Abstract
Clear cell sarcoma (CCS) usually arises in the lower extremities of young adults and is typically associated with a t(12;22) translocation resulting in the fusion of EWS (EWSR1) with ATF1, a gene encoding a member of the cyclic AMP-responsive element binding protein (CREB) family of transcription factors. CCS arising in the gastrointestinal tract is rare and its pathologic and molecular features are not well defined. We report a novel variant fusion of EWS to CREB1, a gene at 2q32 encoding another CREB family member highly related to ATF1, detected in three women with gastrointestinal CCS. All three cases contained an identical EWS-CREB1 fusion transcript that was shown by reverse transcription-PCR. In two of the cases tested, EWS gene rearrangement was also confirmed by fluorescence in situ hybridization and the EWS-CREB1 genomic junction fragments were isolated by long-range DNA PCR. Morphologically, all three tumors lacked melanin pigmentation. By immunohistochemistry, there was a strong and diffuse S100 protein reactivity, whereas all melanocytic markers were negative. Ultrastructurally, two of the cases lacked melanosomes. The melanocyte-specific transcript of MITF was absent in two cases, and only weakly expressed in the third case. The Affymetrix gene expression data available in one case showed lower expression of the melanocytic genes MITF, TYR, and TYRP1, compared with four EWS-ATF1-positive CCSs of non-gastrointestinal origin. EWS-CREB1 may define a novel subset of CCS that occurs preferentially in the gastrointestinal tract and shows little or no melanocytic differentiation. Thus, evidence of melanocytic lineage or differentiation is not a necessary feature of sarcomas with gene fusions involving CREB family members.
Highlights
Clear cell sarcoma (CCS), known as melanoma of soft parts, typically presents in the deep soft tissues of the lower extremity, in close proximity to tendons, fascia, or aponeuroses
We report three cases of CCS of the gastrointestinal tract showing distinctive pathologic and molecular characteristics compared with their soft tissue counterparts, including lack of melanocytic differentiation and the presence of a novel EWS-CREB1 fusion transcript
The classic cytogenetic hallmark of CCS, first described in cases arising in somatic soft tissues, is a recurrent t(12;22)(q13;q12) translocation, resulting in the EWS-activating transcription factor-1 gene (ATF1) fusion [3, 5, 6], an alteration which was, until recently, not observed in any other tumor type
Summary
Clear cell sarcoma (CCS), known as melanoma of soft parts, typically presents in the deep soft tissues of the lower extremity, in close proximity to tendons, fascia, or aponeuroses. CCS are genetically distinct from melanomas, as they lack BRAF mutations [2] and show, in most cases, a recurrent chromosomal translocation t(12;22)(q13;q12),. Gastrointestinal CCS includes a histologic variant rich in osteoclast-type giant cells which uniformly express S100 protein, but lack melanocytic differentiation by immunohistochemistry, being negative for HMB45 and Mart-1 [9]. As a result of its rarity in the gastrointestinal tract, the differential diagnosis of CCS in this site includes more common mesenchymal or neuroectodermal neoplasms, such as gastrointestinal stromal tumors, schwannoma, carcinoid, or metastatic melanoma. We report three cases of CCS of the gastrointestinal tract showing distinctive pathologic and molecular characteristics compared with their soft tissue counterparts, including lack of melanocytic differentiation and the presence of a novel EWS-CREB1 fusion transcript
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