Angiogenesis as a Prognostic Indicator of Survival in Non-Small-Cell Lung Carcinoma: a Prospective Study

Abstract

Background: Tumors acquire nutrients that are essential for continued growth and an avenue for dissemination to the rest of the body by inducing angiogenesis (i.e., the formation of new blood vessels). Preliminary studies involving a number of different kinds of cancer have indicated that an assessment of tumor angiogenesis may be useful in predicting disease outcome. Purpose: In a prospective study, we evaluated the relationship between tumor angiogenesis and survival for 407 patients with nonsmall- cell lung carcinoma who were treated with potentially curative surgery. Methods: The study population consisted of 360 male and 47 female patients who underwent surgery consecutively at the Department of Surgery, University of Pisa, Italy, from March 1991 through December 1994. Followup lasted through February 1996, with a median follow-up for living patients of 29 months (range, 15-60 months). An anti-CD34 monoclonal antibody, which is specific for endothelial cells, and standard immunohistochemical techniques were used to measure angiogenesis in tumor samples. Angiogenesis was quantified in terms of microvessel counts; the counts for single, highpower microscopic fields (magnification ×250) in the three most intense areas of blood vessel growth for each sample were averaged. The median microvessel count in this series was 20, and the counts were categorized as follows: 1) low versus high (⩽20 versus >20 microvessels) or 2) in five categories (1-10, 11-20, 21-30, 31-40, and ⩾41 microvessels). Disease-free and overall survival during follow-up were assessed. Kaplan-Meier survival curves were modeled in a univariate analysis of patient and tumor characteristics; the Cox proportional hazards model was used in multivariate analysis. Reported P values are two-sided. Results and Conclusions: In the univariate analysis, patients with larger tumors ( P for trend <.00001), a more advanced tumor stage ( P for trend <.00001), a greater degree of regional lymph node involvement (P for trend <.00001), or more vascularized tumors (high versus low microvessel count, P <.00001) experienced significantly reduced overall survival. When microvessel counts were analyzed in five categories, a highly significant trend ( P <.00001) toward worse prognosis was observed with increasing tumor vascularity. In multivariate analysis, tumor microvessel count ( P <.00001), tumor size ( P = .0006), and regional lymph node status ( P <.00001) retained independent prognostic value with respect to overall survival; among these variables, tumor microvessel count, considered as a continuous variable, was the most important, with a relative hazard of death of 8.38 (95% confidence interval = 4.19- 16.78) associated with the highest microvessel counts. Implications: An evaluation of tumor angiogenesis may be useful in the postsurgical staging of patients with non-small-cell lung carcinoma and in identifying subsets of patients who may benefit from different postsurgical treatments.