Pathological and Clinical Features and Management of Central Nervous System Hemangioblastomas in von Hippel-Lindau Disease

Main Article Content

Hiroshi Kanno
Natsuki Kobayashi
Satoshi Nakanowatari

Keywords

Hemangioblastoma, VHL, von Hippel-Lindau disease

Abstract

Central nervous system (CNS) hemangioblastoma is the most common manifestation of von Hippel-Lindau (VHL) disease. It is found in 70-80% of VHL patients. Hemangioblastoma is a rare form of benign vascular tumor of the CNS, accounting for 2.0% of CNS tumors. It can occur sporadically or as a familial syndrome. CNS hemangioblastomas are typically located in the posterior fossa and the spinal cord. VHL patients usually develop a CNS hemangioblastoma at an early age. Therefore, they require a special routine for diagnosis, treatment and follow-up. The surgical management of symptomatic tumors depend on many factors such as symptom, location, multiplicity, and progression of the tumor.  The management of asymptomatic tumors in VHL patients are controversial since CNS hemangioblastomas grow with intermittent quiescent and rapid-growth phases. Preoperative embolization of large solid hemangioblastomas prevents perioperative hemorrhage but is not necessary in every case. Radiotherapy should be reserved for inoperable tumors. Because of complexities of VHL, a better understanding of the pathological and clinical features of hemangioblastoma in VHL is essential for its proper management.

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References

1. Huntoon K, Lonser RR. Nervous system manifestations of von Hippel-Lindau disease. J Transl Med Epidemiol. 2014; 2(1): 1015.

2. Vortmeyer AO, Frank S, Jeong SY, Yuan K, Ikejiri B, Lee YS, Bhowmick D, Lonser RR, Smith R, Rodgers G, Oldfield EH, Zhuang Z. Developmental arrest of angioblastic lineage initiates tumorigenesis in von Hippel-Lindau disease. Cancer Res. 2003; 63(21):7051-7055. [Pubmed]

3. Glasker S, Li J, Xia JB, Okamoto H, Zeng W, Lonser RR, Zhuang Z, Oldfield EH, Vortmeyer AO. Hemangioblastomas share protein expression with embryonal hemangioblast progenitor cell. Cancer Res. 2006; 66(8):4167-4172.
DOI: http://dx.doi.org/10.1158/0008-5472.CAN-05-3505

4. Hasselblatt M, Jeibmann A, Gerss J, Behrens C, Rama B, Wassmann H, Paulus W. Cellular and reticular variants of haemangioblastoma revisited: a clinicopathologic study of 88 cases. Neuropathol Appl Neurobiol. 2005; 31(6):618-622. DOI: http://dx.doi.org/10.1111/j.1365-2990.2005.00669.x

5. Bohling T1, Maenpaa A, Timonen T, Vantunen L, Paetau A, Haltia M. Different expression of adhesion molecules on stromal cells and endothelial cells of capillary hemangioblastoma. Acta Neuropathol. 1996;92(5):461-466.
DOI: http://dx.doi.org/10.1007/s004010050547

6. Bohling T, Hatva E, Kujala M, Claesson-Welsh L, Alitalo K, Haltia M. Expression of growth factors and growth factor receptors in capillary hemangioblastoma. J Neuropathol Exp Neurol. 1996; 55(5):522-527.
DOI: http://dx.doi.org/10.1097/00005072-199605000-00004

7. Reifenberger G, Reifenberger J, Bilzer T, Wechsler W, Collins VP. Coexpression of transforming growth factor-alpha and epidermal growth factor receptor in capillary hemangioblastomas of the central nervous system. Am J Pathol 147(2):245-250, 1995. [Pubmed]

8. Wizigmann-Voos S, Breier G, Risau W, Plate KH. Up-regulation of vascular endothelial growth factor and its receptors in von Hippel-Lindau disease-associated and sporadic hemangioblastomas. Cancer Res. 1995;55(6):1358-1364. [Pubmed]

9. Hatva E, Bohling T, Jaaskelainen J, Persico MG, Haltia M, Alitalo K. Vascular growth factors and receptors in capillary hemangioblastomas and hemangiopericytomas. Am J Pathol. 1996;148(3):763-775. [Pubmed]

10. Flamme I, Krieg M, Plate KH. Up-regulation of vascular endothelial growth factor in stromal cells of hemangioblastomas is correlated with up-regulation of the transcription factor HRF/HIF-2alpha. Am J Pathol. 1998;153(1):25-29. DOI: http://dx.doi.org/10.1016/S0002-9440(10)65541-1

11. Latif F, Tory K, Gnarra J, Yao M, Duh FM, Orcutt ML, Stackhouse T, Kuzmin I, Modi W, Geil L, Schmidt, L., Thou, F., Li H., Wei M. H., Chen, F.,Glenn, G., Choyke, P., Walther, M. M., Weng, Y., Duan, D. R., Dean, M., Glavac, D.,Richards, F. M., Crossey, PA., Ferguson-Smith, M. A., Linehan, W. M., Thar, B., Lerman, M. Identification of the von Hippel-Lindau disease tumor suppressor gene.Science. 1993; 260(5112):1317-20. DOI: http://dx.doi.org/10.1126/science.8493574

12. Gnarra, J. R., Tory, K., Weng, Y., Schmidt, L., Wei, M. W., Li, H., Latif, F., Liu, S.,Chen, F., Dub, F-M., Lubensky, I., Duan, D-S. R., Florence, C., Pozzatia, R., Walther, M. M., Bander, N. H., Grossman, H. B., Bauch, H., Brooks, J. D., Isaacs, W. B., Lerinan, M. I., Zbar, B., and Linehan, W. M. Mutations of the VHLtumor suppressor gene in renal carcinoma. Nat. Genet., 7(1): 85-90,1994. DOI: http://dx.doi.org/10.1038/ng0594-85

13. Kanno, H., Kondo, K., Ito, S., Yamamoto, I., Fujii, S., Torigoe, S., Sakai, N., Hosaka,M., Shuin, T., and Yao, M. Somatic mutations of the von Hippel-Lindau tumor suppressor gene in sporadic central nervous system hemangioblastomas. Cancer Res., 54(18): 4845-4847, 1994. [Pubmed]

14. Shuin, T., Kondo, K., Torigoe, S., Kishida, T., Kubota, Y., Hosaka, M., Nagashima, Y., Kitamura, H., Latif, F., Thar, B., Lerman, M. I., and Yao, M. Frequent somatic mutation and loss of heterozygosity of the von Hippel-Lindau tumor suppressor gene in primary human renal cell carcinomas. Cancer Res., 54(11): 2852-2855, 1994. [Pubmed]

15. Corless CL, Kibel AS, Iliopous O, Kaelin WG Jr. Immunostaining of the von Hippel-Lindau gene product in normal and neoplastic human tissues. Hum Pathol 28(4): 459-464, 1997. DOI: http://dx.doi.org/10.1016/S0046-8177(97)90035-6

16. Sakashita N, Takeya M, Kishida T, Stackhouse TM, Zbar B, Takahashi K. Expression of von Hippel-Lindau protein in normal and pathological human tissues. Histochem J. 1999 ;31(2):133-144.
DOI: http://dx.doi.org/10.1023/A:1003554712386

17. Los M1, Jansen GH, Kaelin WG, Lips CJ, Blijham GH, Voest EE. Expression pattern of the von Hippel-Lindau protein in human tissues. Lab Invest. 1996;75(2):231-238. [Pubmed]

18. Nagashima Y, Miyagi Y, Udagawa K, Taki A, Misugi K, Sakai N, Kondo K, Kaneko S, Yao M, Shuin T. Von Hippel-Lindau tumour suppressor gene. Localization of expression by in situ hybridization. J Pathol. 1996;180(3):271-274.
DOI: http://dx.doi.org/10.1002/(SICI)1096-9896(199611)180:3<271::AID-PATH664>3.0.CO;2-2

19. Duan, D. R., Pause, A., Burgess, W. H., Aso, T., Chen, D. Y. T., Garreu, K. P.,Conaway, R. C., Conaway, 3. W., Linehan, W. M., and Klauser, R. D. Inhibition of transcription elongation by the VHL tumor suppressor protein. Science (WashingtonDC), 269(5229): 1402-1406,1995. DOI: http://dx.doi.org/10.1126/science.7660122

20. Iliopoulos, 0., Levy, A. P., Jiang, C., Kaelin, W. G., Jr., and Goldberg, M. A.Negative regulation of hypoxia-inducible genes by the von Hipple-Lindau protein. Proc. Natl. Acad. Sci. USA, 93(20): 10595-105991,1996.
DOI: http://dx.doi.org/10.1073/pnas.93.20.10595

21. Gnarra, J. R., Zhou, S., Merrill, M. J., Wagner, J. R., Krumm, A., Papavassiliou, E.,Oldfield, E. H., Klausner, R. D., Linehan, W. M. Post-transcriptional regulation of vascular endothelial growth factor mRNA by the product of the VJIL tumor suppressor gene. Proc. Nail. Acad. Sci. USA, 93(20): 10589-10594, 1996.
DOI: http://dx.doi.org/10.1073/pnas.93.20.10589

22. Zbar B, Kishida T, Chen F, Schmidt L, Maher ER, Richards FM, Crossey PA, Webster AR, Affara NA, Ferguson-Smith MA, Brauch H, Glavac D, Neumann HP, Tisherman S, Mulvihill JJ, Gross DJ, Shuin T, Whaley J, Seizinger B, Kley N, Olschwang S, Boisson C, Richard S, Lips CH, Linehan WM, Lerman M. Germline mutations in the Von Hippel-Lindau disease (VHL) gene in families from North America, Europe, and Japan. Hum Mutat. 1996; 8(4):348-357.
DOI: http://dx.doi.org/10.1002/(SICI)1098-1004(1996)8:4<348::AID-HUMU8>3.0.CO;2-3

23. Neumann HP, Bender BU. Genotype-phenotype correlations in von Hippel-Lindau disease. J Intern Med 1998; 243(6):541-545. DOI: http://dx.doi.org/10.1046/j.1365-2796.1998.00336.x

24. Olschwang S, Richard S, Boisson S, Giraud S, Laurent-Puig P, Resche F, Thomas G. Germline mutation profile of the VHL gene in von Hippel-Lindau disease and sporadic hemangioblastomas. Hum Mutat 1998; 12(6): 424-430.
DOI: http://dx.doi.org/10.1002/(SICI)1098-1004(1998)12:6<424::AID-HUMU9>3.0.CO;2-H

25. Shuin T, Yamasaki I, Tamura K, Okuda H, Furihata M, Ashida S. Von Hippel–Lindau Disease: Molecular Pathological Basis, Clinical Criteria, Genetic Testing, Clinical Features of Tumors and Treatment. Jpn J Clin Oncol 2006;36(6)337–343. DOI: http://dx.doi.org/10.1093/jjco/hyl052

26. The committee of brain tumor registry of Japan. Report of brain tumor registry of Japan (1984–2000). Neurol Med Chir 2009;49(suppl):PS1-96. [Pubmed]

27. Kanno H, Kuratsu J, Nishikawa R, Mishima K, Natsume A, Wakabayashi T, Houkin K, Terasaka S, Shuin T. Clinical features of patients bearing central nervous system hemangioblastoma in von Hippel-Lindau disease. Acta Neurochirurgica.2013; 155(1):1-7. DOI: http://dx.doi.org/10.1007/s00701-012-1514-y

28. Maher ER, Yates JR, Ferguson-Smith MA. Statistical analysis of the two stage mutation model in von Hippel-Lindau disease, and in sporadic cerebellar haemangioblastoma and renal cell carcinoma. J Med Genet 1990; 27(5):311-314. DOI: http://dx.doi.org/10.1136/jmg.27.5.311

29. Lonser RR, Glenn GM, Walther M, Chew EY, Libutti SK, Linehan WM, Oldfield EH. von Hippel-Lindau disease. Lancet 2003; 361(9374): 2059-2067. DOI: http://dx.doi.org/10.1016/S0140-6736(03)13643-4

30. Glasker S, Van Velthoven V. Risk of hemorrhage in hemangioblastomas of the central nervous system. Neurosurgery. 2005; 57(1):71-76. DOI: http://dx.doi.org/10.1227/01.NEU.0000163250.71951.18

31. Lonser RR, Butman JA, Huntoon K, Asthagiri AR, Wu T, Bakhtian KD, Chew EY, Zhuang Z, Linehan WM, Oldfield EH. Prospective natural history study of central nervous system hemangioblastomas in von Hippel-Lindau disease. J Neurosurg. 2014; 120(5):1055-1062. DOI: http://dx.doi.org/10.3171/2014.1.JNS131431

32. 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. 2003; 98(1):82-94. DOI: http://dx.doi.org/10.3171/jns.2003.98.1.0082

33. Lonser RR, Weil RJ, Wanebo JE, DeVroom HL, Oldfield EH. Surgical management of spinal cord hemangioblastomas in patients with von Hippel-Lindau disease. J Neurosurg. 2003, 98(1):106-116.
DOI: http://dx.doi.org/10.3171/jns.2003.98.1.0106

34. Kruger MT, Klingler JH, Steiert C, Cordula Jilg, Stefan Zschiedrich, Birke Bausch, Vera Van Velthoven, Sven Glasker. Current diagnostic and therapeutic strategies in treatment of CNS hemangioblastomas in patients with VHL. J Trans Med Epidemiol. 2014; 2(1): 1016.

35. Van Velthoven V, Reinacher PC, Klisch J, Neumann HP, Glasker S. Treatment of intramedullary hemangioblastomas, with special attention to von Hippel-Lindau disease. Neurosurgery 2003; 53(6):1306-1313.
DOI: http://dx.doi.org/10.1227/01.NEU.0000093497.81390.29

36. Kanno H,Yamamoto I, Nishikawa R, Matsutani M, Wakabayashi T, Yoshida J, Shitara N, Yamasaki I, Shuin T; Clinical VHL Research Group in Japan. Spinal cord hemangioblastomas in von Hippel–Lindau disease. Spinal Cord 2009; 47(6):447-452. DOI: http://dx.doi.org/10.1038/sc.2008.151

37. Lonser RR, Oldfield EH. Microsurgical resection of spinal cord hemangioblastomas. Neurosurgery 2005; 57 (4 Suppl):372-376. DOI: http://dx.doi.org/10.1227/01.NEU.0000176849.76663.E4

38. Glasker S, Klingler JH, Muller K, Wurtenberger C, Hader C, Zentner J, Neumann HP, Velthoven VV. Essentials and pitfalls in the treatment of CNS hemangioblastomas and von Hippel-Lindau disease. Cent Euro Neurosurg 2010; 71(2):80-87. DOI: http://dx.doi.org/10.1055/s-0029-1234040

39. Lonser RR, Vortmeyer AO, Butman JA, Glasker S, Finn MA, Ammerman JM, Merrill MJ, Edwards NA, Zhuang Z, Oldfield EH. Edema is a precursor to central nervous system peritumoral cyst formation. Ann Neurol. 2005; 58(3):392-399. DOI: http://dx.doi.org/10.1002/ana.20584

40. Glasker S, Vortmeyer AO, Lonser RR, Lubensky IA, Okamoto H, Xia JB, Li J, Milne E, Kowalak JA, Oldfield EH, Zhuang Z. Proteomic analysis of hemangioblastoma cyst fluid. Cancer Biol Ther 2006; 5(5):549-553. DOI: http://dx.doi.org/10.4161/cbt.5.5.2657

41. Utsuki S, Oka H, Sato K, Shimizu S, Suzuki S, Fujii K. Fluorescence diagnosis of tumor cells in hemangioblastoma cysts with 5-aminolevulinic acid. J Neurosurg 2010; 112(1): 130-132. DOI: http://dx.doi.org/10.3171/2009.5.JNS08442

42. Murai Y, Adachi K, Matano F, Tateyama K, Teramoto A. Indocyanin green videoangiography study of hemangioblastomas. Can J Neurol Sci. 2011; 38(1):41-47. [Pubmed]

43. Kanno H, Ozawa Y, Sakata K, Sato H, Tanabe Y, Shimizu N, Yamamoto I. Intraoperative power Doppler ultrasonography with a contrast-enhancing agent for intracranial tumors. J Neurosurg. 2005; 102(2): 295-301.
DOI: http://dx.doi.org/10.3171/jns.2005.102.2.0295

44. Glasker S, Shah MJ, Hippchen B, Neumann HP, van Velthoven V. Doppler-sonographically guided resection of central nervous system hemangioblastomas. Neurosurgery. 2011; 68 (2 Suppl Operative):267-275. [Pubmed]

45. Asthagiri AR, Mehta GU, Zach L, Li X, Butman JA, Camphausen KA, Lonser RR. Prospective evaluation of radiosurgery for hemangioblastomas in von Hippel-Lindau disease. Neuro Oncol, 2010; 12(1): 80-86.
DOI: http://dx.doi.org/10.1093/neuonc/nop018

46. Moss JM, Choi CY, Adler JR Jr, Soltys SG, Gibbs IC, Chang SD. Stereotactic radiosurgical treatment of cranial and spinal hemangioblastomas. Neurosurgery. 2009;65(1):79-85. DOI: http://dx.doi.org/10.1227/01.NEU.0000348015.51685.D2

47. Koh ES, Nichol A, Millar BA, Menard C, Pond G, Laperriere NJ. Role of fractionated external beam radiotherapy in hemangioblastoma of the central nervous system. Int J Radiat Oncol Biol Phys. 2007; 69(5):1521-1526.
DOI: http://dx.doi.org/10.1016/j.ijrobp.2007.05.025

48. Simone CB 2nd, Lonser RR, Ondos J, Oldfield EH, Camphausen K, Simone NL. Infratentorial craniospinal irradiation for von Hippel-Lindau: a retrospective study supporting a new treatment for patients with CNS hemangioblastomas. Neuro Oncol. 2011; 13(9): 1030-1036. DOI: http://dx.doi.org/10.1093/neuonc/nor085

49. Bamps S, Calenbergh FV, Vleeschouwer SD, Loon JV, Sciot R, Legius E, Goffin J.: What the neurosurgeon should know about hemangioblastoma, both sporadic and in Von Hippel-Lindau disease: A literature review. Surg Neurol Int. 2013;4:145. DOI: http://dx.doi.org/10.4103/2152-7806.121110