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

Report of four cases

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✓ 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.

Article Information

Address reprint requests to: Edward H. Oldfield, M.D., Surgical Neurology Branch, Room 5D37, Building 10, National Institute of Neurological Disorders and Stroke, 9000 Rockville Pike, Bethesda, Maryland 20892–1414. email: oldfield@box-o.nih.gov.

© AANS, except where prohibited by US copyright law.

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Figures

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    Case 1. Magnetic resonance images. a: A gadolinium-enhanced axial view of the brain demonstrating the superior extent of subarachnoid spread of tumor into the premesencephalic and parasellar spaces. b: A contrast-enhanced axial view of the brain demonstrating prepontine tumor surrounding the junction of the vertebral and basilar arteries and distorting the brainstem. c: A coronal view of multiple tumor deposits at the lower brainstem and upper cervical spinal cord. d: An unenhanced sagittal view of the cervical spinal cord revealing en plaque coating of the posterior cord; tortuous, dilated vessels are seen as flow voids. e: Similar view to that in d, after gadolinium administration. f and g: Unenhanced (f) and enhanced (g) sagittal sections of the thoracic spinal cord demonstrating en plaque tumor, with severe compression of the cord. h: An enhanced axial view at T2–3 showing extreme compression of the spinal cord (white arrowhead) by tumor (black arrowhead). i: A contrast-enhanced axial view at the T-5 level showing circumferential coating of the spinal cord by hemangioblastoma (arrowhead).

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    Case 1. Macroscopic and microscopic views of the spinal cord at autopsy. a: A low-power view of the thoracic spinal cord showing the extensive deposition of tumor in the subarachnoid space, with cord compression, from approximately the T2–7 levels. b: A high-power view of the cauda equina, showing en plaque tumor deposits beneath a diaphanous arachnoid. c: Axial sections of the thoracic spinal cord showing hemangioblastoma compressing and distorting the spinal cord architecture. Small areas of hemorrhage are visible. d: Higher-magnification view of four selected axial sections of the spinal cord showing the compressing tumor deposits. e: Low-power photomicrograph of tumor (left) compressing and focally invading the thoracic spinal cord (right). H & E, original magnification × 4. f: Higher-power photomicrograph of a typical region of tumor. H & E, original magnification × 20. g: Low-power photomicrograph of tumor encasing multiple nerve roots (arrows) of the cauda equina. H & E, original magnification × 4.

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    Case 2. Magnetic resonance images of the brain and spine. a: A contrast-enhanced axial view of tumor deposition in the perimesencephalic and parasellar spaces. b: A coronal view of these deposits. c: A sagittal view of the subarachnoid deposition of tumor from the parasellar region to the cervicomedullary junction, with distortion and compression of the midbrain, pons, and medulla. d: A coronal view of tumor at the cervicomedullary junction. e: Axial views of the tumors seen in d. f: A more posterior coronal view of tumors at the cervicomedullary junction. g and h: Unenhanced (g) and gadolinium-enhanced (h) sagittal views of the cervical spinal cord revealing severe compression at the cervicomedullary junction, with subarachnoid seeding along the surface of the remainder of the cervical spinal cord. i and j: Axial (i) and sagittal (j) contrast-enhanced views of the thoracic tumor deposits.

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    Fluorescence in situ hybridization analysis demonstrating allelic deletion of the VHL gene in individual tumors. Green signal, α-satellite centromeric marker for chromosome 3; red signal, chromosome 3p25 cosmid probe containing the VHL gene. A: Schematic representation of a normal chromosome 3, showing the location of the VHL gene and the cosmid probe for the VHL gene. B: Photomicrograph of a touch preparation of a cerebellar hemangioblastoma obtained in a patient with known VHL disease, showing LOH in a stroma-rich portion of the tumor. Only one red signal is seen per cell, whereas there are two green signals per cell. Original magnification × 100. C: Photomicrograph of a touch preparation from a metastatic tumor obtained in the patient in Case 2, showing LOH in approximately 50% of cells (a mixture of tumor cells and vascular cells). Original magnification × 100. D: Photomicrograph of a touch preparation from a spinal tumor obtained in the patient in Case 1, showing LOH in four of six cells visualized. Original magnification × 100.

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    Case 1. Clonality analysis of three different tumors (T) obtained in this patient. The X chromosome—inactivation method (HUMARA) is based on the fact that one of two X chromosomes in females is randomly inactivated by methylation during embryogenesis. Tumors derived from a single clone are expected to contain cells with identically methylated alleles. Three informative tumors are demonstrated, which show inactivation of the same allele, compared with adjacent normal (N) brain tissue obtained at the same time as the tumor; arrowheads mark the two alleles under study. Tumor tissue consistently shows significant signal reduction of the upper allele at all three sites. The retention of a faint upper allele is likely due to the presence of reactive polyclonal vascular cells with the tumor.

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    Case 1. A CGH study; hybridization pattern seen in a tumor obtained in this patient. An average ratio profile for the tumor is computed as the mean ratio of 10 metaphase spreads. Parallel vertical lines represent tumor/reference ratios; the gray, vertical lines indicate a ratio of 1 (balanced status); and the red and green lines indicate a ratio of 0.9 and 1.1, respectively. Red bars along the left side of an individual chromosome ideogram represent losses and green bars along the right side identify gains. In the ideograms the numbers and letters designate individual chromosomes. As expected, there are two copies of chromosome X.

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