Evaluation of combined bcl-2/mdm-2 immunohistochemical expression as a prognostic factor in early stages of invasive cervical carcinomas

Abstract

BACKGROUND: The present study was designed to evaluate the immunohistochemical expression of apoptosis regulating proteins (bcl-2, mdm-2 and p53) in correlation with proliferation (Ki-67), human papillomavirus (HPV) infection and other histopathological and clinical parameters in early stage cervical carcinomas and the estimation of their prognostic significance. Special attention was given to combined bcl-2/mdm-2 immunophenotypes in predicting the recurrence of the disease. METHOD: The subject of this study was a series of 83 surgically treated patients with cervical carcinoma confined to the uterine cervix (pT1b1/1b2), who subsequently received complete radiotherapy. The presence of HPV DNA was determined by the conventional method of in situ hybridization (ISH) and catalyzed reporter deposition signal amplification ISH. The immunostaining was performed using avidin-biotin-peroxidase complex method and the expression of the biological markers was semiquantitatively evaluated as the percentage of immunostained cells. RESULTS: During the clinical follow-up (mean 120.7, range 4.4-181 months) a relapse was diagnosed in 9 (10.8%) patients and the expected 5-, 10- and 15- year disease-free survival was 92.7%, 90.8% and 86.6%, respectively. The results of the univariate analysis indicate that significant predictive indicators for recurrence are: lymphonodal status, maximal tumor diameter, depth of stromal invasion, histological type and HPV DNA presence and type. Immunohistochemical markers showed the following correlations: increased expression of Ki-67 (P=0.031) and bcl-2 negativity (P=0.047) correlated with poor disease-free survival, while mdm-2 positivity showed borderline significance (P=0.051) and p53 expression had no influence on disease-free survival. Additional evaluation of combined bcl-2/mdm-2 expression showed that cases with bcl-2+/mdm-2- and bcl-2-/mdm-2+ immunophenotype had better survival (P=0.048) compared to bcl-2+/mdm-2+ and bcl-2-/mdm-2- phenotype. In the multivariate analysis, histological type, HPV DNA presence and the expression of Ki-67 have been selected as the most significant independent prognostic parameters (P=0.0024). CONCLUSION: The evaluation of combined bcl-2/mdm-2 immunohistochemical expression provides more relevant information for the prediction of the recurrence of the disease than their individual expression. However, neither individual expression of bcl-2 and mdm-2 nor their combined immunohistochemical expressions are independent predictors of prognosis in early stages of invasive cervical carcinomas.