Ki-67 expression in the invasive front as an additional independent significant prognostic factor influencing recurrence in early stage cervical carcinomas.

Abstract

The aims of this study were to correlate alterations of cell proliferation, growth, differentiation and apoptosis regulatory proteins in early stage cervical carcinomas with human papillomavirus (HPV) infection, histopathological and clinical parameters, and to estimate their prognostic significance. Expression of Ki-67, p53, mdm-2, bcl-2, c-erbB-2, EGFR protein, as well as estrogen and progesterone receptors was evaluated by immunohistochemistry in operative specimens of 83 patients with cervical carcinoma. The results were assessed semiquantitatively in the surface area, centre and invasive front of each tumor as a percentage of immunostained cells and/or intensity of immunostaining for each protein. The presence of HPV was assessed by conventional in situ hybridization (ISH) technique and catalyzed reporter deposition signal amplification ISH using mixed biotinylated probes to identify types 6/11, 16/18 and 31/33 or 31/33/51. Among the 18 variables, pelvic lymph node involvement (P=0.0008), tumor diameter (P=0.035), depth of stromal invasion (P=0.029), histotype (P=0.0009), grade (P=0.056), HPV DNA presence (P=0.056), HPV type (P=0.043), as well as bcl-2 (P=0.035), mdm-2 (P=0.051), EGFR (P<0.0001), and Ki-67 (P=0.031) expression in the tumor’s invasive front were identified as important predictive indicators of recurrence in the univariate analysis. Independent significant prognostic factors for disease-free survival in multivariate analysis were the histotype, HPV DNA presence and Ki-67 expression. The invasive front of carcinomas proved to be the most important area for tumor prognosis. In addition to the detection of HPV presence and morphological parameters, Ki-67 evaluation could also be used in selecting appropriate therapeutical approaches in patients with early stage cervical cancer.