ANGI-13HISTOPATHOLOGICAL INVESTIGATION OF GLIOBLASTOMAS RESECTED UNDER CONTROL OF NEOADJUVANT BEVACIZUMAB

There has been no clinical observation about histopathological changes in human gliomas under control of the anti-angiogenic treatment, and the tissue-based observation is likely crucial to understand mechanism of action of these treatment. We collected 4 glioblastomas resected under control of neoadjuvant bevacizumab (Bev). Histopathological investigation was performed by hematoxilyn- eosin staining and immunohistochemistry for CD34, VEGF, VEGFR1/2, HIF-1α, and Nestin as compared to 6 control glioblastomas to assess changes in histological features, microvessel density, expression of VEGF and its receptors, tumor hypoxic condition, and cancer stem cells. Tumor resection under control of Bev was uneventful in all of the 4 cases. Intraoperatively, the tumors were clearly less vasculized than usual. Histopathologically, vascular morphology was quite different from usual glioblastomas with universal disappearance of microvascular proliferation. Microvessel density was significantly decreased in the 4 tumors as compared to control tumors. The expression of VEGF and its receptors was decreased in 2 cases of partial response, suggesting possible correlation with radiologic response. The expression of HIF-1α was similar or somewhat decreased in the 4 tumors. The expression of Nestin was significantly decreased in the 4 tumors as compared to control tumors, but there still remained numerous Nestin-positive cells especially around vessels. We provide the first clinicopathological evidence that the anti-angiogenic therapy induces vascular normalization and decrease of microvessel density in glioblastomas. These in situ observation will help to elucidate the mechanism of resistance to Bev and to optimize therapy.