Clinicopathological, Molecular and DNA Methylation Analysis of Ossifying Fibromyxoid Tumors Delineates the ZC3H7B::BCOR Subset as a Distinct Entity

Ossifying fibromyxoid tumor (OFMT) is a rare mesenchymal neoplasm of uncertain lineage of differentiation driven by a broad spectrum of gene fusions. It manifests primarily in soft tissues of the extremities. In this study, we performed a comprehensive clinicopathological, molecular-genetic, and epigenetic analysis of 70 cases of OFMT, with a specific focus on rare fusion subtypes, particularly ZC3H7B::BCOR , PHF1::TFE3 and MEAF6::PHF1 . In addition, we included seven tumors with novel fusions, namely AFF3::PHF1 , PHF1::KLF15 , PHF1::PRKAG1 , CREBBP::PHF1 , EPC1::BMI1 , MEAF6::BCOR , and EP300::BCORL1 . The clinicopathological characteristics revealed a correlation between specific fusions and aggressive clinical behavior; notably, tumors with ZC3H7B::BCOR fusions were always classified as morphologically atypical or malignant and were associated with significantly higher recurrence and metastatic rates compared to other fusion groups, particularly EP400::PHF1 . Immunohistochemical analysis further revealed a distinct immunophenotype in the ZC3H7B::BCOR group. While immunopositivity for cytokeratins and myogenic markers was observed in approximately one-quarter and more than one-third of OFMT cases overall, respectively, ZC3H7B::BCOR -rearranged tumors were negative for both. In contrast, the majority showed immunopositivity for pan-Trk. Additionally, DNA methylation profiling distinguished ZC3H7B::BCOR- rearranged cases from other fusion-positive OFMT, whereas the former clustered closely with a subset of high-grade endometrial stromal sarcomas. This study supports the recognition of ZC3H7B::BCOR -positive tumors as a distinct clinicopathological entity, contributing to the refined molecular taxonomy of this neoplasm.