Expression And Significance Of MTOR, EIF4E And PCNA In Edometrial Proliferative Lesion And Endometrioid Adenocarcinoma

Objective: Uterine endometrial carcinoma is one of the most frequently seen malignant neoplasms in female reproductive system, accouting for about 20%~30% of all female malignant neoplasms. Recent years have witnessed an increasing tendency in the incidence of EC around the world. Pathologically, uterine endometrial carcinoma is divided into two types, usual (type I) and special variant types (type II), with endometrioid adenocarcinoma (the usual type) being the most common one. Endometrial proliferative lesion, including simple and complex hyperplasia, is also a common gynaecologic disease and some endometrial hyperplasia with atypical hyperplasia has the canceration potentiality. It is sometimes quite difficult in the differentiating diagnosis from endometrioid adenocarcinoma in pathological practice. Thus,the evaluation of the differentiating diagnosis markers for endometrioid adenocarcinoma and study of the biological behaviors of endometrioid adenocarcinoma are of important significance in the proper management of endometrioid adenocarcinoma.mTOR (mammalian target of rapamycin) is a serine-threonine kinase, which regulates important celluar processes such as control of cell cycle, cell size, translation initiation and transcription. Eukaryotic initiation factor 4E(eIF4E) is thought to be of key importance in mediating nomal,cap-dependent, translation initiation, which up-regulates some proteins closely related to growth such as cyclin D and C-myc. mTOR directly precipitates 4E-BP1 phosphorylation, leading to the release of eIF4E from 4E-BP1, and then promotes the initiation of translation,which makes the cells abnormal proliferate. At present, many researches have refered to the relationship between mTOR and eIF4E in some malignant tumors. Although it was reported that rapamycin the inhibitor of mTOR was effective in treating EC, the expression of mTOR in endometrial hyperplasia and endometriod adenocarcinoma and the correlation with eIF4E were not seen.To evaluate the significance of mTOR, eIF4E and PCNA expression in the differentiating diagnosis between endometrial hyperplasia and endometriod adenocarcinoma, and to explore the putative roles of them on the carcinogenesis of endometriod adenocarcinoma, we studied the expression and significance of mTOR, eIF4E and PCNA in endometriod adenocarcinoma, comlpex endometrial hyperplasia , simple endometrial hyperplasia and proliferative phase of the endometrium with immunohistochemical methods.Methods: The expressions of mTOR, eIF4E and PCNA in 44 cases of endometriod adenocarcinoma, 47cases of complex hyperplasia (among them, 34 cases of complex hyperplasia were with atypical endometrial hyperplasia), 19 cases of simple endometrial hyperplasia and 17 cases of proliferative endometrium were immunohistochemically studied with EliVision TM plus two step method. The experimental datas were treated by SPSS11.0.Results:1 The expression of mTOR in endometrial proliferative lesion and endometriod adenocarcinomamTOR positive immunoreaction was located in the cytoplasm of endometrial epithelial cells or carcinoma cells as granular brown staining. No strong positive expression of mTOR in proliferative endometrium and simple endometrial hyperplasia could be seen(0/20 and 0/19, respectively). While the strong positive expression rate of mTOR in complex endometrial hyperplasia and endometriod adenocarcinoma was 23.4% and 52.3% respectively, which was significant higher than that in the former two groups. The strong positive expression of mTOR in endometriod adenocarcinoma was significantly higher than that in complex endometrial hyperplasias as well as complex hyperplasia with atypical endometrial hyperplasia (P<0.05). No significant difference in mTOR expression was found between the complex hyperplasia with atypical endometrial hyperplasia and that without (P>0.05).In endometriod adenocarcinoma cases, the expression of mTOR was closely related with differentiation of tumor. The strong positive expression rate in grade II and III cases was significantly higher than that in grade I (72.41% vs 13.33%, P<0.05). No significant correlation was found between the expression of mTOR and TNM stage as well as lymph node metastasis in endometriod adenocarcinoma (P>0.05).2 The expression of eIF4E in endometrial proliferative lesion and endometriod adenocarcinomaUnder light microscope, eIF4E positive immunostaining was located in the cytoplasm of cell as brown granules. The positive expression of eIF4E in proliferative endometrium and simple endometrial hyperplasia was 52.94% and 73.68% respectively, while that in complex endometrial hyperplasia and endometriod adenocarcinoma was respectively 85.1% and 90.9%, which was significantly higher that the former two(P<0.05). The eIF4E positive expression in endometriod adenocarcinoma was statistically not significantly diiferent from that in complex endometrial hyperplasia as well as complex hyperplasia with atypical hyperplasia (P>0.05). There was no significant difference in eIF4E expression between complex hyperplasia with atypical hyperplasia and that without (P>0.05).The positive expression of eIF4E in endometriod adenocarcinoma was not significantly related with TNM stage, pathological grade and lymph node metastasis (P>0.05).3 The expression of PCNA in endometrial proliferative lesion and endometriod adenocarcinomaThere were a few positive PCNA nuclear stained cells in proliferative endometrium and simple endometrial hyperplasia, but no strong positive expression as evaluated by the criteria of this study was found.The strong positive expression rate in complex endometrial hyperplasia and endometriod adenocarcinoma was 23.40% and 68.18% respectively, which were significant higher than that in the former two groups.The strong positive expression of PCNA in endometriod adenocarcinoma was significant higher than that in complex endometrial hyperplasia as well as complex hyperplasia with atypical hyperplasia (P<0.05). No significant difference in strong positive expression of PCNA between complex hyperplasia without atypical hyperplasia and complex hyperplasia with atypical hyperplasia was found (P>0.05).The expression of PCNA in endometriod adenocarcinoma was closely related with hisytological grades of tumor.The strong positive expression rate of PCNA in gradeâ…¡~III was significant higher in grade I (P<0.05).The strong positive expression of PCNA was not significantly related with TNM stage and lymp node metastasis((P>0.05).4 The relationship among the expression of mTOR, eIF4E and PCNA in endometriod adenocarcinomaAll the 23 mTOR strong positive expression endometriod adenocarcinoma cases showed eIF4E positive expression. Among the 21 mTOR weak positive expression endometriod adenocarcinoma cases, 17 cases showed eIF4E positive expression. Statistical analysis showed that there was positive correlation between mTOR and eIF4E expression in endometriod adenocarcinoma(r=0.331 P <0.05). Among the 23 mTOR strong positive expression endometriod adenocarcinoma cases , 19 cases showed PCNA strong positive expression, and 4 cases showed PCNA weak positive expression; A positive correlation between mTOR and PCNA expression in endometriod adenocarcinoma was found (r=0.324 P<0.05). Of the 40 eIF4E positive expression endometriod adenocarcinoma cases, 28 cases showed PCNA strong positive expression. Among 4 eIF4E negative expression endometriod adenocarcinoma cases, 2 cases showed PCNA strong positive expression, and 2 cases showed PCNA weak positive expression. Statistical analysis showed that there was no significant correlation between eIF4E and PCNA expression in endometriod adenocarcinoma(r=0.123 , P>0.05).Conclusions:1 The expression of mTOR, eIF4E and PCNA in complex endometrial hyperplasia and endometriod adenocarcinoma was significantly higher than other groups, suggesting that they may all be involved in that carcinomgesis of endometriod adenocarcinoma.2 The mTOR and PCNA positive expression in endometriod adenocarcinoma was significantly higher than that in complex hyperplasia with atypical hyperplasia. mTOR and PCNA may be of some usage in the differentiating diagnosis between the two diseases.3 In the endometriod adenocarcinoma cases, the expression of mTOR and PCNA was closely related to differentiation of tumors and increased as the histological grade increased.The expression of eIF4E was not related to the differentiation, clinical stage and lymph node metastasis.4 Positive correlation could be found in the expression between mTOR and eIF4E, mTOR and PCNA in endometriod adenocarcinoma.