Malignant epithelioid tumors with EWSR1::CREB fusion involving the kidney: a report of two cases

Soft tissue tumors with EWSR1/FUS fusion to genes encoding the cyclic adenosine monophosphate response element-binding (CREB) transcription factor family (ATF1, CREB1, and CREM) are rare and heterogeneous aggressive tumors, often found in the peritoneal cavity. Here, we report two cases of malignant epithelioid tumors with EWSR1::CREB fusion involving the kidney in females in their 30 s. Both tumors appeared as solitary masses, measuring 5.4 cm and 4.0 cm in diameter. Histologically, the tumors were similar, growing invasively with unclear boundaries and composed of epithelial cells with eosinophilic and clear cytoplasm arranged in sheets, nests, and trabeculae. Immunohistochemically, case 1 showed focal AE1/AE3 positivity, whereas case 2 was negative. Anaplastic lymphoma kinase was diffusely positive in case 1 and focally positive in case 2. Both cases were positive for epithelial membrane antigen, mucin-4, and synaptophysin. High-throughput sequencing identified EWSR1::CREM fusion in case 1, whereas fluorescence in situ hybridization detected EWSR1::CREB1 fusion in case 2. These cases expand the morphological and immunophenotypic characteristics of malignant epithelioid tumors with EWSR1::CREB fusion, highlighting the diagnostic challenges of immunohistochemistry and value of molecular testing for accurate diagnosis.