Angiogenic Histogenesis of Stromal Cells in Hemangioblastoma: Ultrastructural and Immunohistochemical Study

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Abstract
Controversy regarding the origin of characteristic stromal cells (SC) is responsible for the placement of hemangioblastoma as a single entity in the category of "tumors of uncertain histogenesis" in the current WHO classification of brain tumors. This subclassification of hemangioblastoma is, to a large extent, a consequence of a remarkable antigenic heterogeneity of SC demonstrated in many, often contradictory immunohistochemical studies. In contrast, most of the electron microscopic studies demonstrated a number of features indicating angiogenic nature of SC and, therefore, hemangioblastoma. This study reevaluated the histogenesis of SC, applying immunohistochemistry as well as electron microscopy and immunoelectron microscopy. Immunohistochemical studies confirmed most of the previous results indicating a very frequent expression of vimentin, S-100 protein, neuron-specific enolase, and cytokeratins. SC were less commonly immunoreactive for desmin, factor XIIIa, and Ricinus communis lectin receptors, and only occasionally for factor VIII and Ulex europeus lectin. They were negative for other markers of endothelial, neuronal, glial, neuroendocrine, and smooth muscle differentiation. Approximately 1% of SC showed Ki67 immunoreactivity, indicating their slight proliferative activity, consistent with the benign nature of the tumor. In contrast to the inconclusive results of the immunohistochemistry, electron microscopy demonstrated a clear relationship of SC to endothelial cells, smooth muscle cells, and pericytes. Occasional SC were found within the vascular lumina. SC often showed intracellular caveolae consistent with the formation of early capillary lumina. Moreover, occasional SC contained small Weibel-Palade bodies positive for factor VIII in immunoelectron microscopy. SC represent a heterogeneous population of abnormally differentiating mesenchymal cells of angiogenic lineage, with some morphological features of endothelium, pericytes, and smooth muscle cells. Occurrence of SC in hemangioblastoma could be related to a limited ability of angioformative stromal cells to develop an architecture of capillary lumina integrated with the vascular network of the tumor. Hemangioblastoma should be reclassified and included together with other vascular tumors of the central nervous system.