Vascular endothelial growth factor expression and vascular density as prognostic markers of survival in patients with low-grade astrocytoma

Abstract

It has long been recognized that some patients with low-grade astrocytoma may survive for many years, whereas in others the disease follows a more malignant course resulting in a short survival time, usually due to malignant transformation into higher-grade tumors.

Object: The aim of this study was to investigate angiogenesis in the initial biopsy specimen of tumor tissue as a biological marker to identify patients with low-grade astrocytoma who are at high risk of malignant tumor transformation or death.

Methods: Tumor tissue was studied in 74 consecutively treated adult patients in whom a diagnosis of diffuse supratentorial hemispheric histologically proven fibrillary low-grade astrocytoma was made and who underwent surgery between January 1972 and January 1994. Studies were conducted using monoclonal antibodies to the antigens of the proliferation-associated Ki-67 (MIB-1), factor VIII, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and epidermal growth factor (EGF). The overall 5-year survival rate for the entire patient population was 65%, with a median survival time of 7.5 years. The total mean follow-up period was 6.1 years. All tumors showed a low proliferative potential at the time of the initial operation, as demonstrated by an MIB-1 labeling index of less than 1.5%. Patients with more than seven microvessels in tumor tissue (29 cases) had a shorter survival time (mean 3.8 years) than those with seven or fewer microvessels (mean survival 11.2 years). This difference in survival times was significant by univariate (p = 0.001) and stepwise multivariate analyses (p < 0.001). Tumors with a larger number of microvessels also had a greater chance of undergoing malignant transformation (p = 0.001). Similarly, significant staining for VEGF was correlated with shorter survival times when using univariate (p = 0.003) and multivariate (p = 0.008) analyses and with a greater chance of malignant transformation (p = 0.002). Patients with tumors staining positive for VEGF (39 individuals) had a median survival time of 5.3 years, and those with tumors negative for VEGF (35 patients) had a median survival time of 11.2 years. No association was observed between bFGF, EGF, and survival or malignant transformation. The stepwise multivariate analysis included histological and clinical variables simultaneously.

Conclusions: The authors have shown that microvessel density and VEGF levels are independent prognostic markers of survival in fibrillary low-grade astrocytoma. This finding leads them to propose that fibrillary diffuse low-grade astrocytoma is not a single pathological entity but is composed of a spectrum of tumors with differing propensities to undergo malignant transformation that is at least partly based on their inherent angiogenic potential.