Extrauterine RAD51B-Rearranged Soft Tissue Tumors

A subset of uterine smooth muscle tumors and PEComas has been recently shown to harbor RAD51B rearrangement. To date, occurrence of RAD51B -rearranged mesenchymal neoplasms in sites outside the uterus is exceedingly rare. In this study, we describe a series of 10 extrauterine RAD51B -rearranged soft tissue tumors to further expand the clinicopathologic and molecular spectrum of this emerging entity. Patients included 4 males and 6 females with age at presentation ranging from 4 months to 72 years (median: 53.5 y). Seven tumors occurred in the somatic soft tissues, including the scalp, nuchal region, abdominal wall, perineum, vulva, pelvic cavity, and palm. Three tumors originated in non-uterus visceral organs, including the lung, gastric cardia, and kidney. Grossly, they ranged from 2 to 20 cm (median, 7 cm) in size. Histologically, 5 cases were composed predominantly of round to epithelioid cells, whereas 4 cases consisted of spindled to ovoid cells and 1 case comprised of primitive small round cells. Tumor cells showed variable degree of cytological atypia, pleomorphism, and mitotic activity. By immunohistochemistry, among the 10 cases, 9 showed variable expression of at least one myogenic marker (smooth muscle actin, desmin, and h-caldesmon), 4 expressed at least 2 markers, and 2 were positive for all 3 markers. None of the tumors expressed melanocytic markers (HMB45, Melan-A). One case did not show any cell lineage differentiation. Targeted RNA-sequencing identified CEP170 :: RAD51B fusion in 6 cases, and NUDT3::RAD51B, PUM1 :: RAD51B, RBM43::RAD51B, ZFYVE26::RAD51B fusion in 1 case each. RAD51B rearrangement was confirmed by subsequent fluorescence in situ hybridization analysis. Targeted DNA-sequencing performed in 8 cases revealed pathogenic/likely pathogenic variants in 3 cases, involving TERT , CDKN2A , TP53 , RB1 , CDH4 , and NF1 genes, liked to high-grade morphology and aggressive behavior. DNA methylation profiling demonstrated that RAD51B -rearranged soft tissue tumors form a distinct epigenetic cluster separate from leiomyosarcoma, leiomyoma, and angioleiomyoma/myopericytoma, supporting their classification as a unique molecular subtype. At follow-up, 3 patients (30%) died of disease, whereas the other 7 patients were alive without disease. Our study demonstrates that RAD51B -rearranged soft tissue tumors represent a distinct clinicopathologic entity with a broad morphologic spectrum. Despite significant heterogeneity in histology and biological behavior, the shared DNA methylation profile underpins their unified identity. RAD51B -rearranged soft tissue tumors should be included in the differential diagnosis of morphologically undifferentiated or unclassified mesenchymal neoplasms with myogenic differentiation.