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

J Neurosurg. 1998 Mar;88(3):513-20. doi: 10.3171/jns.1998.88.3.0513.


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.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Analysis of Variance
  • Antibodies, Monoclonal
  • Astrocytoma / blood supply*
  • Astrocytoma / genetics
  • Astrocytoma / pathology
  • Astrocytoma / surgery
  • Biomarkers, Tumor / analysis*
  • Biomarkers, Tumor / genetics
  • Capillaries / pathology
  • Cell Division
  • Cell Transformation, Neoplastic / pathology
  • Coloring Agents
  • Endothelial Growth Factors / analysis*
  • Endothelial Growth Factors / genetics
  • Epidermal Growth Factor / analysis
  • Epidermal Growth Factor / genetics
  • Factor VIII / analysis
  • Factor VIII / genetics
  • Female
  • Fibroblast Growth Factor 2 / analysis
  • Fibroblast Growth Factor 2 / genetics
  • Follow-Up Studies
  • Gene Expression Regulation, Neoplastic
  • Glioblastoma / pathology
  • Humans
  • Ki-67 Antigen / analysis
  • Ki-67 Antigen / genetics
  • Lymphokines / analysis*
  • Lymphokines / genetics
  • Male
  • Microcirculation / pathology
  • Middle Aged
  • Multivariate Analysis
  • Neovascularization, Pathologic / genetics
  • Neovascularization, Pathologic / pathology
  • Prognosis
  • Supratentorial Neoplasms / blood supply*
  • Supratentorial Neoplasms / genetics
  • Supratentorial Neoplasms / pathology
  • Supratentorial Neoplasms / surgery
  • Survival Rate
  • Treatment Outcome
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • Venules / pathology


  • Antibodies, Monoclonal
  • Biomarkers, Tumor
  • Coloring Agents
  • Endothelial Growth Factors
  • Ki-67 Antigen
  • Lymphokines
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • Fibroblast Growth Factor 2
  • Epidermal Growth Factor
  • Factor VIII