Undifferentiated Uterine Sarcomas Represent Under-Recognized High-grade Endometrial Stromal Sarcomas

Abstract

Undifferentiated uterine sarcoma is a diagnosis of exclusion with limited molecular genetic data available. Recent recognition of high-grade endometrial stromal sarcomas with diverse genotypes suggests that some tumors classified as undifferentiated uterine sarcomas may represent misdiagnosed high-grade endometrial stromal sarcomas. Archival material from 10 tumors diagnosed as undifferentiated uterine sarcomas in 2009-2017 were collected. BCOR immunohistochemistry and fluorescence in situ hybridization (FISH) using break-apart probes flanking BCOR, ZC3H7B, CCNB3, YWHAE, NUTM2, JAZF1, and BCORL1 were performed.

Uterine mesenchymal tumours: recent advances

“…These findings suggest that LMS variants, recently described fusion‐driven sarcomas and other possibly distinctive clinicopathological entities with as‐yet undiscovered translocations probably contribute to the perceived morphological and genetic diversity of UUS. Similar observations were made in our separate study, which showed that 70% of UUS were in fact misdiagnosed HGESS harbouring YWHAE – NUTM2 , ZC3H7B–BCOR and BRD8‐PHF1 fusions as well as BCOR ITD by FISH and targeted RNA sequencing . These mutations were found among tumours showing uniform cytological atypia.…”

“…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. Most tumours classified as UUS, at least for the subset composed of cells with uniform nuclear features, represent misdiagnosed HGESS with known genetic abnormalities and as such, UUS should be a diagnosis of exclusion . BCOR expression in ≥50% of tumour cells corresponds to the presence of BCOR fusion or ITD in almost 90% of previously diagnosed UUS …”

“…Most tumours classified as UUS, at least for the subset composed of cells with uniform nuclear features, represent misdiagnosed HGESS with known genetic abnormalities and as such, UUS should be a diagnosis of exclusion . BCOR expression in ≥50% of tumour cells corresponds to the presence of BCOR fusion or ITD in almost 90% of previously diagnosed UUS …”

“…UUS is morphologically and genetically diverse in publications and practice due probably to contamination by misdiagnosed morphological variants of common sarcoma entities and recently described sarcoma subtypes . Four molecular groups – extracellular matrix, LMS‐like, developmental and low proliferation – were detected by RNA expression analysis of UUS after exclusion of tumours harbouring YWHAE–NUTM2 and JAZF1–SUZ12 fusions .…”

“…Most tumours classified as UUS, at least for the subset composed of cells with uniform nuclear features, represent misdiagnosed HGESS with known genetic abnormalities and as such, UUS should be a diagnosis of exclusion. 14 Tumours harbouring YWHAE-NUTM2 fusion and BCOR abnormalities are morphologically high-grade, because the cytological atypia exceeds that acceptable for LGESS. Reports suggest aggressive behaviour among all three HGESS subtypes, with a 50% rate of lymph node involvement in BCOR mutant HGESS compared to 19% in LGESS.…”