Von Hippel-Lindau Syndrome: Medical Syndrome or Surgical Syndrome? A Surgical Perspective

Main Article Content

Danilo Coco
Silvana Leanza

Keywords

clear cell renal cancer, Pheocromocytoma, PNET, Von Hippel-Lindau

Abstract

Von Hippel-Lindau syndrome (VHL) is an autosomal dominant disease caused by a genetic aberration of the tumor suppressor gene VHL and characterized by multi-organ tumors. The most common neoplasm is retinal or cerebral hemangioblastoma, although spinal hemangioblastomas, Renal Clear Cell Carcinoma (RCCC), pheochromocytomas (Pheo), paragangliomas, Pancreatic Neuroendocrine Tumors (PNETs), cystadenomas of the epididymis, and tumors of the lymphatic sac can also be found. Neurological complications from retinal or CNS hemangioblastoma and metastases of RCCC are the most common causes of death. There is a strong association between pheochromocytoma and VHL syndrome, and pheochromocytoma is often a classic manifestation of the syndrome. RCCCs are often incidental and identified during other tests. Between 35 and 70% of patients with VHL have pancreatic cysts. These can manifest as simple cysts, serous cysto-adenomas, or PNETs with a risk of malignant degeneration or metastasis of no more than 8%. The objective of this retrospective study is to analyze abdominal manifestations of VHL from a surgical point of view.

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References

1. Collins E. Intra-ocular growths (two cases, brother and sister, with peculiar vascular new growth, probably retinal, affecting both eyes).Trans Ophthalmol Soc U K. 1894;14:141–9.

2. von Hippel E. U¨ ber eine sehr seltene Erkrankung der Netzhaut. Gra¨fe Arch Ophthallmol. 1904;59:83–106. 10.1007/BF01994821

3. Lindau A. Zur Frage der Angiomatosis retinae und ihrer Hirnkomplikation. Acta Ophthalmol. 1927;4:193–224. 10.1111/j.1755-3768.1926.tb07786.x

4. Seizinger BR, Rouleau GA, Ozelius LJ, et al. Von Hippel–Lindau disease maps to the region of chromosome 3 associated with renal cell carcinoma. Nature. 1988;332:268–9. 10.1038/332268a0

5. Latif F, Tory K, Gnarra J, Yao M, Duh FM, Orcutt ML, Stackhouse T, Kuzmin I, Modi W, Geil L, et al. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science. 1993 May 28;260(5112):1317–20. 10.1126/science.8493574. PMid: 8493574.

6. Wilding A, Ingham SL, Lalloo F, Clancy T, Huson SM, Moran A, Evans DG. Life expectancy in hereditary cancer predisposing diseases: an observational study. J Med Genet. 2012 Apr;49(4):264–9. 10.1136/jmedgenet-2011-100562. Epub 2012 Feb 23. PMid: 22362873.

7. Poulsen ML, Budtz-Jørgensen E, Bisgaard ML. Surveillance in von Hippel-Lindau disease (VHL). Clin Genet. 2010 Jan;77(1):49–59. 10.1111/j.1399-0004.2009.01281.x

8. Maher ER. Von Hippel-Lindau disease. Eur J Can. 1994 Jan;30(13):1987–90. 10.1016/0959-8049(94)00391-H

9. Zbar B, Kishida T, Chen F, Schmidt L, Maher ER, Richards FM, et al. Germline mutations in the Von Hippel-Lindau disease (VHL) gene in families from North America, Europe, and Japan. Hum Mutat. 1996;8(4):348–57. 10.1002/(SICI)1098-1004(1996)8:4<348::AID-HUMU8>3.0.CO;2-3. PMid: 8956040.

10. Maher ER, Yates JR, Harries R, Benjamin C, Harris R, Moore AT, Ferguson-Smith MA. Clinical features and natural history of von Hippel-Lindau disease. Q J Med. 1990 Nov;77(283):1151–63. 10.1093/qjmed/77.2.1151. PMid: 2274658.

11. Lonser RR, Glenn GM, Walther M, Chew EY, Libutti SK, Linehan WM, Oldfield EH. von Hippel-Lindau disease. Lancet. 2003 Jun 14;361(9374):2059-67. 10.1016/S0140-6736(03)13643-4. PMid: 12814730.

12. Maher ER, Neumann HP, Richard S. von Hippel-Lindau disease: A clinical and scientific review. Eur J Hum Genet. 2011 Jun;19(6):617–23. 10.1038/ejhg.2010.175

13. Blansfield JA, Choyke L, Morita SY, Choyke PL, Pingpank JF, Alexander HR, Seidel G, Shutack Y, Yuldasheva N, Eugeni M, Bartlett DL, Glenn GM, Middelton L, Linehan WM, Libutti SK. Clinical, genetic and radiographic analysis of 108 patients with von Hippel-Lindau disease (VHL) manifested by pancreatic neuroendocrine neoplasms (PNETs). Surgery. 2007 Dec;142(6):814–8; discussion 818.e1-2. 10.1016/j.surg.2007.09.012. Erratum In: Surgery. 2008 Feb;143(2):302. PMid: 18063061; PMCID: PMC6771023.

14. Cassol C, Mete O. Endocrine manifestations of von Hippel-Lindau disease. Arch Pathol Lab Med. 2015;139(2):263–8. 10.5858/arpa.2013-0520-RS

15. Woodward ER, Maher ER. Von Hippel-Lindau disease and endocrine tumour susceptibility. Endocr Relat Cancer. 2006;13(2):415–25. 10.1677/erc.1.00683

16. Zwolak A, S´wirska J, Tywanek E, Dudzin´ska M, Tarach JS, Matyjaszek-Matuszek B. Pancreatic neuroendocrine tumours in patients with von Hippel-Lindau disease. Endokrynol Pol. 2020;71(3):256–259. 10.5603/EP.a2020.0027. PMid: 32797472.

17. Hes FJ, Hoöppener JWM, Lips CJM. Pheochromocytoma in Von Hippel-Lindau Disease. JClin Endocrinol Metab.2003;88(3):969–74. 10.1210/jc.2002-021466

18. Varshney N, Kebede AA, Owusu-Dapaah H, Lather J, Kaushik M, Bhullar JS. A review of Von Hippel-Lindau syndrome. J Kidney Cancer VHL. 2017 Aug 2;4(3):20–9. 10.15586/jkcvhl.2017.88

19. Baghai M, Thompson GB, Young WF Jr, Grant CS, Michels VV, van Heerden JA. Pheochromocytomas and paragangliomas in von Hippel-Lindau disease: A role for laparoscopic and cortical-sparing surgery. Arch Surg. 2002 Jun;137(6):682–8; discussion 688–9. 10.1001/archsurg.137.6.682

20. Melmon KL, Rosen SW. Lindau’s disease: Review of the literature and study of a large kindred. Am J Med. 1964;36:595–617.10.1016/0002-9343(64)90107-X

21. Tampieri D, Leblanc R, TerBrugge K, Rengachary SS, Berenstein A. Preoperative embolization of brain and spinal hemangioblastomas. Neurosurgery.1993;33(3):502–5. 10.1227/00006123-199309000-00022

22. Bratslavsky G. Functional and oncologic outcomes of partial adrenalectomy for pheochromocytoma in patients with von Hippel-Lindau syndrome after at least 5 years of follow-up. J Urol. 2010 Nov;184(5):1855–9. 10.1016/j.juro.2010.06.102

23. Walther MM, Reiter R, Keiser HR, Choyke PL, Venzon D, Hurley K, et al. Clinical and genetic characterization of pheochromocytoma in von Hippel-Lindau families: comparison with sporadic pheochromocytoma gives insight into natural history of pheochromocytoma. J Urol. 1999 Sep;162(3 Pt 1):659–64. 10.1097/00005392-199909010-00004. PMid: 10458336.

24. Michels V, Van Heerden JA. Pheochromocytomas and paragangliomas in von Hippel-Lindau disease: A role for laparoscopic and cortical-sparing surgery. ArchSurg. 2002;137(6):682–9.10.1001/archsurg.137.6.682

25. Eisenhofer G, Walther MM, Huynh TT, Li ST, Bornstein SR, Vortmeyer A, et al. Pheochromocytomas in von Hippel-Lindau syndrome and multiple endocrine neoplasia type 2 display distinct biochemical and clinical phenotypes. J Clin Endocrinol Metab. 2001 May;86(5):1999–2008. 10.1210/jcem.86.5.7496. PMid: 11344198.

26. Chittiboina P, Lonser RR. Von Hippel–Lindau disease. Handb Clin Neurol. 2015;132:139–56. 10.1016/B978-0-444-62702-5.00010-X

27. Young EE, Castle SM, Gorbatiy V, Leveillee RJ. Comparison of safety, renal function outcomes and efficacy of laparoscopic and percutaneous radio frequency ablation of renal masses. J Urol. 2012 Apr;187(4):1177–82. 10.1016/j.juro.2011.11.099. Epub 2012 Feb 20. PMid: 22357170.

28. Charlesworth M, Verbeke CS, Falk GA, Walsh M, Smith AM, Morris-Stiff G. Pancreatic lesions in von Hippel-Lindau disease? A systematic review and meta-synthesis of the literature. J Gastrointest Surg. 2012 Jul;16(7):1422–8. 10.1007/s11605-012-1847-0. Epub 2012 Feb 28. PMid: 22370733.

29. Libutti SK, Choyke PL, Bartlett DL, Vargas H, Walther M, Lubensky I, et al. Pancreatic neuroendocrine tumors associated with von Hippel Lindau disease: diagnostic and management recommendations. Surgery. 1998 Dec;124(6):1153–9. 10.1067/msy.1998.91823. PMid: 9854597.

30. Horton WA, Wong V, Eldridge R. Von Hippel-Lindau disease: Clinical and pathological manifestations in nine families with 50 affected members. Arch Intern Med. 1976;136(7):769–77. 10.1001/archinte.136.7.769

31. Tamura K, Nishimori I, Ito T, Yamasaki I, Igarashi H, Shuin T. Diagnosis and management of pancreatic neuroendocrine tumor in von Hippel-Lindau disease. World J Gastroenterol. 2010 Sep 28;16(36):4515–8. 10.3748/wjg.v16.i36.4515. PMid: 20857520; PMCID: PMC2945481.

32. Kos-Kudła B, Hubalewska-Dydejczyk A, Kus´nierz K, Lampe P, Marek B, Nasierowska-Guttmejer A, Nowakowska-Duława E, et al. Consensus Conference; olish Network of Neuroendocrine Tumours. Pancreatic neuroendocrine neoplasms–management guidelines (recommended by the Polish Network of Neuroendocrine Tumours). Endokrynol Pol. 2013;64(6):459–79. 10.5603/EP.2013.0031. PMid: 24431118.

33. Hammel PR, Vilgrain V, Terris B, Penfornis A, Sauvanet A, Correas JM, et al. Pancreatic involvement in von Hippel-Lindau disease. The Groupe Francophone d’Etude de la Maladie de von Hippel-Lindau. Gastroenterology. 2000 Oct 119(4):1087–95. 10.1053/gast.2000.18143. PMid: 11040195.

34. Benhammou JN, Boris RS, Pacak K, Pinto PA, Linehan WM, Bratslavsky G. Functional and oncologic outcomes of partial adrenalectomy for pheochromocytoma in patients with von Hippel-Lindau syndrome after at least 5 years of followup. J Urol. 2010 Nov;184(5):1855–9. 10.1016/j.juro.2010.06.102

35. Weil RJ, Lonser RR, DeVroom HL, Wanebo JE, Oldfield EH. Surgical management of brainstemhemangioblastomas in patients with von Hippel-Lindau disease. J Neurosurg.2003;98(1):95–105. 10.3171/jns.2003.98.1.0095

36. Peng S, Zhang J, Tan X, Huang Y, Xu J, Silk N, et al. The VHL/HIF Axis in the Development and Treatment of Pheochromocytoma/Paraganglioma. Front Endocrinol (Lausanne). 2020 Nov 24;11:586857. 10.3389/fendo.2020.586857. PMid: 33329393; PMCID: PMC7732471.

37. Maharjan CK, Ear PH, Tran CG, Howe JR, Chandrasekharan C, Quelle DE. Pancreatic neuroendocrine tumors: Molecular mechanisms and therapeutic targets. Cancers (Basel). 2021;13(20):5117. 10.3390/cancers13205117

38. Flores SK, Estrada-Zuniga CM, Thallapureddy K, Armaiz-Peña G, Dahia PLM. Insights into mechanisms of pheochromocytomas and paragangliomas driven by known or new genetic drivers. Cancers (Basel). 2021;13(18):4602. 10.3390/cancers13184602

39. Tung I, Sahu A. Immune checkpoint inhibitor in first-line treatment of metastatic renal cell carcinoma: A review of current evidence and future directions. Front Oncol. 2021;11:707214. 10.3389/fonc.2021.707214