Clinical and molecular analysis of disseminated hemangioblastomatosis of the central nervous system in patients without von Hippel-Lindau disease

Report of four cases

Robert J. Weil, Alexander Vortmeyer, Zhengping Zhuang, Svetlana D. Pack, Nicholas Theodore, Robert K. Erickson, Edward H. Oldfield

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

Hemangioblastomas of the central nervous system (CNS) may occur sporadically or in association with von Hippel-Lindau (VHL) syndrome. The authors present four patients with no family history or clinical evidence of VHL syndrome in whom extensive, progressive, en plaque coating of the brainstem and spinal cord with hemangioblastomas developed 1 to 8 years after complete resection of a solitary cerebellar hemangioblastoma. Analysis included detailed physical, biochemical, radiological, and pathological examinations in all four patients, combined with family pedigree analysis. In addition, a detailed investigation of the VHL gene was undertaken. Allelic loss, comparative genomic hybridization (CGH), single-stranded conformational polymorphism screening, CpG island methylation status, and X chromosome inactivation clonality analyses were performed. Although there was no evidence of germline alterations in the VHL gene on clinical and radiological examination or in the family history (all four patients) or analysis of peripheral blood (three patients), somatic deletion of one copy of the VHL gene occurred in these tumors. These findings indicate that the multiple, separate deposits of tumors were likely derived from a single clone. Results of CGH indicate that one or several additional genes are probably involved in the malignant behavior of the hemangioblastomas in these patients. Furthermore, the malignant biological and clinical behavior of these tumors, in which multiple sites of subarachnoid dissemination developed 1 to 8 years after initial complete resection, followed by progressive tumor-growth and death of the patients, occurred despite a histological appearance typical of benign hemangioblastomas. Malignant hemangioblastomatosis developed 1 to 8 years after resection of an isolated cerebellar hemangioblastoma. Alterations of the VHL gene may be permissive in this setting, but other genes are likely to be the source of the novel biological and clinical presentation of the disseminated hemangioblastomas in these patients. This appears to represent a novel condition in which the product of one or more mutations in several genes permits malignant tumor-behavior despite retention of a benign histological picture, a circumstance previously not recognized in CNS tumors.

Original languageEnglish (US)
Pages (from-to)775-787
Number of pages13
JournalJournal of neurosurgery
Volume96
Issue number4
DOIs
StatePublished - Jan 1 2002
Externally publishedYes

Fingerprint

Hemangioblastoma
von Hippel-Lindau Disease
Central Nervous System
Genes
Comparative Genomic Hybridization
Neoplasms
Single-Stranded Conformational Polymorphism
X Chromosome Inactivation
Central Nervous System Neoplasms
CpG Islands
Loss of Heterozygosity
Pedigree
Methylation
Brain Stem
Spinal Cord
Clone Cells
Mutation
Growth

Keywords

  • Comparative genomic hybridization
  • DNA methylation
  • Fluorescence in situ hybridization
  • Immunohistochemistry
  • Tumor suppressor gene
  • Von Hippel-Lindau disease

ASJC Scopus subject areas

  • Surgery
  • Clinical Neurology

Cite this

Clinical and molecular analysis of disseminated hemangioblastomatosis of the central nervous system in patients without von Hippel-Lindau disease : Report of four cases. / Weil, Robert J.; Vortmeyer, Alexander; Zhuang, Zhengping; Pack, Svetlana D.; Theodore, Nicholas; Erickson, Robert K.; Oldfield, Edward H.

In: Journal of neurosurgery, Vol. 96, No. 4, 01.01.2002, p. 775-787.

Research output: Contribution to journalArticle

Weil, Robert J. ; Vortmeyer, Alexander ; Zhuang, Zhengping ; Pack, Svetlana D. ; Theodore, Nicholas ; Erickson, Robert K. ; Oldfield, Edward H. / Clinical and molecular analysis of disseminated hemangioblastomatosis of the central nervous system in patients without von Hippel-Lindau disease : Report of four cases. In: Journal of neurosurgery. 2002 ; Vol. 96, No. 4. pp. 775-787.
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