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. Author manuscript; available in PMC: 2026 Oct 8.
Published in final edited form as: Int J Dermatol. 2026 Oct;65 Suppl 1:S67–S74. doi: 10.1111/ijd.70616

What is Pediatric Melanoma? Clinical and Genomic Features and the Role of Next-Generation Sequencing in Tumor Classification

Michael R Sargen 1
PMCID: PMC13643153  NIHMSID: NIHMS2214069  PMID: 42808951

Abstract

Pediatric melanoma is rare and often poses diagnostic challenges because benign and malignant melanocytic tumors in children can share overlapping clinicopathologic features. Epidemiologic and genomic studies have provided important insights into the etiology of pediatric melanocytic tumors and the genetic alterations associated with malignant transformation. This review summarizes environmental, host, and genetic factors associated with the development of the major pediatric melanoma subtypes, including Spitz melanoma, low-cumulative solar damage (superficial spreading) melanoma, melanoma arising in congenital melanocytic nevi, and melanoma arising in blue nevi. It also highlights key molecular biomarkers associated with pediatric melanoma and presents a diagnostic approach to atypical pediatric melanocytic tumors that illustrates how molecular data can be integrated into tumor classification.

Keywords: Pediatric melanoma, Spitz tumor, Spitz melanocytoma, spitzoid, congenital melanocytic nevus, melanoma arising in congenital melanocytic nevi, superficial spreading melanoma, low-cumulative solar damage melanoma, melanoma arising in blue nevi, genomics, next-generation sequencing, gene fusions, familial melanoma, hereditary melanoma, ultraviolet radiation

Graphical Abstract

graphic file with name nihms-2214069-f0001.webp

Diagnostic Workflow for Atypical Pediatric Melanocytic Tumors. This figure summarizes the diagnostic approach to atypical pediatric melanocytic neoplasms and illustrates how molecular data can be incorporated into tumor classification.

INTRODUCTION

Cutaneous melanoma in pediatric patients (age <18 years) is rare and accounts for less than 0.5% of melanomas diagnosed in the United States and globally.1,2 Four main World Health Organization (WHO)-defined subtypes of melanoma occur in children: Spitz melanoma, low-cumulative solar damage/superficial spreading (low-CSD/SSM) melanoma, melanoma arising in congenital melanocytic nevi (MCMN), and melanoma arising in blue nevi (MBN).3 These subtypes are distinguished by their unique epidemiologic, clinicopathologic, and genetic characteristics (Table 1).3 “Spitzoid” is a descriptive term that refers to the morphology of melanocytes (large epithelioid and/or spindle cells with abundant cytoplasm) and should not be used interchangeably with “Spitz”. Moreover, spitzoid morphology can occur in non-Spitz melanoma subtypes including low-CSD/SSM and MCMN.4,5

Table 1.

Potential Findings that would Support Consideration of Next-Generation Sequencing for Atypical Pediatric Melanocytic Tumorsa

Clinical tumor diameter >1 cm
Ulceration
Mitotic rate >6 per mm2
Tumor involvement of subcutaneous fat
Expansile dermal nodule
BRAF V600E staining in atypical melanocytic tumor with spitzoid morphology
Complete or geographic loss of p16 staining
Ki-67 proliferative index ≥20%
Diffuse PRAME nuclear staining
Pathology review determines that neoplasm has additional features that are concerning for melanoma
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a

These potential indications for consideration of next-generation sequencing do not apply to melanocytic neoplasms arising within congenital melanocytic nevi.

Pediatric melanoma typically has all or almost all of the following Children’s Oncology Group (COG) high-risk clinicopathologic features: age at diagnosis >10 years (does not apply to MCMN), clinical tumor diameter >1 cm, ulceration, tumor extension into the subcutaneous fat, mitotic rate ≥6/mm2, high-grade cytologic atypia, and expansile dermal nodule. Distinguishing pediatric melanoma from benign precursor lesions can be challenging due to overlapping clinicopathologic features. However, next-generation sequencing (NGS) has emerged as a powerful tool for subtype classification and for characterizing the biology of atypical melanocytic neoplasms in children, including their metastatic potential.

This article reviews environmental, genetic, and host factors associated with the development of pediatric melanoma and examines the role of NGS in classifying pediatric melanocytic tumors and identifying lesions with metastatic potential that warrant management as melanoma.

RISK FACTORS FOR PEDIATRIC MELANOMA

Hereditary Factors

Germline pathogenic variants in high- and moderate- penetrance familial melanoma genes (ACD, BAP1, CDKN2A, CDK4, MITF E318K, POT1, TERF2IP, TERT promoter) contribute to the development of early-onset melanoma.6 Melanomas associated with germline pathogenic variants in familial melanoma genes often develop in adolescence or later, but rarely can occur before age 10 years.4,7,8 CDKN2A is the most common cause of familial melanoma, with germline pathogenic alterations of this gene observed in 20–40% of melanoma-prone families (≥3 members affected by melanoma).9,10 CDKN2A germline pathogenic variants increase risk for cutaneous melanoma, which are typically low-CSD/SSM subtype, as well as tobacco-related cancers, including pancreas, lung, head and neck, and esophagus.4,8,11,12 CDKN2A germline pathogenic variants can also cause a Neurofibromatosis type 1-like syndrome with affected individuals developing multiple benign and malignant neural tumors.13,14

In a recent genome-first analysis of two large population-scale genomic cohorts (UK Biobank in the United Kingdom [n=469,379] and Geisinger MyCode in the United States [n=227,286]) that link germline exome/genome and cancer registry data, the prevalence of having a germline pathogenic variant in one of the major familial melanoma genes (ACD, BAP1, CDKN2A, CDK4, MITF E318K, POT1, TERF2IP, TERT promoter) among individuals diagnosed with melanoma before age 40 years exceeded the 2.5% threshold commonly used to recommend germline testing for high- and moderate-penetrance cancer susceptibility genes.6,15 These genome-first data suggest that germline testing should be considered for individuals with early-onset melanoma (age<40 years) regardless of family history.6

Germline pathogenic variants in POT1 have been associated with melanomas exhibiting spitzoid morphology.4,12 Melanomas with spitzoid morphology have also been observed in individuals with germline pathogenic variants in other telomere biology genes (e.g., ACD, TERF2IP), suggesting that altered telomere maintenance may contribute to spitzoid histology in melanocytic tumors.12 Moreover, these findings support the inclusion of telomere biology genes (ACD, POT1, TERF2IP, TERT promoter) in genetic testing panels for pediatric melanoma, especially when tumors exhibit spitzoid differentiation. Further studies are needed to determine whether these melanomas exhibiting spitzoid morphology in individuals with germline pathogenic variants in telomere biology genes are Spitz or low-CSD/SSM lineage.

Xeroderma pigmentosum is an autosomal recessive condition caused by germline pathogenic variants in genes involved in the nucleotide excision repair pathway and translesion synthesis.16 Affected individuals exhibit severe photosensitivity and can develop low-CSD/SSMs and keratinocyte cancers within the first decade of life.16

Environmental Factors

Ultraviolet radiation (UVR) from natural sunlight and/or tanning beds contributes to the development of low-CSD/SSMs.3,17 However, UVR does not appear to be an important driver of Spitz melanoma, MCMN, or MBN.3

Host Factors

Chronic immunosuppression in the setting of solid organ transplantation increases risk for cutaneous melanoma approximately two-fold compared to the general population.18,19 These data were largely derived from adult solid organ transplant recipients, and therefore, the contribution of chronic immunosuppression to melanoma formation during childhood remains unclear. Cutaneous melanoma has been reported in pediatric solid organ transplant recipients; however, these transplant recipients typically develop melanoma in their third decade of life or later.20

PEDIATRIC MELANOMA SUBTYPES

Spitz Melanoma

Beginning with the 4th edition of the WHO Classification of Skin Tumours, published in 2018, and reaffirmed in the 5th edition (2025), Spitz melanomas are defined by the presence of spitzoid morphology plus a Spitz lineage driver event, which includes HRAS activating variants or fusion kinases involving ALK, ROS1, NTRK1, NTRK3, MET, RET, BRAF, or MAP3K8.3,21,22

Spitz tumors are considered to exist on a spectrum ranging from benign Spitz nevi to Spitz melanoma. Spitz melanocytomas, previously referred to as “atypical Spitz tumors”, are considered intermediate lesions with a low, but increased risk for progression to melanoma compared to banal nevi.1,3 Distinguishing Spitz melanocytomas from Spitz melanoma can sometimes be challenging based on histomorphology and immunohistochemistry alone.

TERT genetic alterations, including activating variants in the promoter region of the gene (NM_198253.3(TERT):c.−124C>T and c.−146C>T) and gene rearrangement, are rare in Spitz neoplasms, but when present, appear to be associated with aggressive tumor behavior, including distant metastasis and death.23–25 Biallelic inactivation of CDKN2A can also occur in Spitz melanomas; however, this alteration is also identified in benign Spitz tumors, which limits its usefulness as a diagnostic biomarker.26–28 Therefore, Spitz tumors with biallelic inactivation of CDKN2A should not necessarily be interpreted as melanoma in the absence of other genetic or clinicopathologic features supporting a melanoma diagnosis. This is particularly relevant for Spitz tumors driven by MAP3K8 and BRAF fusion kinases, which often exhibit high-grade cytologic atypia and may be misclassified as melanoma.29,30

To date, biologically aggressive Spitz melanomas, defined by the development of distant metastases, have only been observed in Spitz tumors harboring MAP3K8 or BRAF fusions.23–25 However, prospective follow-up data are insufficient to determine whether Spitz tumors with other Spitz lineage driver events (e.g., ALK) can progress to melanoma with metastatic potential.

CRTC1::TRIM11-rearranged tumors (CTRTs) and MED15::ATF1-rearranged tumors (MARTs) express melanocytic markers (SOX-10 positive and variable expression of Melan-A) and can exhibit spitzoid morphology, leading to potential misclassification as Spitz melanocytoma or Spitz melanoma.1,31,32 RNA sequencing is needed to distinguish CTRTs and MARTs from Spitz melanocytic tumors. Moreover, this distinction is important due to the potential aggressive behavior of pediatric CTRTs and MARTs, in contrast to Spitz melanocytic tumors, which typically exhibit more indolent behavior.1,31,33 Additional genomic and epigenomic data are needed to determine whether CTRTs and MARTs should be considered variants of melanoma or clear cell sarcoma, or whether they would be better classified as their own category.34,35

Low-CSD/SSM

The driver event for this melanoma subtype, which typically occurs in adults, is usually BRAF V600E, and less commonly NRAS.3,36 In contrast to Spitz tumor evolution, TERT promoter variants tend to occur earlier in tumor evolution during progression from nevus to an intermediate lesion (dysplastic nevus) or melanoma in situ.37 Biallelic inactivation of CDKN2A and alterations in genes associated with SWI/SNF subunits (e.g., ARID2) are associated with progression from in situ to invasive melanoma, while TP53 and PTEN alterations typically occur later during the vertical growth phase of melanoma and contribute to metastatic potential.36,37

This subtype of melanoma can often be diagnosed based on histopathology and immunohistochemistry. A subset of atypical melanocytic neoplasms exhibiting spitzoid morphology will have BRAF V600E (which can be detected with immunohistochemistry) as the driver event. The histopathologic differential diagnosis for these tumors is BRAF-mutated and morphologically spitzoid (BAMS) neoplasm (benign tumor) vs. low-CSD/SSM. NGS can be helpful to accurately classify these BRAF-mutated tumors with spitzoid morphology and exclude genetic alterations (e.g., CDKN2A, ARID2, TP53, PTEN) that would support malignant transformation.

BAP1-inactivated melanoma (sporadic cases or those associated with germline pathogenic variants in BAP1), WNT-activated deep penetrating melanoma, and melanoma arising in a pigmented epithelioid melanocytoma, are each considered low-CSD melanomas according to WHO classification.3 Like SSM, inactivating alterations of TP53 and/or PTEN would support a malignant diagnosis for these low-CSD melanocytic tumors.38–40 However, in contrast to SSM, pathogenic alterations in TERT promoter are highly concerning for malignant transformation of both BAP1-inactivated melanocytic tumors and WNT-activated deep penetrating melanocytic tumors.38,39

Melanoma Arising in Congenital Melanocytic Nevi

Congenital melanocytic nevi (CMN) develop in utero and are caused most commonly by NRAS or BRAF activating variants, and less commonly by fusion kinases involving BRAF, ALK, and NTRK1.1,5,41–43 MCMN often develop in the large and giant variants of CMN (adult projected diameters of >20 cm and >40 cm, respectively), and in contrast to other pediatric melanoma subtypes, often develop within the first decade of life.1,44,45 Further, large and giant congenital melanocytic nevi (LGCMN) can be associated with leptomeningeal deposits of melanocytes, which can transform into primary central nervous system melanoma.45

Individuals with LGCMN often develop nodular proliferations within their nevus, which can be difficult to distinguish from melanoma based on clinical and histopathologic features. Molecular biomarkers associated with malignant transformation of congenital melanocytic nevi include TP53 variants and MYC amplification; these abnormalities can be evaluated with NGS.46,47 Further, TERT gene activation via hypermethylation of the gene promoter has also been associated with MCMN and poor survival.48 Despite the emerging role of methylation profiling in the classification of melanocytic tumors, assessment for TERT promoter hypermethylation is largely only available in research laboratories.

Melanoma Arising in Blue Nevi

This melanoma subtype is especially rare in pediatric patients, with most pediatric cases forming within giant congenital blue nevi.49,50 Precursor lesions in this WHO pathway form as a result of genetic alterations in the G-protein signaling pathway, most commonly involving genes GNAQ and GNA11, and less commonly CYSLTR2.3 Somatic loss of function variants involving EIF1AX, SF3B1, and BAP1 have been associated with malignant transformation of these lesions.3,51

NEXT-GENERATION SEQUENCING

DNA and RNA sequencing allow for the identification of the tumor driver event (determines WHO lineage) and assessment for genetic alterations (e.g., pathogenic alterations in the TERT promoter, TP53, and/or PTEN) that can support a melanoma diagnosis and predict aggressive tumor behavior. According to COG guidelines, NGS should be considered for pediatric melanocytic tumors when COG high-risk clinicopathologic features are present (see Introduction section), there is an abnormal immunohistochemistry profile (e.g., absence of p16 staining in the entire lesion or geographic loss in a portion of the tumor, Ki-67 proliferative index ≥20%, diffuse PRAME nuclear staining), or pathology review determines that there are other concerning features for melanoma.1 These indications for considering genetic testing are summarized in Table 1.

Although TERT promoter variants have been linked with distant metastasis in Spitz tumors, additional studies are needed to identify molecular biomarkers that reliably predict aggressive tumor behavior for Spitz and non-Spitz melanocytic tumors in children. Achieving this goal will require prospective studies linking tumor genomic data with longitudinal clinical outcomes.

Size and tumor purity in a biopsy specimen can limit the number of molecular assays that can be performed for pediatric melanocytic tumors. Therefore, NGS should be prioritized over other molecular tests for atypical pediatric melanocytic tumors, and is the recommended molecular diagnostic assay in COG guidelines.1

Molecular assays that evaluate gains and losses in DNA segments (copy number variations [CNV]), including fluorescence in situ hybridization (FISH) and array-based approaches, may aid in the classification of atypical spitzoid tumors.52–54 However, CNV analysis does not assist in tumor lineage classification, which is critical for the interpretation of NGS data. For example, a pathogenic TERT promoter variant is more concerning for malignant transformation in a Spitz lineage tumor than in a BRAF-mutated melanocytic lesion.1

Genetic alterations associated with malignant transformation across the major pediatric melanocytic tumor subtypes are summarized in Table 2. Despite substantial advances in the molecular characterization of these tumors, some cases of pediatric melanoma lack identifiable genetic mechanisms to explain their malignant transformation. These cases suggest that additional molecular biomarkers remain to be discovered and may further refine the molecular classification of pediatric melanocytic tumors. Unidentified genetic and epigenetic alterations, as well as changes in the tumor microenvironment, may contribute to tumor progression in these cases. Further studies are needed to comprehensively characterize the spectrum of molecular alterations within pediatric melanocytic tumors and their microenvironment that drive the malignant transformation of precursor lesions.

Table 2.

Clinical and Genomic Characteristics of Major Pediatric Melanoma Subtypes

Spitz Melanoma Low-CSD Melanoma MCMN MBN
CSD-associated tumor No Yes No No
Precursor lesion(s) Spitz nevus, Spitz melanocytoma (intermediate lesion) Dysplastic nevus, BAP1-inactivated melanocytoma, WNT-activated deep penetrating melanocytoma, pigmented epithelioid melanocytoma Proliferative nodule Blue nevus, atypical cellular blue nevus
Tumor lineage driver event HRASa or fusion kinaseb BRAF V600Ea, NRASa NRASa, BRAF V600Ea > fusion kinasesc GNAQa, GNA11a > CYSLTR2a
Genetic alterations associated with malignant transformation and/or aggressive tumor behavior TERT d TERTe, TP53f, PTENf TERTg, TP53f, MYCh BAP1f, EIF1AXi, SF3B1i
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Abbreviations: Cumulative solar damage (CSD); melanoma arising in congenital melanocytic nevi (MCMN); melanoma arising in blue nevi (MBN)

a

Activating variant.

b

fusion kinases involving ALK, ROS1, NTRK1, NTRK3, MET, RET, BRAF, or MAP3K8.

c

fusion kinases involving ALK, NTRK1, or BRAF.

d

Activating variants in the promoter region of the gene (NM_198253.3(TERT):c.−124C>T and c.−146C>T) or gene rearrangement.

e

Activating variants in the promoter region of the gene (NM_198253.3(TERT):c.−124C>T and c.−146C>T) are concerning for malignant transformation of BAP1-inactivated melanocytic tumors and WNT-activated deep penetrating melanocytic tumors, but not for dysplastic nevi, which may harbor these genetic alterations. Limited genomic data is available for pigmented epithelioid melanocytic tumors to determine if TERT promoter variants contribute to malignant transformation.

f

Loss of function alteration.

g

Hypermethylation of TERT promoter.

h

Amplification.

i

Change of function variant.

Although NGS can substantially aid in the classification of pediatric melanocytic tumors, a diagnosis of malignant melanoma should not rely solely on a tumor’s genetic profile. Rather, diagnosis should integrate the clinical, histopathologic, immunohistochemistry, and molecular features of each case. The graphical abstract summarizes the diagnostic approach to atypical pediatric melanocytic neoplasms and illustrates how molecular data can be incorporated into tumor classification.

DEFINITION OF PEDIATRIC MELANOMA

Biologically malignant pediatric melanocytic tumors with metastatic potential and the capacity to cause death typically exhibit three or more Children’s Oncology Group (COG) high-risk clinicopathologic features (age at diagnosis >10 years [not applicable to MCMN], clinical tumor diameter >1 cm, ulceration, extension into the subcutaneous fat, mitotic rate ≥6/mm2, high-grade cytologic atypia, and an expansile dermal nodule) in conjunction with molecular alterations that support malignant transformation, such as TERT promoter variants in Spitz-lineage tumors.1 However, no single factor or combination of findings definitively establishes malignancy in pediatric melanocytic tumors. Accordingly, histopathologic and molecular findings should be interpreted within the context of the clinical presentation and tumor lineage when classifying pediatric melanocytic neoplasms. Furthermore, pediatric melanoma requires a diagnostic approach distinct from that used for adult melanoma because of its generally more indolent clinical behavior and unique spectrum of driver alterations, including gene fusions. Prospective studies are needed to further refine diagnostic criteria for pediatric melanoma.

MANAGEMENT OF PEDIATRIC MELANOMA

In October 2024, COG published a guidance paper with recommendations for the diagnostic evaluation and surgical management of pediatric cutaneous melanoma and atypical melanocytic neoplasms that were based on the expert opinion of 33 cutaneous melanoma specialists (adult and pediatric oncology, adult and pediatric dermatology, dermatopathology, pediatric surgery) and data from 87 peer-reviewed publications.1 These guidelines provide surgical margin recommendations for atypical pediatric melanocytic neoplasms (e.g., Spitz melanocytoma) and pediatric melanoma.1

CONCLUSIONS

Identifying pediatric melanocytic tumors with metastatic potential is challenging due to overlapping clinicopathologic features between benign and malignant lesions. NGS can identify tumor lineage (e.g., Spitz vs. low-CSD/SSM vs. MCMN) and assess for genetic alterations (e.g., TERT promoter, TP53, PTEN) associated with aggressive tumor behavior, and should be prioritized over other diagnostic assays. Methylation profiling may also improve pediatric melanocytic tumor classification, but validated epigenomic assays are lacking in most clinical laboratories. For pediatric melanoma subtypes not associated with ultraviolet radiation exposure (e.g., Spitz, MCMN, MBN), further research is needed to understand environmental and host factors contributing to their development.

ACKNOWLEDGMENTS

Funding/Support:

This work was supported by the Intramural Research Program of the National Institutes of Health (NIH). The contributions of Dr. Sargen were made as part of his official duties as an NIH federal employee, are in compliance with agency policy requirements, and are considered Works of the United States Government. However, the findings and conclusions presented in this paper are those of the author and do not necessarily reflect the views of the NIH or the U.S. Department of Health and Human Services. Research support for Dr. Michael Sargen was provided through the Lasker Clinical Research Scholars Program, an NIH initiative developed in partnership with the Lasker Foundation to support early-career physician-scientists.

Abbreviations:

CSD

Cumulative Solar Damage

SSM

Superficial Spreading Melanoma

MCMN

Melanoma arising in Congenital Melanocytic Nevus/Nevi

MBN

Melanoma arising in Blue Nevus/Nevi

NGS

Next-Generation Sequencing

CTRT

CRTC1::TRIM11-rearranged Tumor

MART

MED15::ATF1-rearranged Tumor

(BAMS) Neoplasm

BRAF-mutated and Morphologically Spitzoid

LGCMN

Large and Giant Congenital Melanocytic Nevus/Nevi

WHO

World Health Organization

COG

Children’s Oncology Group

Footnotes

Original Publication: This manuscript contains original, unpublished work and is not being submitted for publication elsewhere.

Conflict of Interest Disclosures: None

Declaration of Generative AI in Scientific Writing: Generative AI was not used to write this manuscript.

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