YAP1::KMT2A-rearranged sarcomas harbor a unique methylation profile and are distinct from sclerosing epithelioid fibrosarcoma and low-grade fibromyxoid sarcoma

Sclerosing epithelioid fibrosarcoma (SEF) was originally described as a peculiar variant of fibrosarcoma in 1995. Subsequent studies showed that conventional SEF was associated with both immunohistochemical expression of MUC4 and EWSR1/FUS gene rearrangements with CREB3L1 as the predominant fusion partner. Since then, a distinct group of fibrous tumors characterized by YAP1::KMT2A and KMT2A::YAP1 gene rearrangements and SEF-like morphology has been described. These YAP1::KMT2A-rearranged sarcomas were further shown to lack both immunohistochemical expression of MUC4 and canonical EWSR1/FUS gene rearrangements. To better understand whether the YAP1::KMT2A-rearranged sarcomas represent a subset of MUC4-negative SEF or a distinct entity, we studied 22 cases of YAP1::KMT2A-rearranged sarcomas, the largest series to date, and performed a literature review of all previously reported next-generation sequencing (NGS)-confirmed cases. These sarcomas often arose in young adults with a median age of 38 years and a male to female (M:F) ratio of 1.4:1. They predominantly involved somatic soft tissue; however, we report the first case of a tumor that primarily developed inside bone. Immunohistochemical studies showed that the tumors often demonstrated expression of YAP1 and EMA, while all tested cases were negative for MUC4. NGS confirmed the presence of YAP1::KMT2A gene fusions in all cases, some of which initially had false negative results with targeted FISH and solid tumor panel testing. Clinical follow-up information was available in 14 patients with a median follow-up of 25 months (range 1 to 170 months). Local recurrence occurred in three patients (21%) and metastasis developed in seven patients (50%). DNA methylation analysis further showed that YAP1::KMT2A-rearranged sarcomas formed a distinct cluster, which was clearly separate from both conventional SEF and low-grade fibromyxoid sarcoma (LGFMS). These results suggest that YAP1::KMT2A-rearranged sarcomas likely represent a unique sarcoma subtype with propensity for aggressive behavior.