Endometrial stromal tumors: immunohistochemical and molecular analysis of potential targets of tyrosine kinase inhibitors

Abstract

BackgroundThe systemic treatment of malignant endometrial stromal tumors (EST) is not well established. A few reports describe objective responses to imatinib, which suggest a novel therapeutic strategy for these tumors. Due to these facts, we aimed to perform a retrospective analysis of possible molecular targets of tyrosine kinase inhibitors (TKI) in EST: KIT, PDGFRA and EGFR.Methods52 endometrial stromal sarcomas and 13 undifferentiated endometrial sarcomas were examined and reviewed. Mutational analysis were performed for exons 9, 11, 13, and 17 of the KIT gene, exons 12 and 18 of the PDGFRA gene and exons 18, 19, 20 and 21 of the EGFR gene. The incidence and distribution of the KIT, PDGFRA, and EGFR expression were examined by immunohistochemistry, and EGFR amplification was assessed by fluorescence in situ hybridization.ResultsNo mutations in KIT, PDGFRA and EGFR genes were detected. Overexpression of KIT, PDGFRA, EGFR, was detected in 2 (3%), 23 (35.4%), 7 (10.8%) cases respectively, whereas amplification of EGFR gene was not found.ConclusionsAbsence of significant expression, amplification and activating mutations on these tyrosine kinase receptors suggest that it is unlikely that EST can benefit from therapies such as TKI on the systemic setting.

Investigation of New Therapeutic Targets in Undifferentiated Endometrial Sarcoma

“…C-ABL was reported to be expressed in a moderate proportion of UES tumors, ranging from 25 to 40% in previous studies [13,14] . PDGFR has shown a moderate frequency of expression in previous studies [12][13][14]20] , and we obtained a similar result for this biomarker in our present series. There are few studies on the expression of VEGF in uterine sarcoma.…”

“…Also, c-ABL, PDGFR, mTOR, WT1, and HDAC3/5 showed a high frequency of weak to moderate expression. There have been several previous studies that have analyzed EGFR expression in UES, but there were discrepancies in the 17,20,22] . HER2 showed no expression in UES cases in a previous study [17] .…”

“…We also could not detect the expression of either EGFR or HER2 in our series. In many previous studies also, there were considerable discrepancies in the frequency of c-KIT expression, ranging from 0 to 100% [12][13][14][15][19][20][21][22][23][24] . C-ABL was reported to be expressed in a moderate proportion of UES tumors, ranging from 25 to 40% in previous studies [13,14] .…”

Gynecologic Cancer InterGroup (GCIG) Consensus Review for Mullerian Adenosarcoma of the Female Genital Tract

“…Given that most tumors have ESS as the malignant component, it is possible that they will share the molecular features with de novo ESSs. 19 Amant et al has written a Gynecologic Cancer Intergroup review on ESSs, and the molecular pathology is described in detail. Briefly, ESSs represent a genetically heterogeneous group of tumors, many of which may arise through distinctive molecular genetic pathways, through gene rearrangements, which most frequently are a JAZF1-SUZ12 rearrangement.…”

Molecular mechanisms of endometrial stromal sarcoma and undifferentiated endometrial sarcoma as premises for new therapeutic strategies

“…Furthermore, a complete metabolic response to imatinib mesylate in a patient with a low-grade ESS has been reported [19]. In contrast, a retrospective immunohistochemical and molecular analysis of potential targets of TKI in 52 ESS and 13 UES highly question the use of TKI in endometrial stromal tumors [20].…”