Malignant epithelioid mesenchymal neoplasms with EWSR1/FUS::CREM fusions: clinicopathological and molecular genetic analysis of seven cases highlighting immunophenotypic heterogeneity, frequent aggressive behaviour, and diagnostic pitfalls.
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AIMS: Tumours harbouring FET::CREB fusions, particularly those involving EWSR1/FUS and CREM, represent an emerging group that is distinct from and unclassifiable into established categories such as angiomatoid fibrous histiocytoma, clear cell sarcoma of soft tissue, or malignant gastrointestinal neuroectodermal tumour. This study aims to further delineate the clinicopathological, immunohistochemical, and molecular features of these rare mesenchymal neoplasms with EWSR1/FUS::CREM fusions, focusing on diagnostic challenges and aggressive potential. METHODS AND RESULTS: We analysed seven cases of mesenchymal neoplasms with EWSR1/FUS::CREM fusions through detailed clinicopathological evaluation, extensive immunohistochemical profiling, and molecular genetic analysis [RNA sequencing and fluorescence in situ hybridization (FISH)]. The cohort included five females and two males (age range: 5-55 years) with tumours involving diverse intra-abdominal and extra-abdominal locations. Histologically, all tumours were composed predominantly of monomorphic epithelioid to round cells, with one case showing focal spindling. The neoplastic cells were arranged in solid sheets, nests, and trabeculae, set within a variably collagenous stroma. Mitotic activity was variable, and tumour necrosis was present in two cases. A prominent lymphoplasmacytic infiltrate was noted in three cases. Immunohistochemistry revealed a strikingly heterogeneous profile, which directly led to a wide spectrum of initial misdiagnoses. These included: epithelial malignant mesothelioma in two intra-abdominal tumours co-expressing AE1/AE3 and WT1; Ewing sarcoma in one CD99-positive tumour; a sex cord-stromal tumour in one ovarian neoplasm co-expressing S100, SOX10, and α-inhibin; epithelioid hemangioendothelioma in one case co-expressing CD34 and ERG; a neurogenic tumour in one case with synaptophysin expression; and metastatic carcinoma in a lymph node in one case, which was misdiagnosed due to diffuse expression of AE1/AE3 and a dense lymphoplasmacytic infiltrate mimicking a nodal metastasis. Molecular analysis via targeted RNA sequencing identified in-frame EWSR1::CREM fusions in five cases and a FUS::CREM fusion in two cases, all of which were confirmed by FISH. Clinically, two patients presented with disseminated disease, and all three with follow-up had aggressive courses (recurrence or metastasis). CONCLUSIONS: Our series solidifies epithelioid mesenchymal neoplasms with EWSR1/FUS::CREM fusions, which constitute a distinct sarcoma characterized by a misleading immunophenotype, with potential for aggressive clinical behaviour. Accurate diagnosis requires molecular confirmation to avoid diagnostic pitfalls and guide management.