Implications of Von Hippel-Lindau Syndrome and Renal Cell Carcinoma

Main Article Content

Kenan Ashouri
Sophia Mohseni
John Tourtelot
Pranav Sharma
Philippe E. Spiess

Keywords

Clear cell carcinoma, Hereditary cancer syndrome, Kidney cancer, Management, Renal cell carcinoma, VHL, von-Hippel Lindau

Abstract

Von Hippel-Lindau syndrome (VHLS) is a rare hereditary neoplastic disorder caused by mutations in the vhl gene leading to the development of tumors in several organs including the central nervous system, pancreas, kidneys, and reproductive organs. Manifestations of VHLS can present at different ages based on the affected organ and subclass of disease. In the subclasses of VHLS that cause renal disease, renal involvement typically begins closer to the end of the second decade of life and can present in different ways ranging from simple cystic lesions to solid tumors. Mutations in vhl are most often associated with clear cell renal carcinoma, the most common type of renal cancer, and also play a major role in sporadic cases of clear cell renal carcinoma. The recurrent, multifocal nature of this disease presents difficult challenges in the long-term management of patients with VHLS. Optimization of renal function warrants the use of several different approaches common to the management of renal carcinoma such as nephron-sparing surgery, enucleation, ablation, and targeted therapies. In VHLS, renal lesions of 3 cm or bigger are considered to have metastatic potential and even small lesions often harbor malignancy. Many of the aspects of management revolve around optimizing both oncologic outcome and long-term renal function. As new surgical strategies and targeted therapies develop, the management of this complex disease evolves.  This review will discuss the key aspects of the current management of VHLS.

Abstract 2811 | PDF Downloads 1312 HTML Downloads 1837

References

1. Barontini M, Dahia PL. VHL disease. Best Pract Res Clin Endocrinol Metab. 2010;24(3):401-13. http://dx.doi.org/10.1016/j.beem.2010.01.002 PMid:20833332
2. Safo AO, Pambuccian SE. Pancreatic manifestations of von Hippel-Lindau disease. Arch Pathol Lab Med. 2010;134(7):1080-3. PMid:20586642
3. Banks RE, Tirukonda P, Taylor C, et al. Genetic and epigenetic analysis of von Hippel-Lindau (VHL) gene alterations and relationship with clinical variables in sporadic renal cancer. Cancer Res. 2006;66(4):2000-11. http://dx.doi.org/10.1158/0008-5472.CAN-05-3074 PMid:16488999
4. Ong KR, Woodward ER, Killick P, et al. Genotype-phenotype correlations in von Hippel-Lindau disease. Hum Mutat. 2007;28(2):143-9. http://dx.doi.org/10.1002/humu.20385 PMid:17024664
5. Glenn GM. Von Hippel-Lindau Syndrome. Encyclopedia of endocrine Diseases. 2008; 4:674-687.
6. Crossey PA, Foster K, Richards FM, et al. Molecular genetic investigations of the mechanism of tumourigenesis in von Hippel-Lindau disease: analysis of allele loss in VHL tumours. Hum Genet. 1994;93(1):53-8. http://dx.doi.org/10.1007/BF00218913 PMid:8270255
7. Calzada MJ. Von Hippel-Lindau syndrome: molecular mechanisms of the disease. Clin Transl Oncol. 2010;12(3):160-5. http://dx.doi.org/10.1007/s12094-010-0485-9 PMid:20231120
8. Pause A, Lee S, Worrell RA, et al. The von Hippel-Lindau tumor-suppressor gene product forms a stable complex with human CUL-2, a member of the Cdc53 family of proteins. Proc Natl Acad Sci U S A. 1997;94(6):2156-61. http://dx.doi.org/10.1073/pnas.94.6.2156 PMid:9122164 PMCid:PMC20057
9. Pause A, Peterson B, Schaffar G, et al. Studying interactions of four proteins in the yeast two-hybrid system: structural resemblance of the pVHL/elongin BC/hCUL-2 complex with the ubiquitin ligase complex SKP1/cullin/F-box protein. Proc Natl Acad Sci U S A. 1999;96(17):9533-8. http://dx.doi.org/10.1073/pnas.96.17.9533 PMid:10449727 PMCid:PMC22243
10. Stebbins CE, Kaelin WG, Jr., Pavletich NP. Structure of the VHL-ElonginC-ElonginB complex: implications for VHL tumor suppressor function. Science. 1999;284(5413):455-61. http://dx.doi.org/10.1126/science.284.5413.455 PMid:10205047
11. Kim JJ, Rini BI, Hansel DE. Von Hippel Lindau syndrome. Adv Exp Med Biol. 2010;685:228-49. http://dx.doi.org/10.1007/978-1-4419-6448-9_22 PMid:20687511
12. Latif F, Tory K, Gnarra J, et al. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science. 1993;260(5112):1317-20. http://dx.doi.org/10.1126/science.8493574 PMid:8493574
13. Woodward ER, Buchberger A, Clifford SC, et al. Comparative sequence analysis of the VHL tumor suppressor gene. Genomics. 2000;65(3):253-65. http://dx.doi.org/10.1006/geno.2000.6144 PMid:10857749
14. Stadler W. Chromosomes, hypoxia, angiogenesis, and trial design: A brief history of renal cancer drug development. Clinical Cancer Research. 2007;13(6):1630-1633. http://dx.doi.org/10.1158/1078-0432.CCR-06-2721 PMid:17363513
15. Semenza GL. Hypoxia-inducible factors: mediators of cancer progression and targets for cancer therapy. Trends Pharmacol Sci. 2012;33(4):207-14. http://dx.doi.org/10.1016/j.tips.2012.01.005 PMid:22398146 PMCid:PMC3437546
16. Wang GL, Semenza GL. General involvement of hypoxia-inducible factor 1 in transcriptional response to hypoxia. Proc Natl Acad Sci U S A. 1993;90(9):4304-8. http://dx.doi.org/10.1073/pnas.90.9.4304
17. Ivan M, Kondo K, Yang H, et al. HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science. 2001;292(5516):464-8. http://dx.doi.org/10.1126/science.1059817 PMid:11292862
18. Brinke A, Green PM, Giannelli F. Characterization of the gene (VBP1) and transcript for the von Hippel-Lindau binding protein and isolation of the highly conserved murine homologue. Genomics. 1997;45(1):105-12. http://dx.doi.org/10.1006/geno.1997.4902 PMid:9339366
19. Yu F, White SB, Zhao Q, et al. HIF-1alpha binding to VHL is regulated by stimulus-sensitive proline hydroxylation. Proc Natl Acad Sci U S A. 2001;98(17):9630-5. http://dx.doi.org/10.1073/pnas.181341498 PMid:11504942 PMCid:PMC55503
20. Min JH, Yang H, Ivan M, et al. Structure of an HIF-1alpha -pVHL complex: hydroxyproline recognition in signaling. Science. 2002;296(5574):1886-9. http://dx.doi.org/10.1126/science.1073440 PMid:12004076
21. Iliopoulos O, Levy AP, Jiang C, et al. Negative regulation of hypoxia-inducible genes by the von Hippel-Lindau protein. Proc Natl Acad Sci U S A. 1996;93(20):10595-9. http://dx.doi.org/10.1073/pnas.93.20.10595 PMid: 8855223 PMCid:PMC38198
22. Jaakkola P, Mole DR, Tian YM, et al. Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science. 2001;292(5516):468-72. http://dx.doi.org/10.1126/science.1059796 PMid:11292861
23. Semenza GL. Oxygen sensing, homeostasis, and disease. N Engl J Med. 2011;365(6):537-47. http://dx.doi.org/10.1056/NEJMra1011165 PMid:21830968
24. Gnarra JR, Zhou S, Merrill MJ, et al. Post-transcriptional regulation of vascular endothelial growth factor mRNA by the product of the VHL tumor suppressor gene. Proc Natl Acad Sci U S A. 1996;93(20):10589-94. http://dx.doi.org/10.1073/pnas.93.20.10589 PMid:8855222 PMCid:PMC38197
25. Maxwell PH, Wiesener MS, Chang GW, et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature. 1999;399(6733):271-5. http://dx.doi.org/10.1038/20459 PMid:10353251
26. Knebelmann B, Ananth S, Cohen HT, et al. Transforming growth factor alpha is a target for the von Hippel-Lindau tumor suppressor. Cancer Res. 1998;58(2):226-31. PMid:9443397
27. Gunaratnam L, Morley M, Franovic A, et al. Hypoxia inducible factor activates the transforming growth factor-alpha/epidermal growth factor receptor growth stimulatory pathway in VHL(-/-) renal cell carcinoma cells. J Biol Chem. 2003;278(45):44966-74. http://dx.doi.org/10.1074/jbc.M305502200 PMid:12944410
28. Evans AJ, Russell RC, Roche O, et al. VHL promotes E2 box-dependent E-cadherin transcription by HIF-mediated regulation of SIP1 and snail. Mol Cell Biol. 2007;27(1):157-69. http://dx.doi.org/10.1128/MCB.00892-06 PMid:17060462 PMCid:PMC1800649
29. Petrella BL, Lohi J, Brinckerhoff CE. Identification of membrane type-1 matrix metalloproteinase as a target of hypoxia-inducible factor-2 alpha in von Hippel-Lindau renal cell carcinoma. Oncogene. 2005;24(6):1043-52. http://dx.doi.org/10.1038/sj.onc.1208305 PMid:15592504 PMCid:PMC1847637
30. Sendoel A, Kohler I, Fellmann C, et al. HIF-1 antagonizes p53-mediated apoptosis through a secreted neuronal tyrosinase. Nature. 2010;465(7298):577-83. http://dx.doi.org/10.1038/nature09141 PMid:20520707 PMCid:PMC3328299
31. Baba M, Hirai S, Yamada-Okabe H, et al. Loss of von Hippel-Lindau protein causes cell density-dependent deregulation of CyclinD1 expression through hypoxia-inducible factor. Oncogene. 2003;22(18):2728-38. http://dx.doi.org/10.1038/sj.onc.1206373 PMid:12743597
32. Sato Y, Yoshizato T, Shiraishi Y, et al. Integrated molecular analysis of clear-cell renal cell carcinoma. Nat Genet. 2013;45(8):860-7. http://dx.doi.org/10.1038/ng.2699 PMid:2379773
33. Kurban G, Duplan E, Ramlal N, et al. Collagen matrix assembly is driven by the interaction of von Hippel-Lindau tumor suppressor protein with hydroxylated collagen IV alpha 2. Oncogene. 2008;27(7):1004-12. http://dx.doi.org/10.1038/sj.onc.1210709 PMid:17700531
34. Kurban G, Hudon V, Duplan E, et al. Characterization of a von Hippel Lindau pathway involved in extracellular matrix remodeling, cell invasion, and angiogenesis. Cancer Res. 2006;66(3):1313-9. http://dx.doi.org/10.1158/0008-5472.CAN-05-2560 PMid:16452184
35. Ohh M, Yauch RL, Lonergan KM, et al. The von Hippel-Lindau tumor suppressor protein is required for proper assembly of an extracellular fibronectin matrix. Mol Cell. 1998;1(7):959-68. http://dx.doi.org/10.1016/S1097-2765(00)80096-9
36. Tsuchiya H, Iseda T, Hino O. Identification of a novel protein (VBP-1) binding to the von Hippel-Lindau (VHL) tumor suppressor gene product. Cancer Res. 1996;56(13):2881-5. PMid:8674032
37. Lonser RR, Glenn GM, Walther M, et al. von Hippel-Lindau disease. Lancet. 2003;361(9374):2059-67. http://dx.doi.org/10.1016/S0140-6736(03)13643-4
38. Maher ER, Yates JR, Harries R, et al. Clinical features and natural history of von Hippel-Lindau disease. Q J Med. 1990;77(283):1151-63. http://dx.doi.org/10.1093/qjmed/77.2.1151 PMid:2274658
39. Meister M, Choyke P, Anderson C, et al. Radiological evaluation, management, and surveillance of renal masses in Von Hippel-Lindau disease. Clin Radiol. 2009;64(6):589-600. http://dx.doi.org/10.1016/j.crad.2008.10.010 PMid:19414081
40. Nickerson ML, Jaeger E, Shi Y, et al. Improved identification of von Hippel-Lindau gene alterations in clear cell renal tumors. Clin Cancer Res. 2008;14(15):4726-34. http://dx.doi.org/10.1158/1078-0432.CCR-07-4921 PMid:18676741 PMCid:PMC2629664
41. Kwon T, Jeong IG, Pak S, et al. Renal tumor size is an independent prognostic factor for overall survival in von Hippel-Lindau disease. J Cancer Res Clin Oncol. 2014;140(7):1171-7. http://dx.doi.org/10.1007/s00432-014-1654-y PMid:24671227
42. Walther MM, Choyke PL, Glenn G, et al. Renal cancer in families with hereditary renal cancer: prospective analysis of a tumor size threshold for renal parenchymal sparing surgery. J Urol. 1999;161(5):1475-9. http://dx.doi.org/10.1016/S0022-5347(05)68930-6
43. Jilg CA, Neumann HP, Glasker S, et al. Growth kinetics in von Hippel-Lindau-associated renal cell carcinoma. Urol Int. 2012;88(1):71-8. http://dx.doi.org/10.1159/000333348 PMid:22156657
44. Poston CD, Jaffe GS, Lubensky IA, et al. Characterization of the renal pathology of a familial form of renal cell carcinoma associated with von Hippel-Lindau disease: clinical and molecular genetic implications. J Urol. 1995;153(1):22-6. http://dx.doi.org/10.1097/00005392-199501000-00009 PMid:7966777
45. Walther MM, Lubensky IA, Venzon D, et al. Prevalence of microscopic lesions in grossly normal renal parenchyma from patients with von Hippel-Lindau disease, sporadic renal cell carcinoma and no renal disease: clinical implications. J Urol. 1995;154(6):2010-4; discussion 2014-5.
46. Choyke PL, Glenn GM, Walther MM, et al. von Hippel-Lindau disease: genetic, clinical, and imaging features. Radiology. 1995;194(3):629-42. http://dx.doi.org/10.1148/radiology.194.3.7862955 PMid:7862955
47. Bosniak MA. The current radiological approach to renal cysts. Radiology. 1986;158(1):1-10. http://dx.doi.org/10.1148/radiology.158.1.3510019 PMid:3510019
48. Karmazyn B, Tawadros A, Delaney LR, et al. Ultrasound classification of solitary renal cysts in children. J Pediatr Urol. 2015;11(3):149 e1-6.
49. Hes FJ, Feldberg MA. Von Hippel-Lindau disease: strategies in early detection (renal-, adrenal-, pancreatic masses). Eur Radiol. 1999;9(4):598-610. http://dx.doi.org/10.1007/s003300050717 PMid:10354869
50. Tattersall DJ, Moore NR. von Hippel-Lindau disease: MRI of abdominal manifestations. Clin Radiol. 2002;57(2):85-92. http://dx.doi.org/10.1053/crad.2001.0747 PMid:11977939
51. Novick AC, Zincke H, Neves RJ, et al. Surgical enucleation for renal cell carcinoma. J Urol. 1986;135(2):235-8. PMid: 3944851
52. Novick AC, Streem SB. Long-term followup after nephron sparing surgery for renal cell carcinoma in von Hippel-Lindau disease. J Urol. 1992;147(6):1488-90. PMid:1593671
53. Herring JC, Enquist EG, Chernoff A, et al. Parenchymal sparing surgery in patients with hereditary renal cell carcinoma: 10-year experience. J Urol. 2001;165(3):777-81. http://dx.doi.org/10.1016/S0022-5347(05)66524-X
54. Steinbach F, Novick AC, Zincke H, et al. Treatment of renal cell carcinoma in von Hippel-Lindau disease: a multicenter study. J Urol. 1995;153(6):1812-6. http://dx.doi.org/10.1016/S0022-5347(01)67318-X
55. Singer EA, Vourganti S, Lin KY, et al. Outcomes of patients with surgically treated bilateral renal masses and a minimum of 10 years of follow-up. J Urol. 2012;188(6):2084-8. http://dx.doi.org/10.1016/j.juro.2012.08.038 PMid:23083858 PMCid:PMC3810017
56. Metwalli AR, Linehan WM. Nephron-sparing surgery for multifocal and hereditary renal tumors. Curr Opin Urol. 2014;24(5):466-73. http://dx.doi.org/10.1097/MOU.0000000000000094 PMid:25014245 PMCid:PMC4441729
57. Jilg CA, Neumann HP, Glasker S, et al. Nephron sparing surgery in von Hippel-Lindau associated renal cell carcinoma; clinicopathological long-term follow-up. Fam Cancer. 2012;11(3):387-94. http://dx.doi.org/10.1007/s10689-012-9525-7 PMid:22426863
58. Ploussard G, Droupy S, Ferlicot S, et al. Local recurrence after nephron-sparing surgery in von Hippel-Lindau disease. Urology. 2007;70(3):435-9. http://dx.doi.org/10.1016/j.urology.2007.04.040 PMid:17905091
59. Singer EA, Bratslavsky G. Management of locally recurrent kidney cancer. Curr Urol Rep. 2010;11(1):15-21. http://dx.doi.org/10.1007/s11934-009-0085-9 PMid:20425632
60. Matin SF, Ahrar K, Wood CG, et al. Patterns of intervention for renal lesions in von Hippel-Lindau disease. BJU Int. 2008;102(8):940-5. http://dx.doi.org/10.1111/j.1464-410X.2008.07718.x PMid:18485044
61. McDougal WS, Gervais DA, McGovern FJ, et al. Long-term followup of patients with renal cell carcinoma treated with radio frequency ablation with curative intent. J Urol. 2005;174(1):61-3. http://dx.doi.org/10.1097/01.ju.0000162046.45024.2b PMid:15947578
62. Gill IS, Remer EM, Hasan WA, et al. Renal cryoablation: outcome at 3 years. J Urol. 2005;173(6):1903-7. http://dx.doi.org/10.1097/01.ju.0000158154.28845.c9 PMid:15879772
63. Pavlovich CP, Walther M, Choyke PL, et al. Percutaneous radio frequency ablation of small renal tumors: initial results. J Urol. 2002;167(1):10-5. http://dx.doi.org/10.1016/S0022-5347(05)65371-2
64. Shingleton WB, Sewell PE. Percutaneous cryoablation of renal cell carcinoma in a transplanted kidney. BJU Int. 2002;90(1):137-8. http://dx.doi.org/10.1046/j.1464-410X.2002.02761.x
65. Joly D, Mejean A, Correas JM, et al. Progress in nephron sparing therapy for renal cell carcinoma and von Hippel-Lindau disease. J Urol. 2011;185(6):2056-60. http://dx.doi.org/10.1016/j.juro.2011.02.007 PMid:21496837
66. Park BK, Kim CK. Percutaneous radio frequency ablation of renal tumors in patients with von Hippel-Lindau disease: preliminary results. J Urol. 2010;183(5):1703-7. http://dx.doi.org/10.1016/j.juro.2010.01.022
PMid:20299060
67. Yang B, Autorino R, Remer EM, et al. Probe ablation as salvage therapy for renal tumors in von Hippel-Lindau patients: the Cleveland Clinic experience with 3 years follow-up. Urol Oncol. 2013;31(5):686-92. http://dx.doi.org/10.1016/j.urolonc.2011.05.008 PMid:21723752
68. Rini BI, Small EJ. Biology and clinical development of vascular endothelial growth factor-targeted therapy in renal cell carcinoma. J Clin Oncol. 2005;23(5):1028-43. http://dx.doi.org/10.1200/JCO.2005.01.186 PMid:15534359
69. Coppin C, Porzsolt F, Awa A, et al. Immunotherapy for advanced renal cell cancer. Cochrane Database Syst Rev 2005; 10.1002/14651858.CD001425.pub2(1):CD001425.
70. McDermott DF. Update on the application of interleukin-2 in the treatment of renal cell carcinoma. Clin Cancer Res. 2007;13(2 Pt 2):716s-720s. http://dx.doi.org/10.1158/1078-0432.CCR-06-1872 PMid:17255299
71. Randall JM, Millard F, Kurzrock R. Molecular aberrations, targeted therapy, and renal cell carcinoma: current state-of-the-art. Cancer Metastasis Rev. 2014;33(4):1109-24. http://dx.doi.org/10.1007/s10555-014-9533-1 PMid:25365943
72. Motzer RJ, Hutson TE, Tomczak P, et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009;27(22):3584-90. http://dx.doi.org/10.1200/JCO.2008.20.1293 PMid:19487381 PMCid:PMC3646307
73. Jonasch E, McCutcheon IE, Waguespack SG, et al. Pilot trial of sunitinib therapy in patients with von Hippel-Lindau disease. Ann Oncol. 2011;22(12):2661-6. http://dx.doi.org/10.1093/annonc/mdr011 PMid:22105611 PMCid:PMC4542805
74. Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007;356(2):125-34. http://dx.doi.org/10.1056/NEJMoa060655 PMid:17215530
75. Sternberg CN, Davis ID, Mardiak J, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol. 2010;28(6):1061-8. http://dx.doi.org/10.1200/JCO.2009.23.9764 PMid:20100962
76. Sternberg CN, Hawkins RE, Wagstaff J, et al. A randomised, double-blind phase III study of pazopanib in patients with advanced and/or metastatic renal cell carcinoma: final overall survival results and safety update. Eur J Cancer. 2013;49(6):1287-96. http://dx.doi.org/10.1016/j.ejca.2012.12.010 PMid:23321547
77. Escudier B, Pluzanska A, Koralewski P, et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet. 2007;370(9605):2103-11. http://dx.doi.org/10.1016/S0140-6736(07)61904-7
78. Lockhart AC, Rothenberg ML, Dupont J, et al. Phase I study of intravenous vascular endothelial growth factor trap, aflibercept, in patients with advanced solid tumors. J Clin Oncol. 2010;28(2):207-14. http://dx.doi.org/10.1200/JCO.2009.22.9237 PMid:19949018 PMCid:PMC281571
79. Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007;356(22):2271-81. http://dx.doi.org/10.1056/NEJMoa066838 PMid:17538086
80. Motzer RJ, Escudier B, Oudard S, et al. Phase 3 trial of everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic factors. Cancer. 2010;116(18):4256-65. http://dx.doi.org/10.1002/cncr.25219 PMid:20549832
81. Motzer RJ, Escudier B, Oudard S, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008;372(9637):449-56. http://dx.doi.org/10.1016/S0140-6736(08)61039-9