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Malignant melanoma in childhood and adolescence: Report of 13 cases
Malignant melanoma in childhood and adolescence: Report of 13 cases Fatemeh Jafarian, MD,a Julie Powell, MD, FRCPC,a Victor Kokta, MD, FRCPC,c Martin Champagne, MD, FRCPC,b Afshin Hatami, MD, FRCPC,a Catherine McCuaig, MD, FRCPC,a Danielle Marcoux, MD, FRCPC,a and Pascal Savard, MD, FRCPCa Montreal, Quebec, Canada We reviewed all cases of malignant melanoma in children younger than 17 years of age who were evaluated at Sainte Justine Hospital, a tertiary care pediatric center, between 1980 and 2002. The medical records and histologic features of all cases were reviewed. Thirteen cases were identified, 4 boys and 9 girls. Fifty-three percent of patients were prepubescent. None of the patients had a predisposing condition (eg, giant congenital nevi, dysplastic nevus syndrome, or xeroderma pigmentosum). One patient had had chemoradiotherapy previously for an undifferentiated pleuropulmonary malignant tumor (blastoma) and another patient had Down syndrome. The most frequent reason for initial consultation was a recent increase in size of the lesion. Three patients had pyogenic granulomaelike lesions. Eighty-five percent of the observed melanomas were nodular in type. Tumor thickness ranged from 0 to 6 mm with a median and mean thickness of 2.8 and 3.2 mm, respectively. The overall 5-year survival rate was 58.8%. Lack of awareness and delay in diagnosis may lead to a higher incidence of thick and intermediate melanoma in children. Because it appears that the majority of melanomas in childhood and adolescence occur de novo, clinicians should consider this condition in the differential diagnosis of any suspect lesion in children and adolescents even without an identified predisposing factor. ( J Am Acad Dermatol 2005;53:816-22.)
M
elanoma is considered an uncommon entity in children and adolescents. Only 2% of melanomas occur in patients younger than 20 years1 and 0.3% to 0.4% occur in prepubertal children.2,3 It accounts for 3% of malignancies in patients younger than 20 years.4 As the overall incidence of melanoma is increasing worldwide,5,6 it is expected that the incidence of childhood and adolescence melanoma will follow.7 Childhood and adolescent melanoma is considered more prevalent From the Department of Pediatrics, Divisions of Dermatologya and Hemato-oncology,b and the Department of Pathology,c SainteJustine Hospital, University of Montreal. Funding sources: Dr Jafarian’s fellowship has been supported by an unrestricted educational grant from Fujisawa Canada. Conflicts of interest: None identified. Presented in part at the 78th Annual Meeting of the Canadian Dermatology Association, Ottawa, Canada, 2003, and at the 10th World Congress of Pediatric Dermatology, Rome, Italy, 2004. Accepted for publication July 5, 2005. Reprints not available from the authors. Correspondence to: Julie Powell, MD, Sainte Justine Hospital, 3175 chemin coˆte Sainte Catherine, Montreal, Que´bec, Canada H3T 1C5. E-mail: [email protected]. Published online October 4, 2005. 0190-9622/$30.00 ª 2005 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2005.07.013
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in certain groups, such as patients with giant congenital nevi,8,9 xeroderma pigmentosum,10,11 immunosuppression,12 and dysplastic nevus syndrome.13 As a result, most physicians are more concerned about malignant changes in these patients and less inclined to suspect malignant melanoma in patients without known predisposing factors. Reluctance to put a diagnosis of malignant melanoma in this age group could also be in part due to the fact that most acquired melanocytic nevi and Spitz nevi develop during childhood and adolescence. In this study, we report 13 cases of malignant melanoma in patients 17 years of age or younger. Emphasis is given to clinical characteristics, pathologic features, and outcomes.
MATERIAL AND METHODS A retrospective chart review was performed of all patients younger than 17 years old who had a diagnosis of skin or mucous membrane melanoma identified in Sainte Justine Hospital’s archives database from 1980 to 2002. This information was crosschecked with the oncology clinic database and the pathology database. Histologic slides of these patients were reviewed by one of the authors (V. K.). Histologic review led to reclassification of one case as Spitz nevus and its exclusion from the study. Cases with no histologic material available for review
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and/or with an unconfirmed diagnosis were also excluded. Therefore 13 cases of malignant melanoma were retrieved for our study. The following pathologic parameters were evaluated: histologic classification, tumor thickness (Breslow method), Clark’s anatomical level of invasion, ulceration, vascular invasion, lymphatic invasion, regression, and number of mitoses per square millimeter. Tumors with Breslow depth of less than 1 mm were considered thin melanomas, those between 1 and 1.5 mm were defined as intermediate, and those more than 1.5 mm as thick melanomas. Medical records were reviewed for ethnic origin, sex, age at diagnosis, anatomic location, and clinical description of the primary tumor, association with congenital nevi, and predisposing conditions. The most recent follow-up data were obtained from either clinical notes or telephone interviews with patients or their parents. All patients were staged with the use of the American Joint Committee on Cancer staging classification.14 Work-up for staging purposes included medical history; physical examination; complete blood cell count; liver function tests; lactate dehydrogenase level; chest x-ray; regional lymph node and abdominal ultrasonography; radionuclide scan of bone, liver, and spleen; computed tomographicscanning of abdomen, chest, and brain; and sentinel lymph node biopsy. Some methods were not used in all patients. Life-table analysis was used to determine 5-year survival.
RESULTS The main clinical characteristics are shown in Table I. The patients consisted of 4 boys and 9 girls. Twelve patients were Caucasian; one patient was of mixed African Caucasian ethnic origin. Seven patients were younger than 10 years and 6 were 10 to 16 years of age at diagnosis. We did not have sufficient data about the pubertal status of these patients, so we arbitrarily considered the first group to be prepubertal children. Primary melanomas were found in different body sites. Five lesions were on the trunk, 4 on the legs, 2 on the foot, and 1 on the forearm. In one patient, the primary site of melanoma was the oral mucosa. The most common primary site in boys was the trunk. The melanomas in girls were most frequently located on the trunk and legs. None of our 13 patients had a documented family history of dysplastic nevus syndrome or melanoma, but one had a family history of prostate and liver carcinoma in first- and second-degree relatives. None of our cases were associated with giant congenital melanocytic nevi, dysplastic nevus syndrome, or xeroderma pigmentosum. In two patients,
melanoma arose in small congenital nevi, according to the history obtained from parents. One of our patients had a previous history of chemoradiotherapy for a malignant undifferentiated pleuropulmonary blastoma 1 year before the melanoma was diagnosed. However, this patient did not develop melanoma in a zone of previous radiotherapy. One of our patients had Down syndrome. Eighty-five percent of patients (11/13) described one or more symptoms directly related to the lesion. The most common symptom was recent growth of the lesion (n = 10). The other presentations included pain (n = 1), ulceration (n = 2), itching (n = 1), bleeding (n = 3), and change in color (n = 2). Three patients had pyogenic granulomaelike lesions. One patient was diagnosed after an incidental excision of a pigmented lesion during an orthopedic surgical procedure. One patient had massive cervical lymphadenopathy. No photograph was available of any of those lesions. Histologic classification of the melanomas was nodular in 11 cases and superficial spreading in two cases. Spitzoid features were cited in 7 cases of nodular melanoma. There were no cases of lentigo maligna or acral lentiginous melanoma. Tumor thickness in our cases ranged from 0 to 6 mm, with a median and mean of 2.8 and 3.2 mm, respectively. No associated congenital nevi were identified histopathologically, including the two cases reported by parents to be congenital. Pathologic features of the melanomas are shown in Table II. Three of our patients underwent sentinel node biopsy (cases 3, 5, 10). Sentinel node metastasis was detected in one patient (case 3); the other two patients had a negative sentinel lymph node. However, one of these patients developed regional lymph node and widespread metastasis 9 months later (case 10). Primary treatment of 12 patients included wide local excision of their primary lesions. One patient (case 7) had an unresectable mucosal melanoma of the mouth and chemotherapy was given without local excision. In addition to local treatment, patients with regional lymph node involvement at presentation or on follow-up underwent regional lymph node dissection and received chemotherapy. Three patients who developed metastasis (cases 2,10,11) after regional lymph node involvement were given complementary chemotherapy. Eleven patients had localized disease (stage 0 to IIc) at the time of presentation. The other two patients were considered to have stage III disease. One of these patients had positive findings from sentinel node biopsy. He underwent regional lymph node dissection, which did not reveal any additional
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Table I. Clinical characteristics of patients with malignant melanoma Case no.
Age (y)/ sex
Site
Stage
Treatment
Follow-up (mo)/status
SE SE, LND, Chemo SE, LND, Chemo
152/Alive 14/Dead 15/Alive
SE SE, Chemo SE Chemo
16/Alive 7/Alive 219/Alive 10/Dead
SE
22/Alive
Metastasis
1 2 3
2/M 9/F 4/M
Foot Trunk Leg
IIC IIA III
4 5 6 7
9/F 4/F 6/F 8/F
Trunk Foot Forearm Oral mucosa
0 IIC IIA III
8
11/F
Leg
IA
No Axillary LNM after 6 mo Regional sentinel node metastasis at diagnosis No No No Cervical LNM at diagnosis No
9 10 11 12
11/F 14/F 16/F 12/M
Leg Trunk Leg Trunk
IIA IIB IIA IIB
No Axillary LNM after 9 mo Inguinal LNM after 12 mo Axillary LNM after 7 mo
SE SE, LND, Chemo SE, LND, Chemo SE, LND, Chemo
137/Alive 26/Dead 39/Dead 92/Alive
13
12/M
Trunk
IIB
No
SE
159/Alive
Comments
SCMN association
FH of prostate and liver carcinoma PH of pleuropulmonary blastoma Down syndrome SCMN association Second primary melanoma 4 y after first one
Chemo, Chemotherapy; F, female; FH, family history; LND, lymph node dissection; LNM, lymph node metastasis; M, male; PH, past history; SCMN, small congenital melanocytic nevus; SE, surgical excision.
involvement. He remains free of disease at 15 months (case 3). The second patient (case 7) was an 8-yearold girl with massive cervical lymphadenopathy. The primary site of melanoma was the oral mucosa. Generalized metastases developed 8 months later, and she died 10 months after the initial diagnosis. Follow-up ranged from 7 to 219 months, with a median of 26 months. The 5-year survival rate was 58.8%. Four patients with localized disease at presentation had disease progression. Three of these patients (cases 2, 10, 11) died. Regional lymph node involvement and then widespread metastases developed. In one patient (case 12) axillary lymph node metastasis developed 7 months after diagnosis. At that time, he underwent lymph node dissection and chemotherapy. A second primary melanoma developed 4 years later, which was surgically excised (melanoma in situ). This patient did not have any further disease progression during a follow-up period of 92 months.
DISCUSSION Although prepubertal melanoma is rare2,3 and melanoma is more common in adolescents,2 in our series 53% of patients were younger than 10 years. We found a female preponderance of 69% in our cases. This female predominance in sex distribution is in accordance with previous case series.15-17 However,
a recent composite study of 503 patients younger than 20 years revealed no sex predilection.18 Clinical symptoms indicative of malignant melanoma in children and adolescents are rapid increase in lesion size, bleeding, color change, pruritus, irregularity of border and pigment distribution, and enlargement of regional lymph nodes.19-21 In our series, the most frequent symptom was increase in lesion size. The infrequency of asymmetry, border irregularity, and color change are in accordance with the findings of Handfield-Jones and Smith.22 As in their series, this could be attributed to the small number of superficial spreading melanomas in our cases. Three of our patients (20%) presented with a pyogenic granulomaelike lesion. This presentation has also been reported in other case series.22,23 Therefore malignant melanoma should be considered in the differential diagnosis of pyogenic granuloma in children. Giant congenital melanocytic nevi (GCMN) are considered to be potential precursors of melanoma.8,9 Watt, Kotsis, and Chung,24 in a systematic analysis of data from existing literature, found that, in 2.8% of patients with GCMN, malignant melanoma developed during the reported follow-up periods. However, data about the frequency with which pediatric malignant melanoma is associated with GCMN are conflicting. In two early literature-based
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Table II. Pathological features of melanomas Case no.
Histologic type
Clark level
Breslow depth (mm)
Ulceration
Vascular invasion
Lymphatic invasion
Regression
Mitosis (/mm2)
1 2 3 4 5 6 7 8 9 10 11 12 13
NM (SF) NM (SF) NM (SF) SSM NM (SF) NM NM (SF) SSM NM (SF) NM NM (SF) NM NM
V IV IV I IV III V III IV IV IV IV IV
4.8 1.55 4.7 0 6 1.4 6 0.8 3.6 5.58 2.3 2.8 2.5
1 1 e e 1 1 1 N/A e e e 1 1
e e e e e 1 e e e e e e e
e 1 e e e 1 e N/A e e 1 1 1
e e e e e N/A e e e e e e e
6 12 2 e 3 1 25 2 1 3 12 10 10.5
N/A, Not available; NM, nodular melanoma; SF, spitzoid feature; SSM, superficial spreading melanoma.
surveys, Skov-Jensen, Hastrup, and Lambrethesen25 and Trozak, Rowland, and Hu26 reported that one third of childhood melanomas arise within GCMN. In a more recent review, Williams and Pennella18 concluded that only 3% of reported childhood melanomas occurred in giant congenital nevi. They attributed this marked difference in the proportion of melanoma arising within GCMN to elimination of the bias of literature reports in their study. Melanomas associated with GCMN can develop at any age but usually occur during the first decade of life. Because melanoma in GCMN might arise in deep cutaneous or subcutaneous levels, its early diagnosis could be difficult.27,28 Therefore many authors recommend early and total prophylactic excision of these nevi.28,29 However, deep infiltration of fascia or muscle with nevus cells28,30 suggests that removal of the skin lesion could not completely eliminate the melanoma risk in these patients. Estimates of risk of malignant melanoma arising within small congenital melanocytic nevi (SCMN) vary greatly. Some studies suggest that there may not be a clinically significant increased risk for melanoma in SCMN,31 whereas several series noted that a substantial percentage of melanomas were associated with SCMN, mostly after puberty.32-34 In contrast to GCMN, melanoma in SCMN usually arises at the dermoepidermal junction, making its early diagnosis much easier.33 Because SCMN occur in 1% to 2% of newborns,35 systematic removal of these lesions may not be feasible. Therefore periodic clinical surveillance seems a better alternative in the management of these lesions.36-38 None of our patients had GCMN. According to the parents, melanoma originated from SCMN in two patients. However, histopathologic examination of these tumors did not reveal any evidence of associ-
ated nevus. This could be attributed either to recall bias by the parents or obliteration of nevus cells by melanoma.39 Malignant melanoma may also arise de novo or from an acquired melanocytic nevus. Caro and Bronstein40 have stated: ‘‘Because a malignant melanoma may remain quiescent for long periods of time, the clinical identification of a pre-existing lesion as an [acquired] nevus is subject to error since such a lesion may have been a melanoma from its inception.’’ None of our cases had confirmed association with congenital nevi. This is in accordance with the findings of many other authors.41,42 Therefore, although there is evidence that the risk of melanoma in patients with congenital nevi is higher than in the unaffected population, the majority of melanomas occur de novo. Suspect changes in lesions other than congenital nevi might be a sign of melanoma and should be recognized early to prevent disease progression. Dysplastic nevus syndrome,13 xeroderma pigmentosum,10,11 and immunodeficiency12 are considered to be predisposing conditions for the development of malignant melanoma in childhood and adolescence. None of our patients had dysplastic nevus syndrome or xeroderma pigmentosum. One of our patients had a history of malignant undifferentiated pleuropulmonary neoplasm, possibly blastoma treated with chemotherapy and regional radiotherapy 1 year before the diagnosis of melanoma. One year after successful surgical treatment of her melanoma, this patient developed nonlymphoblastic acute leukemia, which was treated with bone marrow transplantation. The immune system function is important in the development of melanoma.43 Risk of acquiring malignant melanoma is increased 3- to 6-fold in immunodeficient patients.12 In our patient, melanoma might be attributed either to chemotherapy-induced
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immunomodulation or to a genetic susceptibility for the development of malignancies. One of our patients had Down syndrome (case 9). The co-occurrence of malignant melanoma and Down syndrome has been previously described in one adult patient.44 In this instance the patient was a 39-year-old woman with an acral lentiginous melanoma. To our knowledge, our patient represents the first report of childhood melanoma associated with Down syndrome. Down syndrome is a frequent chromosomal aberration with phenotypical characteristics such as mental retardation, premature aging, immunodeficiency,45 and increased risk of some malignancies such as myeloid leukemia,46 germ cell tumors, and retinoblastoma.47 Melanoma in this patient might be attributed to the immunodeficiency state of Down syndrome. However, melanoma may have occurred incidentally. In one of our patients a second primary melanoma developed 4 years after excision of the first one. Patients with a history of melanoma are at significant risk of second primary melanoma developing. Patients with hereditary melanoma syndrome as well as patients without any risk factor may develop a second melanoma. Nashan et al,48 in a cohort of 535 patients with melanoma, found that the relative risk of a second primary melanoma in patients without any predisposing factors is increased more than 30 times. Most of the second melanomas occur within 5 years of the original one.48 However, the second melanoma can develop many years later.49 Therefore it is recommended that patients with melanoma be followed up carefully by thorough and regular clinical examinations, not only for detection of recurrences and metastasis but also for newly developed melanomas.49 Malignant melanoma occurs not only in the skin but also in some mucosal surfaces, including the mouth. Oral mucosal melanoma is a rare entity and only accounts for 0.2% to 0.8% of all melanomas.50 It arises from melanocytes lying in the buccal epithelial layer. The lesions appear as black, brown, and amelanotic macules, patches, or nodules.51,52 They tend to grow and form metastases in cervical lymph nodes.53 The prognosis of oral mucosal melanoma is poor, with 5-year survival rates reported between 13% and 20%.54,55 To date, only 5 cases have been reported in patients younger than 20 years.54,56-58 There are no follow-up data for 3 of these patients. The two other patients were alive at the time of publication, 18 and 117 months after diagnosis and treatment.56,57 One of our patients (case 7) had massive cervical lymphadenopathy, and further work-up revealed the oral floor mucosa as the primary site of melanoma. She died with general
metastases 10 months later. It seems that the amelanotic nature of the primary lesion led to its late detection after regional metastases. Therefore a high index of suspicion is necessary for early diagnosis of amelanotic melanoma of the oral mucosa. Sentinel lymph node biopsy is a minimally invasive procedure providing valuable staging information for patients with malignant melanoma.59 Although patients with a tumor-positive sentinel node have a higher risk of metastasis, patients with a negative sentinel node are also at risk of metastasis.60 In one of our patients who had a histologically negative sentinel node, regional lymph node metastasis developed 9 months later. Despite surgical excision and chemotherapy, widespread metastases developed, and she died 15 months later. Before the description of Spitz nevi by Sophie Spitz61 in 1948, it was thought that melanoma in children and adolescents was associated with a better prognosis than in adults. The delineation of histopathologic features of Spitz nevi resulted in the ability to distinguish between this benign entity and malignant melanoma. Since then, malignant melanoma in the pediatric age group is considered to be as malignant as in adults. However, melanoma that occurs in prepubertal children can demonstrate architectural and cytopathologic features resembling Spitz nevus (spitzoid melanoma).62,63 In our series, 70% of prepubertal melanomas showed spitzoid features, histologically. Only 33% of the postpubertal cases had spitzoid features. Since many childhood and adolescent melanomas had spitzoid features in our series, it is critical to differentiate nodular melanoma from Spitz nevi. Clinically, Spitz nevi are typically red or brown, dome-shaped, less than 1 cm in diameter, and appear in the first or second decade of life. Histopathologically, these nevi are composed of spindle and epithelioid melanocytic cells. From the architectural point of view, they are rather symmetric, present a sharp lateral demarcation, epidermal hyperplasia, and dermal maturation. In addition, one often finds Kamino bodies, retraction spaces around junctional nests, telangiectases, and associated edema. The most useful histopathologic criteria for differentiating nodular melanoma from Spitz nevi are (1) lack of dermal maturation, (2) deep dermal mitoses, (3) numerous dermal mitoses, (4) atypical dermal mitoses, and (5) abundant and lateral pagetoid ascension.64-66 Although superficial spreading melanoma is considered the most frequent type of melanoma in adults, conclusive data on histologic classification of pediatric melanoma are lacking. Only a few case series have included histologic classification. Nodular melanoma was the most common subtype
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in the study by Schmid-Wendtner et al16 of 36 patients younger than 18 years of age. On the other hand, Tate et al67 and Scalzo et al15 found superficial spreading melanoma to be the most frequent type in pediatric patients. Histologic classification of melanoma revealed 85% of our cases as nodular melanoma. Moreover, 64% of nodular melanomas (7/11) in our series had spitzoid features. In our study, 11 cases had Clark level IV or V melanoma, which is associated with intermediate or thick melanoma according to Breslow’s method ([1 mm). In some other case series similar results have been reported.68,69 Lack of awareness and delay in diagnosis could explain the high incidence of thicker melanoma in pediatric patients.69 Our series showed a 5-year survival rate of 58.8%. None of the patients with thin malignant melanoma died. This emphasizes the importance of early recognition and treatment. In our series 75% of patients who died had nodular melanoma with spitzoid features, indicating aggressive behavior of melanomas with spitzoid features in children and adolescents. Despite its rarity, malignant melanoma does occur in pediatric patients and appears to be as aggressive as in adults. Although the risk of malignant melanoma is increased in some conditions (eg, giant congenital nevi, xeroderma pigmentosum, dysplastic nevus syndrome, immunodeficiency), the majority of childhood and adolescence melanomas occur without any predisposing condition. The lack of awareness and reluctance to diagnose pediatric melanoma can lead to higher incidence of thick melanomas. We recommend early total excision of any clinically suspect skin lesion, even in children without any risk factor to preclude delay in diagnosis and treatment. Risk of late recurrence and development of second primary melanoma necessitates long-term dermatologic follow-up. The authors thank Dr Ali Akbar Haghdoost for his statistical advice and Ms Danielle Gosselin for her excellent secretarial support. REFERENCES 1. Bader JL, Li FP, Olmstead PM, Strickman NA, Green DM. Childhood malignant melanoma. Incidence and etiology. Am J Pediatr Hematol Oncol 1985;7:341-5. 2. Myhre E. Malignant melanomas in children. Acta Pathol Microbiol Scand 1963;59:184-8. 3. Allen AC, Spitz S. Malignant melanoma: a clinicopathological analysis of the criteria for diagnosis and prognosis. Cancer 1953;6:1-45. 4. Young JL, Percy CL, Asire AJ, Berg JW, Cusano MM, Gloeckler LA, et al. Cancer incidence and mortality in the United States, 1973-77. Natl Cancer Inst Monogr 1981;57:1-187. 5. Boyle P, Day NE, Magnus K. Mathematical modelling of malignant melanoma trends in Norway, 1953-1978. Am J Epidemiol 1983;118:887-96.
6. Kopf AW, Rigel DS, Friedman RJ. The rising incidence and mortality rate of malignant melanoma. J Dermatol Surg Oncol 1982;8:760-1. 7. Zuckerman R, Maier JP, Guiney WB Jr, Huntsman WT, Mooney EK. Pediatric melanoma: confirming the diagnosis with sentinel node biopsy. Ann Plast Surg 2001;46:394-9. 8. Swerdlow AJ, English JS, Qiao Z. The risk of melanoma in patients with congenital nevi: a cohort study. J Am Acad Dermatol 1995;32:595-9. 9. Bittencourt FV, Marghoob AA, Kopf AW, Koenig KL, Bart RS. Large congenital melanocytic nevi and the risk for development of malignant melanoma and neurocutaneous melanocytosis. Pediatrics 2000;106:736-41. 10. Kraemer KH, Lee MM, Scotto J. Xeroderma pigmentosum. Cutaneous, ocular, and neurologic abnormalities in 830 published cases. Arch Dermatol 1987;123:241-50. 11. Fazaa B, Zghal M, Bailly C, Zeglaoui F, Goucha S, Mokhtar I, et al. Melanoma in xeroderma pigmentosum: 12 cases. Ann Dermatol Venereol 2001;128:503-6. 12. Greene MH, Young TI, Clark WH Jr. Malignant melanoma in renal-transplant recipients. Lancet 1981;1:1196-9. 13. Greene MH, Clark WH Jr, Tucker MA, Kraemer KH, Elder DE, Fraser MC. High risk of malignant melanoma in melanomaprone families with dysplastic nevi. Ann Intern Med 1985; 102:458-65. 14. Balch CM, Sober AJ, Soong SJ, Gershenwald JE. AJCC Melanoma Staging Committee. The new melanoma staging system. Semin Cutan Med Surg 2003;22:42-54. 15. Scalzo DA, Hida CA, Toth G, Sober AJ, Mihm MC Jr. Childhood melanoma: a clinicopathological study of 22 cases. Melanoma Res 1997;7:63-8. 16. Schmid-Wendtner MH, Berking C, Baumert J, Schmidt M, Sander CA, Plewig G, et al. Cutaneous melanoma in childhood and adolescence: an analysis of 36 patients. J Am Acad Dermatol 2002;46:874-9. 17. Temple WJ, Mulloy RH, Alexander F, Marx LH, Jenkins M, Jerry LM. Childhood melanoma. J Pediatr Surg 1991;26:135-7. 18. Williams ML, Pennella R. Melanoma, melanocytic nevi, and other melanoma risk factors in children. J Pediatr 1994; 124:833-45. 19. Ceballos PI, Ruiz-Maldonado R, Mihm MC Jr. Melanoma in children. N Engl J Med 1995;332:656-62. 20. Boddie AW Jr, Smith JL Jr, McBride CM. Malignant melanoma in children and young adults: effect of diagnostic criteria on staging and end results. South Med J 1978; 71:1074-8. 21. Ruiz-Maldonado R, Orozco-Covarrubias ML. Malignant melanoma in children. A review Arch Dermatol 1997;133:363-71. 22. Handfield-Jones SE, Smith NP. Malignant melanoma in childhood. Br J Dermatol 1996;134:607-16. 23. McKiernan MV, Malcolm AJ, Chrystal KMR. Minerva. Br Med J 1995;310:814. 24. Watt AJ, Kotsis SV, Chung KC. Risk of melanoma arising in large congenital melanocytic nevi: a systematic review. Plast Reconstr Surg 2004;113:1968-74. 25. Skov-Jensen T, Hastrup J, Lambrethsen E. Malignant melanoma in children. Cancer 1966;19:620-6. 26. Trozak DJ, Rowland WD, Hu F. Metastatic malignant melanoma in prepubertal children. Pediatrics 1975;55:191-204. 27. Kaplan EN. The risk of malignancy in large congenital nevi. Plast Reconstr Surg 1974;53:421-8. 28. Rhodes AR, Wood WC, Sober AJ, Mihm MC Jr. Nonepidermal origin of malignant melanoma associated with a giant congenital nevocellular nevus. Plast Reconstr Surg 1981;67:782-90.
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29. Arons MS, Hurwitz S. Congenital nevocellular nevus: a review of the treatment controversy and a report of 46 cases. Plast Reconstr Surg 1983;72:355-65. 30. Dellon AL, Edelson RL, Chretien PB. Defining the malignant potential of the giant pigmented nevus. Plast Reconstr Surg 1976;57:611-8. 31. Sahin S, Levin L, Kopf AW. Risk of melanoma in medium-sized congenital melanocytic nevi: a follow-up study. J Am Acad Dermatol 1998;39:428-33. 32. Illig L, Weidner F, Hundeiker M, Gartmann H, Biess B, Leyh F, Paul E. Congenital nevi less than or equal to 10 cm as precursors to melanoma. 52 cases, a review, and a new conception. Arch Dermatol 1985;121:1274-81. 33. Betti R, Inselvini E, Vergani R, Crosti C. Small congenital nevi associated with melanoma: case reports and considerations. J Dermatol 2000;27:583-90. 34. MacKie RM, Watt D, Doherty V, Aitchison T. Malignant melanoma occurring in those aged under 30 in the west of Scotland 1979-1986: a study of incidence, clinical features, pathological features and survival. Br J Dermatol 1991;124:560-4. 35. Walton RG, Jacobs AH, Cox AJ. Pigmented lesions in newborn infants. Br J Dermatol 1976;95:389-96. 36. Bono A, Bartoli C, Zurrida SM, Del Prato I, Clemente C, Cascinelli N. Let’s stop worrying about pigmented skin lesions in children. Eur J Cancer 1994;30A:417. 37. From L. Congenital nevielet’s be practical. Pediatr Dermatol 1992;9:345-6. 38. Tannous ZS, Mihm MC, Sober AJ, Duncan LM. Congenital melanocytic nevi: clinical and histopathological features, risk of melanoma, and clinical management. J Am Acad Dermatol 2005;52:197-203. 39. Stolz W, Schmoeckel C, Landthaler M, Braun-Falco O. Association of early malignant melanoma with nevocytic nevi. Cancer 1989;63:550-5. 40. Caro WA, Bronstein BR. Tumors of the skin. In: Moschella SL, Hurley HJ, editors. Dermatology. Philadelphia: Saunders; 1985. pp. 1533-638. 41. Massi D, Carli P, Franchi A, Santucci M. Naevus-associated melanomas: cause or chance? Melanoma Res 1999;9:85-91. 42. Melnik MK, Urdaneta LF, Al-Jurf AS, Foucar E, Jochimsen PR, Soper RT. Malignant melanoma in childhood and adolescence. Am Surg 1986;52:142. 43. Bystryn JC. The immunobiology of human malignant melanoma. Int J Dermatol 1980;19:375-8. 44. Nakano J, Muto M, Arikawa K, Hirota T, Asagami C. Acral lentiginous melanoma associated with Down’s syndrome. J Dermatol 1993;20:59-60. 45. Ugazio AG. Down’s syndrome: problems of immunodeficiency. Hum Genet Suppl 1981;2:33-9. 46. Hasle H, Clemmensen IH, Mikkelsen M. Incidence of cancer in individuals with Down syndrome. Tidsskr Nor Laegeforen 2000; 120:2878-81. 47. Hasle H. Pattern of malignant disorders in individuals with Down’s syndrome. Lancet Oncol 2001;2:429-36. 48. Nashan D, Kocer B, Schiller M, Luger T, Grabbe S. Significant risk of a second melanoma in patients with a history of melanoma but no further predisposing factors. Dermatology 2003;206:76-7.
49. Beardmore GL, Davis NC. Multiple primary cutaneous melanomas. Arch Dermatol 1975;111:603-9. 50. Strauss JE, Strauss SI. Oral malignant melanoma: a case report and review of literature. J Oral Maxillofac Surg 1994;52:972-6. 51. Sooknundun M, Kacker SK, Kapila K, Verma K, Narayan P. Oral malignant melanoma (a case report and review of literature). J Laryngol Otol 1986;100:371-5. 52. Trodahl JN, Sprague WG. Benign and malignant melanocytic lesions of the oral mucosa. An analysis of 135 cases. Cancer 1970;25:812-23. 53. Manolidis S, Donald PJ. Malignant mucosal melanoma of the head and neck: review of the literature and report of 14 patients. Cancer 1997;80:1373-86. 54. Rapini RP, Golitz LE, Greer RO Jr, Krekorian EA, Poulson T. Primary malignant melanoma of the oral cavity. A review of 177 cases. Cancer 1985;55:1543-51. 55. Liversedge RL. Oral malignant melanoma. Br J Oral Surg 1975;13:40-55. 56. D’Silva NJ, Kurago Z, Polverini PJ, Hanks CT, Paulino AF. Malignant melanoma of the oral mucosa in a 17-year-old adolescent girl. Arch Pathol Lab Med 2002;126:1110-3. 57. Owens JM, Gomez JA, Byers RM. Malignant melanoma in the palate of a 3-month-old child. Head Neck 2002;24:91-4. 58. Tremblay JF, O’Brien EA, Chauvin PJ. Melanoma in situ of the oral mucosa in an adolescent with dysplastic nevus syndrome. J Am Acad Dermatol 2000;42:844-6. 59. Chakera AH, Drzewiecki KT, Eigtved A, Juhl BR. Sentinel node biopsy for melanoma: a study of 241 patients. Melanoma Res 2004;14:521-6. 60. Moehrle M, Schippert W, Rassner G, Garbe C, Breuninger H. Micrometastasis of a sentinel lymph node in cutaneous melanoma is a significant prognostic factor for disease-free survival, distant-metastasis-free survival, and overall survival. Dermatol Surg 2004;30:1319-28. 61. Spitz S. Melanoma of childhood. Am J Pathol 1948;24:591-609. 62. Mones JM, Ackerman AB. Melanomas in prepubescent children: review comprehensively, critique historically, criteria diagnostically, and course biologically. Am J Dermatopathol 2003;25:223-38. 63. Chao MM, Schwartz JL, Wechsler DS, Thornburg CD, Griffith KA, Williams JA. High-risk surgically resected pediatric melanoma and adjuvant interferon therapy. Pediatr Blood Cancer 2005;44:441-8. 64. Mooi WJ. Spitz nevus and its histologic simulators. Adv Anat Pathol 2002;9:209-21. 65. Mooi WJ. Histopathology of Spitz naevi and ‘‘Spitzoid’’ melanomas. Curr Top Pathol 2001;94:65-77. 66. Crotty KA, Scolyer RA, Li L, Palmer AA, Wang L, McCarthy SW. Spitz naevus versus Spitzoid melanoma: when and how can they be distinguished? Pathology 2002;34:6-12. 67. Tate PS, Ronan SG, Feucht KA, Eng AM, Das Gupta TK. Melanoma in childhood and adolescence: clinical and pathological features of 48 cases. J Pediatr Surg 1993;28:217-22. 68. Fisher SR, Reintgen DS, Seigler HF. Juvenile malignant melanoma of the head and neck. Laryngoscope 1988;98:184-9. 69. Rao BN, Hayes FA, Pratt CB, Fleming ID, Kumar AP, Lobe T, et al. Malignant melanoma in children: its management and prognosis. J Pediatr Surg 1990;25:198-203.
M
elanoma is considered an uncommon entity in children and adolescents. Only 2% of melanomas occur in patients younger than 20 years1 and 0.3% to 0.4% occur in prepubertal children.2,3 It accounts for 3% of malignancies in patients younger than 20 years.4 As the overall incidence of melanoma is increasing worldwide,5,6 it is expected that the incidence of childhood and adolescence melanoma will follow.7 Childhood and adolescent melanoma is considered more prevalent From the Department of Pediatrics, Divisions of Dermatologya and Hemato-oncology,b and the Department of Pathology,c SainteJustine Hospital, University of Montreal. Funding sources: Dr Jafarian’s fellowship has been supported by an unrestricted educational grant from Fujisawa Canada. Conflicts of interest: None identified. Presented in part at the 78th Annual Meeting of the Canadian Dermatology Association, Ottawa, Canada, 2003, and at the 10th World Congress of Pediatric Dermatology, Rome, Italy, 2004. Accepted for publication July 5, 2005. Reprints not available from the authors. Correspondence to: Julie Powell, MD, Sainte Justine Hospital, 3175 chemin coˆte Sainte Catherine, Montreal, Que´bec, Canada H3T 1C5. E-mail: [email protected]. Published online October 4, 2005. 0190-9622/$30.00 ª 2005 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2005.07.013
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in certain groups, such as patients with giant congenital nevi,8,9 xeroderma pigmentosum,10,11 immunosuppression,12 and dysplastic nevus syndrome.13 As a result, most physicians are more concerned about malignant changes in these patients and less inclined to suspect malignant melanoma in patients without known predisposing factors. Reluctance to put a diagnosis of malignant melanoma in this age group could also be in part due to the fact that most acquired melanocytic nevi and Spitz nevi develop during childhood and adolescence. In this study, we report 13 cases of malignant melanoma in patients 17 years of age or younger. Emphasis is given to clinical characteristics, pathologic features, and outcomes.
MATERIAL AND METHODS A retrospective chart review was performed of all patients younger than 17 years old who had a diagnosis of skin or mucous membrane melanoma identified in Sainte Justine Hospital’s archives database from 1980 to 2002. This information was crosschecked with the oncology clinic database and the pathology database. Histologic slides of these patients were reviewed by one of the authors (V. K.). Histologic review led to reclassification of one case as Spitz nevus and its exclusion from the study. Cases with no histologic material available for review
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and/or with an unconfirmed diagnosis were also excluded. Therefore 13 cases of malignant melanoma were retrieved for our study. The following pathologic parameters were evaluated: histologic classification, tumor thickness (Breslow method), Clark’s anatomical level of invasion, ulceration, vascular invasion, lymphatic invasion, regression, and number of mitoses per square millimeter. Tumors with Breslow depth of less than 1 mm were considered thin melanomas, those between 1 and 1.5 mm were defined as intermediate, and those more than 1.5 mm as thick melanomas. Medical records were reviewed for ethnic origin, sex, age at diagnosis, anatomic location, and clinical description of the primary tumor, association with congenital nevi, and predisposing conditions. The most recent follow-up data were obtained from either clinical notes or telephone interviews with patients or their parents. All patients were staged with the use of the American Joint Committee on Cancer staging classification.14 Work-up for staging purposes included medical history; physical examination; complete blood cell count; liver function tests; lactate dehydrogenase level; chest x-ray; regional lymph node and abdominal ultrasonography; radionuclide scan of bone, liver, and spleen; computed tomographicscanning of abdomen, chest, and brain; and sentinel lymph node biopsy. Some methods were not used in all patients. Life-table analysis was used to determine 5-year survival.
RESULTS The main clinical characteristics are shown in Table I. The patients consisted of 4 boys and 9 girls. Twelve patients were Caucasian; one patient was of mixed African Caucasian ethnic origin. Seven patients were younger than 10 years and 6 were 10 to 16 years of age at diagnosis. We did not have sufficient data about the pubertal status of these patients, so we arbitrarily considered the first group to be prepubertal children. Primary melanomas were found in different body sites. Five lesions were on the trunk, 4 on the legs, 2 on the foot, and 1 on the forearm. In one patient, the primary site of melanoma was the oral mucosa. The most common primary site in boys was the trunk. The melanomas in girls were most frequently located on the trunk and legs. None of our 13 patients had a documented family history of dysplastic nevus syndrome or melanoma, but one had a family history of prostate and liver carcinoma in first- and second-degree relatives. None of our cases were associated with giant congenital melanocytic nevi, dysplastic nevus syndrome, or xeroderma pigmentosum. In two patients,
melanoma arose in small congenital nevi, according to the history obtained from parents. One of our patients had a previous history of chemoradiotherapy for a malignant undifferentiated pleuropulmonary blastoma 1 year before the melanoma was diagnosed. However, this patient did not develop melanoma in a zone of previous radiotherapy. One of our patients had Down syndrome. Eighty-five percent of patients (11/13) described one or more symptoms directly related to the lesion. The most common symptom was recent growth of the lesion (n = 10). The other presentations included pain (n = 1), ulceration (n = 2), itching (n = 1), bleeding (n = 3), and change in color (n = 2). Three patients had pyogenic granulomaelike lesions. One patient was diagnosed after an incidental excision of a pigmented lesion during an orthopedic surgical procedure. One patient had massive cervical lymphadenopathy. No photograph was available of any of those lesions. Histologic classification of the melanomas was nodular in 11 cases and superficial spreading in two cases. Spitzoid features were cited in 7 cases of nodular melanoma. There were no cases of lentigo maligna or acral lentiginous melanoma. Tumor thickness in our cases ranged from 0 to 6 mm, with a median and mean of 2.8 and 3.2 mm, respectively. No associated congenital nevi were identified histopathologically, including the two cases reported by parents to be congenital. Pathologic features of the melanomas are shown in Table II. Three of our patients underwent sentinel node biopsy (cases 3, 5, 10). Sentinel node metastasis was detected in one patient (case 3); the other two patients had a negative sentinel lymph node. However, one of these patients developed regional lymph node and widespread metastasis 9 months later (case 10). Primary treatment of 12 patients included wide local excision of their primary lesions. One patient (case 7) had an unresectable mucosal melanoma of the mouth and chemotherapy was given without local excision. In addition to local treatment, patients with regional lymph node involvement at presentation or on follow-up underwent regional lymph node dissection and received chemotherapy. Three patients who developed metastasis (cases 2,10,11) after regional lymph node involvement were given complementary chemotherapy. Eleven patients had localized disease (stage 0 to IIc) at the time of presentation. The other two patients were considered to have stage III disease. One of these patients had positive findings from sentinel node biopsy. He underwent regional lymph node dissection, which did not reveal any additional
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Table I. Clinical characteristics of patients with malignant melanoma Case no.
Age (y)/ sex
Site
Stage
Treatment
Follow-up (mo)/status
SE SE, LND, Chemo SE, LND, Chemo
152/Alive 14/Dead 15/Alive
SE SE, Chemo SE Chemo
16/Alive 7/Alive 219/Alive 10/Dead
SE
22/Alive
Metastasis
1 2 3
2/M 9/F 4/M
Foot Trunk Leg
IIC IIA III
4 5 6 7
9/F 4/F 6/F 8/F
Trunk Foot Forearm Oral mucosa
0 IIC IIA III
8
11/F
Leg
IA
No Axillary LNM after 6 mo Regional sentinel node metastasis at diagnosis No No No Cervical LNM at diagnosis No
9 10 11 12
11/F 14/F 16/F 12/M
Leg Trunk Leg Trunk
IIA IIB IIA IIB
No Axillary LNM after 9 mo Inguinal LNM after 12 mo Axillary LNM after 7 mo
SE SE, LND, Chemo SE, LND, Chemo SE, LND, Chemo
137/Alive 26/Dead 39/Dead 92/Alive
13
12/M
Trunk
IIB
No
SE
159/Alive
Comments
SCMN association
FH of prostate and liver carcinoma PH of pleuropulmonary blastoma Down syndrome SCMN association Second primary melanoma 4 y after first one
Chemo, Chemotherapy; F, female; FH, family history; LND, lymph node dissection; LNM, lymph node metastasis; M, male; PH, past history; SCMN, small congenital melanocytic nevus; SE, surgical excision.
involvement. He remains free of disease at 15 months (case 3). The second patient (case 7) was an 8-yearold girl with massive cervical lymphadenopathy. The primary site of melanoma was the oral mucosa. Generalized metastases developed 8 months later, and she died 10 months after the initial diagnosis. Follow-up ranged from 7 to 219 months, with a median of 26 months. The 5-year survival rate was 58.8%. Four patients with localized disease at presentation had disease progression. Three of these patients (cases 2, 10, 11) died. Regional lymph node involvement and then widespread metastases developed. In one patient (case 12) axillary lymph node metastasis developed 7 months after diagnosis. At that time, he underwent lymph node dissection and chemotherapy. A second primary melanoma developed 4 years later, which was surgically excised (melanoma in situ). This patient did not have any further disease progression during a follow-up period of 92 months.
DISCUSSION Although prepubertal melanoma is rare2,3 and melanoma is more common in adolescents,2 in our series 53% of patients were younger than 10 years. We found a female preponderance of 69% in our cases. This female predominance in sex distribution is in accordance with previous case series.15-17 However,
a recent composite study of 503 patients younger than 20 years revealed no sex predilection.18 Clinical symptoms indicative of malignant melanoma in children and adolescents are rapid increase in lesion size, bleeding, color change, pruritus, irregularity of border and pigment distribution, and enlargement of regional lymph nodes.19-21 In our series, the most frequent symptom was increase in lesion size. The infrequency of asymmetry, border irregularity, and color change are in accordance with the findings of Handfield-Jones and Smith.22 As in their series, this could be attributed to the small number of superficial spreading melanomas in our cases. Three of our patients (20%) presented with a pyogenic granulomaelike lesion. This presentation has also been reported in other case series.22,23 Therefore malignant melanoma should be considered in the differential diagnosis of pyogenic granuloma in children. Giant congenital melanocytic nevi (GCMN) are considered to be potential precursors of melanoma.8,9 Watt, Kotsis, and Chung,24 in a systematic analysis of data from existing literature, found that, in 2.8% of patients with GCMN, malignant melanoma developed during the reported follow-up periods. However, data about the frequency with which pediatric malignant melanoma is associated with GCMN are conflicting. In two early literature-based
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Table II. Pathological features of melanomas Case no.
Histologic type
Clark level
Breslow depth (mm)
Ulceration
Vascular invasion
Lymphatic invasion
Regression
Mitosis (/mm2)
1 2 3 4 5 6 7 8 9 10 11 12 13
NM (SF) NM (SF) NM (SF) SSM NM (SF) NM NM (SF) SSM NM (SF) NM NM (SF) NM NM
V IV IV I IV III V III IV IV IV IV IV
4.8 1.55 4.7 0 6 1.4 6 0.8 3.6 5.58 2.3 2.8 2.5
1 1 e e 1 1 1 N/A e e e 1 1
e e e e e 1 e e e e e e e
e 1 e e e 1 e N/A e e 1 1 1
e e e e e N/A e e e e e e e
6 12 2 e 3 1 25 2 1 3 12 10 10.5
N/A, Not available; NM, nodular melanoma; SF, spitzoid feature; SSM, superficial spreading melanoma.
surveys, Skov-Jensen, Hastrup, and Lambrethesen25 and Trozak, Rowland, and Hu26 reported that one third of childhood melanomas arise within GCMN. In a more recent review, Williams and Pennella18 concluded that only 3% of reported childhood melanomas occurred in giant congenital nevi. They attributed this marked difference in the proportion of melanoma arising within GCMN to elimination of the bias of literature reports in their study. Melanomas associated with GCMN can develop at any age but usually occur during the first decade of life. Because melanoma in GCMN might arise in deep cutaneous or subcutaneous levels, its early diagnosis could be difficult.27,28 Therefore many authors recommend early and total prophylactic excision of these nevi.28,29 However, deep infiltration of fascia or muscle with nevus cells28,30 suggests that removal of the skin lesion could not completely eliminate the melanoma risk in these patients. Estimates of risk of malignant melanoma arising within small congenital melanocytic nevi (SCMN) vary greatly. Some studies suggest that there may not be a clinically significant increased risk for melanoma in SCMN,31 whereas several series noted that a substantial percentage of melanomas were associated with SCMN, mostly after puberty.32-34 In contrast to GCMN, melanoma in SCMN usually arises at the dermoepidermal junction, making its early diagnosis much easier.33 Because SCMN occur in 1% to 2% of newborns,35 systematic removal of these lesions may not be feasible. Therefore periodic clinical surveillance seems a better alternative in the management of these lesions.36-38 None of our patients had GCMN. According to the parents, melanoma originated from SCMN in two patients. However, histopathologic examination of these tumors did not reveal any evidence of associ-
ated nevus. This could be attributed either to recall bias by the parents or obliteration of nevus cells by melanoma.39 Malignant melanoma may also arise de novo or from an acquired melanocytic nevus. Caro and Bronstein40 have stated: ‘‘Because a malignant melanoma may remain quiescent for long periods of time, the clinical identification of a pre-existing lesion as an [acquired] nevus is subject to error since such a lesion may have been a melanoma from its inception.’’ None of our cases had confirmed association with congenital nevi. This is in accordance with the findings of many other authors.41,42 Therefore, although there is evidence that the risk of melanoma in patients with congenital nevi is higher than in the unaffected population, the majority of melanomas occur de novo. Suspect changes in lesions other than congenital nevi might be a sign of melanoma and should be recognized early to prevent disease progression. Dysplastic nevus syndrome,13 xeroderma pigmentosum,10,11 and immunodeficiency12 are considered to be predisposing conditions for the development of malignant melanoma in childhood and adolescence. None of our patients had dysplastic nevus syndrome or xeroderma pigmentosum. One of our patients had a history of malignant undifferentiated pleuropulmonary neoplasm, possibly blastoma treated with chemotherapy and regional radiotherapy 1 year before the diagnosis of melanoma. One year after successful surgical treatment of her melanoma, this patient developed nonlymphoblastic acute leukemia, which was treated with bone marrow transplantation. The immune system function is important in the development of melanoma.43 Risk of acquiring malignant melanoma is increased 3- to 6-fold in immunodeficient patients.12 In our patient, melanoma might be attributed either to chemotherapy-induced
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immunomodulation or to a genetic susceptibility for the development of malignancies. One of our patients had Down syndrome (case 9). The co-occurrence of malignant melanoma and Down syndrome has been previously described in one adult patient.44 In this instance the patient was a 39-year-old woman with an acral lentiginous melanoma. To our knowledge, our patient represents the first report of childhood melanoma associated with Down syndrome. Down syndrome is a frequent chromosomal aberration with phenotypical characteristics such as mental retardation, premature aging, immunodeficiency,45 and increased risk of some malignancies such as myeloid leukemia,46 germ cell tumors, and retinoblastoma.47 Melanoma in this patient might be attributed to the immunodeficiency state of Down syndrome. However, melanoma may have occurred incidentally. In one of our patients a second primary melanoma developed 4 years after excision of the first one. Patients with a history of melanoma are at significant risk of second primary melanoma developing. Patients with hereditary melanoma syndrome as well as patients without any risk factor may develop a second melanoma. Nashan et al,48 in a cohort of 535 patients with melanoma, found that the relative risk of a second primary melanoma in patients without any predisposing factors is increased more than 30 times. Most of the second melanomas occur within 5 years of the original one.48 However, the second melanoma can develop many years later.49 Therefore it is recommended that patients with melanoma be followed up carefully by thorough and regular clinical examinations, not only for detection of recurrences and metastasis but also for newly developed melanomas.49 Malignant melanoma occurs not only in the skin but also in some mucosal surfaces, including the mouth. Oral mucosal melanoma is a rare entity and only accounts for 0.2% to 0.8% of all melanomas.50 It arises from melanocytes lying in the buccal epithelial layer. The lesions appear as black, brown, and amelanotic macules, patches, or nodules.51,52 They tend to grow and form metastases in cervical lymph nodes.53 The prognosis of oral mucosal melanoma is poor, with 5-year survival rates reported between 13% and 20%.54,55 To date, only 5 cases have been reported in patients younger than 20 years.54,56-58 There are no follow-up data for 3 of these patients. The two other patients were alive at the time of publication, 18 and 117 months after diagnosis and treatment.56,57 One of our patients (case 7) had massive cervical lymphadenopathy, and further work-up revealed the oral floor mucosa as the primary site of melanoma. She died with general
metastases 10 months later. It seems that the amelanotic nature of the primary lesion led to its late detection after regional metastases. Therefore a high index of suspicion is necessary for early diagnosis of amelanotic melanoma of the oral mucosa. Sentinel lymph node biopsy is a minimally invasive procedure providing valuable staging information for patients with malignant melanoma.59 Although patients with a tumor-positive sentinel node have a higher risk of metastasis, patients with a negative sentinel node are also at risk of metastasis.60 In one of our patients who had a histologically negative sentinel node, regional lymph node metastasis developed 9 months later. Despite surgical excision and chemotherapy, widespread metastases developed, and she died 15 months later. Before the description of Spitz nevi by Sophie Spitz61 in 1948, it was thought that melanoma in children and adolescents was associated with a better prognosis than in adults. The delineation of histopathologic features of Spitz nevi resulted in the ability to distinguish between this benign entity and malignant melanoma. Since then, malignant melanoma in the pediatric age group is considered to be as malignant as in adults. However, melanoma that occurs in prepubertal children can demonstrate architectural and cytopathologic features resembling Spitz nevus (spitzoid melanoma).62,63 In our series, 70% of prepubertal melanomas showed spitzoid features, histologically. Only 33% of the postpubertal cases had spitzoid features. Since many childhood and adolescent melanomas had spitzoid features in our series, it is critical to differentiate nodular melanoma from Spitz nevi. Clinically, Spitz nevi are typically red or brown, dome-shaped, less than 1 cm in diameter, and appear in the first or second decade of life. Histopathologically, these nevi are composed of spindle and epithelioid melanocytic cells. From the architectural point of view, they are rather symmetric, present a sharp lateral demarcation, epidermal hyperplasia, and dermal maturation. In addition, one often finds Kamino bodies, retraction spaces around junctional nests, telangiectases, and associated edema. The most useful histopathologic criteria for differentiating nodular melanoma from Spitz nevi are (1) lack of dermal maturation, (2) deep dermal mitoses, (3) numerous dermal mitoses, (4) atypical dermal mitoses, and (5) abundant and lateral pagetoid ascension.64-66 Although superficial spreading melanoma is considered the most frequent type of melanoma in adults, conclusive data on histologic classification of pediatric melanoma are lacking. Only a few case series have included histologic classification. Nodular melanoma was the most common subtype
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in the study by Schmid-Wendtner et al16 of 36 patients younger than 18 years of age. On the other hand, Tate et al67 and Scalzo et al15 found superficial spreading melanoma to be the most frequent type in pediatric patients. Histologic classification of melanoma revealed 85% of our cases as nodular melanoma. Moreover, 64% of nodular melanomas (7/11) in our series had spitzoid features. In our study, 11 cases had Clark level IV or V melanoma, which is associated with intermediate or thick melanoma according to Breslow’s method ([1 mm). In some other case series similar results have been reported.68,69 Lack of awareness and delay in diagnosis could explain the high incidence of thicker melanoma in pediatric patients.69 Our series showed a 5-year survival rate of 58.8%. None of the patients with thin malignant melanoma died. This emphasizes the importance of early recognition and treatment. In our series 75% of patients who died had nodular melanoma with spitzoid features, indicating aggressive behavior of melanomas with spitzoid features in children and adolescents. Despite its rarity, malignant melanoma does occur in pediatric patients and appears to be as aggressive as in adults. Although the risk of malignant melanoma is increased in some conditions (eg, giant congenital nevi, xeroderma pigmentosum, dysplastic nevus syndrome, immunodeficiency), the majority of childhood and adolescence melanomas occur without any predisposing condition. The lack of awareness and reluctance to diagnose pediatric melanoma can lead to higher incidence of thick melanomas. We recommend early total excision of any clinically suspect skin lesion, even in children without any risk factor to preclude delay in diagnosis and treatment. Risk of late recurrence and development of second primary melanoma necessitates long-term dermatologic follow-up. The authors thank Dr Ali Akbar Haghdoost for his statistical advice and Ms Danielle Gosselin for her excellent secretarial support. REFERENCES 1. Bader JL, Li FP, Olmstead PM, Strickman NA, Green DM. Childhood malignant melanoma. Incidence and etiology. Am J Pediatr Hematol Oncol 1985;7:341-5. 2. Myhre E. Malignant melanomas in children. Acta Pathol Microbiol Scand 1963;59:184-8. 3. Allen AC, Spitz S. Malignant melanoma: a clinicopathological analysis of the criteria for diagnosis and prognosis. Cancer 1953;6:1-45. 4. Young JL, Percy CL, Asire AJ, Berg JW, Cusano MM, Gloeckler LA, et al. Cancer incidence and mortality in the United States, 1973-77. Natl Cancer Inst Monogr 1981;57:1-187. 5. Boyle P, Day NE, Magnus K. Mathematical modelling of malignant melanoma trends in Norway, 1953-1978. Am J Epidemiol 1983;118:887-96.
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