Immunohistochemical markers of cell cycle control applied to ovarian and primary peritoneal surface epithelial neoplasms: p21 [formula omitted] predicts survival and good response to platinin-based chemotherapy

Abstract

Immunohistochemistry for p53, p21 WAF1 CIP1 , and Ki-67 provides insight into the molecular events controlling the cell cycle. We tested the hypothesis that these cell cycle markers will aid in the clinical evaluation of ovarian and primary peritoneal surface epithelial neoplasms (SENs). Paraffin sections from a retrospective surgical series of 117 SENs were immunostained with anti-p53 (clone DO7, Novacastra Laboratories, UK), anti-p21 WAF1 CIP1 (clone EA10, Oncogene Science, Cambridge, MA), and anti-Ki-67 (clone MIB-1, Immunotech, Westbrook, ME). The Ki-67 proliferation index (Ki-67PI) and immunoreactivity were evaluated. One hundred seventeen SENs reacted as follows: p53 50%+ and p21 WAF1 CIP1 65%+. Ki-67PI ranged from 4% to 88% (mean/median = 44/46%). p53 reactivity associated with transitional cell histology, decreased p21 WAF1 CIP1 staining, increased Ki-67PI, architectural/nuclear grade, and stage ( P < .05, 1 × 10 −7, .01, .05/.0001, .001,). p21 WAF1 CIP1 staining was associated with endometrioid/clear cell histology, decreased Ki-67PI, architectural/nuclear grade, and stage ( P < 05/.05, .05, .01/1 × 10 −8, 1 × 10 −5). Ki-67PI associated with increased architectural/nuclear grade but not mucinous histology ( P < 1 × 10 −5/1 × 10 −6, .01). Sixty-seven patients had disease at last follow-up; 53 were dead of disease at 0 to 67 months (mean/median, 21/18), and 14 were alive with disease at 12 to 224 months (mean/median, 56/40). Fifty patients were disease free at 5 to 214 months (mean/median, 59/41). Predictors of survival include decreased Ki-67PI, stage, architectural/nuclear grade ( P < 1 × 10 −6, 1 × 10 −10, 1 × 10 −10/.005) and p21 WAF1 CIP1 IMS (multivariate P < 1 × 10 −6). p21 WAF1 CIP1 , a potent inhibitor of cyclin-dependent kinases necessary for cell cycle progression, functions as a key checkpoint in cell cycle control. Immunoreactivity for p21 WAF1 CIP1 provides prognostic information independent of other histological and clinical predictors, p53 IMS, and Ki-67PI in this series of 117 PTs with SENs. Our preliminary data suggest an interrelationship between p21 WAF1 CIP1 expression and an effective clinical response to platinin-based chemotherapy, both associated with apoptosis. Further investigation seems warranted.