The prognostic significance of p53 and bcl-2 expression in lung adenocarcinoma and its correlation with Ki-67 growth fraction.
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.
Ishida
H
H
Department of Pathology, Saga Medical School, Japan.
Irie
K
K
Itoh
T
T
Furukawa
T
T
Tokunaga
O
O
D000230:Adenocarcinoma / Q000737:chemistry* / Q000473:pathology / Q000601:surgery; D000368:Aged; D018076:DNA, Complementary; D004273:DNA, Neoplasm / Q000737:chemistry; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000032:analysis*; D008175:Lung Neoplasms / Q000737:chemistry* / Q000473:pathology / Q000601:surgery; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D016133:Polymerase Chain Reaction; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis*; D016019:Survival Analysis; D016159:Tumor Suppressor Protein p53 / Q000032:analysis*
D018076:DNA, Complementary; D004273:DNA, Neoplasm; D019394:Ki-67 Antigen; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53