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Journal of Pediatric Hematology/Oncology:
doi: 10.1097/MPH.0b013e31824e3852
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Management of Melanomas in Children and Young Adults

Neier, Michelle MD*; Pappo, Alberto MD; Navid, Fariba MD

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Author Information

*Valerie Fund Center, Goryeb Children's Hospital, Morristown, NJ

St Jude Children’s Research Hospital, Memphis, TN

The authors declare no conflict of interest.

Reprints: Michelle Neier, MD, Valerie Fund Center, Goryeb Children's Hospital, 100 Madison Avenue, #70, Morristown, NJ 07962 (e-mail: Michelle.Neier@atlantichealth.org).

Received January 23, 2012

Accepted February 1, 2012

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Abstract

Melanoma is rare in children and young adults. The incidence is rising yearly in this population. The clinical features of the disease in the pediatric population have been well documented through single-institution experiences and population-based analyses. Still, our understanding of the etiologic factors in the majority of children remains unclear, and diagnosis of melanoma remains challenging in certain cases. Because of its rarity, the staging, management and treatment of melanoma in this population is adopted from adult guidelines. In this review, we provide information on the epidemiology, clinical presentation, staging, prognosis and management of melanoma in children and young adults.

Melanoma is the most common skin cancer in children, followed by basal-cell and squamous-cell carcinoma. Melanoma accounts for <3% of all cancers seen in children, and the incidence in children and adolescents accounts for only approximately 1% of all new cases diagnosed in the United States annually.1 Its incidence, however, is rising yearly and increases with age. According to the SEER adolescents and young adults monograph from 2006, melanoma accounts for only about 1% of all malignancies in patients less than 15 years of age compared with 7% in those between the ages of 15 and 19 years and 12% in those between the ages of 20 and 24 years.2 The rate of increase in diagnosis of melanoma in adolescents and young adults (age, 10 to 24 years) is 3% per year, whereas in children less than 10 years of age, the rate of increase is only 1% per year.3

Whites are more likely to develop melanoma than any other racial-ethnic group. However, there is a proportionately higher incidence of melanoma in nonwhite children (less than 10 years of age).3 The female-to-male ratio increases with age during adolescence and young adulthood.2 Melanoma can present at any site; however, the extremity is the most common primary site of disease in patients less than 20 years of age, followed by trunk and head and neck.3

The exact etiology of melanoma in children is unclear. It is likely that there is interplay of both inherited and environmental factors. There are, however, a few known risk factors in children, including large congenital nevi, retinoblastoma, Werner syndrome, acquired dysplastic nevi, xeroderma pigmentosum, both inherited and iatrogenic immunosuppression, and familial melanoma.4 CDKN2A, along with other genetic mutations, has been implicated in the development of familial melanoma.5,6 Uribe and colleagues demonstrated evidence of impaired DNA repair (microsatellite instability) at low levels in adults with melanoma. This study of pediatric and adult melanomas and melanocytic nevi revealed deletions in the chromosomal regions 1p, 6p, 9p, 10q, and 11q in the adult cases but more evidence of microsatellite instability in the pediatric cases.7

Patients with a strong family history of melanoma or other malignancies should be referred for genetic counseling and testing. They should also receive more frequent and thorough screenings by a dermatologist. Familial melanoma patients tend to be younger and may have multiple primary melanomas or precursor lesions such as melanocytic nevi. Melanomas sometimes occur in association with familial retinoblastoma, Li-Fraumeni syndrome, and Lynch syndrome type II. Other associations include pancreatic cancer and astrocytoma.8,9 Exposure to ultraviolet rays from sunlight is the most important etiologic factor and significantly raises the risk of melanomas. Individuals of northern European descent represent the typical phenotypes of at-risk individuals with little skin pigmentation, light hair, poor tanning ability, and a likelihood of sunburns. Individuals with xeroderma pigmentosum, a genetic condition characterized by extreme light sensitivity, keratosis, and various neurological manifestations, are at an increased risk for melanoma and other skin cancers. Melanomas can, however, occur in any ethnic group and even on areas of the body without substantial sun exposure.10–13 Recent concern regarding etiologic risk factors is the use of indoor tanning facilities, which increase exposure to ultraviolet light. One study reported use of tanning facilities (3 or more times) among female adolescents increased with age, from 11.2% of the 13- to 14-year-olds to 47.0% of 18- to 19-year-olds.14

Recent understanding of the molecular mechanism of melanomas has identified new therapeutic targets. Melanoma development has been linked to germline mutations in genes encoding CDKN2A, CDK4, and MCIR as well as to somatic mutations in protooncogenes B-RAF, N-RAS, KIT and tumor suppressor genes CDKN2A, p53, and PTEN. Somatic mutations in B-RAF are the most common genetic alterations in melanoma occurring in up to 66% of malignant melanomas. There are at least 30 documented mutations of B-RAF that activate the MAPK pathway. The most common B-RAF mutation is V600E.15 Targeting these mutations with specific inhibitors offers an exciting new therapeutic approach for these tumors.

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CLINICAL PRESENTATION

In children, melanoma can arise in an existing nevi (usually congenital or dysplastic nevi) or de novo. The ABCDE clinical rule (asymmetry, border irregularity, color variability, diameter >6 mm, and evolving) often used in identifying concerning skin lesions in adults may be difficult to apply to pediatric skin lesions, because common pediatric lesions, such as pyogenic granulomas, Spitz nevi, and benign nevi that grow as the child grows, can have these features. Further, pediatric patients are more likely to present with amelanotic lesions, which is not a common feature in adult melanoma.16 The atypical presentation and the low index of suspicion for melanoma in children and adolescents often lead to a delay in diagnosis. Most patients (>80%) present with localized disease at diagnosis; the remainder either have regional lymph node disease (10% to 15%) or distant metastasis (1% to 3%). Any organ may be involved by metastasis, including lung, liver, lymph nodes, subcutaneous tissue, and brain. Lactate dehydrogenase may be elevated in patients with metastatic disease and is a poor prognostic factor.

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STAGING

Staging is important in classifying melanomas, because it provides information regarding prognosis and treatment. To date, there has been no validated staging system for melanoma in children. Both clinical and pathologic staging of melanoma in adults have been well defined by the American Joint Committee on Cancer Melanoma Staging Committee, with the most recent updates and changes described in 2009.17 The updated 2009 American Joint Committee on Cancer staging criteria for melanoma divides melanoma into 4 distinct stages and incorporates pathologic “microstaging attributes,” including Breslow depth, mitotic rate and ulceration, all of which are important predictive parameters. Stages I and II are localized melanoma, stage III is regional metastasis, and stage IV is distant metastasis. The TNM classification is used in each stage to determine disease stage clinically. According to staging criteria, important prognostic criteria are thickness of primary tumor, presence or absence of ulceration, nodal status, and presence or absence of metastasis. The 2009 guidelines include using mitotic rate, instead of Clark level of invasion, as a prognostic factor in staging, particularly for thinner lesions <1 mm (T1). It was noted that a higher mitotic rate portends a worse prognosis.18

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PROGNOSIS

Overall survival from melanoma in a pediatric population is directly related to disease stage at presentation. There is clearly an overall decrease in survival with higher stages of disease. Analysis of data from the National Cancer Data Base revealed that the overall 5-year survival rates were 98.7% for in situ disease, 93.6% for localized invasive disease, 68.0% for regionally metastatic disease, and 11.8% for distant disease in patients aged 1 to 19 years. In that report, overall survival was significantly decreased in patients aged 1 to 9 years (77% vs. 88%) compared with those greater than 9 years of age. Younger patients were also more likely to present with thicker lesions and metastases possibly related to delayed diagnosis.19 A single-institution study found no significant difference in survival between prepubescent and adult patients.20 Other studies have noted a better outcome in younger patients.16 There have been conflicting reports of retrospective data from single-institution studies due to the small number of patients. Given the small numbers of patients less than 13 years of age, it is difficult to gather enough data to determine the overall prognosis of these young patients.

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DIAGNOSIS AND MANAGEMENT

The management of patients with melanoma is stage dependent. Proper staging requires a thorough clinical, histopathologic, laboratory, and imaging evaluation that is dictated by the initial surgical evaluation. Early detection, biopsy, and removal of any suspicious lesion are keys in the early diagnosis of melanoma. Suspicious lesions should never be shaved off or cauterized. Rather, these lesions should be excised such that the depth of the lesion can be adequately assessed. Reporting by a dermatopathologist should include type of melanoma, presence or absence of ulceration, thickness of the lesion, mitotic rate and assessment of the surgical margins. This information will determine the need for further surgery to achieve an adequate surgical margin and the need for nodal staging. Adequate surgical margins free of disease are based on the depth of the lesion as follows: depth ≤1 mm, 1-cm margin; depth >1 and ≤2 mm, 1 to 2-cm margin; and depth >2 mm, 2-cm margin.21 Resection should be performed by a trained surgical oncologist.

Nodal staging includes sentinel lymphoscintigraphy followed by sentinel lymph node (SLN) biopsy. SLN biopsy has become standard of care for adult patients with lesions >1-mm thick and lesions ≤1-mm thick with ulceration and Clark level of invasion IV or V. The safety and feasibility of this procedure in children and adolescents has recently been reported.22–24 Patients whose sentinel nodes are found to harbor tumor cells should then undergo complete lymph node dissection of the involved nodal basin and metastatic workup as described above. Every effort should be made to perform lymphoscintigraphy with the primary lesion intact or after excisional biopsy. Cutaneous lymphatic flow may not be the same after wide local excision of a primary melanoma. In cases in which the diagnosis of melanoma versus Spitz lesion is difficult to make, SLN biopsy can aid in the final diagnosis.25,26 The significance of positive SLNs in children is not completely clear, but use of this surgical procedure can aid in the diagnosis.22,24,27–30

The evidence in the literature supports use of computed tomography (CT) scans to assess for distant disease in children with thicker lesions. In an adult study, CT scan of the chest and abdomen revealed mostly isolated pulmonary or liver lesions that were frequently found to be benign.31 A small retrospective study of children showed that almost 25% of patients with thicker lesions had metastatic lesions revealed by CT scan of chest and abdomen.32 There have been no large prospective studies evaluating the role of imaging in the initial evaluation of pediatric patients with melanoma. There has been a recent review of the literature using positron emission tomography (PET) and PET-CT scanning in adults with melanoma concluding that PET-CT may be useful in the evaluation of patients with thicker lesions to diagnose distant metastasis.33 There is no good evidence documenting the routine use of magnetic resonance imaging of the brain to detect metastasis in the absence of symptoms or physical findings. Given the current evidence, patients with thin lesions (<1 mm) who are at lower risk for regional spread do not need imaging studies for further diagnostic evaluation.

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Localized Disease

Surgical treatment alone with an adequate margin as defined above is curative for most patients, adult and pediatric, with melanoma who present with early stage, localized disease. The presence of thick lesions (>4 mm) is associated with higher risk of mortality. These patients should be considered for adjuvant therapy.18,27,34

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Regional Nodal Disease

The reported 5-year survival rates for adult patients with regional lymph node involvement range from 24% to 67%.18,20,35 The limited pediatric data would suggest a similar prognosis for patients with nodal disease.36–39

Three multi-institutional adult trials for high-risk, resected melanoma (primarily patients with regional nodal disease) have demonstrated that the “Kirkwood regimen,” high-dose interferon α-2b at 20×106 U/m2/d intravenously, 5 times/wk for 4 weeks, followed by 10×106 U/m2/d subcutaneously, 3 times/wk for 48 weeks, improves relapse-free survival of these patients. Low and intermediate doses of interferon have not shown any survival benefit in patients with melanoma.40–42

To date, 3 studies have been published evaluating the feasibility of the Kirkwood regimen in children. Chao et al42 reported on a retrospective review of 12 patients with high-risk lesions who received interferon therapy. They found that overall, the patients tolerated the therapy with fewer side effects than adults previously studied. Another study reported on 11 pediatric patients who underwent SLN biopsy at The Hospital for Sick Children in Toronto. Five of these patients received adjuvant interferon therapy as per the Kirkwood regimen. They also found that the regimen was tolerated overall with 2 patients requiring dose modification during induction and 2 during maintenance.43 The third study was a prospective study that included 15 patients treated as above. This study found that neutropenia was the most common grade 3/4 toxicity. Overall, these patients experienced fewer side effects and tolerated therapy better than the adult population.22 With respect to the adult and pediatric studies, the best available therapy that has been shown to have some effect remains the Kirkwood regimen in patients with stage III disease. There is speculation that the relative benefit of adjuvant interferon therapy may be a result of the first month of high-dose intravenous therapy. Current studies through Children's Oncology Group and Eastern Cooperative Oncology Group, therefore, are investigating the benefit of 1 month of high-dose interferon therapy versus observation alone.

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Metastatic Disease

Melanoma that has spread to distant sites is rarely curable with standard therapy, including chemotherapy (eg, dacarbazine, temozolomide, paclitaxel, carboplatin, cisplatin, and vinblastine) or biological agents such as interleukin-2 (IL-2) or interferon. High-dose IL-2, however, has been reported to produce durable responses in a small number of adult patients.44 Experience with IL-2 in children is limited, and there are no reports of its efficacy in pediatric patients with melanoma.45 In occasional adult patients, complete surgical resection of all sites of metastatic disease has resulted in long-term survival.46,47 These circumstances are rare, and most patients with metastatic disease die of their disease. Thus, as with adults, it is appropriate to consider pediatric patients with metastatic disease for participation in clinical trials. Clinical trials are ongoing to develop novel approaches to treat melanoma, including exploitation of its highly immunogenic nature with vaccines, cytokines, and small molecules, as well as targeting growth factor pathways and the tumor vasculature with tyrosine-kinase inhibitors and antibodies. One important antibody is anti-CTLA-4 or ipilimumab that targets activated T cells and has potential immunomodulatory effects. This has been an important drug in beginning to understand the role of the immune system in both the development and treatment of melanoma and other tumors.48 Another treatment option is targeting molecular targets with selective inhibitors. Vemurafenib (PLEX-4032, Zelboraf®, Genentech, Inc, San Francisco, CA) is the first selective B-RAF inhibitor clinically testedapproved by the Food and Drug Administration for use in adult patients with unresectable or metastatic melanoma containing the BRAFV600E mutation.49

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SCREENING/PREVENTION

Because of the fact that low-stage melanoma is highly curable, early detection is of primary importance in this disease. Thus, early diagnosis requires public education and awareness regarding skin self-examinations and the ABCDE of melanoma, as well as screening by primary care physicians, dermatologists, and community-based programs, especially in at-risk individuals (eg, patients with xeroderma pigmentosum, prior skin cancer, a family history of melanoma, giant congenital nevi, suspicious nevi, immunosuppression, genetic predisposition, or exposure to radiation).

Public awareness and education regarding minimizing risk factors, primarily sun exposure, are of paramount importance in curtailing the rising incidence of melanoma. Most studies agree that sun exposure plays an important role in the development of melanoma in older (postpubescent) patients. The role of sun exposure in the younger, prepubescent child remains unclear. Because adult melanoma is clearly linked to sun exposure, parental education and behavioral modification in childhood about the avoidance of intense intermittent exposure to the sun’s ultraviolet radiation, especially in at-risk populations, is a key strategy in prevention, along with general measures, such as wearing sunscreen lotion and wide-brimmed hats, minimizing skin exposure, and avoiding sunburns.

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Keywords:

melanoma; children; young adults

© 2012 Lippincott Williams & Wilkins, Inc.

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