Ó Springer 2005
Journal of Neuro-Oncology (2005) 73: 273–275 DOI 10.1007/s11060-004-5179-0
Letter to the Editor
Treatment of recurrent cerebellar hemangioblastoma with external radiotherapy in a patient with von Hippel-Lindau disease: a case report and review of the literature Gulcin Ertas1, Muzaffer Bedri Altundag1, Ali Riza Ucer1, Fatih Cankal2 and Kadri Altundag3 1 Department of Radiation Oncology, Ankara Oncology Hospital, Ankara, Turkey; 2Med-Mar Radiologic Imaging Center, Ankara, Turkey; 3Department of Medical Oncology, Hacettepe University Faculty of Medicine, Ankara, Turkey
Key words: cerebellar hemangioblastoma, external radiotherapy, von Hippel-Lindau disease Summary Von Hippel-Lindau Disease, a multisystem familial cancer syndrome, is inherited as an autosomal-dominant trait. Common manifestations of the disease are retinal, cerebellar and medullary hemangioblastomas; renal cysts and carcinomas; pancreatic cysts; pheochromocytoma; and papilllary cystadenoma of the epididym. We report the case of a 40-year-old man with type I von Hippel-Lindau disease treated with external radiotherapy for recurrent cerebellar hemangioblastoma.
Introduction Von Hippel-Lindau (VHL) is a multisystem familial cancer syndrome that is inherited as an autosomal-dominant trait with a greater than 90% penetrance and an annual incidence of one per 36,000 live births [1]. The VHL gene is localized at the short arm of chromosome 3 (3p25-26), a tumor-suppressor gene [2]. Hallmark lesions include retinal, cerebellar, and medullary hemangioblastomas; renal cysts and carcinomas; pancreatic cysts; pheochromocytoma; and papilllary cystadenoma of the epididym [3]. According to the National Cancer Institute classifications, VHL is either pheochromocytoma-negative VHL (type I) or pheochromocytoma-positive VHL (type II). Type I VHL is the most common form [4]. Type II is further classified as type IIa (pheochromacytoma and retinal and cerebellar hemangioblastoma) or type IIb (pheochromocytoma, retinal and cerebellar hemangioblastoma, renal cancer, and pancreatic invasion). A method of VHL gene-mutation analysis is available that may also be used for genetic testing within families with VHL disease [5]. Cerebellar hemangioblastomas are important components of the disease. These tumors constitute 2% of all brain tumors and 7–10% of posterior fossa tumors [6]. They may produce symptoms, depending on their size, site, and number’ symptoms are due to local disruption of neurologic function or increased intracranial pressure [7]. The most common symptoms of cerebellar hemangioblastomas are headache, positional vertigo, nausea, vomiting, nystagmus, and paralysis of cranial nerve IX [8]. Diagnosis can be delayed due to periodicity of the symptoms [9]. Cerebellar hemangioblastomas are often cystic. Simple cystic drainage without surgical resection can be insufficient. The standard
management of cerebellar hemangioblastomas is microsurgical resection, as that management strategy can alleviate mass effect and eliminate the need for additional radiation therapy (if a complete resection can be achieved). External radiotherapy and stereotactic radiosurgery are sometimes used for palliative purposes in patients who cannot tolerate surgery [6, 10–15].
Case report A 40-year-old man who had a positive family history for VHL disease (one sister, one aunt, and a grandmother) had undergone surgery for a right cerebellar mass in 1990. Pathologic diagnosis had been reported as hemangioblastoma, and the patient did not have a recurrence during follow-up. Ten years later, he was admitted to the hospital because of headache and vertigo. Cranial magnetic resonance imaging (MRI) showed multiple mass lesions in both cerebellar hemispheres (Figure 1). Palliative surgical intervention was initiated. The pathologic diagnosis was reported as hemangioblastoma. Postoperative MRI showed multiple lesions located in both cerebellar hemispheres. Local postoperative external radiotherapy was undertaken (54 Gy) with a 6-mV lineer accelerator. Meanwhile, abdominal tomography showed multiple hypodense lesions in the pancreas and both kidneys. Pathological diagnosis of fine-needle aspiration biopsy taken from kidney masses was consistent with renal cell carcinoma, so a left nephrectomy was performed. The patient did not experience any progressive lesions in his cerebellum, pancreas, or kidney for about 4 years.
274
Figure 1. T1 coronal post contrast images of left cerebellar and tonsillar mass lesions.
Discussion VHL is an autosomal-dominant transitive disease. The age at diagnosis can vary according to the presence or absence of hereditary events, screening programs or symptoms. However, the majority of cases of cerebellar hemangioblastomas occur around the age of 24, and it is usually diagnosed later than retinal hemangioblastomas [16]. Our patient had a family history of the disease and initially presented with cerebellar hemangioblastoma at the age of 30. Renal cell carcinoma and pancreas pseudocyst, which are the other findings with VHL, were recognized 10 years later with the reoccurrence of the cerebellar hemangioblastoma. The existence of cerebellar hemangioblastoma, renal cell carcinoma and pancreatic cysts without pheochromocytoma in our patient confirmed the diagnosis of type I VHL. Actually, few patients have all the diagnostic criteria of VHL and half of the patients have only one diagnostic criterion of the disease [4]. Hemangioblastoma is a benign vascular central nervous system (CNS) tumor composed of endothelial and stromal cell components. It occurs most often in the cerebellum, where it is the most common primary neoplasm in adults. Hemangioblastomas are less commonly seen in the spinal cord, and they rarely occur elsewhere in the CNS. Single tumors may be sporadic, but multiple tumors are almost always associated with VHL disease. Sporadic tumors appear in the fifth and sixth decades of life, whereas VHL-associated tumors manifest earlier, in the third or fourth decades [17]. Richard et al. [18] have shown that 34% of patients with cerebellar hemangioblastomas have VHL disease. Unlike cerebellar hemangioblastomas, only 5–31% of which are said to be associated with this disease, 80% of spinal cord hemangioblastomas occur with VHL disease [16]. Detection of CNS hemangioblastomas has improved substantially with the use of modern imaging techniques
and preventive screening of VHL patients to identify presymptomatic or asymptomatic tumors. The current preferred method for detection of CNS lesions in VHL is gadolinium-enhanced MRI, for both intracranial and intraspinal tumors [19]. The natural history of CNS hemangioblastomas in patients with VHL disease has not been well characterized, and the introduction of MRI and advances in molecular genetics are facilitating the understanding of this disease process. The observations indicate that these tumors grow in an unpredictable manner, as in the patient who is the subject of this case report [20]. Microsurgical resection is the standard therapy for these tumors [21], as this management strategy can alleviate mass effect and eliminate the need for additional radiation therapy (if a complete resection can be achieved). Surgery is not, however, in many cases curative, and additional treatment with radiation has been shown in many instances to provide a good outcome, as has been documented in this case. In addition, as in this case, radiation (radiation therapy or radiosurgery) can address multiple foci of disease with greater ease than microsurgical resection. Which lesions require treatment and the optimal time to treat them depend on the natural history of the tumors. Although multiple surgical resections are often feasible, increased operative morbidity is likely, and the development of multiple tumors is also still a major problem. CNS involvement is an important cause of morbidity and mortality in patients with VHL [22]. For some patients, the risk of repeated operations has led to the use of conventionally fractionated, externalbeam irradiation for treatment of residual or unresectable hemangioblastomas [6]. Studies suggest that control of hemangioblastomas depends upon achieving a high dose. One study of 24 patients noted a 10-year survival rate of 57% for patients treated with more than 36 Gy, compared with a survival rate of 27% for patients treated with less than 36 Gy [6]. In another review of 27 patients irradiated postoperatively (19 with gross residual disease and 6 with VHL disease), local control was achieved for 33% of patients treated with less than 50 Gy, compared with 57% of those who received more than 50 Gy [10]. Although conventionally fractionated irradiation seems to increase the probability of hemangioblastoma control, local control even with increased radiation doses is less than optimal. Reports from several institutions suggest that linear accelerator-based or gamma knife radiosurgery results in high rates of stabilization and/or shrinkage of hemangioblastoma, with low rates of complications [13–15]. In conclusion, because of the rarity and complexity of these tumors, mainly when associated with VHL disease, a prospective multicenter study could be useful to assess the optimal use and combination of these treatment modalities.
References 1. Maher ER, Iselius L, Yates JR: Von Hippel-Lindau disease: a genetic study. J Med Genet 28: 443–447, 1991
275 2. Latif F, Tory K, Gnarra J: Identification of the von HippelLindau disease tumor suppressor gene. Science 260: 1317–1320, 1993 3. Huson SM, Harper PS, Hourihan MD, Cole G, Weeks RD, Compston DA: Cerebellar haemangioblastoma and von HippelLindau disease. Brain 109: 1297–1310, 1986 4. Neumann HPH, Wiestler OD: Clustering of features of von Hippel-Lindau syndrome: evidence for a complex genetic locus. Lancet 337: 1052–1054, 1991 5. Stolle C, Glenn G, Zbar B: Improved detection of germline mutations in the von Hippel-Lindau disease tumor suppressor gene. Hum Mutat 12: 417–423, 1998 6. Sung DI, Chang CH, Harisiadis L: Cerebellar hemangioblastomas. Cancer 49: 553–555, 1982 7. Couch V, Lindor NM, Karnes PS, Michels VV: Von HippelLindau disease. Mayo Clin Proc 75: 265–272, 2000 8. Lodrini S, Lasio G, Cimino C, Pluchino F: Hemangioblastomas: clinical characteristics, surgical results and immunohistochemical studies. J Neuro Sci 35: 179–185, 1991 9. Neumann HP, Eggert HR, Weigel K, Friedburg H, Wiestler OD, Schollmeyer P: Hemangioblastomas of the central nervous system. A 10-year study with special reference to von HippelLindau syndrome. J Neurosurg 70: 24–30, 1989 10. Smalley SR, Schomberg PJ, Earle JD, Laws ER Jr, Scheithauer BW, O’Fallon JR: Radiotherapeutic considerations in the treatment of hemangioblastomas of the central nervous system. Int J Radiat Oncol Biol Phys 18: 1165–1171, 1990 11. Richardson RG, Griffin TW, Parker RG: Intramedullary hemangioblastoma of the spinal cord: definitive management with irradiation. Cancer 45: 49–52, 1980 12. Page KA, Wayson K, Steinberg GK: Stereotaxic radiosurgical ablation: an alternative treatment for recurrent and multifocal hemangioblastomas. Surg Neurol 40: 424–428, 1993 13. Niemela¨ M, Lim YJ, So¨derman M, Ja¨a¨skela¨inen J, Lindquist C: Gamma knife radiosurgery in 11 hemangioblastomas. J Neurosurg 85: 591–596, 1996 14. Patrice SJ, Sneed PK, Flickinger JC, Shrieve DC, Pollock BE, Alexander E III, Larson DA, Kondziolka DS, Gutin PH, Wara
15.
16.
17.
18.
19.
20.
21.
22.
WM, McDermott MW, Lunsford LD, Loeffler JS: Radiosurgery for hemangioblastoma: results of a multi-institutional experience. Int J Radiat Oncol Biol Phys 35: 493–499, 1996 Chang SD, Meisel JA, Hancock SL, Martin DP, McManus M, Adler JR Jr: Treatment of hemangioblastomas in von HippelLindau disease with linear accelerator-based radiosurgery. Neurosurgery 43: 28–34, 1998 Maher ER, Yates JRW, Harries R: Clinical features and natural history of von Hippel-Lindau disease. Q J Med 77: 1151–1163, 1990 Choyke PL, Glenn GM, Walther MM, Patronas NJ, Linehan WM, Zbar B: Von Hippel-Lindau disease: genetic, clinical and imaging features. Radiology 194: 629–642, 1995 Richard S, Campello C, Taillandier L, Parker F, Resche F: Haemangioblastoma of the central nervous system in von HippelLindau disease. French VHL study group. J Int Med 243: 547– 553, 1998 Karsdorp N, Elderson A, Wittebol-Post D, Hene RJ, Vos J, Feldberg MA, van Gils AP, Jansen-Schillhorn van Veen JM, Vroom TM, Hoppener JW: Von Hippel-Lindau disease: new strategies in early detection and treatment. Am J Med 97: 158– 168, 1994 Wanebo JE, Lonser RR, Glenn GM, Oldfield EH: The natural history of hemangioblastomas of the central nervous system in patients with von Hippel-Lindau disease. J Neurosurg 98: 82–94, 2003 Slater A, Moore NR, Huson SM: The natural history of cerebellar hemangioblastomas in von Hippel-Lindau disease. Am J Neuroradiol 24: 1570–1574, 2003 Neumann HP, Eggert HR, Scheremet R, Schumacher M, Mohadjer M, Wakhloo AK, Volk B, Hettmannsperger U, Riegler P, Schollmeyer P: Central nervous system lesions in von HippelLindau syndrome. J Neurol Neurosurg Psychiat 55: 898–901, 1992
Address for offprints: Kadri Altundag, MD, 8181 Fannin street No. 728, Houston-TX 77054, USA; Tel.: +1-713-795-0438; Fax: +1-713794-4385; E-mail:
[email protected]
