Gene fusions of Ewing sarcoma breakpoint region 1 (EWSR1) with members of the cAMP response element-binding protein family (CREB) of transcription factors (CREB1, activating transcription factor 1 (ATF1), and cAMP response element modulator (CREM)) have been described in histopathologically diverse mesenchymal neoplasms such as AFH, hyalinising clear cell carcinomas of salivary glands, primary pulmonary myxoid sarcoma, and clear cell sarcoma.
Although some investigators argue that CMCT is a variant of CCS, we think it should be separated from CCS, and subcutaneous/dermal CCS should be confined to tumors with EWSR1-ATF1/ CREB1 fusion.
Gene fusions of Ewing sarcoma breakpoint region 1 (EWSR1) with members of the cAMP response element-binding protein family (CREB) of transcription factors (CREB1, activating transcription factor 1 (ATF1), and cAMP response element modulator (CREM)) have been described in histopathologically diverse mesenchymal neoplasms such as AFH, hyalinising clear cell carcinomas of salivary glands, primary pulmonary myxoid sarcoma, and clear cell sarcoma.
In the new review all the tumors were re-classified as, ES (n=16), Ewing-like tumor with EWSR1 rearrangement and amplification and possible EWSR1-NFATC2 gene fusion (n=1), CIC-rearranged sarcomas or undifferentiated sarcoma, most consistent with CIC-rearranged sarcoma (n=7), sarcoma with BCOR-alteration or undifferentiated sarcoma, consistent with BCOR-associated sarcoma (n=3), neuroblastoma (n=2), unclassifiable neoplasm with neuroblastic differentiation (n=1), malignant rhabdoid tumor (n=2), lymphoblastic lymphoma (n=1), clear cell sarcoma of the gastrointestinal tract (n=1), small cell carcinoma (n=1), sclerosing rhabdomyosarcoma (n=1), desmoplastic small round cell tumor (n=1), malignant peripheral sheath nerve tumor (n=1), poorly-differentiated synovial sarcoma (n=1), Possible gastrointestinal stromal tumor/GIST with predominant round cells (n=1) and possible SMARCA4-deficient-sarcoma (n=1).
Given the high specificity of the EWSR1 FISH assay and significant complexity in the diagnosis of CCS, this ancillary study is helpful in distinguishing CCS from melanoma.
Recurrent gene fusions involving EWSR1 with members of the cAMP response element binding protein (CREB) family (ATF1 and CREB1) have been reported in a diverse group of tumors including angiomatoid fibrous histiocytoma (AFH), soft tissue and gastrointestinal clear cell sarcoma, primary pulmonary myxoid sarcoma, and hyalinizing clear cell carcinoma of salivary gland.
EWSR1 rearrangements were first identified in Ewing sarcoma, but the spectrum of EWSR1-rearranged neoplasms now includes many soft tissue tumour subtypes including desmoplastic small round cell tumour (DSRCT), myxoid liposarcoma (MLPS), extraskeletal myxoid chondrosarcoma (EMC), angiomatoid fibrous histiocytoma (AFH), clear cell sarcoma (CCS) and myoepithelial neoplasms.
Clear cell sarcoma (CCS) of tendons and aponeuroses, also known as melanoma of soft parts, represents an aggressive rare malignancy that is characterized by a nested or fascicular pattern of spindled cells and a pathognomonic reciprocal translocation, t(12;22)(q13;q12), that results in the fusion of EWSR1 and ATF1 genes.
Rearrangements of the EWSR1 gene are found in an increasing number of human neoplasms, including several tumors that can involve the skin: Ewing sarcoma/primitive neuroectodermal tumor, angiomatoid (malignant) fibrous histiocytoma, myoepithelioma of soft tissue, and clear cell sarcoma.
Clear cell sarcoma (CCS) of tendons and aponeuroses, also known as melanoma of soft parts, represents an aggressive rare malignancy that is characterized by a nested or fascicular pattern of spindled cells and a pathognomonic reciprocal translocation, t(12;22)(q13;q12), that results in the fusion of EWSR1 and ATF1 genes.
Fluorescence in situ hybridization confirmed Ewing's sarcoma breakpoint region 1 (EWSR1) rearrangement in 70% of the tumor cells, thereby supporting the diagnosis of metastatic CCS.
The sequencing of obtained fragments revealed the presence of a novel chimerical transcript-the in-frame fusion between EWSR1 exon 7 and ATF1 exon 6 that represents the fourth in-frame type of EWSR1/ATF1 fusion identified in clear cell sarcomas.
The sequencing of obtained fragments revealed the presence of a novel chimerical transcript-the in-frame fusion between EWSR1 exon 7 and ATF1 exon 6 that represents the fourth in-frame type of EWSR1/ATF1 fusion identified in clear cell sarcomas.
In this study, we performed mutation analysis of BRAF and NRAS, investigated the EWSR1 gene rearrangement and evaluated the protein expression of insulin-like growth factor 2 and insulin-like growth factor 1R in 31 cases of malignant melanoma and 16 cases of clear cell sarcoma.