Malignant melanoma is genetically distinct from clear cell sarcoma of tendons and aponeurosis (malignant melanoma of soft parts)

Abstract

Summary Clear cell sarcoma of tendons and aponeuroses (malignant melanoma of soft parts) and conventional malignant melanoma may demonstrate significant morphologic overlap at the light microscopic and ultrastructural level. Consequently, the clinically relevant distinction between primary clear cell sarcoma and metastatic melanoma in the absence of a known primary cutaneous, mucosal or ocular tumour may occasionally cause diagnostic problems. A balanced translocation, t(12;22)(q13;q13), which can be detected, amongst others, using the reverse transcriptase polymerase chain reaction (RT-PCR) or fluorescent in situ hybridization (FISH), has been identified in a high percentage (50-75%) of clear cell sarcomas and is presumed to be tumour specific. Whether this chromosomal rearrangement is present in malignant melanoma has, to date, not as yet been studied by molecular genetic or molecular cytogenetic techniques. Using RT-PCR and FISH, a series of metastases from 25 known cutaneous melanomas and 8 melanoma cell lines (5 uveal and 3 cutaneous) were screened for the t(12;22)(q13;q13) translocation. Primers for RT-PCR were chosen based upon published breakpoint sequences. The Cosmids G9 and CCS2.2, corresponding to the 5′ region of EWS and 3′ region of ATF-1 respectively, were used as probes. The translocation was not identified in any of the melanomas or melanoma cell lines analysed in this study; in contrast this translocation was identified in 3 out of 5 clear cell sarcomas using these techniques. This allows distinction between translocation positive cases of clear cell sarcoma and malignant melanoma at a molecular genetic level. Consequently, in diagnostically challenging cases, this represents a valuable tool for the clinicopathologic differentiation between these two entities, with an important impact on patient management and prognosis.

Molecular genetic characterization of the EWS/ATF1 fusion gene in clear cell sarcoma of tendons and aponeuroses

“…EWS/ATF1 transcript types 1, 2 and 3 had been found in 9, 3 and 1 tumors, respectively. 10,11,[13][14][15][16][17][18][19] In the present study, 3 cases showed multiple transcripts as the result of alternative splicing. The most common fusion transcript was type 1 (EWS exon 8 fused with ATF1 exon 4), found in 8 patients, followed by type 2 (EWS exon 7 fused with ATF1 exon 5), found in 4 patients, though only in 1 case as the sole chimeric transcript (Fig.…”

“…13 To date, only 13 cases of CCS have been analyzed for fusion genes at the transcription level and there is no information about the breakpoints at the genomic level. 10,11,[13][14][15][16][17][18][19] In the present study, we describe the molecular genetic characteristics of CCS from 10 patients.…”

Dual-color, break-apart fluorescence in situ hybridization for EWS gene rearrangement distinguishes clear cell sarcoma of soft tissue from malignant melanoma

“…6 At the molecular level, alterations of the p16INK4a/ p14ARF pathway are present in both clear cell sarcoma and malignant melanoma. 25 Although originally reported to be genetically distinct from malignant melanoma, 16 recent genomic profiling data suggest that clear cell sarcoma is a subtype of melanoma. 26 However, in contradistinction to malignant melanoma, clear cell sarcoma harbors EWS gene rearrangements in up to 90% of cases.…”

“…26 However, in contradistinction to malignant melanoma, clear cell sarcoma harbors EWS gene rearrangements in up to 90% of cases. [11][12][13][14][15][16][17][18][19]27 Thus, translocations involving EWS are diagnostically useful for distinguishing clear cell sarcoma from its most important mimic malignant melanoma. 19 Although not a hypothesis tested in this study, clear cell sarcoma could conceivably be distinguished from benign melanocytic proliferations that mimic malignant melanoma, such as cellular blue nevi, deep penetrating nevi, and proliferative nodules arising within congenital nevi, as these lesions have not been reported to contain EWS gene rearrangements.…”

“…2,[6][7][8][9][10] In contrast to malignant melanoma, a unique and recurrent t(12;22)(q13;q12) involving the EWS gene has been identified in 70% to over 90% of clear cell sarcomas by cytogenetics, reverse-transcriptase polymerase chain reaction (RT-PCR) looking for the resultant EWS-ATF1 fusion protein, and by fluorescence in situ hybridization (FISH). [11][12][13][14][15][16][17][18][19] Clear cell sarcoma is rare and the true incidence of this neoplasm is not well established; however, the increased utilization of molecular studies for the …”