Melanoma, although rare, is the most common skin cancer in children, followed by basal cell carcinomas and squamous cell carcinomas.[1,2,3,4,5,6,7,8] In a retrospective study of 22,524 skin pathology reports in patients younger than 20 years, investigators identified 38 melanomas, 33 of which occurred in patients aged 15 to 19 years. Study investigators reported that the number of lesions that needed to be excised to identify one melanoma was 479.8, which is 20 times higher than in the adult population.
Approximately 400 cases of melanoma are diagnosed each year in patients younger than 20 years in the United States, accounting for less than 1% of all new cases of melanoma. Melanoma annual incidence in the United States (2011–2015) increases with age, as follows:
The incidence of pediatric melanoma increased by an average of 1.7% per year between 1975 and 1994, but then decreased by 0.6% per year from 1995 to 2014. Increased exposure to ambient ultraviolet radiation increases the risk of the disease. However, a review of United States Surveillance, Epidemiology, and End Results Program data from 2000 to 2010 suggested that the incidence of melanoma in children and adolescents decreased over that interval.
Conditions associated with an increased risk of developing melanoma in children and adolescents include the following:
Patients with central nervous system melanoma arising in the context of congenital melanocytic nevi syndrome have a poor prognosis, with 100% mortality. Most of these patients will have NRAS mutations; therefore, there is potential rationale for treatment with mitogen-activated protein kinase pathway inhibitors. Transient symptomatic improvement was noted in four children receiving a MEK inhibitor, but all patients eventually died from disease progression.
A multinational consortium performed a retrospective review of germline variants in the MC1R gene. The investigators analyzed data from 233 young patients (aged ≤20 years), 932 adult patients (aged ≥35 years), and 932 healthy adult controls. MC1R variants were more prevalent in childhood and adolescent melanoma than in adult melanoma, especially in patients aged 18 years or younger.
Familial melanoma comprises 8% to 12% of melanoma cases. p16 germline mutations have been described in up to 7% of families with two first-degree relatives with melanoma and in up to 80% of families having one member with multiple primary melanomas.
In a prospective study of 60 families who had more than three members with melanoma, one-half of the 60 families studied had a germline CDKN2A mutation. Regardless of CDKN2A status, melanoma-prone families were found to have sixfold to 28-fold higher percentages of members with pediatric melanoma compared with the general population of patients with melanoma in the United States. Within CDKN2A-positive families, pediatric patients with melanoma were significantly more likely to have multiple melanomas compared with their relatives who were older than 20 years at diagnosis (71% vs. 38%, respectively; P = .004). CDKN2A-positive families had significantly higher percentages of pediatric patients with melanoma compared with CDKN2A-negative families (11.1% vs. 2.5%, respectively; P = .004).
Pediatric melanoma shares many similarities with adult melanoma, and the prognosis is dependent on stage. As in adults, most pediatric cases (about 75%) are localized and have an excellent outcome.[2,3,4] More than 90% of children and adolescents with melanoma are expected to be alive 5 years after their initial diagnosis.[1,3,5,6]
The outcome for patients with nodal disease is intermediate, with about 60% expected to survive long term.[3,4,5] In one study, the outcome for patients with metastatic disease was favorable, but this result was not duplicated in another study from the National Cancer Database.
Children younger than 10 years who have melanoma often present with poor prognostic features, are more often non-White, have head and neck primary tumors, thicker primary lesions, a higher incidence of spitzoid morphology vascular invasion and nodal metastases, and more often have syndromes that predispose them to melanoma.[1,3,5,7]
The use of sentinel lymph node biopsy for staging pediatric melanoma has become widespread, and the thickness of the primary tumor, as well as ulceration, have been correlated with a higher incidence of nodal involvement. Studies addressing nodal involvement and the lack of effect on outcome include the following:
The association of thickness with clinical outcome is controversial in pediatric melanoma.[3,4,5,14,15,16,17,18] In addition, it is unclear why some variables that correlate with survival in adults are not replicated in children. One possible explanation for this difference might be the inclusion of patients who have lesions that are not true melanomas in the adult series, considering the problematic histological distinction between true melanoma and melanocytic lesions with unknown malignant potential. These patients are not included in pediatric trials.[19,20]
The European Cooperative Study Group for Pediatric Rare Tumors within the PARTNER project (Paediatric Rare Tumours Network - European Registry) has published recommendations for the diagnosis and treatment of children and adolescents with cutaneous melanoma. Some of these recommendations have been incorporated and summarized in the sections below.
The diagnostic evaluation of melanoma includes the following:
The role of complete lymph node dissection after a positive sentinel node and the value of adjuvant therapies in these patients is discussed in the Treatment of Childhood Melanoma section of this summary.
Patients who present with conventional or adult-type melanoma should undergo laboratory and imaging evaluations on the basis of adult guidelines (refer to the Stage Information for Melanoma section in the PDQ summary on adult Melanoma Treatment for more information). In contrast, patients who are diagnosed with spitzoid melanomas have a low risk of recurrence and excellent clinical outcomes and do not require extensive radiographic evaluation either at diagnosis or follow-up.
The diagnosis of pediatric melanoma may be difficult, and many of these lesions may be confused with the so-called melanocytic lesions with unknown malignant potential. These lesions are biologically different from melanoma and benign nevi.[11,12] The terms Spitz nevus and spitzoid melanoma are also commonly used, creating additional confusion. One retrospective study found that children aged 10 years or older were more likely to present with amelanotic lesions, bleeding, uniform color, variable diameter, and elevation (such as a de novo bump).[Level of evidence: 3iiA]
Melanoma-related conditions with malignant potential that arise in the pediatric population can be classified into the following three general groups:
The genomic characteristics of each tumor are summarized in Table 1.
The genomic landscape of conventional melanoma in children is represented by many of the genomic alterations that are found in adults with melanoma. A report from the Pediatric Cancer Genome Project observed that 15 cases of conventional melanoma had a high burden of somatic single-nucleotide variations, TERT promoter mutations (12 of 13), and activating BRAF V600 mutations (13 of 15), as well as a mutational spectrum signature consistent with ultraviolet (UV) light damage. In addition, two-thirds of the cases had MC1R variants associated with an increased susceptibility to melanoma. An Australian study compared the whole-genome sequencing of melanomas in adolescents and young adults (age range, 15–30 years) with the sequencing of melanomas in older adults. The frequencies of somatic mutations in BRAF (96%) and PTEN (36%) in the adolescent and young adult cohort were double the rates observed in the adult cohort. Adolescent and young adult melanomas contained a higher proportion of mutation signatures unrelated to UV radiation than did mature adult melanomas, as a proportion of total mutation burden.
The genomic landscape of spitzoid melanomas is characterized by kinase gene fusions involving various genes, including RET, MAP3K8, ROS1, NTRK1, ALK, MET, and BRAF.[3,4,5,6] These fusion genes have been reported in approximately 50% of cases and occur in a mutually exclusive manner.[1,4]TERT promoter mutations are uncommon in spitzoid melanocytic lesions and were observed in only 4 of 56 patients evaluated in one series. However, each of the four cases with TERT promoter mutations experienced hematogenous metastases and died of their disease. This finding supports the potential of TERT promoter mutations in predicting aggressive clinical behavior in children with spitzoid melanocytic neoplasms, but additional study is needed to define the role of wild-type TERT promoter status in predicting clinical behavior in patients with primary site spitzoid tumors.
Large congenital melanocytic nevi are reported to have activating NRAS Q61 mutations with no other recurring mutations noted. Somatic mosaicism for NRAS Q61 mutations has also been reported in patients with multiple congenital melanocytic nevi and neuromelanosis.
Accurate diagnosis of pediatric melanocytic lesions, especially those categorized as Spitz lesions, is challenging. Morphological assessment alone has significant limitations, with low interobserver expert agreement.
Integrating genomic analysis in the evaluation of pediatric melanocytic lesions can optimize diagnostic accuracy and provide important prognostic information for the treating physician. In a prospective registry of 70 patients with pediatric melanocytic lesions, the use of an integrated clinicopathological and genomic assessment optimized the pathological diagnosis and improved the ability to predict clinical outcomes in these patients. Patients with atypical Spitz tumors/Spitz melanomas were younger and had tumors predominantly located in the extremities. Genomic lesions in these patients were characterized by kinase fusions most often involving MAP3K8 and ALK. Even though 62% of patients who had nodes sampled had nodal disease, none developed distant metastases and two developed locoregional recurrences. Of the 33 patients tested, no patients had TERT promoter mutations. However, CDKN2A was deleted in 15 patients. These findings suggest that TERT promoter mutations might be a better predictor of aggressive clinical behavior (development of metastases) in these lesions. Patients with conventional melanoma (n = 17) were older and their tumors were more commonly located on the scalp or trunk. Seven of 12 patients had a positive sentinel node, and genomic abnormalities in 11 of 17 patients revealed BRAF V600E mutations. Seven of 16 patients had TERT promoter mutations, and three of these patients died of their disease. Of the four patients with melanoma arising in a giant nevi, all had NRAS Q61 mutations and all succumbed to their disease.
In another study, 128 lesions were classified as Spitz tumors on the basis of morphology (80 Spitz tumors, 26 Spitz melanomas, 22 melanomas with Spitz features). Kinase fusions or truncations were present in 81% of Spitz tumor cases and in 77% of Spitz melanoma cases. By comparison, 84% of melanomas with Spitz features had BRAF, NRAS, or NF1 mutations, and 61% of these had TERT promoter mutations. Among patients in the Spitz tumor group whose melanoma recurred, one patient diagnosed with a BRAF V600E mutation and a TERT promoter mutation developed a distant recurrence and died. A second patient with a MAP3K8 fusion had a local recurrence. Two patients with Spitz melanoma had a recurrence and both had BRAF V600E mutations. Of the three patients in the melanoma with spitzoid features group who had a recurrence, all had a BRAF or NRAS mutation with concomitant TERT promoter mutations. After reclassifying these patients on the basis of their clinical and genomic characteristics, and by incorporating the BRAF or NRAS mutations into the melanoma with Spitz features category, a significant difference in recurrence-free survival rates could be detected among the groups with Spitz tumors. This finding suggests that incorporation of genomic features can greatly improve the classification of these lesions.
|Spitz melanoma||Kinase fusions (RET,ROS,MET,ALK,BRAF,MAP3K8,NTRK1);BAP1loss in the presence ofBRAFmutation|
|Spitz nevus||HRAS;BRAFandNRAS(uncommon); kinase fusions (ROS,ALK,NTRK1,BRAF,RET,MAP3K8)|
Cancer in children and adolescents is rare, although the overall incidence has been slowly increasing since 1975. Referral to medical centers with multidisciplinary teams of cancer specialists experienced in treating cancers that occur in childhood and adolescence should be considered. This multidisciplinary team approach incorporates the skills of the following health care professionals and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life:
(Refer to the PDQ Supportive and Palliative Care summaries for specific information about supportive care for children and adolescents with cancer.)
The American Academy of Pediatrics has outlined guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer. At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate is offered to most patients and their families. Clinical trials for children and adolescents diagnosed with cancer are generally designed to compare potentially better therapy with current standard therapy. Most of the progress made in identifying curative therapy for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI website.
Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2010, childhood cancer mortality decreased by more than 50%. Childhood and adolescent cancer survivors require close monitoring because side effects of cancer therapy may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)
Childhood cancer is a rare disease, with about 15,000 cases diagnosed annually in the United States in individuals younger than 20 years. The U.S. Rare Diseases Act of 2002 defines a rare disease as one that affects populations smaller than 200,000 people. Therefore, all pediatric cancers are considered rare.
The designation of a rare tumor is not uniform among pediatric and adult groups. In adults, rare cancers are defined as those with an annual incidence of fewer than six cases per 100,000 people. They account for up to 24% of all cancers diagnosed in the European Union and about 20% of all cancers diagnosed in the United States.[5,6] Also, the designation of a pediatric rare tumor is not uniform among international groups, as follows:
Most cancers in subgroup XI are either melanomas or thyroid cancer, with other types accounting for only 1.3% of cancers in children aged 0 to 14 years and 5.3% of cancers in adolescents aged 15 to 19 years.
These rare cancers are extremely challenging to study because of the low number of patients with any individual diagnosis, the predominance of rare cancers in the adolescent population, and the lack of clinical trials for adolescents with rare cancers.
Information about these tumors may also be found in sources relevant to adults with cancer, such as the PDQ summary on adult Melanoma Treatment.
Treatment options for childhood melanoma include the following:
Surgery is the treatment of choice for patients with localized melanoma. Current guidelines recommend margins of resection as follows:
Sentinel lymph node biopsy should be considered in patients with thin lesions (≤1 mm) and ulceration, mitotic rate greater than 1 mm2, young age, and lesions larger than 1 mm with or without adverse features. Young patients have a higher incidence of sentinel lymph node positivity, and this feature adversely affects clinical outcomes.[1,2]
If the sentinel lymph node is positive, the option to undergo a complete lymph node dissection should be discussed. An adult trial randomly assigned 1,934 patients with a positive sentinel node, identified by either immunohistochemistry or polymerase chain reaction, to either complete lymph node dissection or observation. The 3-year melanoma-specific survival rate was similar in both groups (86%), whereas the disease-free survival (DFS) rate was slightly higher in the dissection group (68% vs. 63%; P = .05). This advantage in DFS was related to a decrease in the rate of nodal recurrences because there was no difference in the distant metastases–free survival rates. It remains unknown how these results will affect the future surgical management of children and adolescents with melanoma.
Immune Checkpoint Inhibitors or BRAF/MEK Inhibitors
Patients with high-risk primary cutaneous melanoma, such as those with regional lymph node involvement, may be offered adjuvant treatment with immune checkpoint or BRAF inhibitors, as recently described in adults.[4,5,6] Specific trials evaluating these adjuvant therapies have not been conducted in pediatric patients.
Targeted therapies and immunotherapy that have been shown to be effective in adults with melanoma should be pursued in pediatric patients with conventional melanoma and metastatic, recurrent, or progressive disease.
Evidence (targeted therapy and immunotherapy):
Ipilimumab and nivolumab or nivolumab alone, as well as combinations of BRAF and MEK inhibitors for BRAF-mutant melanoma, have become the standard of care for adult patients with advanced-stage, metastatic melanoma.[3,10,11,12,13,14] Triple-combination therapy with checkpoint inhibitors, BRAF inhibitors, and MEK inhibitors have shown promising responses.
The use of BRAF and MEK inhibitors, as well as PD-L1 inhibitors, in the adjuvant setting have also become the standard of care for adult patients with high-risk, resected melanoma. This treatment may be considered for children with conventional melanoma and high-risk features such as stage IIIA or higher disease.[5,6,16]
(Refer to the PDQ summary on adult Melanoma Treatment for more information.)
Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
The following are examples of national and/or institutional clinical trials that are currently being conducted:
Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the NCI website and ClinicalTrials.gov website.
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Editorial changes were made to this summary.
This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of pediatric melanoma. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Childhood Melanoma Treatment are:
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Levels of Evidence
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PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Melanoma Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/skin/hp/child-melanoma-treatment-pdq. Accessed <MM/DD/YYYY>.
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Last Revised: 2022-04-19
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