Topoisomerase II alpha: Prognostic predictor and cell cycle marker in surface epithelial neoplasms of the ovary and peritoneum

Immunohistochemistry for Topoisomerase II alpha (TopoIIa), a nuclear protei n important for the separation of chromosomes and deoxyribonucleic acid rep lication, provides insight into the molecular events in the cell cycle and the response to chemotherapeutic agents, which target TopoIIa. We test the hypothesis that the percentage of TopoIIa immunoreactive nuclei (TopoIIaI) aids in the treatment and prognostic evaluation of ovarian and primary peri toneal surface epithelial neoplasms (SENs) and correlates with established cell cycle control markers: p53, p21(WAF1/CIP1) (p21), and Ki67. Paraffin s ections from a retrospective surgical series of 108 SENs were immunostained with anti-TopoIIa, anti-p53, anti-p21, and anti-Ki67. The TopoIIaI, the Ki 67 proliferation index (Ki67PI), and the immunoreactivity score for p53 and p21 (IMS: S1, S2, S3 <10%, 10 to 50%, >50% of strong staining cells, respe ctively) were evaluated manually. TopoIIaI and Ki67PI ranged from 5 to 84% and 4 to 88% (mean/median: 31/30 and 44/46%), respectively, and were correl ated (coefficient 0.62, p < 10(-11)). LMS of 108 SENs was as follows: p53 5 0% + (2S1, 52S3) and p21 66% + (38S1, 12S2, 21S3). The TopoIIaI associated directly with p53 (p < 10(-5)) and inversely with p21 (p < 0.005) LMS. Topo IIaI correlated with SEN architectural/nuclear grade (p < 10(-5)/10(-7)), b ut not histologic type. Sixty-seven patients had disease at last follow-up, 55 were dead from disease at 2 to 67 months (mean/median 24/21), and 14 we re alive with disease at 31 to 230 months (mean/median 73/59). Forty-one pa tients were disease free at 5 to 228 months (mean/median 75/54). TopoIIaI c orrelated with presence of disease (p < 0.01) and poor survival (p < 1 x 10 (-9)), even when only 93 invasive SEN cases are considered (p < 0.005). Top oIIaI correlates with poor prognosis and other cell cycle control markers. The patients in this retrospective series of SEN were treated primarily wit h platinum-based chemotherapy. These data may suggest further prospective s tudies in which patients with SENs exhibiting high TopoIIaI are treated wit h chemotherapy targeted against TopoIIa (e.g., etoposide). In this retrospe ctive series, high SEN TopoIIaI predicted poor survival when treated with p latinum-based chemotherapy, which does not target TopoIIa.