The association between vascular endothelial growth factor, microvessel density and clinicopathological features in invasive cervical cancer

Abstract

Objective: The aim of this study was to analyse the vascular endothelial growth factor (VEGF) expression in a series of cervical carcinomas and to compare the results with the microvessel density (MVD) and clinicopathological features. Study design: The immunoreactivity for VEGF was studied in 130 invasive cervical carcinomas and in 22 patients with a carcinoma in situ of the cervix. The results were compared with the MVD. Results: Staining for VEGF of less then 50% per slide occurred in 80% of the invasive carcinomas and in 82% of the in situ carcinomas. The median MVD was 261 vv/mm² (range: 11–1000) in the invasive group and 146 vv/mm² (range: 25–536) in the in situ group. Unlike the microvessel density there was no association between VEGF expression and survival. The MVD was higher in VEGF poorer (<50%) tumours (P=0.055). Beside tumour histology (P=0.012) there were no other significant relationships between the remaining histopathological findings and VEGF expression. Conclusion: Tissue VEGF expression has no prognostic value in contrast with the MVD in patients with invasive cervical cancer.

Introduction

It is generally accepted that solid tumours require angiogenesis for progression and metastasis [1]. The sprouting of new capillaries is essential for tumour growth beyond 1–2 mm² and contributes to the metastatic process by transporting cancer cells into the circulation [1], [2]. The measurement of microvessel density, either manual or computerised, can be performed after immunostaining with CD 31 or factor VIII. The amount of vessels is thought to be a reflection of angiogenic activity and increased vascular density has been shown to correlate with a higher incidence of metastasis and a worse prognosis in different tumours [3], [4], [5]. Various angiogenic and anti-angiogenic factors tune the balance of angiogenesis by either promotion or inhibition. Tumours and their stroma are thought to secrete angiogenic factors, which promote neovascularisation [6]. These factors include: acidic and basic fibroblast growth factor (acidic/basic FGF), transforming growth factor alpha and transforming growth factor beta (TGF alpha/beta), vascular endothelial growth factor (VEGF), interleukin 8 (IL-8), tumour necrosis factor alpha (TNF-alpha), and platelet-derived endothelial cell growth factor (PDECGF)/thymidine phosphorylase (dThdPase) [1], [3], [7]. One of the most important secreted angiogenic factors is probably vascular endothelial growth factor (VEGF). The VEGF acts as an endothelial cell specific mitogen and is a potent mediator of increased vascular permeability by binding to its receptor [8], [9].

In cervical cancer, measurement of the microvessel density has been found to provide prognostic information [5], [10]. Whether a relationship exists between microvessel density and the expression of VEGF in cervical cancer is uncertain. Studies on breast carcinomas, epidermoid lung carcinomas, oesophageal or hepatocellular carcinomas have already demonstrated a correlation between VEGF expression, vascular density and tumour progression [11], [12], [13], [14]. Until now only two studies have been reported in cervical carcinomas. These studies reported controversial findings between VEGF and microvessel density in cervical cancer [15], [16]. Unfortunately only one of these studies had follow-up information. These diversing results prompted us to study VEGF expression and to compare the results with previous findings of a study on microvessel density and clinocopathological factors in cervical tumours with an extensive follow-up information [5].