Uterine Sarcomas with Recurrent KDM2B Gene Fusions: Three Cases of a Possible Novel Subtype of High-Grade Endometrial Stromal Sarcoma.

The advent of widespread genomic testing of uterine mesenchymal tumors has led to novel insights into the biology of these diverse tumors, and many genomically-defined entities have been described in recent years. During a larger study of endometrial stromal sarcomas and unclassified uterine sarcomas, we identified three tumors harboring KDM2B gene fusions. Patients were 32, 61, and 67 years old and all initially underwent incomplete sampling via laparoscopic myomectomy (n=1), laparoscopic biopsy (n=1), or hysteroscopic myomectomy (n=1). One patient's tumor was densely adherent to the pelvic sidewall; she was treated with chemotherapy and died of widely metastatic disease at 29 weeks. Another underwent subsequent recent hysterectomy with tumor confined to the uterus and minimal follow-up to date. The final patient refused further treatment and was alive at 28 weeks, although the status of their disease progression was unknown. On microscopic examination, two tumors showed infiltrative borders while interface with the myometrium was not present in the third. The tumors were variably cellular with alternating hypercellular and hypocellular zones in a myxoid to loosely collagenous stroma. The hypercellular areas contained round to ovoid cells in diffuse (n=3) and sex cord-like arrangements including cords (n=3), nests (n=2), and tubules (n=1); two also contained occasional spindled cells arranged in vague fascicles. These cells showed moderate atypia with open chromatin, numerous mitoses (8, 24, and 25 per 10 high power fields), and frequent apoptoses. The hypocellular areas contained sparse ovoid to spindled cells with minimal atypia. All tumors were diffusely positive for cyclin D1 while BCOR was diffusely positive in one and negative in two; desmin and caldesmon were negative in all three neoplasms. All harbored KDM2B gene fusions; partner genes included EPC1, EP400, and CITED1. MDM2 amplification was also noted in two. Clustering analysis based on RNA expression profiling revealed tight clustering of all three tumors within the broad group of high-grade endometrial stromal sarcomas. Based on the overall clinicopathologic and genomic features, we suggest that these tumors may represent a novel subtype of uterine sarcoma and may be best classified as high-grade endometrial stromal sarcoma, although additional confirmatory studies are needed.