Reappraisal of soft tissue myoepithelial tumors by DNA methylation profiling reveals an epigenetically distinct group of mostly fusion-driven neoplasms.

Soft tissue myoepithelial tumors (METs) are diagnostically challenging tumors that require careful histologic and immunohistochemical characterization for accurate classification. Nearly half of METs show recurrent EWSR1 or FUS gene rearrangements with a diverse set of fusion partners. The diversity of fusion partners and lack of known driver abnormalities in many cases raises the question of whether METs represent a uniformly distinct tumor entity. To address this question, we performed careful histopathologic and molecular analysis, including DNA methylation profiling (DNA-MP) and fusion testing, on a cohort of 30 institutionally diagnosed METs from 29 patients. On histologic and immunophenotypic evaluation, 22 of 30 tumors diagnosed as MET fulfilled strict histologic and immunophenotypic criteria. Among those failing to meet criteria, most were reclassified as another tumor entity by DNA-MP. Seven tumors meeting criteria grouped with another sarcoma reference type by DNA-MP, with confirmation of the characteristic driver abnormality of that tumor in selected cases. The remaining tumors histologically "consistent" with METs (n = 15) formed a distinct epigenetic cluster, independent of other reference entities. Recurrent gene fusions were identified in 11 of 15 tumors in this epigenetically distinct group, including EWSR1::KLF15 (n = 4), EWSR1::PBX3 (n = 2), and EWSR1::POU5F1 (n = 1) rearrangements. Clinicopathologic correlation suggests that EWSR1::KLF15 tumors are enriched in pediatric patients with aggressive histology. Our work shows that at least a subset of METs falls within an epigenetically distinct but heterogenous group. Furthermore, DNA-MP provides a useful adjunct to other molecular testing to help distinguish METs from histologic mimics.