Fluorescence In Situ Hybridization Analysis of Atypical Melanocytic Proliferations and Melanoma in Young Patients

Abstract

Morphologic heterogeneity among melanocytic proliferations is a common challenge in the diagnosis of melanoma. In particular, atypical melanocytic lesions in children, adolescents, and young adults may be difficult to classify because of significant morphologic overlap with melanoma. Recently a four-probe fluorescence in situ hybridization (FISH) protocol to detect chromosomal abnormalities in chromosomes 6 and 11 has shown promise for improving the classification of melanocytic lesions. We sought to determine the correlation between FISH results, morphology, and clinical outcomes in a series of challenging melanocytic proliferations in young patients. We retrospectively performed the standard four-probe FISH analysis on 21 melanocytic neoplasms from 21 patients younger than 25 years of age (range 5–25 years, mean 14.6 years) from Stanford University Medical Center who were prospectively followed for a median of 51 months (range 1–136 months). The study cohort included patients with 5 confirmed melanomas, 2 melanocytic tumors of uncertain malignant potential (MelTUMPs), 10 morphologically challenging atypical Spitz tumors (ASTs), and 4 typical Spitz nevi. FISH detected chromosomal aberrations in all five melanomas and in one MelTUMP, in which the patient developed subsequent lymph node and distant metastasis. All 10 ASTs, 4 Spitz nevi, and 1 of 2 MelTUMPs were negative for significant gains or losses in chromosomes 6 and 11q. Our findings demonstrated a strong correlation between positive FISH results and the histomorphologic impression of melanoma. This finding was also true for the MelTUMP with poor clinical outcome. Therefore FISH may serve as a helpful adjunct in the classification of controversial melanocytic tumors in young patients.

Evidence behind the use of molecular tests in melanocytic lesions and practice patterns of these tests by dermatopathologists

“…The two validation studies suggest qRT-PCR has a sensitivity of 90% to 91.5% and a specificity of 91% to 92.5% for melanoma. 25,50 In one study, there was 97% and 83% concordance with histology for FISH and qRT-PCR in a group of unequivocal melanocytic lesions resulting in a sensitivity and specificity of 93% and 100% for FISH and 62% and 95% for qRT-PCR. The intertest agreement was found to be 80%.…”

“…The melanocytic lesions included in the studies covered a broad range of melanocytic neoplasms, including spitzoid tumors, ambiguous melanocytic lesions, various subtypes of melanoma, metastatic melanoma, dermal melanocytosis, proliferative nodules, and conjunctival and anal melanocytic lesions. Two articles specifically included pediatric‐aged cases in their series (Table S2 in Supporting Information) …”

“…Review of the literature has shown that FISH has the potential to serve as an adjunct to morphology and immunohistochemistry in chal- 25,26 In general, FISH testing for melanoma is a multiplex assay including probes targeting loci that have been found to be frequently altered through CGH technology. 27 The clinical utility of FISH has been explored in a number of studies.…”

Spitzoid Melanoma of Childhood: A Case Series and Review

“…Whether or not SM/AST represent a continuum between benign nevi and aggressive adult type malignant melanoma remains a mystery. Majority of malignant melanomas demonstrate chromosomal aberrations and gene amplifications [17,18], and loss of replicative senescence by telomerase overexpression [19] and angiotropism [20]. While the majority of conventional pediatric melanomas demonstrate a bigger array of chromosomal copy number aberrations, they may also demonstrate 6p25, 8q24 and 11q13 gains, deletions of 6q23 and 9p21, like their Spitzoid counterparts [21][22][23][24][25].…”

Atypical Melanocytic Proliferations: A Review of the Literature

“…The 4-probe FISH assay has also shown promise as an ancillary diagnostic tool. 77,78 As most melanomas have copy-number increases of 11q and 6p, to differentiate from common nevi, the initial assay combined 4 probes targeting genes on 6p25, 6q23, 11q13, and centromere 6. The initial assay had 87% sensitivity and 95% specificity for melanoma and identified 6 of 6 cases as melanomas that were histologically ambiguous and subsequently metastasized.…”