ZFTA::NCOA1/2-Rearranged Epithelioid Mesenchymal Tumor-A Phenotypically Distinct Myoepithelial-Like Neoplasm...

ZFTA (formerly C11orf95) gene rearrangements are recurrent in rare tumors of the central nervous system, such as ependymomas (mostly ZFTA::RELA) and soft tissue tumors, such as chondroid lipomas (ZFTA::MRTFB). To date, among mesenchymal tumors, the ZFTA::NCOA1 fusion has only been reported in a single case of chondroid lipoma. We describe 5 distinct soft tissue tumors harboring ZFTA::NCOA1/2 fusions. The tumors arose from 2 females and 3 males with a median age of 31 years (range, 30-72). All tumors were well circumscribed involving the deep (4 cases) or superficial (1 case) soft tissue of the proximal limbs with a median greatest dimension of 4.2 cm (range, 1.7-6.0). Histologically, they displayed lobulated architecture and were composed of monotonous epithelioid-to-plasmacytoid cells arranged in cords, chains, and nests within myxohyaline or sclerosed stroma. Focal loose myxoid reticulate areas and prominent dilated and hyalinized blood vessels were present. One tumor showed focal spindle cells, whereas another demonstrated necrosis and atypical mitotic figures. Definitive adipocytic, lipoblastic, or clear-cell features were absent, except in 1 case. Immunohistochemistry was nonspecific without any consistent lineage-defining marker expression. Targeted RNA sequencing confirmed ZFTA::NCOA1 fusions in 3 and ZFTA::NCOA2 fusion in 2 cases. DNA methylation profiling, available in 4 cases, demonstrated a shared epigenetic profile with chondroid lipoma but not other tumors with histologic or genetic overlap. Copy number variation analysis showed a flat copy number profile in 3 cases and chr9p arm-level copy number loss in the case with necrosis and mitotic activity. All patients underwent complete excision; no recurrences or metastases were observed over a limited follow-up period (available in 4 cases, range, 8-24 months; median, 10.5 months). In conclusion, ZFTA::NCOA1/2-rearranged epithelioid mesenchymal tumors represent a novel, morphologically distinct entity, genetically and epigenetically overlapping with chondroid lipoma. Expanded cohorts and long-term follow-up are necessary to clarify their precise classification and biologic behavior.