Expert Histopathologic Evaluation and Molecular Analyses for Ambiguous Cutaneous Melanocytic Tumors

Journal of Clinical Oncology, pp. JCO2600432

Abstract

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.

Authors 13

1. Chiel F Ebbelaar corresponding Aachen Department of Dermatology, Leiden University Medical Center

   Leiden University Medical Center · University Medical Center Utrecht

   Affiliation as printed

   Department of Dermatology, Leiden University Medical Center, Leiden, the Netherlands

   Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands

2. Anthonie W.A. Lensing
   Affiliation as printed

   Arianna Foundation, Bologna, Italy

3. Gerben Eise Breimer

   University Medical Center Utrecht

   Affiliation as printed

   Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands

4. Marijke R. van Dijk

   University Medical Center Utrecht

   Affiliation as printed

   Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands

5. Martin H. Prins

   Maastricht University

   Affiliation as printed

   Department of Epidemiology and Technology Assessment, University of Maastricht, Maastricht, the Netherlands

6. Remco van Doorn Aachen Department of Dermatology, Leiden University Medical Center

   Leiden University Medical Center · The Netherlands Cancer Institute

   Affiliation as printed

   Department of Dermatology, Leiden University Medical Center, Leiden, the Netherlands

   Department of Dermatology, Netherlands Cancer Institute, Amsterdam, the Netherlands

7. Anne M.R. Schrader Aachen Department of Pathology, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands

8. Wendy W.J. de Leng

   University Medical Center Utrecht

   Affiliation as printed

   Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands

9. Lourens T. Bloem

   Utrecht University

   Affiliation as printed

   Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands

10. Karijn P.M. Suijkerbuijk

    Utrecht University · University Medical Center Utrecht

    Affiliation as printed

    Department of Medical Oncology, Cancer Center, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands

11. Anne M.L. Jansen

    University Medical Center Utrecht

    Affiliation as printed

    Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands

12. Willeke A.M. Blokx

    University Medical Center Utrecht

    Affiliation as printed

    Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands

13. MOLecular Evaluation of Melanocytic Ambiguous Tumors (MOLEMAT) Investigators