Von Hippel-Lindau gene deletion and expression of hypoxia-inducible factor and ubiquitin in optic nerve hemangioma

Abstract

Purpose: Von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome expressed in multiple organs caused by germline alterations of the VHL gene. We have shown VHL deletion in the "stromal" cells of retinal angiomas. The VHL protein-associated complex is a primary ubiquitin ligase for the ubiquitination of hypoxia-inducible factor (HIF). This study examines VHL and ubiquitin expression in optic nerve hemangiomas and juxtapapillary angiomas.

Methods: Using microdissection and polymerase chain reaction, four optic nerve hemangiomas (one also had juxtapapillary angioma) associated with VHL disease were analyzed for loss of heterozygosity in the VHL gene. In addition, expression of HIF and ubiquitin was evaluated in these tumors by immunohistochemistry.

Results: All informative optic nerve and juxtapapillary lesions showed loss of heterozygosity in the VHL gene detected in vacuolated "stromal" cells. Both HIF and ubiquitin were highly expressed in the hemangiomas of all four VHL cases.

Conclusions: Like retinal angiomas and other VHL tumor lesions, VHL gene deletion is found in optic nerve hemangiomas and juxtapapillary angiomas. These tumor cells also express HIF and ubiquitin, the protein responsible for the negative regulation of HIF that results in the hypervascularization characteristic of VHL disease.

Figure 1

Optic nerve hemangioblastoma involving the optic nerve head in a patient with von Hippel–Lindau disease.

Figure 2

Microphotographs showing optic nerve hemangiomas located inside the optic nerve (A) and above the lamina cribrosa (asterisk, B) in two patients with von Hippel–Lindau disease (hematoxylineosin, original magnification ×200).

Figure 2

Microphotographs showing optic nerve hemangiomas located inside the optic nerve (A) and above the lamina cribrosa (asterisk, B) in two patients with von Hippel–Lindau disease (hematoxylineosin, original magnification ×200).

Figure 3

Autoradiographs showing allelic imbalance indicative of loss of heterozygosity (T) after amplification with VHL gene flanking primers D3S1038, D3S1110, and D3S656. Matched adjacent normal cells (N) show preservation of both alleles of the VHL gene.

Figure 4

Microphotographs showing positive staining for hypoxia-inducible factor-α (A) and ubiquitin (B) in two von Hippel–Lindau hemangioblastomas (avidin-biotin-complex immunoperoxidase, original magnification ×200).

Figure 4

Microphotographs showing positive staining for hypoxia-inducible factor-α (A) and ubiquitin (B) in two von Hippel–Lindau hemangioblastomas (avidin-biotin-complex immunoperoxidase, original magnification ×200).