Prognostic value of cell proliferation, growth and differentiation regulatory proteins in early stage cervical carcinoma

Abstract

Objectives: The aim of this study was to evaluate the immunohistochemical expression of cell proliferation, growth, and differentiation regulatory proteins in early stage cervical carcinoma and to assess their prognostic value by exploring their relationships to various clinicopathological characteristics (age, lymph node involvement, tumor diameter, depth of invasion, thickness of uninvolved cervical stroma, histotype, grade, lymphvascular space invasion, inflammatory infiltrate), human papillomavirus (HPV) status and influence on disease-free survival. Methods: This retrospective study comprised 83 patients, all subjected to radical hysterectomy with bilateral pelvic lymphadenectomy for early stage cervical carcinoma and postoperative irradiation therapy. Expression of Ki-67, c-erbB-2, EGFR protein, as well as estrogen and progesterone receptors was evaluated by immunohistochemistry using avidinbiotin-peroxidase complex method. The results were assessed semiquantitatively in the surface area, center and invasive front of each tumor as the percentage of the 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. RESULTS: In our case series, 73 (88%) patients had a tumor limited to the uterine cervix less than 4 cm in diameter (pT1b1), while 10 (12%) patients had larger neoplasms belonging to pT1b2 category. Pelvic lymph node involvement was found in 20 (24%) patients. During the follow-up period (range, 65-181, mean, 121 months) recurrences were observed in 9 patients. The 5-, 10- and 15-year disease-free survival rate was 92.7%, 90.8% and 86.6%, respectively. Important predictive indicators of recurrence in the univariate analysis were pelvic lymph node involvement (P=0.0008), tumor diameter (P=0.035), depth of stromal invasion (P=0.029), histological type (P=0.0009), grade of differentiation (P=0.056), HPV DNA presence (P=0.056), HPV type (P=0.043), as well as Ki-67 (P=0.031), and EGFR protein (P=0.0066) expression in the tumor’s invasive front. Among these variables, however, the histological type, HPV DNA presence, Ki-67 and EGFR protein expression were identified as independent significant prognostic factors for disease-free survival in multivariate analysis using Cox regression model. Conclusions: The invasive front of carcinomas proved to be the most important area for the evaluation of prognostic significance of the expression of cell proliferation, growth, and differentiation regulatory proteins. In addition to the detection of HPV presence and morphological parameters, the evaluation of Ki-67 and EGFR protein expression may provide additional prognostic information in patients with early stage cervical carcinomas.