Uterine Leiomyosarcoma with a Novel RAB2A-PLAG1 Gene Fusion

Abstract Introduction/Objective Uterine leiomyosarcoma is a malignant neoplasm with three distinct histologic subtypes: spindle, epithelioid, and myxoid. Distinguishing leiomyosarcoma from mesenchymal uterine neoplasms such as endometrial stromal sarcoma can be challenging as they may exhibit a similar histology and immunohistochemical profile. In such cases, molecular studies can help achieve the definitive diagnosis. It has been shown that ~25% of the uterine myxoid leiomyosarcomas harbor TRPS1-PLAG1 and RAD51B-PLAG1 gene fusions. To our knowledge, no uterine leiomyosarcoma with RAB2A-PLAG1 gene fusion has been previously reported in the English literature. Methods/Case Report An 80-year-old woman presented with abnormal uterine bleeding. A large necrotic uterine mass with no evident lymphadenopathy was detected on imaging. Endometrial curettage demonstrated a malignant mesenchymal neoplasm that was positive for CD10, desmin, and vimentin and lacked expression of SMA, SMMH, synaptophysin, and chromogranin. AE1/AE3 highlighted rare foci. The patient underwent total hysterectomy with bilateral salpingo-oophorectomy. The hysterectomy specimen was notable for a 10.8 cm rubbery focally calcified tan- white mass histologically composed of high-grade spindle and epithelioid cells with hypocellular and hyalinized areas. The mitotic activity was >25/10HPF. Immunohistochemically, the neoplastic cells expressed CD10, caldesmon, desmin (patchy), SMA (weak focal), and CAM5.2 (patchy) while they were negative for ER, PR, HMB45, AE1/AE3, WT1, cyclin D1, BCOR, myogenin, pan-NTRK, and ALK. P53 staining showed a wild type expression pattern. Histology and immunohistochemistry could not definitively differentiate between leiomyosarcoma and high grade endometrial stromal sarcoma. RNA sequencing identified a RAB2A-PLAG1 gene fusion. In light of the histology and ancillary studies, a diagnosis of leiomyosarcoma was rendered. Results (if a Case Study enter NA) NA Conclusion This is the first case of a uterine leiomyosarcoma with RAB2A-PLAG1 gene fusion. Pathologists should be cognizant of the extensive morphologic and immunophenotypic overlap between various uterine mesenchymal neoplasms. In challenging cases, molecular analysis is crucial in allowing the pathologist to arrive at the final diagnosis.