Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Department of Pathology, University of British Columbia, Vancouver, BC, Canada.
Mod Pathol. 2021 May;34(5):1008-1016. doi: 10.1038/s41379-020-00705-6. Epub 2020 Oct 19.
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.
高级子宫内膜间质肉瘤 (HGESS) 可能存在 YWHAE-NUTM2A/B 融合、ZC3H7B-BCOR 融合和 BCOR 内部串联重复 (ITD)。在具有相似形态和遗传异常的软组织病变中，报道了 NTRK3 上调和泛 Trk 表达。为了在 HGESS 中证实这些发现，对 11 例 HGESS 和 48 例其他子宫肉瘤进行了基因水平的差异表达分析，包括 9 例低级别子宫内膜间质肉瘤、23 例未分化子宫肉瘤和 16 例平滑肌肉瘤，使用靶向 RNA 测序数据。对 35 例 HGESS 进行了泛 Trk 免疫组织化学分析，包括 10 例有 RNA 表达数据的肿瘤，这些肿瘤的基因型以前通过靶向 RNA 测序、荧光原位杂交和/或基因组 PCR 证实。对差异表达探针前 25%的无监督层次聚类确定了三个分子群：(1)高 NTRK3、FGFR3、RET、BCOR、GLI1 和 PTCH1，ESR1 表达低；(2)低 NTRK3、FGFR3、RET、BCOR、GLI1 和 PTCH1，ESR1 表达高；(3)低 NTRK3、FGFR3、RET、BCOR、GLI1、PTCH1 和 ESR1 表达低。在 HGESS 中，64%的肿瘤聚集在第 1 组，而 27%的肿瘤聚集在第 2 组。91%的 HGESS 可见不同程度和强度的细胞质和/或核泛 Trk 染色，无论 cyclin D1 和/或 BCOR 是否阳性。尽管 ESR1 下调，仍有 44%的 HGESS 表达 ER 和 PR。两名 ER 和 PR 阳性但 ESR1 下调的 I 期 HGESS 患者接受了内分泌治疗，两人均在原发性切除后 12 个月和 36 个月复发。通过 RNA 表达，HGESS 表现出均一性，并通过包括 NTRK3 在内的激酶以及 sonic hedgehog 通路基因的激活，与 ESR1 的下调区分开来。大多数 HGESS 显示泛 Trk 染色，这可能作为一种诊断生物标志物。一些表达 ER 和 PR 的 HGESS 出现 ESR1 下调，这提示在这些患者中内分泌治疗的应用。
