miércoles, 1 de enero de 2020

Childhood Melanoma Treatment (PDQ®)–Health Professional Version - National Cancer Institute

Childhood Melanoma Treatment (PDQ®)–Health Professional Version - National Cancer Institute

National Cancer Institute

Childhood Melanoma Treatment (PDQ®)–Health Professional Version

Go to Patient Version

Incidence

Melanoma, although rare, is the most common skin cancer in children, followed by basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs).[1-8] 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.[9]
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.[10] Melanoma annual incidence in the United States (2011–2015) increases with age, as follows:[11]
  • Children younger than 10 years: <1.8 cases per 1 million.
  • Children aged 10 to 14 years: 3.2 cases per 1 million.
  • Children aged 15 to 19 years: 10.4 cases per 1 million.
Melanoma accounts for about 4% of all cancers in children aged 15 to 19 years.[11,12]
The incidence of pediatric melanoma increased by an average of 1.7% per year between 1975 and 1994,[11] but then decreased by 0.6% per year from 1995 to 2014.[13] 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.[14]
References
  1. Sasson M, Mallory SB: Malignant primary skin tumors in children. Curr Opin Pediatr 8 (4): 372-7, 1996. [PUBMED Abstract]
  2. Fishman C, Mihm MC, Sober AJ: Diagnosis and management of nevi and cutaneous melanoma in infants and children. Clin Dermatol 20 (1): 44-50, 2002 Jan-Feb. [PUBMED Abstract]
  3. Hamre MR, Chuba P, Bakhshi S, et al.: Cutaneous melanoma in childhood and adolescence. Pediatr Hematol Oncol 19 (5): 309-17, 2002 Jul-Aug. [PUBMED Abstract]
  4. Ceballos PI, Ruiz-Maldonado R, Mihm MC: Melanoma in children. N Engl J Med 332 (10): 656-62, 1995. [PUBMED Abstract]
  5. Schmid-Wendtner MH, Berking C, Baumert J, et al.: Cutaneous melanoma in childhood and adolescence: an analysis of 36 patients. J Am Acad Dermatol 46 (6): 874-9, 2002. [PUBMED Abstract]
  6. Pappo AS: Melanoma in children and adolescents. Eur J Cancer 39 (18): 2651-61, 2003. [PUBMED Abstract]
  7. Huynh PM, Grant-Kels JM, Grin CM: Childhood melanoma: update and treatment. Int J Dermatol 44 (9): 715-23, 2005. [PUBMED Abstract]
  8. Christenson LJ, Borrowman TA, Vachon CM, et al.: Incidence of basal cell and squamous cell carcinomas in a population younger than 40 years. JAMA 294 (6): 681-90, 2005. [PUBMED Abstract]
  9. Moscarella E, Zalaudek I, Cerroni L, et al.: Excised melanocytic lesions in children and adolescents - a 10-year survey. Br J Dermatol 167 (2): 368-73, 2012. [PUBMED Abstract]
  10. National Cancer Institute: SEER Stat Fact Sheets: Melanoma of the Skin. Bethesda, Md: National Cancer Institute. Available online. Last accessed June 04, 2019.
  11. Childhood cancer by the ICCC. In: Howlader N, Noone AM, Krapcho M, et al., eds.: SEER Cancer Statistics Review (CSR) 1975-2014. Bethesda, Md: National Cancer Institute, Section 29. Also available online. Last accessed June 04, 2019.
  12. Bleyer A, O’Leary M, Barr R, et al., eds.: Cancer Epidemiology in Older Adolescents and Young Adults 15 to 29 Years of Age, Including SEER Incidence and Survival: 1975-2000. Bethesda, Md: National Cancer Institute, 2006. NIH Pub. No. 06-5767. Also available online. Last accessed August 16, 2019.
  13. Wong JR, Harris JK, Rodriguez-Galindo C, et al.: Incidence of childhood and adolescent melanoma in the United States: 1973-2009. Pediatrics 131 (5): 846-54, 2013. [PUBMED Abstract]
  14. Campbell LB, Kreicher KL, Gittleman HR, et al.: Melanoma Incidence in Children and Adolescents: Decreasing Trends in the United States. J Pediatr 166 (6): 1505-13, 2015. [PUBMED Abstract]

Risk Factors

Conditions associated with an increased risk of developing melanoma in children and adolescents include the following:
  • Giant melanocytic nevi.[1]
  • Xeroderma pigmentosum (a rare recessive disorder characterized by extreme sensitivity to sunlight, keratosis, and various neurologic manifestations).[1]
  • Immunodeficiency or immunosuppression.[2]
  • Hereditary retinoblastoma.[3]
  • Werner syndrome.[4,5]
  • Neurocutaneous melanosis. Neurocutaneous melanosis is an unusual condition that arises in the context of congenital melanocytic nevi and is associated with large or multiple congenital nevi of the skin in association with meningeal melanosis or melanoma; approximately 2.5% of patients with large congenital nevi develop this condition, and those with increased numbers of satellite nevi are at greatest risk.[6,7]
    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.[8]
Phenotypic traits that are associated with an increased risk of melanoma in adults have been documented in children and adolescents with melanoma and include the following:[9-15]
  • Exposure to ultraviolet (UV) sunlight.
  • Red hair.
  • Blue eyes.
  • Poor tanning ability.
  • Freckling.
  • Dysplastic nevi.
  • Increased number of melanocytic nevi.
  • Family history of melanoma.
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.[16]
In a prospective study of 60 families who had more than three members with melanoma,[17] 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).
References
  1. Ceballos PI, Ruiz-Maldonado R, Mihm MC: Melanoma in children. N Engl J Med 332 (10): 656-62, 1995. [PUBMED Abstract]
  2. Pappo AS: Melanoma in children and adolescents. Eur J Cancer 39 (18): 2651-61, 2003. [PUBMED Abstract]
  3. Kleinerman RA, Tucker MA, Tarone RE, et al.: Risk of new cancers after radiotherapy in long-term survivors of retinoblastoma: an extended follow-up. J Clin Oncol 23 (10): 2272-9, 2005. [PUBMED Abstract]
  4. Shibuya H, Kato A, Kai N, et al.: A case of Werner syndrome with three primary lesions of malignant melanoma. J Dermatol 32 (9): 737-44, 2005. [PUBMED Abstract]
  5. Kleinerman RA, Yu CL, Little MP, et al.: Variation of second cancer risk by family history of retinoblastoma among long-term survivors. J Clin Oncol 30 (9): 950-7, 2012. [PUBMED Abstract]
  6. Hale EK, Stein J, Ben-Porat L, et al.: Association of melanoma and neurocutaneous melanocytosis with large congenital melanocytic naevi--results from the NYU-LCMN registry. Br J Dermatol 152 (3): 512-7, 2005. [PUBMED Abstract]
  7. Makkar HS, Frieden IJ: Neurocutaneous melanosis. Semin Cutan Med Surg 23 (2): 138-44, 2004. [PUBMED Abstract]
  8. Kinsler VA, O'Hare P, Jacques T, et al.: MEK inhibition appears to improve symptom control in primary NRAS-driven CNS melanoma in children. Br J Cancer 116 (8): 990-993, 2017. [PUBMED Abstract]
  9. Heffernan AE, O'Sullivan A: Pediatric sun exposure. Nurse Pract 23 (7): 67-8, 71-8, 83-6, 1998. [PUBMED Abstract]
  10. Berg P, Lindelöf B: Differences in malignant melanoma between children and adolescents. A 35-year epidemiological study. Arch Dermatol 133 (3): 295-7, 1997. [PUBMED Abstract]
  11. Elwood JM, Jopson J: Melanoma and sun exposure: an overview of published studies. Int J Cancer 73 (2): 198-203, 1997. [PUBMED Abstract]
  12. Strouse JJ, Fears TR, Tucker MA, et al.: Pediatric melanoma: risk factor and survival analysis of the surveillance, epidemiology and end results database. J Clin Oncol 23 (21): 4735-41, 2005. [PUBMED Abstract]
  13. Whiteman DC, Valery P, McWhirter W, et al.: Risk factors for childhood melanoma in Queensland, Australia. Int J Cancer 70 (1): 26-31, 1997. [PUBMED Abstract]
  14. Tucker MA, Fraser MC, Goldstein AM, et al.: A natural history of melanomas and dysplastic nevi: an atlas of lesions in melanoma-prone families. Cancer 94 (12): 3192-209, 2002. [PUBMED Abstract]
  15. Ducharme EE, Silverberg NB: Pediatric malignant melanoma: an update on epidemiology, detection, and prevention. Cutis 84 (4): 192-8, 2009. [PUBMED Abstract]
  16. Soufir N, Avril MF, Chompret A, et al.: Prevalence of p16 and CDK4 germline mutations in 48 melanoma-prone families in France. The French Familial Melanoma Study Group. Hum Mol Genet 7 (2): 209-16, 1998. [PUBMED Abstract]
  17. Goldstein AM, Stidd KC, Yang XR, et al.: Pediatric melanoma in melanoma-prone families. Cancer 124 (18): 3715-3723, 2018. [PUBMED Abstract]

Prognosis and Prognostic Factors

Pediatric melanoma shares many similarities with adult melanoma, and the prognosis is dependent on stage.[1] As in adults, most pediatric cases (about 75%) are localized and have an excellent outcome.[2-4] 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.[3-5] In one study, the outcome for patients with metastatic disease was favorable,[3] but this result was not duplicated in another study from the National Cancer Database.[5]
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.[8] Studies addressing nodal involvement and the lack of effect on outcome include the following:
  • Younger patients appear to have a higher incidence of nodal involvement; this finding does not appear to significantly impact clinical outcome in this population.[7,9]
  • In other series of pediatric melanoma, a higher incidence of nodal involvement did not appear to impact survival.[10-12]
  • In a retrospective cohort study from the National Cancer Database, all records of patients with an index diagnosis of melanoma from 1998 to 2011 were reviewed. The data were abstracted from medical records, operative reports, and pathology reports and did not undergo central review. A total of 350,928 patients with adequate information were identified; 306 patients were aged 1 to 10 years (pediatric), and 3,659 patients were aged 11 to 20 years (adolescent).[13] Pediatric patients had longer overall survival (OS) than did adolescent patients (hazard ratio [HR], 0.50; 95% confidence interval [CI], 0.25–0.98) and patients older than 20 years (HR, 0.11; 95% CI, 0.06–0.21). Adolescents had longer OS than did adults. No difference in OS was found between pediatric node-positive patients and node-negative patients. In pediatric patients, sentinel lymph node biopsy and completion of lymph node dissection were not associated with increased OS. In adolescents, nodal positivity was a significant negative prognostic indicator (HR, 4.82; 95% CI, 3.38–6.87).[13]
The association of thickness with clinical outcome is controversial in pediatric melanoma.[3-5,14-18] 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]
References
  1. Paradela S, Fonseca E, Pita-Fernández S, et al.: Prognostic factors for melanoma in children and adolescents: a clinicopathologic, single-center study of 137 Patients. Cancer 116 (18): 4334-44, 2010. [PUBMED Abstract]
  2. Wong JR, Harris JK, Rodriguez-Galindo C, et al.: Incidence of childhood and adolescent melanoma in the United States: 1973-2009. Pediatrics 131 (5): 846-54, 2013. [PUBMED Abstract]
  3. Strouse JJ, Fears TR, Tucker MA, et al.: Pediatric melanoma: risk factor and survival analysis of the surveillance, epidemiology and end results database. J Clin Oncol 23 (21): 4735-41, 2005. [PUBMED Abstract]
  4. Brecht IB, Garbe C, Gefeller O, et al.: 443 paediatric cases of malignant melanoma registered with the German Central Malignant Melanoma Registry between 1983 and 2011. Eur J Cancer 51 (7): 861-8, 2015. [PUBMED Abstract]
  5. Lange JR, Palis BE, Chang DC, et al.: Melanoma in children and teenagers: an analysis of patients from the National Cancer Data Base. J Clin Oncol 25 (11): 1363-8, 2007. [PUBMED Abstract]
  6. Howlader N, Noone AM, Krapcho M, et al., eds.: SEER Cancer Statistics Review, 1975-2010. Bethesda, Md: National Cancer Institute, 2013. Also available online. Last accessed March 7, 2019.
  7. Moore-Olufemi S, Herzog C, Warneke C, et al.: Outcomes in pediatric melanoma: comparing prepubertal to adolescent pediatric patients. Ann Surg 253 (6): 1211-5, 2011. [PUBMED Abstract]
  8. Mu E, Lange JR, Strouse JJ: Comparison of the use and results of sentinel lymph node biopsy in children and young adults with melanoma. Cancer 118 (10): 2700-7, 2012. [PUBMED Abstract]
  9. Balch CM, Soong SJ, Gershenwald JE, et al.: Age as a prognostic factor in patients with localized melanoma and regional metastases. Ann Surg Oncol 20 (12): 3961-8, 2013. [PUBMED Abstract]
  10. Gibbs P, Moore A, Robinson W, et al.: Pediatric melanoma: are recent advances in the management of adult melanoma relevant to the pediatric population. J Pediatr Hematol Oncol 22 (5): 428-32, 2000 Sep-Oct. [PUBMED Abstract]
  11. Livestro DP, Kaine EM, Michaelson JS, et al.: Melanoma in the young: differences and similarities with adult melanoma: a case-matched controlled analysis. Cancer 110 (3): 614-24, 2007. [PUBMED Abstract]
  12. Han D, Zager JS, Han G, et al.: The unique clinical characteristics of melanoma diagnosed in children. Ann Surg Oncol 19 (12): 3888-95, 2012. [PUBMED Abstract]
  13. Lorimer PD, White RL, Walsh K, et al.: Pediatric and Adolescent Melanoma: A National Cancer Data Base Update. Ann Surg Oncol 23 (12): 4058-4066, 2016. [PUBMED Abstract]
  14. Rao BN, Hayes FA, Pratt CB, et al.: Malignant melanoma in children: its management and prognosis. J Pediatr Surg 25 (2): 198-203, 1990. [PUBMED Abstract]
  15. Aldrink JH, Selim MA, Diesen DL, et al.: Pediatric melanoma: a single-institution experience of 150 patients. J Pediatr Surg 44 (8): 1514-21, 2009. [PUBMED Abstract]
  16. Tcheung WJ, Marcello JE, Puri PK, et al.: Evaluation of 39 cases of pediatric cutaneous head and neck melanoma. J Am Acad Dermatol 65 (2): e37-42, 2011. [PUBMED Abstract]
  17. Ferrari A, Bisogno G, Cecchetto G, et al.: Cutaneous melanoma in children and adolescents: the Italian rare tumors in pediatric age project experience. J Pediatr 164 (2): 376-82.e1-2, 2014. [PUBMED Abstract]
  18. Stanelle EJ, Busam KJ, Rich BS, et al.: Early-stage non-Spitzoid cutaneous melanoma in patients younger than 22 years of age at diagnosis: long-term follow-up and survival analysis. J Pediatr Surg 50 (6): 1019-23, 2015. [PUBMED Abstract]
  19. Lohmann CM, Coit DG, Brady MS, et al.: Sentinel lymph node biopsy in patients with diagnostically controversial spitzoid melanocytic tumors. Am J Surg Pathol 26 (1): 47-55, 2002. [PUBMED Abstract]
  20. Su LD, Fullen DR, Sondak VK, et al.: Sentinel lymph node biopsy for patients with problematic spitzoid melanocytic lesions: a report on 18 patients. Cancer 97 (2): 499-507, 2003. [PUBMED Abstract]

Diagnostic Evaluation

The diagnostic evaluation of melanoma includes the following:
  • Biopsy or excision. Biopsy or excision is necessary to determine the diagnosis of any skin cancer. Diagnosis is necessary for decisions regarding additional treatment. Although basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs) are generally curable with surgery alone, the treatment of melanoma requires greater consideration because of its potential for metastasis. The width of surgical margins in melanoma is dictated by the site, size, and thickness of the lesion and ranges from 0.5 cm for in situ lesions to 2 cm or more for thicker lesions.[1] To achieve negative margins in children, wide excision with skin grafting may become necessary in selected cases.
  • Lymph node evaluation. Examination of regional lymph nodes using sentinel lymph node biopsy has become routine in many centers [2,3] and is recommended in patients with lesions measuring more than 1 mm in thickness or in those whose lesions are 1 mm or less in thickness and have unfavorable features such as ulceration or mitotic rate of 1 per mm2 or higher.[2,4,5] However, the indications for this procedure in patients with spitzoid melanomas has not been clearly defined. In a systematic review of 541 patients with atypical Spitz tumors, 303 (56%) underwent sentinel lymph node biopsy and 119 (39%) had a positive sentinel node; additional lymph node dissection in 97 of these patients revealed additional positive nodes in 18 patients (19%).[6] Despite the high incidence of nodal metastases, only six patients developed disseminated disease, questioning the prognostic and therapeutic benefit of this procedure in children with these lesions. In the future, molecular markers may help identify which patients might benefit from this procedure.
    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.[7]
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).[8] 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).[10][Level of evidence: 3iiA]
References
  1. Ceballos PI, Ruiz-Maldonado R, Mihm MC: Melanoma in children. N Engl J Med 332 (10): 656-62, 1995. [PUBMED Abstract]
  2. Shah NC, Gerstle JT, Stuart M, et al.: Use of sentinel lymph node biopsy and high-dose interferon in pediatric patients with high-risk melanoma: the Hospital for Sick Children experience. J Pediatr Hematol Oncol 28 (8): 496-500, 2006. [PUBMED Abstract]
  3. Kayton ML, La Quaglia MP: Sentinel node biopsy for melanocytic tumors in children. Semin Diagn Pathol 25 (2): 95-9, 2008. [PUBMED Abstract]
  4. Ariyan CE, Coit DG: Clinical aspects of sentinel lymph node biopsy in melanoma. Semin Diagn Pathol 25 (2): 86-94, 2008. [PUBMED Abstract]
  5. Pacella SJ, Lowe L, Bradford C, et al.: The utility of sentinel lymph node biopsy in head and neck melanoma in the pediatric population. Plast Reconstr Surg 112 (5): 1257-65, 2003. [PUBMED Abstract]
  6. Lallas A, Kyrgidis A, Ferrara G, et al.: Atypical Spitz tumours and sentinel lymph node biopsy: a systematic review. Lancet Oncol 15 (4): e178-83, 2014. [PUBMED Abstract]
  7. Halalsheh H, Kaste SC, Navid F, et al.: The role of routine imaging in pediatric cutaneous melanoma. Pediatr Blood Cancer 65 (12): e27412, 2018. [PUBMED Abstract]
  8. Berk DR, LaBuz E, Dadras SS, et al.: Melanoma and melanocytic tumors of uncertain malignant potential in children, adolescents and young adults--the Stanford experience 1995-2008. Pediatr Dermatol 27 (3): 244-54, 2010 May-Jun. [PUBMED Abstract]
  9. Cerroni L, Barnhill R, Elder D, et al.: Melanocytic tumors of uncertain malignant potential: results of a tutorial held at the XXIX Symposium of the International Society of Dermatopathology in Graz, October 2008. Am J Surg Pathol 34 (3): 314-26, 2010. [PUBMED Abstract]
  10. Cordoro KM, Gupta D, Frieden IJ, et al.: Pediatric melanoma: results of a large cohort study and proposal for modified ABCD detection criteria for children. J Am Acad Dermatol 68 (6): 913-25, 2013. [PUBMED Abstract]

Molecular Features

Melanoma-related conditions with malignant potential that arise in the pediatric population can be classified into the following three general groups:[1]
  • Large/giant congenital melanocytic nevus.
  • Spitzoid melanocytic tumors ranging from atypical Spitz tumors to spitzoid melanomas.
  • Melanoma arising in older adolescents that shares characteristics with adult melanoma (i.e., conventional melanoma).
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.[1] 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.[2] 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.[3-5] 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.[6] Somatic mosaicism for NRAS Q61 mutations has also been reported in patients with multiple congenital melanocytic nevi and neuromelanosis.[7]
Table 1. Characteristics of Melanocytic Lesions
TumorAffected Gene
MelanomaBRAF, NRAS, KIT, NF1
Spitzoid melanomaKinase fusions (RET, ROS, MET, ALK, BRAF, NTRK1); BAP1 loss in the presence of BRAF mutation
Spitz nevusHRAS; BRAF and NRAS (uncommon); kinase fusions (ROS, ALK, NTRK1, BRAF, RET)
Acquired nevusBRAF
Dysplastic nevusBRAF, NRAS
Blue nevusGNAQ
Ocular melanomaGNAQ
Congenital neviNRAS
References
  1. Lu C, Zhang J, Nagahawatte P, et al.: The genomic landscape of childhood and adolescent melanoma. J Invest Dermatol 135 (3): 816-23, 2015. [PUBMED Abstract]
  2. Wilmott JS, Johansson PA, Newell F, et al.: Whole genome sequencing of melanomas in adolescent and young adults reveals distinct mutation landscapes and the potential role of germline variants in disease susceptibility. Int J Cancer 144 (5): 1049-1060, 2019. [PUBMED Abstract]
  3. Wiesner T, He J, Yelensky R, et al.: Kinase fusions are frequent in Spitz tumours and spitzoid melanomas. Nat Commun 5: 3116, 2014. [PUBMED Abstract]
  4. Lee S, Barnhill RL, Dummer R, et al.: TERT Promoter Mutations Are Predictive of Aggressive Clinical Behavior in Patients with Spitzoid Melanocytic Neoplasms. Sci Rep 5: 11200, 2015. [PUBMED Abstract]
  5. Yeh I, Botton T, Talevich E, et al.: Activating MET kinase rearrangements in melanoma and Spitz tumours. Nat Commun 6: 7174, 2015. [PUBMED Abstract]
  6. Charbel C, Fontaine RH, Malouf GG, et al.: NRAS mutation is the sole recurrent somatic mutation in large congenital melanocytic nevi. J Invest Dermatol 134 (4): 1067-74, 2014. [PUBMED Abstract]
  7. Kinsler VA, Thomas AC, Ishida M, et al.: Multiple congenital melanocytic nevi and neurocutaneous melanosis are caused by postzygotic mutations in codon 61 of NRAS. J Invest Dermatol 133 (9): 2229-36, 2013. [PUBMED Abstract]

Treatment of Childhood Melanoma

Treatment options for childhood melanoma include the following:
  1. Surgery and, in certain cases, sentinel lymph node biopsy and lymph node dissection.
  2. Immune checkpoint inhibitors or BRAF/MEK inhibitors.

Surgery

Surgery is the treatment of choice for patients with localized melanoma. Current guidelines recommend margins of resection as follows:
  • 0.5 cm for melanoma in situ.
  • 1 cm for melanoma thickness less than 1 mm.
  • 1 cm to 2 cm for melanoma thickness of 1.01 mm to 2 mm.
  • 2 cm for tumor thickness greater than 2 mm.
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.[3]

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.[4-6] 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):
  1. A phase I trial of ipilimumab in children and adolescents, which used a dose of 5 mg/kg or 10 mg/kg every 3 weeks for four cycles, enrolled 12 patients with melanoma.[7]
    • This treatment demonstrated a similar toxicity profile as that seen in adults.
  2. A phase II study of ipilimumab for adolescents with melanoma failed to achieve accrual goals and was closed; however, there was reported activity in patients with melanoma who were aged 12 years to younger than 18 years, with a similar safety profile as that seen in adults.[8][Level of evidence: 2Div]
    • At 1 year, three of four patients who received 3 mg/kg and five of eight patients who received 10 mg/kg were alive.
    • Two patients who received 10 mg/kg had partial responses, and one patient who received 3 mg/kg had stable disease.
    • In adults, ipilimumab administered at a dose of 10 mg/kg every 3 weeks for four doses followed by one dose every 3 months for up to 3 years has been shown to prolong DFS and overall survival (OS) in patients with completely resected, stage III cutaneous melanoma, with little impairment in health-related quality of life.
  3. Ipilimumab and nivolumab or nivolumab alone, as well as combinations of BRAF and MEK inhibitors for BRAF-mutant melanoma, have now become the standard of care for adult patients with advanced-stage melanoma.[3,9-12]
The studies listed below are investigating the activity of targeted BRAF inhibitors, MEK inhibitors, and PDL-1 inhibitors in pediatric patients with melanoma.[13,14]
(Refer to the PDQ summary on adult Melanoma Treatment for more information.)
References
  1. Mu E, Lange JR, Strouse JJ: Comparison of the use and results of sentinel lymph node biopsy in children and young adults with melanoma. Cancer 118 (10): 2700-7, 2012. [PUBMED Abstract]
  2. Han D, Zager JS, Han G, et al.: The unique clinical characteristics of melanoma diagnosed in children. Ann Surg Oncol 19 (12): 3888-95, 2012. [PUBMED Abstract]
  3. Eggermont AM, Chiarion-Sileni V, Grob JJ, et al.: Prolonged Survival in Stage III Melanoma with Ipilimumab Adjuvant Therapy. N Engl J Med 375 (19): 1845-1855, 2016. [PUBMED Abstract]
  4. Eggermont AMM, Blank CU, Mandala M, et al.: Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma. N Engl J Med 378 (19): 1789-1801, 2018. [PUBMED Abstract]
  5. Weber J, Mandala M, Del Vecchio M, et al.: Adjuvant Nivolumab versus Ipilimumab in Resected Stage III or IV Melanoma. N Engl J Med 377 (19): 1824-1835, 2017. [PUBMED Abstract]
  6. Long GV, Hauschild A, Santinami M, et al.: Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma. N Engl J Med 377 (19): 1813-1823, 2017. [PUBMED Abstract]
  7. Merchant MS, Wright M, Baird K, et al.: Phase I Clinical Trial of Ipilimumab in Pediatric Patients with Advanced Solid Tumors. Clin Cancer Res 22 (6): 1364-70, 2016. [PUBMED Abstract]
  8. Geoerger B, Bergeron C, Gore L, et al.: Phase II study of ipilimumab in adolescents with unresectable stage III or IV malignant melanoma. Eur J Cancer 86: 358-363, 2017. [PUBMED Abstract]
  9. Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al.: Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. N Engl J Med 377 (14): 1345-1356, 2017. [PUBMED Abstract]
  10. Dummer R, Ascierto PA, Gogas HJ, et al.: Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol 19 (5): 603-615, 2018. [PUBMED Abstract]
  11. Davies MA, Saiag P, Robert C, et al.: Dabrafenib plus trametinib in patients with BRAFV600-mutant melanoma brain metastases (COMBI-MB): a multicentre, multicohort, open-label, phase 2 trial. Lancet Oncol 18 (7): 863-873, 2017. [PUBMED Abstract]
  12. Coens C, Suciu S, Chiarion-Sileni V, et al.: Health-related quality of life with adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): secondary outcomes of a multinational, randomised, double-blind, phase 3 trial. Lancet Oncol 18 (3): 393-403, 2017. [PUBMED Abstract]
  13. Chapman PB, Hauschild A, Robert C, et al.: Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 364 (26): 2507-16, 2011. [PUBMED Abstract]
  14. Hodi FS, O'Day SJ, McDermott DF, et al.: Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363 (8): 711-23, 2010. [PUBMED Abstract]

Treatment Options Under Clinical Evaluation for Childhood Melanoma

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:
  • APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using a next-generation sequencing targeted assay of more than 4,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.
    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.
  • NCT02332668 (A Study of Pembrolizumab [MK-3475] in Pediatric Participants With Advanced Melanoma or Advanced, Relapsed, or Refractory PD-L1-Positive Solid Tumors or Lymphoma [MK-3475-051/KEYNOTE-051]): This is a two-part study of pembrolizumab in pediatric participants who have either advanced melanoma or a programmed cell death ligand 1 (PDL1)-positive advanced, relapsed, or refractory solid tumor or lymphoma. Part 1 will find the maximum tolerated dose/maximum administered dose, confirm the dose, and find the recommended phase II dose for pembrolizumab therapy. Part 2 will further evaluate the safety and efficacy at the pediatric recommended phase II dose.
  • NCT02304458 (Nivolumab With or Without Ipilimumab in Treating Younger Patients With Recurrent or Refractory Solid Tumors or Sarcomas): This trial is evaluating the side effects and best dose of nivolumab when given with or without ipilimumab to see how well they work in treating younger patients with solid tumors.
  • NCT01677741 (A Study to Determine Safety, Tolerability, and Pharmacokinetics of Oral Dabrafenib In Children and Adolescent Subjects): This is a two-part study to determine the safety, tolerability, and pharmacokinetics of oral dabrafenib in children and adolescent patients with advanced BRAF V600 mutation–positive solid tumors. Part 1 will identify the recommended dose and regimen using a dose-escalation procedure. Part 2 will treat four disease-specific cohorts of patients with tumors known to have BRAF V600 activation (pediatric low-grade gliomas, pediatric high-grade gliomas, Langerhans cell histiocytosis, and other tumors such as melanoma and papillary thyroid carcinoma) using the dose and regimen determined in part 1.

Special Considerations for the Treatment of Children With Cancer

Cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975.[1] 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:
  • Primary care physicians.
  • Pediatric surgeons.
  • Radiation oncologists.
  • Pediatric medical oncologists/hematologists.
  • Rehabilitation specialists.
  • Pediatric nurse specialists.
  • Social workers.
  • Child-life professionals.
  • Psychologists.
(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.[2] 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%.[3] 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.[4] 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:
  • The Italian cooperative project on rare pediatric tumors (Tumori Rari in Eta Pediatrica [TREP]) defines a pediatric rare tumor as one with an incidence of less than two cases per 1 million population per year and is not included in other clinical trials.[7]
  • The Children's Oncology Group has opted to define rare pediatric cancers as those listed in the International Classification of Childhood Cancer subgroup XI, which includes thyroid cancer, melanoma and nonmelanoma skin cancers, and multiple types of carcinomas (e.g., adrenocortical carcinoma, nasopharyngeal carcinoma, and most adult-type carcinomas such as breast cancer, colorectal cancer, etc.).[8] These diagnoses account for about 4% of cancers diagnosed in children aged 0 to 14 years, compared with about 20% of cancers diagnosed in adolescents aged 15 to 19 years.[9]
    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.
References
  1. Smith MA, Seibel NL, Altekruse SF, et al.: Outcomes for children and adolescents with cancer: challenges for the twenty-first century. J Clin Oncol 28 (15): 2625-34, 2010. [PUBMED Abstract]
  2. Corrigan JJ, Feig SA; American Academy of Pediatrics: Guidelines for pediatric cancer centers. Pediatrics 113 (6): 1833-5, 2004. [PUBMED Abstract]
  3. Smith MA, Altekruse SF, Adamson PC, et al.: Declining childhood and adolescent cancer mortality. Cancer 120 (16): 2497-506, 2014. [PUBMED Abstract]
  4. Ward E, DeSantis C, Robbins A, et al.: Childhood and adolescent cancer statistics, 2014. CA Cancer J Clin 64 (2): 83-103, 2014 Mar-Apr. [PUBMED Abstract]
  5. Gatta G, Capocaccia R, Botta L, et al.: Burden and centralised treatment in Europe of rare tumours: results of RARECAREnet-a population-based study. Lancet Oncol 18 (8): 1022-1039, 2017. [PUBMED Abstract]
  6. DeSantis CE, Kramer JL, Jemal A: The burden of rare cancers in the United States. CA Cancer J Clin 67 (4): 261-272, 2017. [PUBMED Abstract]
  7. Ferrari A, Bisogno G, De Salvo GL, et al.: The challenge of very rare tumours in childhood: the Italian TREP project. Eur J Cancer 43 (4): 654-9, 2007. [PUBMED Abstract]
  8. Pappo AS, Krailo M, Chen Z, et al.: Infrequent tumor initiative of the Children's Oncology Group: initial lessons learned and their impact on future plans. J Clin Oncol 28 (33): 5011-6, 2010. [PUBMED Abstract]
  9. Howlader N, Noone AM, Krapcho M, et al., eds.: SEER Cancer Statistics Review, 1975-2012. Bethesda, Md: National Cancer Institute, 2015. Also available online. Last accessed December 10, 2019.

Changes to This Summary (12/23/2019)

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.
This is a new 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.

About This PDQ Summary

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:
  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.
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:
  • Denise Adams, MD (Children's Hospital Boston)
  • Karen J. Marcus, MD, FACR (Dana-Farber Cancer Institute/Boston Children's Hospital)
  • Paul A. Meyers, MD (Memorial Sloan-Kettering Cancer Center)
  • Thomas A. Olson, MD (Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta - Egleston Campus)
  • Alberto S. Pappo, MD (St. Jude Children's Research Hospital)
  • Arthur Kim Ritchey, MD (Children's Hospital of Pittsburgh of UPMC)
  • Carlos Rodriguez-Galindo, MD (St. Jude Children's Research Hospital)
  • Stephen J. Shochat, MD (St. Jude Children's Research Hospital)
Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

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.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”
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>.
Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

Disclaimer

Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

Contact Us

More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s Email Us.
  • Updated: 
Publicado por en

No hay comentarios:

Publicar un comentario

Suscribirse a: Enviar comentarios (Atom)