A prospective, comprehensive registry that integrates the molecular analysis of pediatric and adolescent melanocytic lesions

Abstract

BACKGROUND: Childhood melanocytic tumors represent a diagnostic and therapeutic challenge, and additional research is needed to better define the natural history of these tumors. METHODS: The authors developed a comprehensive, prospective registry called Molecular Analysis of Childhood Melanocytic Tumors for children and adolescents with an atypical Spitz tumor/Spitz melanoma (AST/ SM), conventional or adult-type melanoma (CM), melanoma arising in a giant congenital nevus (MCM), or atypical melanocytic proliferation of other types (OT) to better define the clinical behavior of these lesions by incorporating an integrated clinicopathologic and molecular analysis using centralized pathology review and various platforms, including fluorescence in situ hybridization; array comparative genomic hybridization; and whole genome, exome, and capture targeted panels. RESULTS: From May 2016 to November 2019, 70 children were enrolled with a median age at diagnosis of 9.1 years. Thirty-seven had AST/SM, 17 had CM, 4 had MCM, and 12 had OT. Patients with AST/SM were younger (median age, 7 years), and their tumor most commonly arose in the extremities and trunk. The most common gene rearrangements included MAP3K8 and ALK. None of the 33 patients who underwent a TERT promoter mutation analysis had a mutation, and all patients were alive. Among the CM patients, the median age was 13 years; 11 had a BRAFV600E mutation, and 7 had a TERT promoter mutation. Three patients died of their disease. All 4 patients with MCM harbored an NRASQ61 mutation and died of their disease. The OT group was heterogenous, and all patients survived. CONCLUSIONS: The incorporation of an integrated clinicopathologic and genomic analysis identifies distinct subgroups of pediatric melanocytic lesions that have different clinical behaviors. The integration of this combined diagnostic modality can help to individualize diagnoses and treatments for these patients.

Risk for second primary cancers among pediatric and young adult melanoma survivors

“…6,7 Childhood and adolescent melanomas, characterized by a high mutation burden, likely represent distinct biologic/genetic entities with variable prognosis. 6,8 The heightened risk for SPM within the first year of initial primary CM diagnosis aligns with previous studies. 3 This is likely due to congenital melanocytic nevi or underlying genetic predisposition, 7,8 underscoring the importance of diligent skin surveillance during this critical period.…”

“…6,8 The heightened risk for SPM within the first year of initial primary CM diagnosis aligns with previous studies. 3 This is likely due to congenital melanocytic nevi or underlying genetic predisposition, 7,8 underscoring the importance of diligent skin surveillance during this critical period.…”

Cutaneous Melanomas Arising during Childhood: An Overview of the Main Entities

“…Breslow thickness, dermal mitotic activity, and epidermal ulceration are to be assessed. A BRAF.pV600E mutation is frequently present (>80%) both in the melanoma and the nevus from which it arose [4,[6][7][8]. The need for an oncogenetic consultation must be evaluated according to the clinical setting.…”

“…These include HRAS mutations, receptor tyrosine kinase fusions, and serine-threonine kinase mutations and fusions, described in Table 1. For benign cases, the most common fusions involve NTRK1/3, ALK1, and ROS1, whereas MAP3K8 and ALK1 predominate in atypical and malignant Spitz tumors [6]. Histologically, Spitz nevi are symmetrical compound lesions with either a pediculated or elevated silhouette.…”

Genomic comparison of malignant melanoma and atypical Spitz tumor in the pediatric population

“…Neither study compared melanoma genetics to that of ASTs. A 2021 study of 70 pediatric melanomas highlights the advancements in our understanding of genomic alterations for distinct clinical presentations of melanomas; in this study, the ASTs and Spitz melanomas are considered together 13 . Our study focused on the challenges of distinguishing AST from melanoma, and presents a genomic comparison of MM and ASTs in the pediatric patients in the context of comprehensive clinical annotation.…”