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J.J. Hackett, E.Y. Chew, M.A. Crawford, D. Shen, C.C. Chan; Immunohistochemistry and Ultrastructure of Angioma in von Hipple–Lindau Disease . Invest. Ophthalmol. Vis. Sci. 2004;45(13):4683. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: von Hippel–Lindau (VHL) disease is a hereditary cancer syndrome in which affected individuals are at risk for developing tumors in multiple organs, including the eyes, cerebellum, spinal cord, kidneys, inner ear, adrenal glands, and pancreas. Retinal angioma occurs in 60% of patients with VHL. We have previously indicated that the "stromal" cells in angiomas are the tumor cells. However, the origin of the "stromal" cells is still unknown. CD31, CD117 and CD133 are currently used as markers for vascular endothelial progenitor–like cells. This study evaluates protein expression and ultrastructure of these "stromal" cells. Methods: Six eyes from 6 cases with VHL disease were evaluated using routine histology and immunohistochemistry utilizing the avidin–biotin complex immunoperoxidase technique, and transmission electron microscopy. The primary antibodies included mouse anti–human factor VIII, CD34, CD117, hypoxia–inducible factor–α (HIF–α), ubiquitin, rabbit anti–human glial fibrillary acidic protein (GFAP), neuron specific enolase (NSE), and vascular endothelial growth factor (VEGF). The secondary antibodies were biotin conjugated horse anti–mouse or goat anti–rabbit IgG, respectively. Results: All eyes had retinal angiomas associated with VHL. They were characterized by numerous small capillary–like vascular channels intermixed with vacuolated "stromal" cells. Ultrastructure of the "stromal" cells showed large vacuolar intracytoplasmic lipid inclusions with homogeneous, medium electron density. NSE, VEGF and ubiquitin were expressed throughout the angiomas. Factor VIII, CD31 and CD34 highlighted the vascular channels. CD133 mainly stained the "stromal" cells. A few scatter cells were positive for CD117. GFAP was expressed only in the glial tissue mingled within the angioma. Conclusions: The "stromal" or tumor cells in VHL retinal angiomas contain stem cell components and release various ischemic angiogenic factors including VEGF and ubiquitin, which can be responsible for the abundant neovascularization seen in the disease. Selective expression of CD31, CD117 and CD133 on the angiomas suggests VHL cells may be closely related to vascular stem cell origin.
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