Copy number variations and clinical outcome in atypical spitz tumors.
ABSTRACT Atypical Spitz tumors (ASTs) are rare spitzoid neoplasms of uncertain biological behavior. Our study was designed to characterize genetic abnormalities that may help to differentiate ASTs from melanoma or Spitz nevi. We examined copy number variation in formalin-fixed, paraffin-embedded samples using an Agilent 44k array comparative genomic hybridization platform. Sixteen patients with AST (8 with positive sentinel lymph node biopsy, 1 with distant metastasis), 8 patients with Spitz nevi, and 3 patients with melanoma (2 spitzoid, 1 superficial spreading) were evaluated. Chromosomal aberrations were found in 7 of 16 ASTs, 1 with fatal outcome, 2 spitzoid melanomas, and 1 conventional melanoma. We found no difference in chromosomal instability between AST patients with positive and negative sentinel lymph node biopsies. Our patient with widely metastatic AST lacked the most frequent aberrations in melanoma involving chromosomes 6 and 11q that are loci targeted by fluorescence in situ hybridization (FISH) probes developed to distinguish malignant melanoma from benign melanocytic lesions. The vast majority of chromosomal abnormalities observed in ASTs are not commonly found in melanomas, suggesting that AST may be a distinct clinical entity and raising additional questions regarding their malignant potential, prognosis, and clinical management. The current FISH probes failed to detect 1 spitzoid melanoma, 1 fatal metastatic AST case, and the other chromosomally aberrant ASTs in our series, but detected 1 spitzoid melanoma and 1 conventional melanoma. Thus, a comprehensive, genome-wide approach to chromosomal abnormalities offered greater sensitivity and specificity than current FISH probes in identifying spitzoid lesions of uncertain malignant potential in this series.
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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.Pediatric Dermatology 06/2014; · 1.52 Impact Factor
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ABSTRACT: Melanoma is a lethal melanocytic neoplasm. Unfortunately, the histological diagnosis can be difficult at times. Distinguishing ambiguous melanocytic neoplasms that are benign nevi from those that represent true melanoma is important both for treatment and prognosis. Diagnostic biomarkers currently used to assist in the diagnosis of melanoma are usually specific only for melanocytic neoplasms and not necessarily for their ability to metastasize. Traditional prognostic biomarkers include depth of invasion and mitotic count. Newer diagnostic and prognostic biomarkers utilize immunohistochemical staining as well as ribonucleic acid, micro-ribonucleic acid, and deoxyribonucleic acid assays and fluorescence in situ hybridization. Improved diagnostic and prognostic biomarkers are of increasing importance in the treatment of melanoma with the development of newer and more targeted therapies. Herein, the authors review many of the common as well as newer diagnostic and prognostic biomarkers used in melanoma.Journal of Clinical and Aesthetic Dermatology 06/2014; 7(6):13-24.
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ABSTRACT: Genetic and genomic analyses of melanocytic tumors have yielded new opportunities for improvements in diagnostic accuracy for the distinction of nevus from melanoma and better selection of patients affected by melanoma for targeted treatment. Since chromosomal copy number changes are commonly found in malignant melanoma, but rare in melanocytic nevi, cytogenetic assays have emerged as a promising ancillary study for the workup of melanocytic tumors with ambiguous light microscopic features. Comparative genomic hybridization (CGH) permits assessment of the full set of chromosomes, but requires a significant amount of lesional tissue, and may fail to detect aberrations in a minor subpopulation of tumor cells. Fluorescence in situ hybridization (FISH) is the cytogenetic assay of choice for limited amounts of tissue. FISH targets only specific chromosomes, with inherent limitations in test sensitivity and specificity. FISH analysis is also heavily dependent on individual experience. Molecular studies have identified distinct sets of mutations in melanoma and/or nevi. These mutations have become clinically relevant for targeted therapy of patients with advanced disease, especially for the treatment of patients with metastatic melanoma carrying the BRAF(V600) or KIT mutations. However, mutation analysis can on occasion also be used for diagnostic purposes.Seminars in Diagnostic Pathology 11/2013; 30(4):362-74. · 1.80 Impact Factor