"Fibrosarcoma-like" Tumors of the Gynecologic Tract Show Distinct Molecular Subgroups: Tyrosine Kinase Fusions and...

In recent years, rare fibrosarcoma-like tumors have been identified in the gynecologic tract characterized by variable CD34 and S-100 positivity and recurrent tyrosine kinase gene fusions in many cases. We identified 17 of these tumors by searching for gynecologic sarcomas expressing S-100 and/or CD34 and supplementing these with cases contributed by collaborating institutions. Tumors involved the uterine cervix (n=11), uterine corpus (n=4), and vagina (n=2). Patients ranged from 28 to 64 (median: 50) years. Fifteen tumors showed overlapping morphologic features including haphazard or fascicular growth of relatively monotonous spindled to ovoid cells with minimal to moderate cytoplasm. Tyrosine kinase gene fusions were identified in 9 tumors, including NTRK fusions in 6 and COL1A1::PDGFB in 3 tumors. Oncogenic variants in ERBB2/ERBB3 were identified in 6 additional tumors. These two subgroups showed distinct immunohistochemical profiles, with all tyrosine kinase fusion-positive tumors being CD34 positive, variably S-100 positive, and SOX10 negative. In contrast, the ERBB-altered tumors were CD34 negative and diffusely positive for S-100 and SOX10. The remaining 2 tumors showed morphologic and immunohistochemical overlap with the tyrosine kinase fusion-positive sarcomas; one was negative for fusion or sequence variants, and sequencing failed in the other. In conclusion, most fibrosarcoma-like tumors of the gynecologic tract are defined by either tyrosine kinase fusions or ERBB2/3 mutations. Immunohistochemistry can be used to predict these subgroups to guide confirmatory genetic testing and targeted therapies.