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

MEF2D::NCOA2 fusion was recently reported in two vulvovaginal myxoid epithelioid smooth muscle tumors. We aimed to performed an integrated approach combining clinical, morphological, immunohistochemical, and molecular profiling analyses, including targeted-RNA-sequencing, targeted-gene expression analysis profiling with clustering, DNA mutational analysis, and array comparative genomic hybridization (aCGH) in a series of three MEF2D::NCOA2 fusion-associated vulvovaginal tumors, to better described 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 SMT 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. Cytological 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 aCGH found simple genomic profiles for all tumors (3/3, 100%). On targeted-gene expression analysis, MEF2D::NCOA2 fusion-associated tumors clustered distinctly from other gynecological mimickers and neoplasms with myxoid stromal changes (vulvovaginal leiomyomas, myxoid-vulvovaginal leiomyomas, deep angiomyxomas, myxoid-leiomyosarcomas, myxoid-endometrial stromal sarcomas, 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 patient 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.