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Original Article
Prognostic Factors for Melanoma in Children and Adolescents A Clinicopathologic, Single-Center Study of 137 Patients Ā“ ndez, MD, PhD2; Sara M. Kantrow, MD3; Sabela Paradela, MD1; Eduardo Fonseca, MD, PhD1; Salvador Pita-Ferna Abdul H. Diwan, MD, PhD4; Cynthia Herzog, MD5; and Victor G. Prieto, MD, PhD4
BACKGROUND: Cutaneous melanoma in childhood is rare; therefore, its prognostic factors and biologic behavior and the effectiveness of adjuvant diagnostic techniques in this group remain mostly unknown. METHODS: The authors conducted a retrospective, observational study on the prognostic significance of clinical and pathologic findings from 137 cutaneous and mucosal melanomas in patients aged 10 years, previous nonmelanocytic malignancy, high Breslow thickness, high Clark level, and the presence of metastases at diagnosis. All patients who died were aged 11 years, and 8 of those patients had metastases at diagnosis. In multivariate analysis, higher Breslow thickness predicted an increased risk of metastases, whereas age >10 years and the presence of metastases at diagnosis were associated with decreased survival. CONCLUSIONS: Similar to adults, the detection of metastases at diagnosis in children with melanoma was 1 of the main factors that influenced overall survival. Melanomas that were detected in children aged 30)
Melanoma in Children/Paradela et al
of melanoma in young patients, all deaths occurred after age 12 years. In a multicenter study of 354 patients aged 100 nevi and a 15-fold increased risk in patients who had 10 large nevi.31 There were numerous nevi in 21% of our patients. Patients with inherited immunodeficiency have a 3fold to 6-fold increased risk for developing melanoma,32 and that increased risk is 4-fold in organ transplantation recipients. In the current series, 1 patient had an immuno-
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deficiency, and another patient had received immunosuppressive therapy. Survivors of childhood cancer have a relative risk of 14.8 of developing a second neoplasm,33 and there seems to be a link between previous malignancies and melanoma.34 In our current series, 2 patients had previous malignancies. Some authors have observed that melanomas tend to be deeper and indicate a poor prognosis in patients who have other malignancies,34 and those investigators have proposed that tumor-related immunodeficiency mechanisms mediated by the neoplasm itself are the cause.34 All of these findings encourage prompt diagnostic and therapeutic interventions in children who have neoplasm or immunosuppression and pigmented lesions.30 Histologic Features Although nodular melanoma was the predominant type in some reports,16,35 in our series, as in several others,10,11,24,25,36,37 superficial spreading melanoma was the most common type. Nodular histology has been related to worse survival in children.21 We detected a greater frequency of metastasis in this group, probably related to a greater Breslow thickness. However, this association was not significant in multivariate analysis or in the analysis of overall survival. A high percentage of reported childhood and adolescent melanomas are relatively thick, possibly because of delayed suspicion of malignancy.14,38,39 In comparisons between adult melanomas and pediatric melanomas,36 the latter tumors were significantly thicker. Like what we observed in the current series, analyses of 2 national cancer databases21,39 revealed that young adults and older teenagers had thinner lesions than children ages 1 to 14 years. When this factor was analyzed, thicker melanoma in children portended a significantly poor prognosis.24,39 Lymph node metastases were detected in up to 66% of children with Clark level IV and V disease or melanomas >1.5 mm thick.40 Conversely, metastases or recurrences were unusual in patients who had melanomas 1 mm reported in adults.6,52,53 In our series, the rate of positivity approached 40% (Table 1). Given the small number of patients, it is unclear whether these findings reflect the higher mean tumor depth38 or are related to an inverse correlation between positive SLNB and age.46 In contrast to findings in adults, we observed that a positive SLNB was not associated significantly with additional positive lymph nodes identified at therapeutic lymph node dissection (10%)41,48,50,51 or with a greater risk of death.37 Similar to other reports,18 we observed a higher SLNB-positive rate in patients aged 10 years (probably related to greater Breslow thickness), although the prognosis for survival was worse in the older group. Some authors have suggested that the better prognosis for children with a positive SLNB may be because of age-related changes in lymphatic flow density and the immune system, which is able to clear micrometastases.54 Long-term follow-up studies will be necessary to determine whether the prognostic value of SLNB in children is different from that in adults. In summary, we studied our single-institution experience in a large series of primary melanomas in children. Age >10 years, high Breslow thickness, and presence of metastasis at diagnosis were associated with an impaired prognosis, whereas patients who had disease associated with a nevus appeared to have a better prognosis. We emphasize that children aged 10 years had better survival despite having thicker tumors and a higher SLNBpositive rate; this may have been caused by the influence of sexual maturity on the biologic tumor behavior.
CONFLICT OF INTEREST DISCLOSURES The authors made no disclosures.
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Melanoma in Children/Paradela et al
REFERENCES 1. World Health Organization, International Agency for Research on Cancer, International Association of Cancer Registries. Melanoma. In: Parkin DM, Kramarova E, Draper GJ, et al., eds. International Incidence of Childhood Cancer, vol II. IARC Scientific Publication No. 144. Lyon, France: IARC; 1998; 43-444. 2. Ries LAG, Smith MA, Gurney JG, et al., eds. Cancer Incidence and Survival Among Children and Adolescents: United States SEER Program 1975-1995, National Cancer Institute, SEER Program. NIH Publ. Mo. 99-4649. Bethesda, Md, National Cancer Institute, SEER Program; 1999. 3. Guidelines for Melanoma. Available at: http://utmext01a.mdacc.tmc.edu/mda/cm/CWTGuide.nsf/LuHTML/ SideBar1?OpenDocument. Accessed September 1, 2008 (last updated February 24, 2009). 4. Paradela S, Fonseca E, Pita S, et al. Spitzoid melanoma in children: clinico-pathologic study and application of immunohistochemistry as an adjunct diagnostic tool. J Cutan Pathol. 2009;36:740-752. 5. Paradela S, Fonseca E, Pita-Fernandez S, et al. Melanoma under 18 years and pregnancy: report of three cases. Eur J Dermatol. 2010;20:186-188. 6. Prieto VG, Clark SH. Processing of sentinel lymph nodes for detection of metastatic melanoma. Ann Diagn Pathol. 2002;6:257-264. 7. Gershenwald JE, Andtbacka RH, Prieto VG, et al. Microscopic tumor burden in sentinel lymph nodes predicts synchronous nonsentinel lymph node involvement in patients with melanoma. J Clin Oncol. 2008;26:4296-4303. 8. Balch CM, Buzaid AC, Soong SJ, et al. Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol. 2001;19:3635-3648. 9. Trozak DJ, Rowland WD, Hu F. Metastatic malignant melanoma in prepubertal children. Pediatrics. 1975;55:191-204. 10. Davidoff AM, Cirrincione C, Seigler HF. Malignant melanoma in children. Ann Surg Oncol. 1994;1:278-282. 11. Spatz A, Ruiter D, Hardmeier T, Renard N, Wechsler J, Bailly C. Melanoma in childhood: an EORTC-MCG multicenter study on the clinico-pathological aspects. Int J Cancer. 1996;68:317-324. 12. Naasan A, al-Nafussi A, Quaba A. Cutaneous malignant melanoma in children and adolescents in Scotland, 19791991. Plast Reconstr Surg. 1996;98:442-446. 13. Karlsson P, Boeryd B, Sander B, et al. Increasing incidence of cutaneous malignant melanoma in children and adolescents 12-19 years of age in Sweden 1973-92. Acta Derm Venereol. 1998;78:289-292. 14. Saenz NC, Saenz-Badillos J, Busam K, et al. Childhood melanoma survival. Cancer. 1999;85:750-754. 15. Schmid-Wendtner MH, Berking C, Baumert J, et al. Cutaneous melanoma in childhood and adolescence: an analysis of 36 patients. J Am Acad Dermatol. 2002;46:874-879. 16. de Sa BC, Rezze GG, Scramim AP, et al. Cutaneous melanoma in childhood and adolescence: retrospective study of 32 patients. Melanoma Res. 2004;14:487-492. 17. Ferrari A, Bono A, Baldi M, et al. Does melanoma behave differently in younger children than in adults? A retrospective study of 33 cases of childhood melanoma from a single institution. Pediatrics. 2005;115:649-654. 18. Howman-Giles R, Shaw HM, Scolyer RA, et al. Sentinel lymph node biopsy in pediatric and adolescent cutaneous melanoma patients. Ann Surg Oncol. 2010;17:138-143.
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September 15, 2010
19. Lewis KG. Trends in pediatric melanoma mortality in the United States, 1968 through 2004. Dermatol Surg. 2008; 34:152-159. 20. Conti EM, Cercato MC, Gatta G, et al; EUROCARE Working Group. Childhood melanoma in Europe since 1978: a population-based survival study. Eur J Cancer. 2001;37:780-784. 21. 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. 2005;23:4735-4741. 22. de Vries E, Steliarova-Foucher E, Spatz A, et al. Skin cancer incidence and survival in European children and adolescents (1978-1997). Report from the Automated Childhood Cancer Information System project. Eur J Cancer. 2006;42: 2170-2182. 23. Berg P, Lindelof B. Differences in malignant melanoma between children and adolescents. A 35-year epidemiological study. Arch Dermatol. 1997;133:295-297. 24. Crotty KA, McCarthy SW, Palmer AA, et al. Malignant melanoma in childhood: a clinicopathologic study of 13 cases and comparison with Spitz nevi. World J Surg. 1992; 16:179-185. 25. Sander B, Karlsson P, Rosdahl I, et al. Cutaneous malignant melanoma in Swedish children and teenagers 1973-1992: a clinico-pathological study of 130 cases. Int J Cancer. 1999; 80:646-651. 26. Busam KJ, Murali R, Pulitzer M, et al. Atypical spitzoid melanocytic tumors with positive sentinel lymph nodes in children and teenagers, and comparison with histologically unambiguous and lethal melanomas. Am J Surg Pathol. 2009;33:1386-1395. 27. Paradela S, Fernandez-Torres R, Fonseca E. Controversias en el nevus congenito. Actas Dermosifiliogr. 2009;100:548-561. 28. Hoang MT, Friedlander SF. Rare cutaneous malignancies of childhood. Curr Opin Pediatr. 1999;11:464-470. 29. Berg P, Wennberg AM, Tuominen R, et al. Germline CDKN2A mutations are rare in child and adolescent cutaneous melanoma. Melanoma Res. 2004;14:251-255. 30. Pappo AS. Melanoma in children and adolescents. Eur J Cancer. 2003;39:2651-2661. 31. Youl P, Aitken J, Hayward N, et al. Melanoma in adolescents: a case-control study of risk factors in Queensland, Australia. Int J Cancer. 2002;98:92-98. 32. Lefkowitz A, Schwartz RA, Janniger CK. Melanoma precursors in children. Cutis. 1999;63:321-324. 33. Oeffinger KC, Mertens AC, Sklar CA, et al. Cancer Survivor Study. Chronic health conditions in adult survivors of childhood cancer. N Engl J Med. 2006;355:1572-1582. 34. McKenna DB, Doherty VR, McLaren KM, et al. Malignant melanoma and lymphoproliferative malignancy: is there a shared aetiology? Br J Dermatol. 2000;143:171-173. 35. Handfield-Jones SE, Smith NP. Malignant melanoma in childhood. Br J Dermatol. 1996;134:607-616. 36. Ceballos PI, Ruiz-Maldonado R, Mihm MC Jr. Melanoma in children. N Engl J Med. 1995;332:656-662. 37. Livestro DP, Kaine EM, Michaelson JS, et al. Melanoma in the young: differences and similarities with adult melanoma: a case-matched controlled analysis. Cancer. 2007;110:614624. 38. Rao BN, Hayes FA, Pratt CB, et al. Malignant melanoma in children: its management and prognosis. J Pediatr Surg. 1990;25:198-203.
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Original Article 39. Lange JR, Palis BE, Chang DC, Soong SJ, Balch CM. Melanoma in children and teenagers: an analysis of patients from the National Cancer Data Base. J Clin Oncol. 2007; 25:1363-1368. 40. Moss AL, Briggs JC. Cutaneous malignant melanoma in the young. Br J Plast Surg. 1986;39:537-541. 41. Kaddu S, Smolle J, Zenahlik P, et al. Melanoma with benign melanocytic naevus components: reappraisal of clinicopathological features and prognosis. Melanoma Res. 2002;12:271-278. 42. Pappo AS, Kuttesch JF, Kaste SC, et al. Malignant melanocytic lesions of unknown primary site in children and adolescents. Med Pediatr Oncol. 1995;24:315-320. 43. Mills O, Messina JL. Pediatric melanoma: a review. Cancer Control. 2009;16:225-233. 44. Downard CD, Rapkin LB, Gow KW. Melanoma in children and adolescents. Surg Oncol. 2007;16:215-220. 45. Navid F, Furman WL, Fleming M, et al. The feasibility of adjuvant interferon alpha-2b in children with high-risk melanoma. Cancer. 2005;103:780-787. 46. Chao C, Martin RC 2nd, Ross MI, et al. Correlation between prognostic factors and increasing age in melanoma. Ann Surg Oncol. 2004;11:259-264. 47. Shah NC, Gerstle JT, Stuart M, Winter C, Pappo A. 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. 2006;28: 496-500.
4344
48. Topar G, Zelger B. Assessment of value of the sentinel lymph node biopsy in melanoma in children and adolescents and applicability of subcutaneous infusion anesthesia. J Pediatr Surg. 2007;42:1716-1720. 49. Kayton ML, La Quaglia MP. Sentinel node biopsy for melanocytic tumors in children. Semin Diagn Pathol 25:95-99, 2008 May. 50. Toro J, Ranieri JM, Havlik RJ, Coleman JJ 3rd, Wagner JD. Sentinel lymph node biopsy in children and adolescents with malignant melanoma. J Pediatr Surg. 2003;38:10631065. 51. Roaten JB, Partrick DA, Bensard D, et al. Survival in sentinel lymph node-positive pediatric melanoma. J Pediatr Surg. 2005;40:988-992. 52. Dessureault S, Soong SJ, Ross MI, et al. American Joint Committee on Cancer (AJCC) Melanoma Staging Committee. Improved staging of node-negative patients with intermediate to thick melanomas (>1 mm) with the use of lymphatic mapping and sentinel lymph node biopsy. Ann Surg Oncol. 2001;8:766-770. 53. Balch CM, Soong SJ, Gershenwald JE, et al. Prognostic factor analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol. 2001;19:3622-3634. 54. Ra JH, McMasters KM, Spitz FR. Should all melanoma patients undergo sentinel lymph node biopsy? Curr Opin Oncol. 2006;18:185-188.
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