It has been widely demonstrated that neo-angiogenesis and its mediators (i.e. vascular endothelial growth factor), represent useful indicators of poor prognosis in non small cell lung carcinoma. In order to verify whether neovascularization and vascular endothelial growth factor may be considered useful markers of clinical outcome also in the small cell lung cancer subgroup, we retrospectively investigated a series of 75 patients with small cell lung carcinoma treated by surgery between 1980 and 1990. Immunohistochemically-detected microvessels and vascular endothelial growth factor expressing cells were significantly associated with poor prognosis, as well as with nodal status and pathological stage. In fact, patients whose tumours had vascular count and vascular endothelial growth factor expression higher than median value of the entire series (59 vessels per 0.74 mm² and 50% of positive cells, respectively), showed a shorter overall and disease-free survival (P=0.001, P=0.001; P=0.008, P=0.03). Moreover, the presence of hilar and/or mediastinal nodal metastasis and advanced stage significantly affected overall and disease-free interval (P=0.00009, P=0.00001; P=0.0001, P=0.00001). At multivariate analysis, only vascular endothelial growth factor expression retained its influence on overall survival (P=0.001), suggesting that angiogenic phenomenon may have an important role in the clinical behaviour of this lung cancer subgroup.

Purpose: The survival rate of non–small cell lung cancer patients is very low, and knowledge of predictors of outcome is inadequate. To improve the curability of lung cancer, we need to identify new specific molecules involved in tumorigenesis and progression. The purpose of this study was to better define the role of osteopontin in non–small cell lung cancer biology by determining its prognostic significance. Experimental Design: Osteopontin expression was evaluated by immunohistochemistry, as percentage of neoplastic cells with cytoplasmic immunoreactivity, in a wide series of patients with stage I-IIIA non–small cell lung cancer (207 cases). The median value of this series (20% of positive cells) was used as the cutoff value to distinguish tumors with low (<20%) from tumors with high (≥20%) osteopontin expression. Results: Taking the series of patients as a whole (207 cases), osteopontin expression was associated with neither overall survival (P = 0.14) nor disease-free survival (P = 0.074). However, among patients with at least 6 years of follow-up (163 cases), 6-year overall survival and disease-free survival were significantly reduced if osteopontin expression was high (P = 0.0085 for overall survival, P = 0.0023 for disease-free survival). Moreover, a statistically significant correlation between high levels of osteopontin and shorter overall survival (P = 0.034) and disease-free survival (P = 0.011) in patients with stage I tumors (136 cases) was shown. Conclusions: Our results support the hypothesis of an association between high osteopontin expression and poor survival of patients with stage I non–small cell lung cancer, suggesting that osteopontin could be a candidate target for cancer therapy.

Following up-regulation of an angiogenesis inhibitor by the wild-type p53 protein proven recently, we have analysed on the one hand the prognostic impact of microvessel count (MC) and p53 protein overexpression in non-small-cell lung carcinoma (NSCLC) progression and, on the other hand, the inter-relation between the microvascular pattern and the p53 protein expression. Moreover, we assessed the expression of vascular endothelial growth factor (VEGF), one of the pivotal mediators of tumour angiogenesis, in order to investigate its relation to p53 protein expression and MC. Tumours from 73 patients resected for NSCLC between March 1991 and April 1992 (median follow-up 47 months, range 32-51 months) were analysed using an immunohistochemical method. In univariate analysis, MC and p53 accumulation were shown to affect metastatic nodal involvement, recurrence and death significantly. Multiple logistic regression analysis showed an important prognostic influence of MC and nodal status on overall (P = 0.0009; P = 0.01) and disease-free survival (P = 0.0001; P = 0.03). Interestingly, a strong statistical association was observed between p53 nuclear accumulation and MC (P = 0.0003). The same inter-relationship was found in non-squamous histotype (P = 0.002). When we analysed the concomitant influence of MC and p53 expression on overall survival, we were able to confirm a real predominant role of MC in comparison with p53. With regard to VEGF expression, p53-negative and lowly vascularized tumours showed a mean VEGF expression significantly lower than p53-positive and highly vascularized cancers (P = 0.02). These results underline the prognostic impact of MC and p53 protein accumulation in NSCLC and their reciprocal inter-relationship, supporting the hypothesis of a wild-type p53 regulation on the angiogenetic process through a VEGF up-regulation.

Purpose: The c-kit protein, also known as CD117, is a member of the type III receptor tyrosine kinase family. Kinase activity has been implicated in the pathophysiology of many tumors, including small-cell lung carcinoma (SCLC). Autocrine or paracrine activation of c-kit by its ligand has been postulated for lung cancer, but this receptor can also be activated by mutations of the c-kit gene. We examined c-kit expression and mutational status in SCLC to verify its putative expression and genetic alterations, as well as its eventual prognostic impact.