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Journal of Clinical Oncology, Vol 23, No 15 (May 20), 2005: pp. 3624-3626 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.01.184
Difficult Diagnostic CasesCASE 2. Hemangioblastomas: Diagnosis of von Hippel-Lindau Disease and Antiangiogenic Treatment With SU5416Departments of Medicine and Neuroradiology, University Hospital Hamburg-Eppendor, University of Hamburg, Hamburg, Germany
Sugen Pharmacia, South San Francisco, CA A 61-year-old man had complete resection of recurrent hemangioblastomas of the right cerebellum in 1989, 1995, and 2000. In November 2000, he developed a spinal cord hemangioblastoma at C5 that was removed by hemilaminectomy. A second lesion at C3/4 was not resectable and the patient was followed by magnetic resonance imaging (MRI). In July 2001, the lesion caused increasing hypalgesia and dysaesthesia in the right arm and proximal paresis in both legs, and the patient was referred to our hospital. MRI imaging demonstrated a well perfused spinal lesion at C4, causing compression of the spinal cord (Fig 1; Sagittal [1A and 1B] and transversal [1C and 1D] T-1 weighted sequences after Gadolinium; large arrow, well perfused spinal lesion at C4 [*]; Figs 1A and 1C; before therapy; Figs 1B and 1D, after 18 months of SU5416; small arrow, physiologic vein). The patient had comorbidity with coronary artery disease, peripheral vascular disease, an infrarenal aortic aneurysm, and recurrent gastric ulcers. His father had died at a young age as a result of an unclassified cerebellar tumor. Genetic testing of the VHL gene was performed. A mutation of codon 78 in exon 1 leading to an exchange of asparagine by serine was found confirming the diagnosis of von Hippel-Lindau syndrome. Abdominal imaging was negative for renal cell carcinoma. Pheochromocytoma could also be excluded.
Von Hippel-Lindau disease is a hereditary cancer syndrome linked to a mutation of the VHL gene responsible for proteolytic degradation of the hypoxia inducible factor (HIF) transcriptional complex. During hypoxia, the HIF transcriptional complex promotes expression of growth factors, such as vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and erythropoietin.1 Loss of VHL function results in uncontrolled HIF activity and overexpression of VEGF and PDGF leading to hemangioblastomas in the retina and the CNS, as well as the development of renal cell carcinomas, phaeochromocytomas, and cystic lesions in various organs.2 Figure 2 shows sections of the spinal hemangioblastoma resected from our patient 1 year before onset of treatment, demonstrating a vascular tumor (Fig 2A) consisting of CD31-positive vessels (Fig 2B). Hemangioblastomas of the CNS are predominantly localized in the cerebellum and spinal cord. Frequently, multiple lesions are found at diagnosis. The treatment of choice is resection with curative intent. However, local and distant recurrences occur frequently.3 In cases with unresectable lesions, alternative treatment options such as radiotherapy and chemotherapy have failed to produce significant responses. Histopathologic studies have shown expression of HIF-family proteins throughout hemangioblastomas.4,5 In addition, expression of VEGF was detected at high levels in clinical samples.6 These findings were the basis for the use of specific antiangiogenic treatment of hemangioblastoma targeting VEGF signaling. In our patient, antiangiogenic therapy with SU5416, a small molecule inhibiting receptor tyrosine kinases such as the VEGF receptor kinase domain region and the PDGF receptor, was initiated in August 2001 after approval by the local institutional review board committee. The therapy, given at a dose of 145 mg/m2 by infusion twice weekly, was well tolerated. Soon after the start of treatment, paresis resolved and pre-existing hypaesthesia and dysaesthesia in the right arm decreased. Treatment was continued and is still ongoing, now for more than 24 months. The spinal lesion was stable as shown by MRI performed every 3 months (Figs 1B and 1D; a physiological vein is indicated by the small arrow). No new spinal or cerebellar lesions were seen. Treatment of von Hippel-Lindau–associated hemangioblastomas with SU5416 has been reported on a series of three patients.7 The follow-up of 3 months was too short to evaluate therapeutic success. Another report described a stable clinical remission in one patient with von Hippel-Lindau disease and optic nerve hemangioblastomas treated with SU5416 over a period of 18 months.8 Recently, clinical improvement of macular edema caused by retinal hemangioblastomas under therapy with SU5416 has been reported in a single case.9 As in our patient, clinical improvement developed within a few weeks, while imaging showed morphologic stable disease for over 24 months. It is thus important to consider von Hippel-Lindau disease in patients with hemangioblastomas, renal cell carcinomas, or pheochromocytomas. In these patients VEGF inhibitors may represent a new treatment option. Authors' Disclosures of Potential Conflicts of Interest The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Served as an officer or member of the Board of a company: Paul Scigalla, Pharmacia, Sugen; Mark S. Jacobs, Pharmacia, Sugen.
REFERENCES 1. Pugh CW, Ratcliffe PJ: The von Hippel-Lindau tumor suppressor, hypoxia inducible factor-1 (HIF-1) degradation and cancer pathogenesis. Semin Cancer Biol 13 : 83 -89, 2003[CrossRef][Medline] 2. Lonser RR, Glenn GM, Walther M, et al: Von Hippel-Lindau disease. Lancet 361 : 2059 -2067, 2003[CrossRef][Medline] 3. Wanebo JE, Lonser RR, Glenn GM, et al: The natural history of hemangioblastomas of the central nervous system in von Hippel-Lindau disease. J Neurosurg 98 : 82 -94, 2003[Medline] 4. Zagzag D, Zhong H, Scalzitti JM, et al: Expression of hypoxia-inducible factor 1 alpha in brain tumors: Association with angiogenesis, invasion, and progression. Cancer 88 : 2606 -2618, 2000[CrossRef][Medline] 5. Krieg M, Haas R, Brauch H, et al: Up-regulation of hypoxia-inducible factors HIF-1 alpha and HIF-2 alpha under normoxic conditions in renal cell carcinoma cells by von Hippel-Lindau suppressor gene loss of function. Oncogene 19 : 5435 -5443, 2000[CrossRef][Medline]
6. Krieg M, Marti HH, Plate KH: Coexpression of erythropoietin and vascular endothelial growth factor in nervous system tumors associated with von Hippel-Lindau tumor suppressor gene loss of function. Blood 92
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7. Richard S, Croisille L, Yvart J, et al: Paradoxical secondary polycythemia in von Hippel-Lindau patients treated with anti-vascular endothelial growth factor therapy. Blood 99
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-3853, 2002 8. Aiello LP, George DJ, Cahill MT, et al: Rapid and durable recovery of visual function in a patient with von Hippel-Lindau syndrome after systemic therapy with vascular endothelial growth factor receptor inhibitor SU5416. Ophthalmology 109 : 1745 -1751, 2002[CrossRef][Medline] 9. Girmens JF, Erginay A, Massin P, et al: Treatment of von Hippel-Lindau retinal hemangioblastoma by the vascular endothelial growth factor receptor inhibitor SU5416 is more effective for associated macular edema than for hemangioblastomas. Am J Ophthalmol 136 : 194 -196, 2003[Medline]
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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