No abstract

Endometrial stromal sarcoma (ESS) characterized by YWHAE-FAM22 genetic fusion is histologically higher-grade and clinically more aggressive than ESS with JAZF1-SUZ12 or equivalent genetic rearrangements, hence it is clinically important to recognize this subset of ESS. To identify diagnostic immunomarkers for this biologically-defined ESS subset, we compared gene expression profiles from YWHAE-FAM22 ESS, JAZF1-rearranged ESS and uterine leiomyosarcomas. These studies showed consistent upregulation of cyclin D1 in YWHAE-FAM22 ESS compared to JAZF1-SUZ12 ESS. Immunohistochemically, the high-grade round cell component of all 12 YWHAE-FAM22 ESS demonstrated diffuse (≥70%) moderate-to-strong nuclear cyclin D1 staining and this diffuse positivity was not seen in 34 ESS with JAZF1 and equivalent genetic rearrangements or in 21 low-grade ESS with no demonstrable genetic rearrangements. In a series of 243 non-ESS pure uterine mesenchymal and mixed epithelial-mesenchymal tumors, only 2 of 8 undifferentiated endometrial sarcomas with nuclear uniformity and 1 of 80 uterine leiomyosarcomas demonstrate diffuse cyclin D1 immunoreactivity. Both cyclin D1-positive undifferentiated endometrial sarcomas showed diffuse strong CD10 staining, which is consistently absent in the high-grade round cell component of YWHAE-FAM22 ESS. The low-grade spindle cell component of YWHAE-FAM22 ESS showed a spatially heterogeneous cyclin D1 staining pattern that was weaker and less diffuse overall. Our findings indicate that cyclin D1 is a sensitive and specific diagnostic immunomarker for YWHAE-FAM22 ESS. When evaluating high-grade uterine sarcomas, cyclin D1 can be included in the immunohistochemical panel as an indicator of YWHAE-FAM22 ESS.

Recognition of high-grade endometrial stromal sarcoma is important because of its aggressive clinical behavior. Morphologic features of YWHAE-NUTM2 high-grade endometrial stromal sarcoma may overlap with other uterine sarcoma types. BCOR immunoexpression was studied in these tumors and their morphologic mimics to assess its diagnostic utility. BCOR immunohistochemical staining was performed on archival tissue from 28 high-grade endometrial stromal sarcomas with classic morphology (20 YWHAE-NUTM2, 5 ZC3H7B-BCOR, 3 BCOR-ZC3H7B), 3 high-grade endometrial stromal sarcomas with unusual morphology and unknown gene rearrangement status, 66 low-grade endometrial stromal sarcomas, 21 endometrial stromal nodules, 38 uterine leiomyosarcomas, and 19 uterine leiomyomas. Intensity of nuclear staining and percentage of positive tumor cells were recorded. Strong diffuse nuclear BCOR staining (defined as >95% of tumor cells) was seen in the round cell component of all 20 (100%) classic YWHAE-NUTM2 high-grade endometrial stromal sarcomas and the 3 unusual high-grade endometrial stromal sarcomas which prompted FISH studies confirming YWHAE rearrangement in 2 tumors. Genomic PCR confirmed the presence of BCOR exon 16 internal tandem duplication in the third case. Diffuse BCOR staining was strong in 3 and weak in 1 BCOR-rearranged high-grade endometrial stromal sarcoma while absent in the remaining 4 BCOR-rearranged tumors. BCOR staining was weakly positive in <5% of tumor cells in 4 of 66 (6%) low-grade endometrial stromal sarcoma and 1 of 18 (6%) endometrial stromal nodules and weakly to moderately positive in <5% to 40% of tumor cells in 6 of 31 (19%) leiomyosarcomas. No BCOR staining was seen in the remaining low-grade endometrial stromal sarcomas, endometrial stromal nodules, leiomyosarcomas, or any of the leiomyomas. BCOR immunohistochemical staining is a highly sensitive marker for YWHAE-NUTM2 high-grade endometrial stromal sarcoma with both classic and unusual morphology and identifies a subset of high-grade endometrial stromal sarcoma with BCOR alterations, including BCOR rearrangement and internal tandem duplication.

Translocations resulting in gene fusion are characteristic of endometrial stromal tumors (ESTs). Rearrangements of JAZF1, SUZ12, PHF1, and EPC1 have been reported in endometrial stromal nodules (ESNs), endometrial stromal sarcomas (ESSs), and rarely in undifferentiated endometrial sarcomas (UESs). Detection of JAZF1, SUZ12, EPC1, and PHF1 rearrangement by fluorescence in situ hybridization was performed on tissue microarrays consisting of 94 ESTs of classic and variant morphology (20 ESNs, 43 primary uterine ESSs, 15 metastatic uterine ESSs, 4 primary extrauterine ESSs, 7 primary uterine UESs, and 5 unclassified ESTs), 16 Müllerian adenosarcomas, 2 malignant mixed Müllerian tumors, 2 uterine tumors resembling ovarian sex-cord tumors, 2 highly cellular leiomyomas, 1 leiomyosarcoma, and 7 polypoid endometriosis. Rearrangements were detected in 42 of 78 (54%) uterine ESTs, with JAZF1-SUZ12 fusion found in 50% of ESNs and in 33% of ESSs and JAZF1-PHF1 and EPC1-PHF1 fusions found in 1% and <1% of ESSs, respectively. PHF1 and JAZF1 were rearranged with unknown partners in 8 uterine ESTs. JAZF1-SUZ12 fusion, EPC1-PHF1 fusion, and PHF1 rearrangement were found in 3 extrauterine ESSs, whereas no rearrangements were observed in UESs or in any other non-EST studied. Our data confirm that gene rearrangements are present in more than 50% of uterine ESTs, with JAZF1-SUZ12 fusion being the most common, followed by rare EPC1-PHF1 and JAZF1-PHF1 fusions. The presence of identical gene rearrangements in both uterine and extrauterine ESTs suggests a similar pathogenesis. The presence of detectable gene rearrangements in uterine ESS may predict better patient outcome.