title: Upregulation of hypoxia-inducible factors and autophagy in von Hippel-Lindau-associated retinal hemangioblastoma.
abstract: OBJECTIVE
  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.
authors.affiliation: Immunopathology Section, Laboratory of Immunology, National Eye Institute, National Institutes of Health, 10 Center Dr., 10/10N103, NIH/NEI, Bethesda, MD, 20892-1857, USA, yujuanwang2013@gmail.com.
authors.forename: Yujuan
authors.initials: Y
authors.lastname: Wang
authors.forename: Mones S
authors.initials: MS
authors.lastname: Abu-Asab
authors.forename: Defen
authors.initials: D
authors.lastname: Shen
authors.forename: Zhengping
authors.initials: Z
authors.lastname: Zhuang
authors.forename: Emily Y
authors.initials: EY
authors.lastname: Chew
authors.forename: Chi-Chao
authors.initials: CC
authors.lastname: Chan
mesh_terms: D000328:Adult; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D001343:Autophagy; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D003131:Combined Modality Therapy; D015353:Eye Enucleation; D005260:Female; D005911:Gliosis / Q000175:diagnosis; D018325:Hemangioblastoma / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics; D007150:Immunohistochemistry; D017075:Laser Coagulation; D008297:Male; D011878:Radiotherapy; D012166:Retinal Hemorrhage / Q000175:diagnosis; D019572:Retinal Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors; D006623:von Hippel-Lindau Disease / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D020533:Angiogenesis Inhibitors; D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human; C467484:VEGFA protein, human