Melanoma, although rare, is the most common skin cancer in children, followed by basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs).[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.
It is estimated that 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 (UV) radiation increases the risk of the disease. However, a review of United States Surveillance, Epidemiology, and End Results 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 very poor prognosis, with 100% mortality. Most of these patients will have NRAS mutations; therefore, there is potential rationale for treatment with mitogen-activated protein kinases (MAPK) 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 (MELTUMP); these patients are not included in pediatric trials.[19,20]
The diagnostic evaluation of melanoma includes the following:
The role of completion 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 related to adult melanoma). 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 (MELTUMP). These lesions are biologically different from melanoma and benign nevi.[8,9] 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, ROS1, NTRK1, ALK, MET, and BRAF.[3,4,5] 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.
|Spitzoid melanoma||Kinase fusions (RET,ROS,MET,ALK,BRAF,NTRK1);BAP1loss in the presence ofBRAFmutation|
|Spitz nevus||HRAS;BRAFandNRAS(uncommon); kinase fusions (ROS,ALK,NTRK1,BRAF,RET)|
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 in patients with 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 was similar in both groups (86%), whereas the disease-free survival (DFS) 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 the opportunity to receive 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):
(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:
Tumor tissue from progressive or recurrent disease must be available for molecular characterization. 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.
Cancer in children and adolescents is rare, although the overall incidence of childhood cancer 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 for children and adolescents with cancer. 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.)
Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics. 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 in these trials 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 therapy that is currently accepted as standard. 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 cancer therapy side effects 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 persons. Therefore, all pediatric cancers are considered rare.
The designation of a rare tumor is not uniform among pediatric and adult groups. Adult rare cancers are defined as those with an annual incidence of fewer than six cases per 100,000 people, and they are estimated to 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 within subgroup XI are either melanomas or thyroid cancer, with the remaining subgroup XI cancer 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 incidence 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.
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.
Added text to state that a multinational consortium performed a retrospective review of germline variants in the MC1R gene. The investigators analyzed data from 233 young patients, 932 adult patients, 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 (cited Pellegrini et al. as reference 16).
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 who care for cancer 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
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
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The preferred citation for this PDQ summary is:
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: 2020-10-06
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