title: Pancreatic endocrine microadenomatosis in patients with von Hippel-Lindau disease: characterization by VHL/HIF pathway proteins expression.
abstract: BACKGROUND
  Von Hippel-Lindau (VHL) disease is an inherited syndrome caused by germline mutation in the VHL tumor suppressor gene predisposing to pancreatic endocrine tumors (PET). Whether these tumors derive from preexisting endocrine microadenomatosis as in multiple endocrine neoplasia type 1 (MEN1) is yet unknown. pVHL regulates hypoxia-inducible factor (HIF) that causes transcription activity of target genes like carbonic anhydrase 9 (CA9), vascular endothelial growth factor (VEGF), and cyclin D1. Our aim was to look for overexpression of these molecules to identify precursor endocrine lesions in the pancreas of VHL patients.
  
  
  METHODS
  Nontumoral pancreas of 18 VHL patients operated on for PET, was examined for microadenomatosis (<or=5 mm) and compared with pancreatic specimen obtained from non-VHL patients or MEN1 patients. The immunohistochemical expression of chromogranin, insulin, glucagon, HIF-1alpha, HIF-2alpha, VEGF, CA9, cyclin D1, and CD34 was assessed.
  
  
  RESULTS
  In addition to 39 macrotumors (1 to 5/patient), chromogranin-positive endocrine microadenomas were found in 13 (72%) patients located within acini or close to ducts or islets. Strong coexpression of HIF-1alpha, cyclin D1, CA9, and VEGF and lack of expression of insulin and glucagon allowed distinction with normal or hyperplastic islets. CD34 identified a high microvessel density in these nodules. Expression of HIF-1alpha and CA9 was not found in islets of controls and in MEN1 microadenomas.
  
  
  CONCLUSIONS
  Pancreatic endocrine microadenomas are present in >70% of VHL patients operated on for PET. These results demonstrate that the pVHL/HIF pathway is involved very early in pancreatic endocrine tumorigenesis in this disease.
authors.affiliation: Department of Pathology, CHUQ-L'Hôtel-Dieu de Québec, Université Laval, Québec, Canada.
authors.forename: Martine
authors.initials: M
authors.lastname: Périgny
authors.forename: Pascal
authors.initials: P
authors.lastname: Hammel
authors.forename: Olivier
authors.initials: O
authors.lastname: Corcos
authors.forename: Olivier
authors.initials: O
authors.lastname: Larochelle
authors.forename: Sophie
authors.initials: S
authors.lastname: Giraud
authors.forename: Stéphane
authors.initials: S
authors.lastname: Richard
authors.forename: Alain
authors.initials: A
authors.lastname: Sauvanet
authors.forename: Jacques
authors.initials: J
authors.lastname: Belghiti
authors.forename: Philippe
authors.initials: P
authors.lastname: Ruszniewski
authors.forename: Pierre
authors.initials: P
authors.lastname: Bedossa
authors.forename: Anne
authors.initials: A
authors.lastname: Couvelard
mesh_terms: D000236:Adenoma / Q000737:chemistry* / Q000235:genetics / Q000601:surgery; D000328:Adult; D018952:Antigens, CD34 / Q000032:analysis; D000951:Antigens, Neoplasm / Q000032:analysis; D051792:Basic Helix-Loop-Helix Proteins / Q000032:analysis*; D014408:Biomarkers, Tumor / Q000032:analysis*; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000032:analysis; D053379:Chromogranin A / Q000032:analysis; D019938:Cyclin D1 / Q000032:analysis; D005260:Female; D005934:Glucagon / Q000032:analysis; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000032:analysis*; D007150:Immunohistochemistry; D007328:Insulin / Q000032:analysis; D008297:Male; D008875:Middle Aged; D018761:Multiple Endocrine Neoplasia Type 1 / Q000737:chemistry / Q000235:genetics; D009154:Mutation; D010179:Pancreas / Q000737:chemistry* / Q000601:surgery; D010180:Pancreatectomy; D010190:Pancreatic Neoplasms / Q000737:chemistry* / Q000235:genetics / Q000601:surgery; D011230:Precancerous Conditions / Q000737:chemistry* / Q000235:genetics / Q000601:surgery; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics*; D006623:von Hippel-Lindau Disease / Q000235:genetics / Q000378:metabolism* / Q000601:surgery; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D018952:Antigens, CD34; D000951:Antigens, Neoplasm; D051792:Basic Helix-Loop-Helix Proteins; D014408:Biomarkers, Tumor; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases; D053379:Chromogranin A; D019938:Cyclin D1; D005934:Glucagon; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007328:Insulin; D042461:Vascular Endothelial Growth Factor A; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1; C530104:CCND1 protein, human; C497442:HIF1A protein, human; C467484:VEGFA protein, human; C089226:CA9 protein, human; C497446:VHL protein, human