Sclerosing epithelioid fibrosarcoma with initial presentation as pulmonary masses: clinicopathological...

Sclerosing epithelioid fibrosarcoma (SEF) initially presenting as pulmonary masses is exceptionally rare, and pathological diagnosis based on lung biopsy specimens is challenging. To enhance the understanding of its clinicopathological characteristics and improve diagnostic accuracy, we performed a comprehensive analysis of four such cases, including clinical, radiological, histological, immunohistochemical, and molecular characteristics. The mean age was 43 years, comprising three females and one male. Radiologically, the lesions appeared as solitary or multiple pulmonary masses. Morphologically, in addition to the classic appearance of monomorphic epithelioid cells in cords, nests, or sheets within a sclerotic stroma, the tumours also displayed alveolar-like architecture, pseudoalveolar pattern, adenofibroma-like morphology, and spread through air spaces (STAS). Significant pleomorphism and necrosis were observed in some cases, and the stroma could be collagen-poor or lymphocyte-rich. Morphological mimicry was evident: the tumours resembled adenofibroma when entrapping respiratory epithelium, lymphoma in lymphocyte-rich areas, neuroendocrine tumours in biopsies containing compressed atypical cells, and normal alveoli when arranged in an alveolar-like architecture. Immunohistochemically, all cases were positive for MUC4. Molecular analysis revealed EWSR1 rearrangement by fluorescence in situ hybridisation (FISH) in two cases. Notably, one case showed a deletion of chromosome 22 and no EWSR1 rearrangement by FISH, but harboured an EWSR1::CREB3L2 fusion by next-generation sequencing (NGS). Furthermore, a separate case exhibited FUS rearrangement independent of EWSR1 involvement. This study demonstrates the diverse morphological characteristics of SEF initially presenting as pulmonary masses and highlights key diagnostic challenges, which may contribute to improved diagnostic accuracy for such lesions.