Nervous system involvement in von Hippel-Lindau disease: Pathology and mechanisms

Alexander Vortmeyer, Eric A. Falke, Sven Gläsker, Jie Li, Edward H. Oldfield

Research output: Contribution to journalReview article

16 Citations (Scopus)

Abstract

Patients with von Hippel-Lindau disease carry a germline mutation of the Von Hippel-Lindau (VHL) tumor-suppressor gene. We discuss the molecular consequences of loss of VHL gene function and their impact on the nervous system. Dysfunction of the VHL protein causes accumulation and activation of hypoxia inducible factor (HIF) which can be demonstrated in earliest stages of tumorigenesis and is followed by expression of VEGF, erythropoietin, nitric oxide synthase and glucose transporter 1 in VHL-deficient tumor cells. HIF-independent functions of VHL, epigenetic inactivation of VHL, pVHL proteostasis, and links between loss of VHL function and developmental arrest are also described. A most intriguing feature in VHL disease is the occurrence of primary hemangioblastic tumors in the nervous system, the origin of which has not yet been entirely clarified, and current hypotheses are discussed. Endolymphatic sac tumors may extend into the brain, but originally arise from proliferation of endolymphatic duct/sac epithelium; the exact nature of the proliferating epithelial cell, however, also has remained unclear, as well as the question why tumors almost consistently develop in the intraosseous portion of the endolymphatic sac/duct only. The epitheloid clear cell morphology of both advanced hemangioblastoma and renal clear cell carcinoma can make the differential diagnosis challenging, recent developments in immunohistochemical differentiation are discussed. Finally, metastasis to brain may not only be caused by renal carcinoma, but may derive from VHL disease-associated pheochromocytoma/paraganglioma, or pancreatic neuroendocrine tumor.

Original languageEnglish (US)
Pages (from-to)333-350
Number of pages18
JournalActa Neuropathologica
Volume125
Issue number3
DOIs
StatePublished - Mar 1 2013
Externally publishedYes

Fingerprint

Endolymphatic Sac
von Hippel-Lindau Disease
Endolymphatic Duct
Nervous System
Pathology
Nervous System Neoplasms
Hemangioblastoma
Paraganglioma
Neoplasms
Neuroendocrine Tumors
Facilitative Glucose Transport Proteins
Germ-Line Mutation
Brain
Pheochromocytoma
Erythropoietin
Tumor Suppressor Genes
Renal Cell Carcinoma
Epigenomics
Nitric Oxide Synthase
Vascular Endothelial Growth Factor A

Keywords

  • Developmental arrest
  • HIF
  • Nervous system
  • VEGF
  • VHL
  • Von Hippel-Lindau disease

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

Nervous system involvement in von Hippel-Lindau disease : Pathology and mechanisms. / Vortmeyer, Alexander; Falke, Eric A.; Gläsker, Sven; Li, Jie; Oldfield, Edward H.

In: Acta Neuropathologica, Vol. 125, No. 3, 01.03.2013, p. 333-350.

Research output: Contribution to journalReview article

Vortmeyer, Alexander ; Falke, Eric A. ; Gläsker, Sven ; Li, Jie ; Oldfield, Edward H. / Nervous system involvement in von Hippel-Lindau disease : Pathology and mechanisms. In: Acta Neuropathologica. 2013 ; Vol. 125, No. 3. pp. 333-350.
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