Unusual morphologic features in molecularly defined high-grade sarcomas of the uterus

Herein we describe unusual or rare morphologic features in two high-grade uterine sarcomas with novel or uncommon genetic alterations, to bring attention to their morphologic diversity, diagnostic challenges, and potential therapeutic implications. We report an uterine sarcoma with a FGFR1::TACC1 fusion, the third reported case in the literature, exhibiting epithelioid morphology not previously documented and negativity for S100 and CD34 immunohistochemistry (IHC). We also report an uterine sarcoma with a novel ACOT7::ERBB4 fusion, which displayed spindle cell morphology and osteosarcomatous differentiation. S100 and SOX10 IHC were both negative. Molecular testing was highly informative in reaching a diagnosis in both cases, due to the unusual morphology and limited immunohistochemical support. Clinical follow-up revealed aggressive behavior in both cases, demonstrated by rapid disease progression and metastatic spread. These two cases expand on the known histologic and molecular spectrum of uterine mesenchymal neoplasms with tyrosine kinase receptor gene fusions. Recognition of these entities is important for appropriate classification, prognostication, and identification of patients eligible for targeted therapies such as TRK or FGFR inhibitors.