Outcomes of Atypical Spitz Tumors With Chromosomal Copy Number Aberrations and Conventional Melanomas in Children

Abstract

Death due to melanoma in childhood (up to 20 y of age) is a rare event, with an average of 18 cases reported annually in the United States. In this study we evaluated 2 subgroups of high-risk melanocytic neoplasms in childhood, specifically atypical Spitz tumors (ASTs) with chromosomal copy number changes and conventional melanomas. We analyzed the clinical, histologic, and molecular features of all cases and performed the Fisher exact test, logistic regression, and multivariate analysis to evaluate features associated with aggressive clinical behavior in these cases. Among the ASTs, all of which had 1 or more chromosomal copy number aberrations, the presence of homozygous 9p21 deletions and a positive sentinel lymph node were each found to be correlated with tumor extension beyond the sentinel lymph node, with P-values of 0.046 and 0.01, respectively. Two patients with ASTs that had homozygous 9p21 deletions developed brain metastasis, one of whom died of disease. Among the 21 conventional melanomas, 3 patients developed distant metastasis and died of disease. Chromosomal copy number aberrations evaluated by fluorescence in situ hybridization were present in the majority of the cases (16/18). Among conventional melanomas, we did not identify any clinical, histologic, or molecular features associated with aggressive behavior. The presence of 8q24 gains was seen almost exclusively in 6 amelanotic small cell melanomas in children of whom 1 died of disease. Characteristic chromosomal copy number aberrations may occur in specific subtypes of melanocytic neoplasms in children and may help with the classification and prognostication of these rare tumors.

Loss of p16 expression and copy number changes of CDKN2A in a spectrum of spitzoid melanocytic lesions

“…Homozygous loss of CDKN2A by fluorescence in situ hybridization (FISH) is associated with more aggressive behavior in spitzoid tumors, whereas heterozygous loss is not diagnostic of malignancy [16][17][18][19]. Few studies have correlated p16 immunohistochemistry with CDKN2A copy number changes to assist diagnosticians in selecting FISH or immunohistochemistry as a diagnostic approach [16], and to our knowledge the correlation between p16 expression and CDKN2A copy number status in SMMs has not been systematically examined.…”

“…An initial report found that 41% of SMMs harbor homozygous 9p21 deletion [17]. Further studies applied to spitzoid lesions classified as ASTs demonstrated that homozygous loss of 9p21 correlated with poor outcome, and may warrant classification of a tumor as malignant [16,18,19]. The significance of heterozygous CDKN2A loss in spitzoid neoplasms is less clear.…”

Fluorescence In Situ Hybridization for Melanoma Diagnosis

“…Despite the above-mentioned data, [62][63][64]66 the prognostic impact of the new melanoma FISH probe cocktail in atypical Spitzoid tumors was recently questioned by Massi et al 68 ; these authors focused on lesions excised in patients younger than 18 years and found no significant correlation between the FISH status and the clinical outcome. Conventional 4-probe FISH was positive in 4/20 (20%) Spitz nevi and in 15/50 (30%) atypical Spitz tumors; in addition, 9p21 deletion was found as homozygous in 2 cases and as heterozygous in 3 cases of atypical Spitz tumor.…”

Pathology of Melanoma

“…17 Using fluorescence in situ hybridization methodology, loss of chromosome region 9P21 has been associated with aggressive behavior in a small subset of these lesions and represents, arguably, the best evidence-based genomic criterion for identification of lesions with potential competence for metastasis and lethal progression. 18,19 Comparative genomic hybridization methodology can identify similar abnormalities, 20 but has not been studied as rigorously in relation to outcome.…”