Journal of Collaborative Healthcare and Translational Medicine

von Hippel-Lindau Disease Associated Pancreatic Neuroendocrine Tumors – Molecular Genetics and Clinical Aspects

Review Article | Open Access

  • 17. Veneto Institute of Oncology, IRCCS and Department of Medicine-DIMED, University of Padova, Italy
  • 16. Department of Nephrology and General Medicine, Albert-Ludwigs University Medical Center of Freiburg, Germany
  • 15. Division of Endocrine Surgery, Department of General Surgery, Ege University Hospital, Turkey
  • 14. Breast & Endocrine Surgery Unit, Marmara University Pendik Research and Training Hospital, Turkey
  • 13. Institute of Pathology, University Hospital of Essen, University Duisburg-Essen, Germany
  • 12. Department of Hematology, Oncology and Stem Cell Transplantation, Albert-Ludwigs University Medical Center of Freiburg, Germany
  • 11. Department of Nuclear Medicine, Albert-Ludwigs University Medical Center of Freiburg, Germany
  • 10. Department of General Radiology, Albert-Ludwigs University Medical Center of Freiburg, Germany
  • 9. Department of Nuclear Medicine, La Timone University Hospital, CERIMED, AixMarseille University, Marseille, Fran
  • 8. Aix-Marseille University, Department of Endocrinology, La Timone Hospital, Franc
  • 7. HAS-SE “Lendület” Hereditary Endocrine Tumor Research Group, Hungarian Academy of Sciences and Semmelweis University, Hungary
  • 6. HAS-SE “Lendület” Hereditary Endocrine Tumor Research Group, Hungarian Academy of Sciences and Semmelweis University, Hungary
  • 5. Department of Endocrinology, University of Lorraine, France
  • 4. Department of Surgery and Center of Minimally Invasive Surgery, Kliniken Essen-Mitte, Germany
  • 3. Departments of Oncologic and Urologic Surgery, The 117th PLA Hospital, PLA Hangzhou Clinical College, Anhui Medical University, China
  • 2. Clinic of General-, Visceral- and Thoracic Surgery, St. Adolf-Stift Reinbek, Academic Teaching Hospital of the University of Hamburg, Germany
  • 1. 2nd Department of Medicine, Albert-Ludwigs University Medical Center of Freiburg, Germany
+ Show More - Show Less
Corresponding Authors
Hartmut P.H. Neumann, Section for Preventive Medicine, Department of Nephrology and General Medicine, University of Freiburg, Freiburg, Germany,

Pancreatic neuroendocrine tumors (PNETs) occur in about 10% of patients with von Hippel-Lindau disease (VHL). Females are more frequently affected than men. VHL associated PNETs are virtually always endocrine inactive. PNETs are mostly detected in patients with already known VHL disease. VHL associated PNETs occur as single or multiple tumors. Magnetic resonance imaging (MRI) is the method of choice to detect PNETs. Imaging in the early arterial phase is of utmost importance. Nuclear medicine imaging with newly introduced and promising agents such as [68Ga]-SST receptor analogs or [18F]-DOPA-PET CT, is recommended preoperatively to confirm the diagnosis, to exclude multifocal tumors and to identify potential metastases. Surgery should be performed for PNETs measuring 3 or more cm in diameter. PNETs of the tail or body of the pancreas can be resected by endoscopic technique. Treatment options for malignant tumors include tumor debulking, nuclear radiation by [90Y] or [177Lu]-labelled DOTA-TATE or DOTA-TOC, somatostatin analogs, and tyrosine kinase inhibitors. Regular follow-up investigations with MRI of the abdomen are recommended for all VHL patients in order to detect and remove these tumors before reaching 3 cm in diameter. Once PNETs are excluded in VHL patients, controls every 2-3 years are adequate.


Bausch B, von Dobschuetz E, Qi XP, Walz MK, Weryha G, et al. (2014) von Hippel-Lindau Disease Associated Pancreatic Neuroendocrine Tumors – Molecular Genetics and Clinical Aspects. J Transl Med Epidemiol 2(1): 1019.


•    von Hippel-Lindau disease
•    Pancreatic neuroendocrine tumors


Pancreatic neuroendocrine tumors (PNETs) is the terminus suggested by the WHO for tumors deriving from the cells of the islets of Langerhans of the pancreas [1]. Other frequently used terms are pancreatic endocrine tumors or islet cell tumors. These tumors belong to the family of neuroendocrine tumors (NETs). NETs can be located in many different sites of the body. NETs are often classified as foregut, midgut and hindgut tumors [2]. They occur as sporadic and syndromic entities. Best known are NETs as a component of multiple endocrine neoplasia type 1 which is mainly formed by parathyroid adenoma, NET and pituitary adenoma. Less known is that NETs are also a component of von Hippel-Lindau disease (VHL). In VHL disease, NETs are almost exclusively located in the pancreas. In addition to PNETs the classic lesions of VHL disease are multiple serous pancreatic cysts or cystadenomas, hemangioblastomas of the retina and the central nervous system (CNS), clear cell renal carcinomas and pheochromocytomas [3].


PNETs may produce a variety of hormones or vasoactive peptides and can thus cause distinct endocrine syndromes. These include gastric ulcer, abdominal pain and diarrhea due to gastrinoma and an over secretion of gastrin, episodes of hypoglycaemia due to insulinoma and an over secretion of insulin, and other syndromes such as Werner Morrison syndrome due to an over secretion of vasoactive intestinal peptide (VIP) and glucagonoma due to an over secretion of glucagon. Such clinical presentations are known from sporadic or MEN1 associated PNETs. In contrast, VHL associated PNETs present almost exclusively as non-secreting endocrine tumors, as space occupying masses or metastases. Therefore, PNETs are mostly diagnosed in early adulthood with a mean age of about 35 years. PNETs associated with VHL are mostly diagnosed in an advanced stage except in individuals subjected to a VHL specific surveillance program. This underlines the importance of specific diagnostic strategies.


Systematic analyses of serum concentrations of hormones in patients with VHL associated PNETs are pending, but secreting PNETs in VHL are extremely rare. Such analyses may include pancreatic polypeptide, gastrin, insulin, C peptide, VIP, glucagon, and somatostatin, and as an additional marker chromogranin A.


PNETs can cause symptoms as local masses or by excretion of several hormones. Since introduction of serial imaging radiology techniques such as ultrasonography, computerized tomography (CT) and magnetic resonance imaging (MRI) the percentage of PNETs diagnosed as “incidentalomas”, as asymptomatic tumors, is rising. Finally the era of molecular genetics and molecular genetic diagnosis opened the doors to preventive medicine allowing the identification of particular tumors as specific manifestations of hereditary syndromic diseases. Once the diagnosis is established, the patients can be offered specific surveillance programs and protocols. Similarly, relatives can be tested for a given pathogenic mutation and can be clinically investigated. This is the way by which asymptomatic PNETs in VHL disease can be detected [4-8].


VHL disease is an autosomal dominant disorder. The penetrance is age dependent, but high in affected subjects older than 40 years of age. The susceptibility genes for hereditary PNETs are the VHL gene located on chromosome 3p25-26 and the MEN1 gene predisposing for multiple endocrine neoplasia type 1 located on chromosome 11q13. The VHL gene has 3 exons and encodes the VHL protein with 213 amino acids. The MEN1 gene consists of 10 exons and encodes the Menin protein with 615 amino acids. Germline mutations are distributed over all exons of both genes, and in addition large deletions encompassing one to all exons of both genes have been described [6,9-15]. In VHL patients with PNETs all types of mutations have been described including missense mutations, stop codon mutations, intraexonic insertions and deletions, splice mutations and large deletions/ rearrangements [5,10,12,14,16] (Table 1).

We have conducted a study to evaluate the frequency of germline mutations in unselected patients with NETs. Our registry-based approach used the German-NET-Registry with 259 patients with the primary diagnosis of a NET. All patients provided blood DNA. All 10 exons of the MEN1 gene and all 3 exons of the VHL genes were analysed for intra-genic mutations and large deletions. In the NET-Registry, 9% of the patients with PNETs had germline mutations, 8 in MEN1 and 1 in VHL [16].

In addition, we evaluated the spectrum of VHL germline mutations and the corresponding phenotypes of all patients registered in the German VHL-Registry. The registry contained 487 molecular genetically confirmed patients. All patients had magnetic resonance imaging or computed tomography of the abdomen. The prevalence of NETs was 53/487 (11%). Remarkably there were striking differences of occurrence of PNETs in patients with different mutations. Among patients with the mutation VHL p.R167W, 47% developed PNETs, compared to only 2% of those with the mutation p.Y98H.

In total, there were 92 truly sporadic, i.e. mutation-negative PNET patients. Comparing these 92 patients to 54 VHL patients, statistically significant differences were predominance of female gender, multifocal PNETs and lower malignancy rate in VHL compared to sporadic cases [16] (Table 2).

In summary, PNETs are rarely the first presentation of VHL disease. Therefore, molecular genetic testing for germline mutations of the VHL gene is not generally recommended for all patients with PNETs, unless they have multifocal tumors, associated, VHL-specific tumors and/or a family history for VHL disease.

Table 1: VHL germline mutations in VHL patients with PNETs [16].

Nucleotide change Consequence VHL Patients with ICT Patients with the given mutation
c.208 G>T p.E70X 1 1
c.221 T/G p.V74G 1 4
c.440_442delTCT p.F76CfsX83 1  
c.240 T>G p.S80R 1 2
c.266 T/C p.L89P 1 7
c.277 G>C p.G93R 1  
c.292 T>C p.Y98H 2 158
c.340 G>A p.G114S 1 1
c.349dupT p.W117LfsX1 1 1
c.357 C>G p.F119L 2 2
c.362 A>G p.D121G 1 1
c.364_365 GC>AT p.A122I 1 1
c. 393 C>A p. N131K 1  
c. 394 C>T p. Q132X 1  
c.445_458del14 p.N150SfsX19 1 2
c.453 C>G p.I151M 1 1
c.461 C>T p.P154L 1 4
c.464-2 A>G Splice 2 4
c. 467 A>G p. Y156C 1  
c.472 C>G p.L158V 1 1
c.478_479delGA p.E160AfsX12 2 3
c.482 G>A p.R161Q 5 8
c.482 G>C p.R161P 1 2
c.488 T>A p.L163H 1 2
c.499 C>T p.R167W 7 15
c.500 G>A p.R167Q 4 5
c.533 T>C p.L178P 1 1
c.548 C>A p.S183X 1 4
c.583 C>T p.Q195X 1 3
c. 593 T>A p. L198Q 2  
Large Deletions*   6 63

* indicates deletions of 1, 2 or 3 exons of the VHL gene.

Table 2: Comparison between VHL-related and sporadic PNETs [16].

Variables VHL Sporadic p-value
Age (years) mean 36.03 57.07 <0.001
  SD 11.13 11.98
Sex female 34 37 0.010
  male 20 55
Tumor Number single 41 64 0.011
  multiple 13 5
Tumor Biology benign 39 24 <0.001
  malignant 15 68
Pancreatic Tumor as First Presentation yes 2 92 <0.001
no 52 0
Family History of VHL positive 32 1 <0.001
negative 22 91

p-values of Chi-square or Fisher test considered to be significant are 
represented in bold.
Abbreviations: SD for standard deviations, VHL for von Hippel-Lindau 


PNETs can be accurately diagnosed by computerized tomography (CT) and magnetic resonance imaging (MRI) (Figures 1 – 4) [17,18]. MRI is the method of choice because of the absence of radiation and no contrast medium side effects in patients with normal renal function. Imaging in the early arterial phase is essential. It must be performed 1st 20 seconds, 2nd between 20 and 40 seconds and 3rd within 2 minutes after i.v. contrast application. All tumors need to be exactly measured in 2, better in 3 dimensions. Actual and former images have to be compared. Newly identified tumors may be visible retrospectively in former images due to a small size or lack of contrast uptake. It takes much of the burden from a patient, if the information can be provided that the tumor is not new and the growth rate can be defined.


Several radiopharmaceuticals are used in the diagnostic of PNETs (Figure 5). The somatostatin receptor (SSTR) ligand 111In-DTPA-octreotide (OctreoScan®) has been extensively used for SSTR scintigraphy and single-photon emission tomography (SPECT; or hybrid SPECT/CT). However, 111In-DTPA-octreotide imaging has been replaced whenever available by positron emission tomography (PET; commonly performed as hybrid PET/CT) using SSTR-ligands. Currently, three DOTA-coupled peptides: DOTATOC (Tyr3-octreotide), DOTATATE (Tyr3- octreotate), and DOTANOC (Nal3-octreotide) have excellent affinity for SST2 receptors (IC50: 2.5 nM; 0.2 nM; and 1.9 nM respectively). DOTA-NOC also binds specifically to SST3, SST4 and SST5 receptors. Physiological distribution is similar to 111In-DTPA-octreotide. Additionally, tracer uptake is frequently found in the pancreas particularly in the processus uncinatus mimicking a focal tumor uptake.

SSTR PET/CT offers superior image resolution, lesion-tobackground contrast and thus overall diagnostic accuracy. Sufficient SSTR expression as imaged by SSTR imaging is also a prerequisite for possible peptide receptor radionuclide therapy (PRRT) in advanced, inoperable cases using beta-particle emitting SSTR ligands like 90Y- or 177Lu-labelled DOTA-TATE or DOTA-TOC (for a recent review see [26]). In addition, PET scanning with [18F] fluorodopa ([18F]-FDOPA) or [18F] fluorodeoxyglucose (FDG; especially in higher proliferating tumors) may be helpful in some cases. Pancreatic NETs exhibit variable [18F]-FDOPA uptake patterns. The main drawback of the technique is related to the intense and prolonged [18F]-FDOPA uptake by the exocrine pancreas, resulting in a low tumor-to-background uptake ratio. The optimal timing for acquisition and the use of oral premedication with carbidopa, a peripheral aromatic amino acid decarboxylase (AADC) inhibitor, remains to be evaluated.


The most relevant differential diagnosis of PNETs in VHL are pancreatic serous cystadenomas. Common in VHL are multiple pancreatic cysts. Cystadenomas consist of micro cystic structures and are related to benign pancreatic cysts. Whenever, seemingly solid lesions of the pancreas have a cystic component, cystadenomas are very likely. In contrast to PNETs, metastases due to VHL associated cystadenomas have not been described. Therefore, surgical removal is rarely indicated. This is of outstanding importance for lesions which cannot be removed by endoscopic organ sparing techniques.

In VHL, NETs outside the pancreas are extremely rare, but a patient with a carcinoid has been described [19].


Pancreatic surgery should only be performed in specialized centers, and experience with VHL patients is extremely important. Excellent imaging is the fundamental platform for successful surgery. Indication for surgery depends on the type of pancreatic lesion. Pancreatic cysts and cystadenomas do not need surgical treatment. Two different surgical methods must be considered for solid lesions depending on the size and number of the tumors. In smaller lesions, where malignancy is very unlikely an organ preserving tumor removal is indicated. In cases of evidence or suspect of malignant PNETs more extended resections should be considered [4,20].

Classical surgery with laparotomy is the method of choice for PNETs of the head, the proximal corpus and the processus uncinatus of the pancreas.

It is important to operate as less invasive as possible. Especially for small tumors enucleation is the procedure of choice. Intraoperative ultrasonography is excellent to screen for undetected, potential multifocal disease and to plan resections close to the pancreatic duct to lower the risk of pancreatic fistula.

Partial pancreaticoduodenectomy is the surgical strategy for large tumors. In the classic Whipple´s procedure duodenum, regional lymph nodes, gastric antrum, gallbladder, and distal bile tract are removed together with the resected pancreatic head. The modification by Traveso and Longmire preserves the pylorus and represents the procedure of choice in most oncologic resections. Removal of tumors infiltrating the portal vein is not contraindicated. For reconstruction of the biliary tract, intestinal passage, and drainage of the pancreatic tail a wide variety of safe surgical techniques are available. Postoperative complications include pancreatic fistula, hemorrhage, delayed gastric emptying, diabetes mellitus and malnutrition; they have been widely avoided by modification of the surgical technique, improved postoperative care and interventional endoscopic and radiologic treatment of complications [21].

Minimally invasive surgery is preferred in selected PNETs of the pancreatic tail and the distal pancreatic body. Best candidates are patients with tumors less than 3 cm in diameter and without lymph node metastases. The approach will be laparoscopic or retroperitoneoscopic. Preservation of the spleen should be intended [22]. In a first series 3 patients were operated by the laparoscopic approach. Operating time ranged between 215 – 360 min. Due to infiltrations and/or adhesions of the splenic vein, the spleen could be preserved only in one case. One patient turned out to have a malignant PNET with lymph node metastases [21].


Immunohistochemical demonstration of the neuroendocrine nature of the tumor is mandatory for the diagnosis of PNET [23]. PNETs are usually positive for the general neuroendocrine markers synaptophysin and chromogranin; additionally immunoreactivity for cytokeratin, insulin, gastrin, glucagon, somatostatin and/or neurospecific enolase (NSE) may be encountered. PNETs may show a trabecular, solid, and/or glandular growth pattern. The cells are often uniform, the finely granulated cytoplasm is usually eosinophilic [24,25]. It is important to emphasize that there is a lack of clearly defined histological criteria for malignancy. Textbooks such as the WHO classification of tumors compare clinical features and histopathological findings, but neither a single morphological criterion nor a combination of criteria, e. g. the “classical” stigmata of malignancy such as cell atypia, mitoses and vascular invasion, can be applied for precise prediction of clinical behaviour. Even the demonstration of tumor infiltration of adjacent tissue is not generally accepted as a hallmark of malignancy. Cellular grading as G2, in contrast to G1, a Ki-67 proliferation index, which is also mandatory for reporting PNETs, of >20% and more than 20 mitoses per 10 high power vision fields are often the basis for reports of malignant neuroendocrine tumors. However, the only proof for malignancy are lymph node or distant metastases [1,24].


Treatment of malignant PNETs is a challenge on its own. In contrast to adenocarcinoma of the pancreas, PNETs are slowly growing tumors, and all activities are justified. The primary goal is complete removal of the tumor and potential metastases. If not possible, as much tumor tissue as possible should be resected (debulking). After surgical treatment, MRI and nuclear medicine imaging (preferably SSTR PET/CT) should be repeated. In case of advanced, inoperable tumors or tumor remnants, PRRT with 90Y or 177Lu-labelled DOTA-TOC or DOTA-TATE is the next option. PRRT is commonly performed in 3 to 6 cycles in 2-3 months intervals [26]. In parallel or after this treatment long acting somatostatin should be started. Systemic treatment on malignant PNET involves multitarget tyrosine kinase inhibitors (semaxanib, sunitinib and vatalanib), thalidomide and interferon alpha-2a which are widely studied to prolong disease stability. Salvage therapy with anti-angiogenesis drugs has also been shown to be of benefit in some patients not suitable for surgery [27-29].


The method of choice for follow up investigations is MRI with early arterial phase imaging. Patients with PNETs need a strict follow up. This is true for patients with small PNETs so far not requiring surgery and for patients who underwent surgery. Since only about 10% of all VHL patients have a risk for PNETs it is of debate how long follow up intervals should be, if an actual MRI gives no evidence for such tumors. There is no general international agreement, but being aware that PNETs are indolent, slowly growing tumors, intervals of 2 or even 3 years seem adequate.


1. Klimstra D, Arnold R, Capella C, et al. Neuroendocrine neoplasms of the pancreas. In WHO Classification of Tumours of the Digestive System. Edited by Bosman F, Carneiro F, Hruban RH, Theise N Lyon, France: IARC Press; 2010: 322-326.

2. Jensen R, Jeffrey A. Norton. Endocrine Tumors of the Gastrotintestinal Tract and Pancreas. In Harrison’s Endocrinology. Volume 22. 2 edition. Edited by Jameson J: McGraw-Hill Companies, Columbus, OH; 2010: 348-366.

3. Lonser RR, Glenn GM, Walther M, Chew EY, Libutti SK, Linehan WM, et al. von Hippel-Lindau disease. Lancet. 2003; 361: 2059-2067.

4. Corcos O, Couvelard A, Giraud S, Vullierme MP, Dermot O’Toole, Rebours V, et al. Endocrine pancreatic tumors in von Hippel-Lindau disease: clinical, histological, and genetic features. Pancreas. 2008; 37: 85-93.

5. 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; 119: 1087-1095.

6. 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; 128: 1022-1027.

7. Binkovitz LA, Johnson CD, Stephens DH. Islet cell tumors in von Hippel-Lindau disease: increased prevalence and relationship to the multiple endocrine neoplasias. AJR Am J Roentgenol. 1990; 155: 501-505.

8. 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; 33: 382- 385.

9. Chandrasekharappa SC, Guru SC, Manickam P, Olufemi SE, Collins FS, Emmert-Buck MR, et al. Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science. 1997; 276: 404-407.

10. Crossey PA, Richards FM, Foster K, Green JS, Prowse A, Latif F, et al. Identification of intragenic mutations in the von Hippel-Lindau disease tumour suppressor gene and correlation with disease phenotype. Hum Mol Genet. 1994; 3: 1303-1308.

11. Giraud S, Zhang CX, Serova-Sinilnikova O, Wautot V, Salandre J, Buisson N, et al. Germ-line mutation analysis in patients with multiple endocrine neoplasia type 1 and related disorders. Am J Hum Genet. 1998; 63: 455-467.

12. Glavac D, Neumann HP, Wittke C, Jaenig H, Masek O, Streicher T, et al. Mutations in the VHL tumor suppressor gene and associated lesions in families with von Hippel-Lindau disease from central Europe. Hum Genet. 1996; 98: 271-280.

13. 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; 30: 665-669.

14. 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: 348-357.

15. Lemmens I, Van de Ven WJ, Kas K, Zhang CX, Giraud S, Wautot V, et al. Identification of the multiple endocrine neoplasia type 1 (MEN1) gene. The European Consortium on MEN1. Hum Mol Genet. 1997; 6: 1177-1183.

16. Erlic Z, Ploeckinger U, Cascon A, Hoffmann MM, von Duecker L, Winter A, et al. Systematic comparison of sporadic and syndromic pancreatic islet cell tumors. Endocr Relat Cancer. 2010; 17: 875-883.

17. Ichikawa T, Peterson MS, Federle MP, Baron RL, Haradome H, Kawamori Y, et al. Islet cell tumor of the pancreas: biphasic CT versus MR imaging in tumor detection. Radiology. 2000; 216: 163-171.

18. Viola KV, Sosa JA. Current advances in the diagnosis and treatment of pancreatic endocrine tumors. Curr Opin Oncol. 2005; 17: 24-27.

19. Kees A. [Malignant carcinoid and phaeochromocytoma in vonHippel-Lindau’s disease--a case report (author’s transl)]. Wien Klin Wochenschr. 1980; 92: 218-221.

20. 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; 142: 814-818.

21. von Dücker L, Walz MK, Voss C, Arnold G, Eng C, Neumann HP. Laparoscopic organ-sparing resection of von Hippel-Lindau disease associated pancreatic neuroendocrine tumors. World J Surg. 2011; 35: 563-567.

22. Engelhardt M, Eber SW, Germing U, Heimpel H, Kern W, Schmugge M. Prävention von Infektionen und Thrombosen nach Splenektomie oder funktioneller Asplenie. 2013.

23. Lam KY, Lo CY. Pancreatic endocrine tumour: a 22-year clinico-pathological experience with morphological, immunohistochemical observation and a review of the literature. Eur J Surg Oncol. 1997; 23: 36-42.

24. Maher E, Nothanson K, Komminoth P, Neumann HP, Plate KH, et al: Von Hippel-Lindau syndrome (VHL). In World Health Organization Classification of Tumours, Pathology and Genetics of Tumours of Endocrine Organs. Edited by DeLellis R, Lloyd RV, Heitz PU, Eng C. Lyon: IARC Press; 2004: 230-237.

25. Lubensky IA, Pack S, Ault D, Vortmeyer AO, Libutti SK, Choyke PL, et al. Multiple neuroendocrine tumors of the pancreas in von Hippel-Lindau disease patients: histopathological and molecular genetic analysis. Am J Pathol. 1998; 153: 223-231.

26. Ambrosini V, Fani M, Fanti S, Forrer F, Maecke HR. Radiopeptide imaging and therapy in Europe. J Nucl Med. 2011; 52: 42S-55S.

27. Raymond E, Dahan L, Raoul JL, Bang YJ, Borbath I, Lombard-Bohas C, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011; 364: 501-513.

28. Capitanio JF, Mazza E, Motta M, Mortini P, Reni M. Mechanisms, indications and results of salvage systemic therapy for sporadic and von Hippel-Lindau related hemangioblastomas of the central nervous system. Crit Rev Oncol Hematol. 2013; 86: 69-84.

29. Burns WR, Edil BH. Neuroendocrine pancreatic tumors: guidelines for management and update. Curr Treat Options Oncol. 2012; 13: 24-34.

Received : 06 Feb 2014
Accepted : 11 Mar 2014
Published : 13 Mar 2014
Annals of Otolaryngology and Rhinology
ISSN : 2379-948X
Launched : 2014
JSM Schizophrenia
Launched : 2016
Journal of Nausea
Launched : 2020
JSM Internal Medicine
Launched : 2016
JSM Hepatitis
Launched : 2016
JSM Oro Facial Surgeries
ISSN : 2578-3211
Launched : 2016
Journal of Human Nutrition and Food Science
ISSN : 2333-6706
Launched : 2013
JSM Regenerative Medicine and Bioengineering
ISSN : 2379-0490
Launched : 2013
JSM Spine
ISSN : 2578-3181
Launched : 2016
Archives of Palliative Care
ISSN : 2573-1165
Launched : 2016
JSM Nutritional Disorders
ISSN : 2578-3203
Launched : 2017
Annals of Neurodegenerative Disorders
ISSN : 2476-2032
Launched : 2016
Journal of Fever
ISSN : 2641-7782
Launched : 2017
JSM Bone Marrow Research
ISSN : 2578-3351
Launched : 2016
JSM Mathematics and Statistics
ISSN : 2578-3173
Launched : 2014
Journal of Autoimmunity and Research
ISSN : 2573-1173
Launched : 2014
JSM Arthritis
ISSN : 2475-9155
Launched : 2016
JSM Head and Neck Cancer-Cases and Reviews
ISSN : 2573-1610
Launched : 2016
JSM General Surgery Cases and Images
ISSN : 2573-1564
Launched : 2016
JSM Anatomy and Physiology
ISSN : 2573-1262
Launched : 2016
JSM Dental Surgery
ISSN : 2573-1548
Launched : 2016
Annals of Emergency Surgery
ISSN : 2573-1017
Launched : 2016
Annals of Mens Health and Wellness
ISSN : 2641-7707
Launched : 2017
Journal of Preventive Medicine and Health Care
ISSN : 2576-0084
Launched : 2018
Journal of Chronic Diseases and Management
ISSN : 2573-1300
Launched : 2016
Annals of Vaccines and Immunization
ISSN : 2378-9379
Launched : 2014
JSM Heart Surgery Cases and Images
ISSN : 2578-3157
Launched : 2016
Annals of Reproductive Medicine and Treatment
ISSN : 2573-1092
Launched : 2016
JSM Brain Science
ISSN : 2573-1289
Launched : 2016
JSM Biomarkers
ISSN : 2578-3815
Launched : 2014
JSM Biology
ISSN : 2475-9392
Launched : 2016
Archives of Stem Cell and Research
ISSN : 2578-3580
Launched : 2014
Annals of Clinical and Medical Microbiology
ISSN : 2578-3629
Launched : 2014
JSM Pediatric Surgery
ISSN : 2578-3149
Launched : 2017
Journal of Memory Disorder and Rehabilitation
ISSN : 2578-319X
Launched : 2016
JSM Tropical Medicine and Research
ISSN : 2578-3165
Launched : 2016
JSM Head and Face Medicine
ISSN : 2578-3793
Launched : 2016
JSM Cardiothoracic Surgery
ISSN : 2573-1297
Launched : 2016
JSM Bone and Joint Diseases
ISSN : 2578-3351
Launched : 2017
JSM Bioavailability and Bioequivalence
ISSN : 2641-7812
Launched : 2017
JSM Atherosclerosis
ISSN : 2573-1270
Launched : 2016
Journal of Genitourinary Disorders
ISSN : 2641-7790
Launched : 2017
Journal of Fractures and Sprains
ISSN : 2578-3831
Launched : 2016
Journal of Autism and Epilepsy
ISSN : 2641-7774
Launched : 2016
Annals of Marine Biology and Research
ISSN : 2573-105X
Launched : 2014
JSM Health Education & Primary Health Care
ISSN : 2578-3777
Launched : 2016
JSM Communication Disorders
ISSN : 2578-3807
Launched : 2016
Annals of Musculoskeletal Disorders
ISSN : 2578-3599
Launched : 2016
Annals of Virology and Research
ISSN : 2573-1122
Launched : 2014
JSM Renal Medicine
ISSN : 2573-1637
Launched : 2016
Journal of Muscle Health
ISSN : 2578-3823
Launched : 2016
JSM Genetics and Genomics
ISSN : 2334-1823
Launched : 2013
JSM Anxiety and Depression
ISSN : 2475-9139
Launched : 2016
Clinical Journal of Heart Diseases
ISSN : 2641-7766
Launched : 2016
Annals of Medicinal Chemistry and Research
ISSN : 2378-9336
Launched : 2014
JSM Pain and Management
ISSN : 2578-3378
Launched : 2016
JSM Women's Health
ISSN : 2578-3696
Launched : 2016
Clinical Research in HIV or AIDS
ISSN : 2374-0094
Launched : 2013
Journal of Endocrinology, Diabetes and Obesity
ISSN : 2333-6692
Launched : 2013
Journal of Substance Abuse and Alcoholism
ISSN : 2373-9363
Launched : 2013
JSM Neurosurgery and Spine
ISSN : 2373-9479
Launched : 2013
Journal of Liver and Clinical Research
ISSN : 2379-0830
Launched : 2014
Journal of Drug Design and Research
ISSN : 2379-089X
Launched : 2014
JSM Clinical Oncology and Research
ISSN : 2373-938X
Launched : 2013
JSM Bioinformatics, Genomics and Proteomics
ISSN : 2576-1102
Launched : 2014
JSM Chemistry
ISSN : 2334-1831
Launched : 2013
Journal of Trauma and Care
ISSN : 2573-1246
Launched : 2014
JSM Surgical Oncology and Research
ISSN : 2578-3688
Launched : 2016
Annals of Food Processing and Preservation
ISSN : 2573-1033
Launched : 2016
Journal of Radiology and Radiation Therapy
ISSN : 2333-7095
Launched : 2013
JSM Physical Medicine and Rehabilitation
ISSN : 2578-3572
Launched : 2016
Annals of Clinical Pathology
ISSN : 2373-9282
Launched : 2013
Annals of Cardiovascular Diseases
ISSN : 2641-7731
Launched : 2016
Journal of Behavior
ISSN : 2576-0076
Launched : 2016
Annals of Clinical and Experimental Metabolism
ISSN : 2572-2492
Launched : 2016
Clinical Research in Infectious Diseases
ISSN : 2379-0636
Launched : 2013
JSM Microbiology
ISSN : 2333-6455
Launched : 2013
Journal of Urology and Research
ISSN : 2379-951X
Launched : 2014
Journal of Family Medicine and Community Health
ISSN : 2379-0547
Launched : 2013
Annals of Pregnancy and Care
ISSN : 2578-336X
Launched : 2017
JSM Cell and Developmental Biology
ISSN : 2379-061X
Launched : 2013
Annals of Aquaculture and Research
ISSN : 2379-0881
Launched : 2014
Clinical Research in Pulmonology
ISSN : 2333-6625
Launched : 2013
Journal of Immunology and Clinical Research
ISSN : 2333-6714
Launched : 2013
Annals of Forensic Research and Analysis
ISSN : 2378-9476
Launched : 2014
JSM Biochemistry and Molecular Biology
ISSN : 2333-7109
Launched : 2013
Annals of Breast Cancer Research
ISSN : 2641-7685
Launched : 2016
Annals of Gerontology and Geriatric Research
ISSN : 2378-9409
Launched : 2014
Journal of Sleep Medicine and Disorders
ISSN : 2379-0822
Launched : 2014
JSM Burns and Trauma
ISSN : 2475-9406
Launched : 2016
Chemical Engineering and Process Techniques
ISSN : 2333-6633
Launched : 2013
Annals of Clinical Cytology and Pathology
ISSN : 2475-9430
Launched : 2014
JSM Allergy and Asthma
ISSN : 2573-1254
Launched : 2016
Journal of Neurological Disorders and Stroke
ISSN : 2334-2307
Launched : 2013
Annals of Sports Medicine and Research
ISSN : 2379-0571
Launched : 2014
JSM Sexual Medicine
ISSN : 2578-3718
Launched : 2016
Annals of Vascular Medicine and Research
ISSN : 2378-9344
Launched : 2014
JSM Biotechnology and Biomedical Engineering
ISSN : 2333-7117
Launched : 2013
Journal of Hematology and Transfusion
ISSN : 2333-6684
Launched : 2013
JSM Environmental Science and Ecology
ISSN : 2333-7141
Launched : 2013
Journal of Cardiology and Clinical Research
ISSN : 2333-6676
Launched : 2013
JSM Nanotechnology and Nanomedicine
ISSN : 2334-1815
Launched : 2013
Journal of Ear, Nose and Throat Disorders
ISSN : 2475-9473
Launched : 2016
JSM Ophthalmology
ISSN : 2333-6447
Launched : 2013
Journal of Pharmacology and Clinical Toxicology
ISSN : 2333-7079
Launched : 2013
Annals of Psychiatry and Mental Health
ISSN : 2374-0124
Launched : 2013
Medical Journal of Obstetrics and Gynecology
ISSN : 2333-6439
Launched : 2013
Annals of Pediatrics and Child Health
ISSN : 2373-9312
Launched : 2013
JSM Clinical Pharmaceutics
ISSN : 2379-9498
Launched : 2014
JSM Foot and Ankle
ISSN : 2475-9112
Launched : 2016
JSM Alzheimer's Disease and Related Dementia
ISSN : 2378-9565
Launched : 2014
Journal of Addiction Medicine and Therapy
ISSN : 2333-665X
Launched : 2013
Journal of Veterinary Medicine and Research
ISSN : 2378-931X
Launched : 2013
Annals of Public Health and Research
ISSN : 2378-9328
Launched : 2014
Annals of Orthopedics and Rheumatology
ISSN : 2373-9290
Launched : 2013
Journal of Clinical Nephrology and Research
ISSN : 2379-0652
Launched : 2014
Annals of Community Medicine and Practice
ISSN : 2475-9465
Launched : 2014
Annals of Biometrics and Biostatistics
ISSN : 2374-0116
Launched : 2013
JSM Clinical Case Reports
ISSN : 2373-9819
Launched : 2013
Journal of Cancer Biology and Research
ISSN : 2373-9436
Launched : 2013
Journal of Surgery and Transplantation Science
ISSN : 2379-0911
Launched : 2013
Journal of Dermatology and Clinical Research
ISSN : 2373-9371
Launched : 2013
JSM Gastroenterology and Hepatology
ISSN : 2373-9487
Launched : 2013
Annals of Nursing and Practice
ISSN : 2379-9501
Launched : 2014
JSM Dentistry
ISSN : 2333-7133
Launched : 2013
Author Information X