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Journal of Clinical Oncology, Vol 22, No 17 (September 1), 2004: pp. 3639-3640 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.08.137
Challenging Manifestations of MalignanciesCASE 1. Polycythemia and High Serum Erythropoietin Level As a Result of HemangioblastomaDepartment of Oncology, Claraspital, Basel; and Institute for Pathology, University of Basel, Switzerland A 44-year-old white male was referred to our hospital for evaluation of asymptomatic polycythemia which had been detected on a routine checkup. On admission, the patient described a mild headache for about 1 month without nausea or vomiting. There was no history of thromboembolism and no pruritus. As a passionate cyclist, he was a nonsmoker and denied using stimulating drugs such as exogenous erythropoietin (EPO). On physical examination the patient seemed in good general health, his blood pressure was 150/100 mmHg, and his pulse rate 60 beats/min. Auscultation of the heart and lungs was unremarkable and no neurologic deficits were found. Laboratory studies showed markedly increased hemoglobin at 20.2 g/dL, a hematocrit of 63%, and slightly elevated uric acid. The white blood and platelet counts were normal. Bone marrow (Fig 1; hematoxylin and eosin, x40) revealed increased, left-shifted erythropoiesis, normal granulopoiesis and megakaryopoiesis, and no evidence of a myeloproliferative disorder. Measurement of the total RBC mass by isotope dilution with cromium-51–labeled red cells demonstrated marked erythrocytosis at 42.4 mL/kg body weight (normal expected value, 27 mL/kg body weight) and reduced plasma volume. The serum EPO level was elevated at 32 U/L (normal, 5 to 25 U/L). Evaluation for secondary erythrocytosis showed no evidence of an EPO-producing tumor on the computed tomography scan of the chest and abdomen, or increased EPO due to hypoxemia. Eventually, because there is a known association of cerebral hemangioblastoma with elevated EPO levels, magnetic resonance imaging (MRI) of the cerebrum was performed. The MRI scan (Fig 2) disclosed a tumor measuring 3 x 4 cm in diameter in the right cerebellar hemisphere (black arrow) with perifocal edema and midline shift (white arrow), resulting in obstruction of the fourth ventricle (thin arrow). Radiologic findings were consistent with the criteria of a solid cerebellar hemangioblastoma. With the clinical diagnosis of an EPO-producing hemangioblastoma in the posterior fossa, the patient was referred to neurosurgery. The tumor could be resected completely and the patient had no neurologic deficit postoperatively. Histology (Fig 3; x40) confirmed the diagnosis, showing the characteristic findings of a capillary hemangioblastoma WHO grade 1 (A, hematoxylin and eosin) with numerous capillaries (B, immunohistochemistry positive for CD34) and intermingled stromal cells (C, immunohistochemistry positive for S-100). Three months after surgery, the patient was in excellent condition with hemoglobin levels within normal range and no residual tumor on MRI of the cerebrum. Given that hemangioblastomas are strongly associated with Von Hippel-Lindau (VHL) disease, investigation for VHL mutation was performed and showed no mutated genes in all three exons.
Hemangioblastomas account for approximately 2% of intracranial tumors and are found especially in the cerebellar hemispheres and the vermis. Clinical features include signs of increased intracranial pressure or cerebellar deficits and in 10% to 20% of patients, a paraneoplastic erythrocytosis.1,2 The tumor originates most probably from endothelial cells, presents as a cystic, highly vascular lesion, and enlarges +slowly. Stromal cells have been identified as the site of EPO production by in situ hybridization.3 Hemangioblastomas may occur sporadically or as a manifestation of VHL disease, a heritable tumor syndrome caused by inactivation of the VHL tumor suppressor gene and characterized by the occurrence of neoplasias in multiple organs.4 Although in healthy individuals the VHL protein (pVHL) is inactivated by hypoxia, the mutated pVHL imitates hypoxia on a molecular basis leading to dysregulation of the hypoxia-inducible factor and as a consequence overexpression of EPO.5 Other mutations in the molecular pathway leading to upregulation of EPO could be postulated in our patient. The fact that 35% to 58% of CNS hemangioblastomas are associated with VHL disease suggests that patients with apparently sporadic hemangioblastoma should be investigated for VHL, including molecular mutational testing, to ensure that the disease is not underdiagnosed.4 Our patient demonstrates that in the presence of unexplained polycythemia and elevated serum EPO levels, even in the absence of CNS symptoms, a CNS tumor has to be excluded by MRI of the brain. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest.
Acknowledgment We thank P. Schraml (Institute for Pathology, University of Basel, Switzerland) for performing the molecular mutational testing, M. Hofer (Department of Neuropathology, University of Freiburg, Germany) for providing the histopathology photo, and the Department of Radiology, University Hospital, Basel, Switzerland, for the photo of the MRI scan. REFERENCES 1. Means RT Jr: Polycythemia: Erythrocytosis, in Lee GR, Foerster J, Lukens J, et al (eds): Wintrobe's Clinical Hematology (ed 10). Baltimore, MD, Williams & Wilkins, 1999, pp 1538-1554 2. Waldmann TA, Levin EH, Baldwin M: The association of polycythemia with cerebellar hemangioblastomas. Am J Med 31:318, 1961
3. 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 92:3388-3393, 1998 4. Richard S, Campello C, Taillandier L, et al.: Haemangioblastoma of the central nervous system in von Hippel-Lindau disease. J Intern Med 243:547-553, 1998[CrossRef][Medline] 5. Ang SO, Chen H, Hirota K, et al: Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia. Nat Genet 32:614-621, 2002[CrossRef][Medline]
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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