Expert histopathologic evaluation followed by molecular analyses when necessary provided a definitive diagnosis in more than 97% of patients with ambiguous primary cutaneous melanocytic tumors, according to findings from a prospective cohort study reported by Ebbelaar et al in the Journal of Clinical Oncology. Long-term follow-up supported the clinical validity of this stepwise diagnostic approach, with no melanoma-related events observed among patients whose tumors were classified as nonmelanoma.
Study Details
Among 258,562 patients nationwide who underwent excision of melanocytic tumors, 2,685 (1.0%) had tumors with ambiguous findings. Of these, 994 patients from 40 hospitals and pathology laboratories across the Netherlands were included in the study. The mean patient age was 40.0 years, and 64.9% were female.
All tumors underwent expert histopathologic evaluation, including immunohistochemistry when indicated, using World Health Organization classification criteria. Cases that remained inconclusive underwent additional molecular analyses, including next-generation sequencing to identify pathogenic mutations, single-nucleotide polymorphism arrays to detect copy-number variations, and targeted RNA sequencing for gene fusions when indicated.
Tumors were ultimately classified as nonmelanoma, melanoma, or borderline melanoma. The investigators assessed the clinical validity of these classifications through long-term follow-up for melanoma-related events, including local recurrence, metastases, and melanoma-related death.
Key Results
Expert histopathologic evaluation alone established an unambiguous diagnosis in 417 patients (42.0%). Among the remaining 577 patients, molecular analyses were feasible in 570 and resolved diagnostic uncertainty in an additional 549 patients (55.2% of the overall cohort). Together, these approaches yielded a definitive diagnosis in 966 of 994 patients (97.2%).
Following the complete diagnostic evaluation, 608 patients (61.2%) received a nonmelanoma diagnosis and 358 (36.0%) received a melanoma diagnosis. The remaining 28 patients (2.8%) were classified as having borderline melanoma.
Among patients classified as having nonmelanoma tumors, no melanoma-related events occurred during a median follow-up of 5.4 years (incidence = 0.0%, 95% confidence interval [CI] = 0.0%–0.6%). Of these patients, 288 (47.4%) underwent re-excision and 8 (1.3%) underwent sentinel node biopsy, all with negative findings.
Among the 358 patients diagnosed with melanoma, 345 (96.4%) underwent reexcision and 186 (52.0%) underwent sentinel node biopsy. Positive sentinel nodes were identified in 33 patients (17.7%). During a median follow-up of 5.0 years, 20 patients experienced melanoma-related events (cumulative incidence = 5.7%, 95% CI = 3.3%–8.1%). Six patients (1.7%) died of melanoma, and the 5-year probability of melanoma-specific survival was 98%.
Among the 28 patients with borderline melanoma, no melanoma-related events occurred during a median follow-up of 5.1 years (incidence = 0.0%, 95% CI = 0.0%–12.3%).
The authors concluded: “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.”
Chiel F. Ebbelaar, MD, PharmD, of the Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands, and the Department of Dermatology, Leiden University Medical Center, Leiden, the Netherlands, is the corresponding author for the Journal of Clinical Oncology article.
DISCLOSURE: The study was supported by the Hanarth Fund. For full disclosures of the study authors, visit ascopubs.org.
