The proliferation markers Ki-67/MIB-1, phosphohistone H3, and survivin may contribute in the identification of aggressive ovarian carcinomas

Abstract

The identification of new proliferation markers could have clinical implications in ovarian carcinoma by stratifying patients for treatment and follow-up. The aim of this study was to evaluate the diagnostic and prognostic value of the proliferation markers Ki-67/MIB-1, phosphorylated histone H3 (PHH3), and survivin in epithelial ovarian tumors. Ninety women with a pelvic mass who underwent surgery at the Department of Gynecological Oncology were included: 68 ovarian carcinomas, 11 borderline tumors, and 11 ovarian cystadenomas. We performed mitotic count and immunohistochemical analyses of Ki-67/MIB-1, PHH3, and survivin, related to clinicopathological parameters. Uni- and multivariate analyses of five-year overall survival were performed. We found statistically significant correlations between mitotic count, Ki-67/MIB-1, PHH3, and survivin. The expression of all proliferation markers was significantly higher in the carcinomas than in the borderline and benign tumors (p<0.05). There was, however an overlap of indices between the different malignancy groups. Women with advanced stage cancers (FIGO stage III and IV) had significantly higher tumor expression of all markers compared to patients with early stage cancers (FIGO stage I and II). Women with advanced disease and complete chemotherapy response had higher Ki67/MIB-1 expression than women without complete chemotherapy response. All markers had an impact on survival in the univariate analyses. In the multivariate analysis, however, only age and stage of disease reached statistical significance as prognostic factors. In conclusion, the proliferation markers Ki-67/MIB-1, PHH3, and survivin are positively correlated with each other and with tumor grade, and may contribute in the identification of aggressive ovarian carcinomas.

Keywords: Ki-67/MIB-1; Ovarian carcinoma; PHH3; diagnosis; ovary; proliferation; survival; survivin.

Figure 1

Mitotic count (A) and expression of Ki-67/MIB-1 (B), PHH3 (C), and survivin (D) in ovarian carcinomas, borderline, and benign ovarian tumors. ***: Carcinoma vs. benign, p<0.001; ###, ##, #: Carcinoma vs. borderline, p<0.001, <0.01, and <0.05, respectively ; ††, †: Borderline vs. benign, <0.01, and <0.05, respectively. LI: Labeling Index, Line marks median.

Figure 2

Images of the MIB-1/Ki-67, PHH3, and survivin immunohistochemical stainings in ovarian serous carcinoma: Expression of MIB-1/Ki-67, PHH3, and survivin, (a), (b) and (c), respectively. The images are from representative specimen.