Cyclooxygenase-2, Vascular Endothelial Growth Factor And Bcl-2 Expression In Nasal NK/T-cell Lymphoma: The Effects On Angiogenesis, Clinical And Prognostic Significance

Background and Objective: The prognosis of nasal nature killer/T-cell lymphoma (NNTCL) is related to many factors. Angiogenesis-related oncogenes play important roles in occurrence and development of tumors. The significance of angiogenesis as a biological and prognostic factor has not been clearly demonstrated in NNTCL. To our knowledge, no joint analysis of angiogenesis in correlation to COX-2,VEGF and Bcl-2 protein expression in NNTCL was performed. Therefore, the aim of this study was to assess the relationship between the expression of above proteins in NNTCL with theirs clinicopathological characteristics and prognostic significance and their potential relevance of angiogenesis.Methods: Archival formalin fixed, paraffin embedded specimens from 43 patients who had undergone surgery for NNTCL between January 1994 and August 2005 in Anhui provincial hospital were recuited in this study. There were 28 male and 15 female with a median age of 50 years (range 13~85 years). COX-2, VEGF and Bcl-2 protein expression were detected in NNTCL tissues by streptavidin-peroxidase immunohistochemistry. Statistical anaysis was performed using SPSS statistical software package(version11.5). Survival curves were calculated according to Kaplan-Meier method and compared with the use of log-rank test. Multivariate analysis was based on Cox regression model with P values lower than 0.05 considered as statistically significant.Results: COX-2, VEGF and Bcl-2 protein expressed significantly in NNTCL, and the corresponding positive rates were 34.9%, 30.2% and 34.9%, respectively. The positive rates of COX-2 and VEGF expression were significantly higher in the group of local tumor invasion beyond nasal cavity than their compared groups (50%vs15.8%, P=0.026; 45.8%vs10.5%, P=0.019); They were remarkably lower in the group of complete remission (CR) achieved in the primary treatment than no CR achieved group (20%vs67.9%, P=0.004; 15.4%vs 66.7%, P=0.003). The positive rates of COX-2 and VEGF were not related to the sex, age, International prognostic index (IPI), Eastern Cooperative Oncology Group(ECOG) performance status(PS) score, Ann Arbor stage, lymph node metastasia and B symptoms (P﹥0.05); while the positive rate of Bcl-2 was not related to all the clinical factors mentioned above (P>0.05). Microvascular density(MVD) were related to COX-2, VEGF, tumor extranasal invasion and CR rates in the primary treatment (P<0.05). Expression of COX-2 were positive correlation with VEGF and Bcl-2, respectively(r=0.687, P=0.000;r=0.386, P=0.011).While the expression of VEGF was negatively correlated with Bcl-2 (r=0.262, P=0.10). Twenty-five patients died at the end of follow-up. The 3-year overall survival(OS) rate and the 5-year OS rate were 48.8% and 34.2%, respectively; and the median suvival time was 41.5 months (range 2～145 months). The 2-year OS rates in COX-2 and VEGF positive expression groups were 37.3% and 32.0%, respectively; and their 5-year OS rates were 43.9% and 41.2%, respectively. The factors with inclusion of COX-2, VEGF expression, age, IPI, PS score, Ann Arbor stage, extranasal cavity invasion, LDH level, anemia and CR rate in the primary treatmen were confirmed to be significantly associated with the survival time of paitents in univariate analysis with Kaplan-Meier mothod (P﹤0.05). The multivariate analysis with Cox hazard model demonstrated that PS score and CR rates in the initial treatment could be independent indicators for the prognosis of patients with NNTCL(P﹤0.05).Conclusions:1. COX-2,VEGF and Bcl-2 expressed in NNTCL tissues. COX-2 and VEGF play important cooperative roles in microvascular angiogenesis in NNTCL. They may promote tumor invasion beyond the nasal cavity and deteriorate treatment response. The two adverse factors decreased CR rates in the primary treatment and survival rates in long term.2. There is a positive correlation between Bcl-2 and COX-2, but the relationship between the expression of Bcl-2 and the prognosis of NNTCL is still unclear.3. PS score and CR rate in the primary treatment were the independent prognostic factors for NNTCL. Including COX-2 protein expression, VEGF protein expression, old age, higer IPI, advanced Ann Arbor stage, extranasal cavity invasion, higher LDH level and anemia may serve as adverse prognostic factors for NNTCL patients.