ZC3H7B-BCOR high-grade endometrial stromal sarcomas: a report of 17 cases of a newly defined entity

Abstract

High-grade endometrial stromal sarcoma likely encompasses underrecognized tumors harboring genetic abnormalities besides YWHAE-NUTM2 fusion. Triggered by three initial endometrial stromal sarcomas with ZC3H7B-BCOR fusion characterized by high-grade morphology and aggressive clinical behavior, we herein investigate the clinicopathologic features of this genetic subset by expanding the analysis to 17 such tumors. All of them occurred in adult women with a median age of 54 (range, 28-71) years. They were predominantly based in the endomyometrium and demonstrated tongue-like and/or pushing myometrial invasion. Most were uniformly cellular and displayed haphazard fascicles of spindle cells with mild to moderate nuclear atypia. Myxoid matrix was seen in 14 of 17 (82%) tumors, and collagen plaques were seen in 8 (47%). The mitotic index was ≥10 mitotic figures/10 high-power fields (HPFs) in 14 of 17 (82%) tumors with a median of 14.5 mitotic figures/10 HPFs. No foci of conventional or variant low-grade endometrial stromal sarcoma were seen. All tumors expressed CD10 with only limited or absent desmin, SMA and/or h-caldesmon staining. ER and PR expression in >5% of cells was seen in 4 of 12 (33%) tumors. Diffuse cyclin D1 and BCOR immunoreactivity was present in 7 of 8 (88%) and 7 of 14 (50%) tumors, respectively. Fluorescence in situ hybridization or targeted RNA sequencing confirmed ZC3H7B-BCOR fusion in all tumors, including four and two previously diagnosed as myxoid leiomyosarcoma and undifferentiated uterine sarcoma, respectively. Limited clinical data suggest that patients present at higher stage and have worse prognosis compared with published outcomes in low-grade endometrial stromal sarcoma. Tumors with ZC3H7B-BCOR fusion constitute a distinct group of endometrial stromal sarcomas with high-grade morphology that should be distinguished from other uterine mesenchymal neoplasms that may demonstrate myxoid morphology.

Uterine mesenchymal tumours: recent advances

“…Abundant myxoid matrix and high‐grade spindle cells are absent in HGESS with YWHAE–NUTM2 fusion, except in rare cases that may exhibit myxoid change and pronounced cytological atypia secondary to chemoradiation . ZC3H7B–BCOR fusion‐positive HGESS lacks the round cell component of lesions with BCOR ITD . Absent BCOR staining favours ZC3H7B–BCOR fusion‐positive HGESS over the occasional purely spindled HGESS with BCOR ITD; however, suspected BCOR genetic abnormalities should be confirmed by molecular methods.…”

“…BCOR plays a role in suppressing gene transcription and maintaining tissue homeostasis and gene silencing through epigenetic mechanisms . Fusion involving exons 6 and 7 of BCOR and exons 6, 11 and 10 of ZC3H7B is more frequent than BCOR exon 15 internal tandem duplications (ITD) among HGESS with BCOR aberrations (Figures and ) …”

“…CD10 positivity with absent smooth muscle markers, particularly desmin, in any myxoid lesion should prompt consideration of ZC3H7B–BCOR fusion‐positive HGESS over myxoid LMS. Endometrial and/or nodal involvement also favours HGESS . An inflammatory infiltrate and ALK expression characterise myxoid inflammatory myofibroblastic tumour (IMT) .…”

Novel EPC1 gene fusions in endometrial stromal sarcoma

“…20 Interestingly, the EPC1-B-COR fusion chimera in this case draws together a promotor heretofore associated with low-grade endometrial stromal sarcoma with a gene region heretofore associated with high-grade endometrial stromal sarcoma. EPC1 fusion genes have, to date, been restricted to low-grade endometrial stromal sarcoma.…”

“…The 2014 World Health Organization Classification only recognized tumors harboring the YWHAE-NUTM2 fusion in this group; however, recent studies have also unveiled the high-grade nature of tumors harboring ZC3H7B-BCOR fusion 17,20 and BCOR internal tandem duplication. 21 There is a recent report of JAZF1-BCORL1 in endometrial stromal sarcoma 22 ; however, it is currently unclear whether this is best classified as a low-grade or more likely high-grade endometrial stromal sarcoma.…”