Endometrial Stromal Sarcomas and Related High-grade Sarcomas: Immunohistochemical and Molecular Genetic Study of 31 Cases

Abstract

Classification and terminology of non-low-grade endometrial sarcomas, which show significant nuclear atypia, have been controversial. Currently, these tumors seem to be classified all together into "undifferentiated endometrial sarcoma (UES)." However, it remains unclear whether these non-low-grade sarcomas are universally "undifferentiated." We divided these sarcomas morphologically into undifferentiated endometrial sarcoma with nuclear uniformity (UES-U) and undifferentiated endometrial sarcoma with nuclear pleomorphism (UES-P), and compared their molecular genetic and immunohistochemical profiles. Eighteen low-grade endometrial stromal sarcomas (ESS-LG), 7 UES-U, and 6 UES-P were examined. All the patients with ESS-LG were still alive, either with or without disease, whereas 4 of the 5 patients with advanced stage UES-U and all 3 of the patients with advanced stage UES-P had died of the disease. JAZF1-JJAZ1 fusion transcript was detected in 6 (50%) out of 12 ESS-LG and in 1 (33%) of 3 UES-U, whereas it was not detected in any of the cases of UES-P. ESS-LG and UES-U frequently showed positive immunoreaction for estrogen receptor (ESS-LG: 94%, UES-U: 57%) and progesterone receptor (ESS-LG: 94%, UES-U: 57%), whereas all the UES-P were negative for these receptors. Nuclear beta-catenin expression was more frequently recognized in ESS-LG (47%) and UES-U (85%), compared with UES-P (33%). Moreover, nuclear accumulation of p53 and TP53 gene missense mutations were limited to 3 UES-P cases. Our data suggest that UES-U shares some molecular genetic and immunohistochemical characteristics with ESS-LG, but UES-P considerably differs from ESS-LG.

Coincident expression of β-catenin and cyclin D1 in endometrial stromal tumors and related high-grade sarcomas

“…1 These cases, other than the eight cases of endometrial stromal nodule, had been previously investigated in our study of immunohistochemical and molecular genetic analyses. 2 As we reported previously, 16 low-grade endometrial stromal sarcomas were mainly composed of uniform tumor cells resembling normal endometrial stromal cells with uniform nuclei showing minimal cytological atypia (Figure 1b). Of the 13 undifferentiated endometrial sarcoma, 7 featured rather monotonous cytological uniformity reminiscent of low-grade endometrial stromal sarcoma, but they were separated from lowgrade endometrial stromal sarcoma because they showed significant nuclear atypia (Figure 1c).…”

“…As in our previous study, we call the former undifferentiated endometrial sarcoma group 'undifferentiated endometrial sarcoma with nuclear uniformity' and the latter group 'undifferentiated endometrial sarcoma with nuclear pleomorphism'. 2 …”

“…2 All these cases, including eight cases of endometrial stromal nodule, were examined at the same time in the previous study, but endometrial stromal nodules were not reported because benign endometrial stromal nodule was outside the scope of that study. Assessment of RNA quality by realtime quantitative RT-PCR for glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was also performed at the same time, as previously described.…”

“…We have also reported that 47% of lowgrade endometrial stromal sarcoma and 85% of undifferentiated endometrial sarcoma featuring uniform nuclei show nuclear b-catenin expression. 2 From these findings, we speculated that the Wnt signaling pathway may be aberrantly activated in these tumors and contribute to tumorigenesis. However, genetic or epigenetic alterations responsible for nuclear b-catenin accumulation have remained obscure in endometrial stromal tumors.…”

“…1 We have reported previously that among the current undifferentiated endometrial sarcomas, those previously labeled as 'high-grade endometrial stromal sarcoma' with monotonous cytological features share several molecular genetic and immunohistochemical characteristics with low-grade endometrial stromal sarcoma, whereas clearly pleomorphic undifferentiated endometrial sarcomas are considerably different from low-grade endometrial stromal sarcoma. 2 Aberrant activation of the Wnt signaling pathway is known to contribute to tumorigenesis of a wide range of tumors, including colorectal cancer. 3 The Wnt signaling pathway is regulated by many components such as APC and b-catenin, and genetic or epigenetic abnormalities of these components can cause dysregulated activation of the Wnt signaling pathway.…”