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Am J Surg Pathol. 2019 Jul;43(7):928-942. doi: 10.1097/PAS.0000000000001265.

Clinicopathologic Characterization of GREB1-rearranged Uterine Sarcomas With Variable Sex-Cord Differentiation.

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Department of Laboratory Medicine and Pathology, University of Alberta and Royal Alexandra Hospital, Edmonton, AB, Canada.
Department of Pathology, Shuang Ho Hospital, Taipei Medical University.
Department and Graduate Institute of Pathology, National Taiwan University Hospital, National Taiwan University College of Medicine.
Institute of Epidemiology and Preventive Medicine, Department of Public Health, National Taiwan University.
Department of Pathology, Taitung MacKay Memorial Hospital, Taitung, Taiwan.
Department of Pathology and Laboratory Medicine, Tri-Service General Hospital, National Defense Medical Center.
Department of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung.
Joint Biobank, Office of Human Research, Taipei Medical University, Taipei.
Department of Pathology, Fu Jen Catholic University Hospital and Fu Jen Catholic University College of Medicine, New Taipei City.
Department of Oncology, National Taiwan University Hospital, National Taiwan University Cancer Center, Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei.
Department of Pathology & Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.


Uterine mesenchymal tumors are genetically heterogenous; those with uniform cytomorphology, best exemplified by endometrial stromal tumors, often contain various fusion genes. Novel fusions involving ESR1 and GREB1, key factors in sex hormone pathways, have been implicated in rare uterine mesenchymal tumors. Particularly, the fusions between 5'-ESR1/GREB1 and 3'-NCOA2/NCOA3 were recently identified in 4 uterine tumors resembling ovarian sex-cord tumor (UTROSCT). By RNA sequencing, pathology review, and FISH screening, we identified 4 uterine sarcomas harboring rearranged GREB1, including GREB1-NCOA2 and the novel GREB1-NR4A3, GREB1-SS18, and GREB1-NCOA1, validated by RT-PCR and/or FISH. They occurred in the myometrium of postmenopausal women and were pathologically similar despite minor differences. Tumor cells were generally uniform and epithelioid, with vesicular nuclei and distinct to prominent nucleoli. Growth patterns included solid sheets, trabeculae/cords, nests, and fascicles. Only 1 tumor showed small foci of definitive sex-cord components featuring well-formed tubules, retiform structures, Leydig-like cells, and lipid-laden cells and exhibiting convincing immunoreactivity to sex-cord markers (calretinin, α-inhibin, and Melan-A). In contrast, all the 4 classic UTROSCT we collected occurred in premenopausal patients, consisted predominantly of unequivocal sex-cord elements, prominently expressed multiple sex-cord markers, and harbored ESR1-NCOA3 fusion. Combined with previously reported cases, GREB1-rearranged tumors involved significantly older women (P=0.001), tended to be larger and more mitotically active, showed more variable and often inconspicuous sex-cord differentiation, and appeared to behave more aggressively than ESR1-rearranged UTROSCT. Therefore, these 2 groups of tumors might deserve separate consideration, despite some overlapping features and the possibility of belonging to the same disease spectrum.

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