Top

Journal of Gastrointestinal Surgery

Published in:

01-07-2012 | Review Article

Pancreatic Lesions in von Hippel–Lindau Disease? A Systematic Review and Meta-synthesis of the Literature

Authors: Michael Charlesworth, Caroline S. Verbeke, Gavin A. Falk, Matthew Walsh, Andrew M. Smith, Gareth Morris-Stiff

Published in: Journal of Gastrointestinal Surgery | Issue 7/2012

Abstract

Background

von Hippel–Lindau (vHL) disease is a rare condition that leads to characteristic lesions within many different body systems. Pancreatic manifestations of vHL cover a wide spectrum of pathologies, and thus, accurate characterization and management is critical.

Methods

A comprehensive and systematic text word and MeSH search of the medical literature was performed to identify studies where information regarding the prevalence, clinical characteristics, and management recommendations could be extracted.

Results

Eleven studies were identified but 2 studies utilized the same data set. Of the 10 remaining studies, a total of 1,442 patients with vHL were available for analysis. Four hundred and twenty patients were examined for any type of pancreatic lesion, 362 for simple cysts or serous cystadenomas (SCAs), and 1,442 for neuroendocrine tumors (NETs). Of the 420 assessed for any pancreatic manifestation of vHL, 252 (60%) had a pancreatic lesion identified. Simple cysts that present as the sole manifestation of pancreatic disease were common and found in 169 of 362 (47%) patients. These are usually asymptomatic and do not normally require intervention. SCAs were reported in 39 of 362 (11%) patients and followed a similar benign course; resection is acceptable in symptomatic patients. NETs were identified in 211 of 1,442 (15%) patients, and 27 of 1,442 (2%) lesions behaved malignantly. Management of NETs depends on size, doubling time, and underlying genetics. Renal cell carcinoma is a characteristic in vHL, but there were no cases of pancreatic metastases identified from the included studies. Adenocarcinomas of the pancreas are not pathogenically linked to vHL.

Conclusions

This review highlights the wide spectrum and high prevalence of pancreatic lesions in vHL. Simple cysts and SCAs are benign, but NETs require careful observation due to their malignant potential.

Hippel EV. Die anatomische Grundlage der mon vir beschriebenen “sehr seltene Erkrankung der Netzhaut”. A von Grafe’s Arch Opthalmol. 1911;79:350–77.

Lindau A. Studien uber kleinhirnzysten: bau, pathogenese and beziehungen zur angiomatosis retinae. Acta Pathol Microbiol Scand Suppl. 1926;1(suppl. II):1–128.

Melmon KL, Rosen SW. Lindau’s Disease. Review of the Literature and Study of a Large Kindred. Am J Med. 1964 Apr;36:595–617.PubMedCrossRef

Lonser RR, Glenn GM, Walther M, Chew EY, Libutti SK, Linehan WM, et al. von Hippel–Lindau disease. Lancet. 2003 Jun 14;361(9374):2059–67.PubMedCrossRef

Seizinger BR, Rouleau GA, Ozelius LJ, Lane AH, Farmer GE, Lamiell JM, et al. Von Hippel–Lindau disease maps to the region of chromosome 3 associated with renal cell carcinoma. Nature. 1988 Mar 17;332(6161):268–9.PubMedCrossRef

Latif F, Tory K, Gnarra J, Yao M, Duh FM, Orcutt ML, et al. Identification of the von Hippel–Lindau disease tumor suppressor gene. Science. 1993 May 28;260(5112):1317–20.PubMedCrossRef

Duan DR, Humphrey JS, Chen DY, Weng Y, Sukegawa J, Lee S, et al. Characterization of the VHL tumor suppressor gene product: localization, complex formation, and the effect of natural inactivating mutations. Proc Natl Acad Sci U S A. 1995 Jul 3;92(14):6459–63.PubMedCrossRef

Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME, et al. The tumor suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature. 1999 May 20;399(6733):271–5.PubMedCrossRef

Knudson AG, Jr. Hereditary cancer, oncogenes, and antioncogenes. Cancer Res. 1985 Apr;45(4):1437–43.PubMed

10.

Richard S, David P, Marsot-Dupuch K, Giraud S, Beroud C, Resche F. Central nervous system hemangioblastomas, endolymphatic sac tumors, and von Hippel–Lindau disease. Neurosurg Rev. 2000 Mar;23(1):1–22; discussion 3–4.PubMedCrossRef

11.

Maher ER, Kaelin WG, Jr. von Hippel–Lindau disease. Medicine (Baltimore). 1997 Nov;76(6):381–91.CrossRef

12.

Maddock IR, Moran A, Maher ER, Teare MD, Norman A, Payne SJ, et al. A genetic register for von Hippel–Lindau disease. J Med Genet. 1996 Feb;33(2):120–7.PubMedCrossRef

13.

Richard S, Campello C, Taillandier L, Parker F, Resche F. Haemangioblastoma of the central nervous system in von Hippel–Lindau disease. French VHL Study Group. J Intern Med. 1998 Jun;243(6):547–53.PubMedCrossRef

14.

Lamiell JM, Salazar FG, Hsia YE. von Hippel–Lindau disease affecting 43 members of a single kindred. Medicine (Baltimore). 1989 Jan;68(1):1–29.

15.

Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA. 2000 Apr 19;283(15):2008–12.PubMedCrossRef

16.

Sanderson S, Tatt ID, Higgins JP. Tools for assessing quality and susceptibility to bias in observational studies in epidemiology: a systematic review and annotated bibliography. Int J Epidemiol. 2007 Jun;36(3):666–76.PubMedCrossRef

17.

Neumann HP, Dinkel E, Brambs H, Wimmer B, Friedburg H, Volk B, et al. Pancreatic lesions in the von Hippel–Lindau syndrome. Gastroenterology. 1991 Aug;101(2):465–71.PubMed

18.

Hough DM, Stephens DH, Johnson CD, Binkovitz LA. Pancreatic lesions in von Hippel–Lindau disease: prevalence, clinical significance, and CT findings. AJR Am J Roentgenol. 1994 May;162(5):1091–4.PubMed

19.

Cheng TY, Su CH, Shyr YM, Lui WY. Management of pancreatic lesions in von Hippel–Lindau disease. World J Surg. 1997 Mar-Apr;21(3):307–12.PubMedCrossRef

20.

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.PubMedCrossRef

21.

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.PubMedCrossRef

22.

Libutti SK, Choyke PL, Alexander HR, Glenn G, Bartlett DL, Zbar B, et al. Clinical and genetic analysis of patients with pancreatic neuroendocrine tumors associated with von Hippel–Lindau disease. Surgery. 2000 Dec;128(6):1022–7;discussion 7–8.PubMedCrossRef

23.

Mukhopadhyay B, Sahdev A, Monson JP, Besser GM, Reznek RH, Chew SL. Pancreatic lesions in von Hippel–Lindau disease. Clin Endocrinol (Oxf). 2002 Nov;57(5):603–8.CrossRef

24.

Delman KA, Shapiro SE, Jonasch EW, Lee JE, Curley SA, Evans DB, et al. Abdominal visceral lesions in von Hippel–Lindau disease: incidence and clinical behavior of pancreatic and adrenal lesions at a single center. World J Surg. 2006 May;30(5):665–9.PubMedCrossRef

25.

Yamasaki I, Nishimori I, Ashida S, Kohsaki T, Onishi S, Shuin T. Clinical characteristics of pancreatic neuroendocrine tumors in Japanese patients with von Hippel–Lindau disease. Pancreas. 2006 Nov;33(4):382–5.PubMedCrossRef

26.

Blansfield JA, Choyke L, Morita SY, Choyke PL, Pingpank JF, Alexander HR, et al. 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 8 e1-2.PubMedCrossRef

27.

Lee KH, Lee JS, Kim BJ, Lee JK, Kim SH, Lee KT. Pancreatic involvement in Korean patients with von Hippel–Lindau disease. J Gastroenterol. 2009;44(5):447–52.PubMedCrossRef

28.

Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(7): e1000097. doi:10.1371/journal.pmed1000097

29.

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 Jan;98(1):82–94.PubMedCrossRef

30.

Filling-Katz MR, Choyke PL, Oldfield E, Charnas L, Patronas NJ, Glenn GM, et al. Central nervous system involvement in Von Hippel–Lindau disease. Neurology. 1991 Jan;41(1):41–6.PubMedCrossRef

31.

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 Jul;136(7):769–77.PubMedCrossRef

32.

Mohr VH, Vortmeyer AO, Zhuang Z, Libutti SK, Walther MM, Choyke PL, et al. Histopathology and molecular genetics of multiple cysts and microcystic (serous) adenomas of the pancreas in von Hippel–Lindau patients. Am J Pathol. 2000 Nov;157(5):1615–21.PubMedCrossRef

33.

Kaelin WG, Jr. Cancer. Many vessels, faulty gene. Nature. 1999 May 20;399(6733):203–4.PubMedCrossRef

34.

Safo AO, Pambuccian SE. Pancreatic manifestations of von Hippel–Lindau disease. Arch Pathol Lab Med. 2010 Jul;134(7):1080–3.PubMed

35.

Jensen RT, Berna MJ, Bingham DB, Norton JA. Inherited pancreatic endocrine tumor syndromes: advances in molecular pathogenesis, diagnosis, management, and controversies. Cancer. 2008 Oct 1;113(7 Suppl):1807–43.PubMedCrossRef

36.

Pawlu C, Bausch B, Reisch N, Neumann HP. Genetic testing for pheochromocytoma-associated syndromes. Ann Endocrinol (Paris). 2005 Jun;66(3):178–85.

37.

Yao JC, Hoff PM. Molecular targeted therapy for neuroendocrine tumors. Hematol Oncol Clin North Am. 2007 Jun;21(3):575–81; x.PubMedCrossRef

38.

Yao JC. Neuroendocrine tumors. Molecular targeted therapy for carcinoid and islet-cell carcinoma. Best Pract Res Clin Endocrinol Metab. 2007 Mar;21(1):163–72.PubMedCrossRef

39.

Walther MM, Choyke PL, Glenn G, Lyne JC, Rayford W, Venzon D, 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 May;161(5):1475–9.PubMedCrossRef

40.

Grubb RL, 3rd, Choyke PL, Pinto PA, Linehan WM, Walther MM. Management of von Hippel–Lindau-associated kidney cancer. Nat Clin Pract Urol. 2005 May;2(5):248–55.PubMedCrossRef

41.

Roland CF, van Heerden JA. Nonpancreatic primary tumors with metastasis to the pancreas. Surg Gynecol Obstet. 1989 Apr;168(4):345–7.PubMed

42.

Minni F, Casadei R, Perenze B, Greco VM, Marrano N, Margiotta A, et al. Pancreatic metastases: observations of three cases and review of the literature. Pancreatology. 2004;4(6):509–20.PubMedCrossRef

43.

Kogire M, Hosotani R, Kondo M, Itoh K, Doi R, Terachi T, et al. Pancreatic lesions in von Hippel–Lindau syndrome: the coexistence of metastatic tumors from renal cell carcinoma and multiple cysts. Surg Today. 2000;30(4):380–2.PubMedCrossRef

44.

Chambers TP, Fishman EK, Hruban RH. Pancreatic metastases from renal cell carcinoma in von Hippel–Lindau disease. Clin Imaging. 1997 Jan-Feb;21(1):40–2.PubMedCrossRef

45.

Sugiyama M, Katsura M, Yamamoto K, Nouchi W, Abe N, Hatano N, et al. Pancreatic metastasis from renal cell carcinoma causing massive gastrointestinal bleeding in von Hippel–Lindau disease. Hepatogastroenterology. 1999 Mar-Apr;46(26):1199–201.PubMed

46.

Maeda H, Okabayashi T, Kobayashi M, Araki K, Kohsaki T, Nishimori I, et al. Emergency pancreatoduodenectomy for pancreatic metastasis from renal cell carcinoma in a patient with von Hippel–Lindau disease: a case report. Dig Dis Sci. 2006 Aug;51(8):1383–7.PubMedCrossRef

Title: Pancreatic Lesions in von Hippel–Lindau Disease? A Systematic Review and Meta-synthesis of the Literature
Authors: Michael Charlesworth
Caroline S. Verbeke
Gavin A. Falk
Matthew Walsh
Andrew M. Smith
Gareth Morris-Stiff
Publication date: 01-07-2012
Publisher: Springer-Verlag
Published in: Journal of Gastrointestinal Surgery / Issue 7/2012
Print ISSN: 1091-255X
Electronic ISSN: 1873-4626
DOI: https://doi.org/10.1007/s11605-012-1847-0

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Pancreatic Lesions in von Hippel–Lindau Disease? A Systematic Review and Meta-synthesis of the Literature

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 7/2012

Comprehensive Analysis of Variables Affecting Delayed Gastric Emptying Following Pancreaticoduodenectomy

Antimesenteric Functional End-to-End Handsewn (Kono-S) Anastomosis

Enteropathy-Associated T Cell Lymphoma Presenting with Acute Abdominal Syndrome: a Case Report and Review of Literature

Pancreatic Enucleation: Improved Outcomes Compared to Resection

Body Mass Index and Survival in Esophageal Adenocarcinoma Treated with Chemoradiotherapy Followed by Esophagectomy

How I Do It: Laparoscopic Paraesophageal Hernia Repair