Tumor vascularity: a histological measure of angiogenesis and hypoxia.

Abstract

In this study we sought to clarify the relationship between tumor vascularity, hypoxia, and angiogenesis in human cervix tumors. Two hypotheses were established: first, that measurement of tumor vascularity can provide a histological assessment of both hypoxia and angiogenesis; and second, that expression of angiogenesis-related proteins will provide a surrogate measure of tumor hypoxia. To test the first hypothesis, we studied the prognostic significance of tumor vascularity measured as both intercapillary distance (ICD; thought to reflect tumor oxygenation) and microvessel density (MVD; the hotspot method that provides a histological assessment of tumor angiogenesis). The relationship was also examined of tumor hypoxia, measured using an Eppendorf needle electrode [percentage of values less than 5 mm Hg (HP5)], with ICD and MVD. To test the second hypothesis we examined the relationship between HP5 and the expression of angiogenesis-associated proteins [vascular endothelial growth factor (VEGF) and platelet-derived endothelial cell growth factor (PD-ECGF)]. All of the biological measurements were made on pretreatment tumors. Analysis of data was carried out using log-rank statistics, Cox multivariate analysis, and Spearman's rank correlation. Both ICD and MVD were significant independent prognostic factors for local control. Patients with poorly vascularized tumors (long ICD) had poor local control (P = 0.042). However, patients with poorly vascularized tumors, measured as low MVD, had good local control (P = 0.036). For 107 patients in whom both of the measurements were obtained on the same tumor sections, ICD and MVD provided independent prognostic information in multivariate analysis. There was a significant correlation between tumor hypoxia and ICD (P < 0.005) but not MVD (P = 0.41). There was no relationship between hypoxia and the expression of angiogenic factors (VEGF, PD-ECGF). These analyses show that measurement of tumor vascularity can provide different biological information that is dependent on the method used. It is, therefore, important that studies measuring vascularity should include an appropriate definition. There is no relationship between hypoxia and angiogenesis in advanced carcinoma of the cervix and examining the levels of angiogenic proteins may not have a role in assessing hypoxia in cervix cancer.