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Upregulation of hypoxia-inducible factors and autophagy in von Hippel–Lindau-associated retinal hemangioblastoma

  • Pathology
  • Published:
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Abstract

Purpose

To describe pathological and molecular changes of three patients with clinically severe von Hippel–Lindau (VHL)-associated retinal hemangioblastoma (RH) with rapid progression.

Methods

Medical records, ocular histopathology, and transmission electron microscopy from three cases of VHL-associated RHs at the National Eye Institute were retrospectively reviewed. One eye of each patient was enucleated. Hypoxia-inducible factor (HIF) 1α and HIF2α expressions were identified by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry.

Results

All three cases had rapidly growing RHs that were resistant to multiple conventional therapies and two (patients 1 and 2) were also resistant to multiple intravitreal anti-vascular endothelial growth factor (VEGF) treatments. Macroscopically, all the enucleated eyes had multiple RHs, serous retinal detachment, severe retinal disorganization and focal hemorrhages. Histopathology showed typical RHs composed of vacuolated foamy VHL cells and capillary networks. Retinal gliosis and hemorrhages were also presented. Additionally, T lymphocytes and macrophages infiltrated in the tumors of two patients resistant to anti-VEGF therapy. Immunohistochemistry, and qRT-PCR found upregulation of HIF1α in the retinal lesions of all eyes. Importantly, upregulation of HIF2α was exclusively detected in the two cases with inflammatory infiltration and resistance to anti-VEGF therapy. Ultrastructural images showed autophagy, lipid droplets, glycogen aggregations, and cytoplasmic degeneration in many VHL cells.

Conclusions

Based on the histopathological and molecular pathological findings, autophagy, inflammation, and/or upregulation of HIF2α could potentially contribute to the aggressive course of RHs, resulting in the resistance to multiple anti-VEGF and radiation therapies in these patients.

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Acknowledgment

The National Eye Institute Intramural Research Program supported the study.

Disclosure/Conflict of interest

The authors declare that they have no conflict of interesst.

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Authors and Affiliations

  1. Immunopathology Section, Laboratory of Immunology, National Eye Institute, National Institutes of Health, 10 Center Dr., 10/10N103, NIH/NEI, Bethesda, MD, 20892-1857, USA

    Yujuan Wang, Defen Shen & Chi-Chao Chan

  2. Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, 510060, China

    Yujuan Wang

  3. Histopathology Core, National Eye Institute, National Institutes of Health, Bethesda, MD, 20892, USA

    Mones S. Abu-Asab & Chi-Chao Chan

  4. Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, 20892, USA

    Zhengping Zhuang

  5. Division of Epidemiology and Clinical Applications, National Eye Institute, National Institutes of Health, Bethesda, MD, 20892, USA

    Emily Y. Chew

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  1. Yujuan Wang
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Correspondence to Chi-Chao Chan.

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Wang, Y., Abu-Asab, M.S., Shen, D. et al. Upregulation of hypoxia-inducible factors and autophagy in von Hippel–Lindau-associated retinal hemangioblastoma. Graefes Arch Clin Exp Ophthalmol 252, 1319–1327 (2014). https://doi.org/10.1007/s00417-014-2660-0

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  • DOI: https://doi.org/10.1007/s00417-014-2660-0

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