Targeted RNA expression profiling identifies high-grade endometrial stromal sarcoma as a clinically relevant molecular subtype of uterine sarcoma

High-grade endometrial stromal sarcoma (HGESS) may harborYWHAE-NUTM2A/Bfusion,ZC3H7B-BCORfusion, andBCORinternal tandem duplication (ITD).NTRK3upregulation and pan-Trk expression were reported in soft tissue lesions that share similar morphology and genetic abnormalities. To confirm these findings in HGESS, differential expression analysis was performed at gene level comparing 11 HGESS with 48 other uterine sarcomas, including 9 low-grade endometrial stromal sarcomas, 23 undifferentiated uterine sarcomas, and 16 leiomyosarcomas, using targeted RNA sequencing data. Pan-Trk immunohistochemistry was performed on 35 HGESS, including 10 tumors with RNA expression data, with genotypes previously confirmed by targeted RNA sequencing, fluorescence in situ hybridization, and/or genomic PCR. Unsupervised hierarchical clustering of the top 25% of differentially expressed probes identified three molecular groups: (1) highNTRK3,FGFR3,RET,BCOR,GLI1, andPTCH1and lowESR1expression; (2) lowNTRK3,FGFR3,RET,BCOR,GLI1, andPTCH1and highESR1expression; and (3) lowNTRK3,FGFR3,RET,BCOR,GLI1,PTCH1, andESR1expression. Among HGESS, 64% of tumors clustered in group 1, while 27% clustered in group 2. Cytoplasmic and/or nuclear pan-Trk staining of variable extent and intensity was seen in 91% of HGESS regardless of cyclin D1 and/or BCOR positivity. ER and PR expression was seen in 44% of HGESS despiteESR1downregulation. Two patients with ER and PR positive butESR1downregulated stage I HGESS were treated with endocrine therapy, and both recurred at 12 and 36 months after primary resection. By RNA expression, HGESS appear homogenous and distinct from other uterine sarcomas by activation of kinases, includingNTRK3, and sonic hedgehog pathway genes along with downregulation ofESR1. Most HGESS demonstrate pan-Trk staining which may serve as a diagnostic biomarker.ESR1downregulation is seen in some HGESS that express ER and PR which raises implications in the utility of endocrine therapy in these patients.

Automated summary

High-grade endometrial stromal sarcoma (HGESS) can harbor various gene fusions and internal tandem duplications, as well as exhibit upregulation of NTRK3 and pan-Trk expression. Most HGESS show distinct molecular characteristics, including activation of kinases and downregulation of ESR1. Some HGESS express ER and PR despite downregulation of ESR1, which may impact the effectiveness of endocrine therapy.