High‐Grade Uterine Sarcoma: First Report of a <i>MEIS2::FOXO4</i> Fusion

Uterine sarcomas are uncommon mesenchymal neoplasms ranging from low- to high-grade or undifferentiated. High-grade sarcomas are characterized by various morphologic, immunohistochemical, and molecular alterations. Here, we report the first description of a patient with uterine sarcoma with a MEIS2::FOXO4 fusion. This tumor showed alternating fascicular and diffuse architecture with a prominent nodular growth displaying striking hyalinization and less prominent myxoid background admixed with more cellular internodular areas. The neoplastic cells ranged from spindled to stellate to epithelioid and exhibited variable cytologic atypia and mitotic activity. Immunohistochemical stains showed diffuse expression of smooth muscle actin, preserved expression of PTEN, ATRX, and Rb1, wild-type expression of p53, weak expression of PLAG1, multifocal expression of MDM2, and no reactivity for desmin. RNA sequencing detected a MEIS2::FOXO4 gene fusion with breakpoints at MEIS2 exon 6 and FOXO4 exon 2. Although this gene fusion has been described in other soft tissue neoplasms, it has not been previously reported in uterine sarcomas and highlights the significance of performing molecular analysis in uterine mesenchymal tumors with unusual morphology and/or immunophenotype.