The MEF2D::NCOA2 Fusion Defines a Distinct Emerging Vulvovaginal Myxoid Epithelioid Tumor With Smooth Muscle Differentiation

Myocyte-specific enhancer factor 2D gene and nuclear receptor coactivator 2 gene fusion (MEF2D::NCOA2) was recently reported in 2 vulvovaginal myxoid epithelioid smooth muscle tumors. We aimed to perform an integrated approach combining clinical, morphologic, immunohistochemical, and molecular profiling analyses, including targeted RNA sequencing, targeted gene expression analysis profiling with clustering, DNA mutational analysis, and array comparative genomic hybridization in a series of 3 MEF2D::NCOA2 fusion-associated vulvovaginal tumors, to better describe this entity. The median age at diagnosis was 45 years. Tumors were well circumscribed and located deeply within the vulva, vaginal wall, or between the bladder and the vagina (1/3, 33.3% each). The median size of tumors was 2.5 cm. All tumors had a similar morphology, reminiscent of smooth muscle tumor with prominent myxoid stromal changes (3/3, 100%). Tumor cells were haphazardly arranged in short fascicles and were mostly spindle cells. Microcystic spaces lined by epithelioid cells and/or sheets of epithelioid cells were observed in all tumors (3/3, 100%), associated with a myxoid background. Cytologic atypia was none to mild, and the mitotic counts were always low (≤1 mitosis/high-power fields). Immunohistochemistry found smooth muscle actin, desmin, h-caldesmon, estrogen receptors, and CD34 to be intensely and diffusely expressed in all tumors (3/3, 100%). A MEF2D::NCOA2 transcript was observed in all tumors (3/3, 100%), which was the driver of molecular alteration. No pathogenic variants were found, and array comparative genomic hybridization found simple genomic profiles for all tumors (3/3, 100%). On targeted gene expression analysis, MEF2D::NCOA2 fusion-associated tumors clustered distinctly from other gynecologic mimickers and neoplasms with myxoid stromal changes (vulvovaginal leiomyomas, myxoid vulvovaginal leiomyomas, deep angiomyxomas, myxoid leiomyosarcomas, myxoid endometrial stromal sarcomas, and inflammatory myofibroblastic tumors). The signaling pathways involved in this entity included the expression of genes encoding smooth muscle phenotype proteins, favoring a smooth muscle (myoid) differentiation. All patients were alive and free of disease at the last follow-up. To conclude, vulvovaginal MEF2D::NCOA2 fusion-associated tumors are distinct and emerging entities, with a rather indolent behavior.