Background: The p53 and bcl-2 gene deregulations are frequently involved in several types of epithelial malignancy. The aims of this study were to determine the relationships between the Ki-67 labeling index (LI) and the expression of p53 and bcl-2 protein in lung adenocarcinoma and to investigate the clinicopathologic features of the tumors and the prognostic significance of p53 and bcl-2.
Methods: Immunohistochemical staining for p53, bcl-2, and Ki-67 was performed on paraffin embedded sections from 114 lung adenocarcinomas from patients who had been treated with complete and potentially curative surgery. To define a cutoff value for p53 immunopositivity, 37 of 114 tumors were examined for p53 gene mutations using cDNA sequencing. The results were compared with clinical outcomes.
Results: Expression of p53 protein was defined as nuclear staining in more than 20% of tumor cells, and the concordance rate between p53 expression and gene mutation was 73%. Expression of p53 (39%) was significantly associated with higher Ki-67 LI (P < 0.001) and with several poor prognostic factors, such as poor histologic grade of differentiation (P < 0.05), lymphatic permeation (P < 0.001), and vascular permeation (P < 0.001). Expression of bcl-2 (38%) was significantly associated with favorable T classification (P < 0.001) and smaller tumor size (<2 cm) (P < 0.05) and tended to be associated with lower Ki-67 LI (P = 0.054). In univariate analysis, p53 expression was significantly correlated with poor prognosis (53% vs. 90% at 5 years, P < 0.001) and bcl-2 expression with favorable prognosis (90% vs. 68% at 5 years, P < 0.05). Proliferative activity was highest when only p53 was expressed; by contrast, proliferative activity was lowest when only bcl-2 was expressed. Among four groups of patients, the group that was positive only for p53 had the shortest survival; this difference was statistically significant. Multivariate analysis showed that T classification (P = 0.002), vascular permeation (P = 0.011), and p53 expression (P = 0.03) were independent prognostic factors.
Conclusions: The results of this study indicated an inverse relationship between the proliferative activity of p53 and bcl-2. Expression of p53 was an independent factor associated with poor prognosis, whereas bcl-2 expression was associated with favorable prognosis.