<p xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="first" id="d10566449e216">High-grade
endometrial stromal sarcoma (HGESS) may harbor YWHAE-NUTM2A/B fusion, ZC3H7B-BCOR
fusion, and BCOR internal tandem duplication (ITD). NTRK3 upregulation 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) high NTRK3, FGFR3, RET, BCOR,
GLI1, and PTCH1 and low ESR1 expression; (2) low NTRK3, FGFR3, RET, BCOR, GLI1, and
PTCH1 and high ESR1 expression; and (3) low NTRK3, FGFR3, RET, BCOR, GLI1, PTCH1,
and ESR1 expression. 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 despite ESR1 downregulation. Two patients with
ER and PR positive but ESR1 downregulated 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, including NTRK3, and sonic hedgehog pathway genes along with downregulation
of ESR1. Most HGESS demonstrate pan-Trk staining which may serve as a diagnostic biomarker.
ESR1 downregulation is seen in some HGESS that express ER and PR which raises implications
in the utility of endocrine therapy in these patients.
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