytic tumors nationwide, 2,685 (1.0%) had ambiguous tumors. We included 994 patients and reached a diagnosis in 966 (97.2%): 417 (42.0%) after expert histopathologic evaluation alone and 549 (55.2%) after additional molecular analyses. Among 608 patients (61.2%) with a nonmelanoma diagnosis, no melanoma-related events occurred during median follow-up of 5.4 years (incidence, 0.0%; 95% CI, 0.0 to 0.6). Among 358 patients (36.0%) with a melanoma diagnosis, 33 of 186 (17.7%) had a positive sentinel node biopsy, and 20 developed melanoma-related events during median follow-up of 5.0 years (cumulative incidence, 5.7%; 95% CI, 3.3 to 8.1). No events occurred in 28 patients (2.8%) with a borderline melanoma diagnosis. Conclusion Expert histopathologic evaluation combined with molecular analyses provided a definitive diagnosis in nearly all patients with ambiguous primary cutaneous melanocytic tumors. Long-term follow-up supported the clinical validity of this stepwise diagnostic approach.