Microvessel density and vascular endothelial growth factor expression as predictors of childrens’ survival from cerebellar medulloblastoma

Abstract

Cerebellar medulloblastoma is the most common malignant brain tumor of childhood. This neoplasm is highly vascular and has a high growth rate. We aimed to determine whether high microvessel density (MVD) and expression of vascular endothelial growth factor (VEGF) in medulloblastoma tissue is correlated with survival time in children with this tumor. Tissue from 32 cerebellar medulloblastomas in 14 girls and 18 boys was studied. The standard-risk group comprised patients older than 3 years, without metastases of medulloblastoma and a residual post-operative tumor with a surface area less than 1.5 cm². The patients assigned to a high-risk group had at least one of the following indicators: younger than 3 years, metastases, or a residual post-operative tumor with a surface area larger than 1.5 cm². For each tumor, MVD was determined and the expression of VEGF was assessed using immunohistochemical techniques. The 5-year survival rate for the 32 patients was 56.2%. Five-year survival rates were 70.6% and 40.0% for patients in the standard-risk and high-risk groups, respectively. The mean (±standard deviation, SD) MVD for all patients was 22.0 ± 9.1 microvessels per 0.7 mm². There was no difference in the survival rate between the groups with above-average MVD and below-average MVD (66.7% and 50.0%, respectively). Testing revealed 7 tumors with VEGF expression and 25 without. The 5-year survival rates for these 2 groups were not significantly different (57.1% vs. 56.0%, respectively). The mean (±SD) MVD values for the VEGF-positive and VEGF-negative groups were not significantly different (19.1 ± 6.5 vs. 22.9 ± 9.7 microvessels per 0.7 mm², respectively, Mann–Whitney U-test = 78.5, Z = −0.41, p = 0.68). There were no significant correlations between risk groups and expression of VEGF or MVD. These results indicate that neither high MVD nor the expression of VEGF in tumor tissue predicts poor prognosis in children with cerebellar medulloblastoma.

Introduction

Cerebellar medulloblastomas are solid neoplasms that account for 30% of all posterior fossa tumors and 20% of all brain tumors in pediatric patients.¹ Most of these neoplasms are diagnosed between 5 years and 7 years of age, and they are more common in boys than in girls.² Cerebellar medulloblastomas in children are most frequently located in the centrum of the posterior fossa. These tumors originate from bipotential embryonic cells located in the roof of the fourth ventricle.[1], [2] The prognosis and survival rate for children with medulloblastoma have improved dramatically since the mid 1970s.³ The 5 year survival rate for standard-risk children after surgery, radiotherapy and chemotherapy is between 70% and 80%, and the rates for high-risk children range from 55% to 76%.⁴

Vascular supply is the most important requirement for organ development and differentiation in multicellular organisms. In a neoplasm, neovascularization allows for the development of tumor tissue. Since formation of new capillaries is essential for tumor infiltration and metastasis,⁵ one would expect a positive correlation between the tumor vascularity and malignancy. Research has been conducted on microvessel density (MVD) and various angiogenic factors (including vascular endothelial growth factor [VEGF], fibroblast growth factor [FGF], angiopoietin-1 and angiopoietin-2 [Ang-1 and Ang-2], transforming growth factor alpha [TGF-α] and platelet-derived growth factor alpha [PDGF-A]) in childhood medulloblastomas.⁶ Investigators have also examined the efficacy of anti-angiogenic drugs as treatment for medulloblastoma because of this tumor’s high vascularity and angiogenic activity. Specifically, MacDonald et al. studied the treatment of brain tumors (medulloblastomas and glioblastomas) with the anti-angiogenic agent EMD 121974, a cyclic peptide antagonist pentapeptide.⁷ Tumor cells were injected into either the forebrain (orthotopic model) or the subcutis (heterotopic model) of nude mice. Once the tumors were established, daily systemic treatment with active EMD 121974 was initiated, which resulted in tumor cell death.⁷

Our aim was to assess whether high MVD or expression of VEGF in medulloblastoma tissue correlate with poor prognosis in children with cerebellar medulloblastoma.