Abstract

Background: Fusions between the EWSR1 gene and CREB family transcription factors have been reported in a variety of rare tumor types, including the head and neck tumors clear cell odontogenic carcinoma (CCOC) and clear cell carcinoma (CCC) of the salivary gland.

Objective: To review the current literature on tumors where EWSR1-CREB fusions have been reported (i.e., EWSR1-ATF1, -CREB1, -CREM) that may act as surrogates for clear cell odontogenic carcinoma (CCOC) and clear cell carcinoma (CCC) of the salivary gland given their rarity.

Methods: The PubMed database was searched for tumors bearing EWSR1 and CREB family transcription factor fusions. The search was conducted independently by two authors between the publication dates of 1985 and 2021. Search parameters included but were not limited to “EWSR1-ATF1,” “EWSR1-CREB1,” and “EWSR1-CREM.” Data collected included tumor name, EWSR1 translocation partner, histology, immunohistochemical (IHC) markers, presence of clear cells, patient demographics and anatomic location when available.

Results: A total of 103 articles were reviewed and 17 different types of tumors (CCOC and CCC included) were identified. The following 6 were found to consistently bear the same translocations characteristic of CCOC and CCC: angiomatoid fIbrous histiocytoma (AFH), clear cell sarcoma (CCS), clear cell sarcoma-like tumor of the gastrointestinal tract (CCSLTGT), intracranial myxoid mesenchymal tumor (IMMT), malignant gastrointestinal neuroectodermal tumor (M-GNET), and primary pulmonary myxoid sarcoma (PPMS). The remaining 9 tumors were either inconsistently identified or rarely harbored and EWSR1-CREB fusion: angiosarcoma, atypical central neurocytoma, malignant epithelioid tumor of the peritoneal cavity, malignant mesothelioma, neuroendocrine neoplasm, primary intracranial neoplasm, pulmonary mesenchymal tumor, small blue round cell tumor and soft tissue myoepithelial tumor.

Conclusion: EWSR1-CREB fusions have been reported in many tumor types and our review of the literature shows that these fusions are a consistent finding in a smaller set of 6 diagnostic entities in addition to CCOC and CCC. While these tumors exhibit differences in demographics, anatomic location and immunohistochemical profiles, the high frequency of EWSR1-CREB fusions suggests that they may be driven by similar oncogenic mechanisms. Identifying similarities among these rare tumor types may thus be advantageous for gaining insights into their pathogenesis.

Keywords: CCOC; CCS; CCC; EWSR1; CREB1; CREM; ATF1; fusion