Clinicopathologic Characterization of GREB1 -rearranged Uterine Sarcomas With Variable Sex-Cord Differentiation

Cheng Han Lee, Yu-Chien Kao, Wan Ru Lee, Yi Wen Hsiao, Tzu Pin Lu, Chia Ying Chu, Yi Jia Lin, Hsuan Ying Huang, Tsung Han Hsieh, Yun Ru Liu, Cher Wei Liang, Tom Wei Wu Chen, Stephen Yip, Amy Lum, Kuan Ting Kuo, Yung Ming Jeng, Shih Chen Yu, Yung Chuan Chung, Jen Chieh Lee

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Uterine mesenchymal tumors are genetically heterogenous; those with uniform cytomorphology, best exemplified by endometrial stromal tumors, often contain various fusion genes. Novel fusions involving ESR1 and GREB1, key factors in sex hormone pathways, have been implicated in rare uterine mesenchymal tumors. Particularly, the fusions between 5′-ESR1/GREB1 and 3′-NCOA2/NCOA3 were recently identified in 4 uterine tumors resembling ovarian sex-cord tumor (UTROSCT). By RNA sequencing, pathology review, and FISH screening, we identified 4 uterine sarcomas harboring rearranged GREB1, including GREB1-NCOA2 and the novel GREB1-NR4A3, GREB1-SS18, and GREB1-NCOA1, validated by RT-PCR and/or FISH. They occurred in the myometrium of postmenopausal women and were pathologically similar despite minor differences. Tumor cells were generally uniform and epithelioid, with vesicular nuclei and distinct to prominent nucleoli. Growth patterns included solid sheets, trabeculae/cords, nests, and fascicles. Only 1 tumor showed small foci of definitive sex-cord components featuring well-formed tubules, retiform structures, Leydig-like cells, and lipid-laden cells and exhibiting convincing immunoreactivity to sex-cord markers (calretinin, -inhibin, and Melan-A). In contrast, all the 4 classic UTROSCT we collected occurred in premenopausal patients, consisted predominantly of unequivocal sex-cord elements, prominently expressed multiple sex-cord markers, and harbored ESR1-NCOA3 fusion. Combined with previously reported cases, GREB1-rearranged tumors involved significantly older women (P=0.001), tended to be larger and more mitotically active, showed more variable and often inconspicuous sex-cord differentiation, and appeared to behave more aggressively than ESR1-rearranged UTROSCT. Therefore, these 2 groups of tumors might deserve separate consideration, despite some overlapping features and the possibility of belonging to the same disease spectrum.

Original languageEnglish
Pages (from-to)928-942
Number of pages15
JournalAmerican Journal of Surgical Pathology
Volume43
Issue number7
DOIs
Publication statusPublished - Jul 1 2019

Fingerprint

Sex Differentiation
Sarcoma
Neoplasms
Endometrial Stromal Tumors
MART-1 Antigen
RNA Sequence Analysis
Calbindin 2
Inhibins
Leydig Cells
Myometrium
Gene Fusion
Gonadal Steroid Hormones

Keywords

  • ESR1
  • GREB1
  • sex cord tumor
  • uterine sarcoma

ASJC Scopus subject areas

  • Anatomy
  • Surgery
  • Pathology and Forensic Medicine

Cite this

Clinicopathologic Characterization of GREB1 -rearranged Uterine Sarcomas With Variable Sex-Cord Differentiation. / Lee, Cheng Han; Kao, Yu-Chien; Lee, Wan Ru; Hsiao, Yi Wen; Lu, Tzu Pin; Chu, Chia Ying; Lin, Yi Jia; Huang, Hsuan Ying; Hsieh, Tsung Han; Liu, Yun Ru; Liang, Cher Wei; Chen, Tom Wei Wu; Yip, Stephen; Lum, Amy; Kuo, Kuan Ting; Jeng, Yung Ming; Yu, Shih Chen; Chung, Yung Chuan; Lee, Jen Chieh.

In: American Journal of Surgical Pathology, Vol. 43, No. 7, 01.07.2019, p. 928-942.

Research output: Contribution to journalArticle

Lee, CH, Kao, Y-C, Lee, WR, Hsiao, YW, Lu, TP, Chu, CY, Lin, YJ, Huang, HY, Hsieh, TH, Liu, YR, Liang, CW, Chen, TWW, Yip, S, Lum, A, Kuo, KT, Jeng, YM, Yu, SC, Chung, YC & Lee, JC 2019, 'Clinicopathologic Characterization of GREB1 -rearranged Uterine Sarcomas With Variable Sex-Cord Differentiation', American Journal of Surgical Pathology, vol. 43, no. 7, pp. 928-942. https://doi.org/10.1097/PAS.0000000000001265
Lee, Cheng Han ; Kao, Yu-Chien ; Lee, Wan Ru ; Hsiao, Yi Wen ; Lu, Tzu Pin ; Chu, Chia Ying ; Lin, Yi Jia ; Huang, Hsuan Ying ; Hsieh, Tsung Han ; Liu, Yun Ru ; Liang, Cher Wei ; Chen, Tom Wei Wu ; Yip, Stephen ; Lum, Amy ; Kuo, Kuan Ting ; Jeng, Yung Ming ; Yu, Shih Chen ; Chung, Yung Chuan ; Lee, Jen Chieh. / Clinicopathologic Characterization of GREB1 -rearranged Uterine Sarcomas With Variable Sex-Cord Differentiation. In: American Journal of Surgical Pathology. 2019 ; Vol. 43, No. 7. pp. 928-942.
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