Molecular pathology of eyes with von Hippel-Lindau (VHL) Disease: a review

Abstract

Background: von Hippel-Lindau Disease (VHL) is an autosomal dominant inherited systemic cancer syndrome. Recently, many advances have contributed to the understanding of VHL pathophysiology.

Methods: In this article we review recent developments and summarize our findings in VHL molecular pathology related to retinal and optic nerve diseases.

Results: Loss of heterozygosity (LOH) within the VHL gene is detected in the stromal cells surrounding the capillary endothelial cells and admixed with glial cells in ocular hemangioblastomas. This finding is in line with similar findings in VHL-associated CNS hemangioblastoma and renal clear cell carcinomas. Increases of vascular endothelial growth factor (VEGF), hypoxia induced factor (HIF), and ubiquitin are found in ocular hemangioblastomas.Interestingly, tumorlet cells, which are composed of poorly differentiated small cells with prominent dark nuclei and little cytoplasm, as well as several stem cell markers, such as erythropoietin (Epo), Epo receptor (EpoR), and CD133, are present in ocular VHL lesions. CXCR4, a CXC chemokine receptor is also expressed in retinal VHL hemangioblastomas.

Conclusions: These findings imply that VHL cells with LOH of the tumor suppressor gene, most likely originate from a hematopoietic/vascular lineage. Targeting these proteins and ischemic factors, not VEGF alone, may be a potential therapeutic approach for VHL-associated ocular hemangioblastomas.

Fig. 1

Funduscopic photograph showing a typical hemangioblastoma in the peripheral retina of a patient with von Hippel–Lindau disease.

Fig. 2

Funduscopic photograph showing a hemangioblastoma in the optic nerve head of a patient with von Hippel–Lindau disease.

Fig. 3

Macroscopic photograph showing multiple retinal hemangio-blastomas in the eye of a patient with von Hippel–Lindau disease.

Fig. 4

A, Transmission electron micrograph showing many electron homogenous globules in the cytoplasm of a stomal cell (x30,000). B, Microphotograph showing many foamy cells composing the stroma of a von Hippel–Lindau-associated retinal hemangioblastoma (hematoxylin & eosin, x400).

Fig. 5

Microphotograph showing small clusters of tumorlet like cells in a von Hippel–Lindau-associated optic nerve head hemangioblastoma (hematoxylin & eosin, x400).

Fig. 6

Microphotographs showing (A) a preretinal neovascular membrane removed from a patient with von Hippel–Lindau disease (hematoxylin & eosin, x400) and (B) expression of vascular endothelial growth factor (dark black-bluish color) in the membrane (avidin-biotin-complex immunoperoxidase, x400).