PMID- 19238077
OWN - NLM
STAT- MEDLINE
DCOM- 20090507
LR  - 20181201
IS  - 1532-0979 (Electronic)
IS  - 0147-5185 (Linking)
VI  - 33
IP  - 5
DP  - 2009 May
TI  - Pancreatic endocrine microadenomatosis in patients with von Hippel-Lindau 
      disease: characterization by VHL/HIF pathway proteins expression.
PG  - 739-48
LID - 10.1097/PAS.0b013e3181967992 [doi]
AB  - INTRODUCTION: 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.
FAU - Perigny, Martine
AU  - Perigny M
AD  - Department of Pathology, CHUQ-L'Hotel-Dieu de Quebec, Universite Laval, Quebec, 
      Canada.
FAU - Hammel, Pascal
AU  - Hammel P
FAU - Corcos, Olivier
AU  - Corcos O
FAU - Larochelle, Olivier
AU  - Larochelle O
FAU - Giraud, Sophie
AU  - Giraud S
FAU - Richard, Stephane
AU  - Richard S
FAU - Sauvanet, Alain
AU  - Sauvanet A
FAU - Belghiti, Jacques
AU  - Belghiti J
FAU - Ruszniewski, Philippe
AU  - Ruszniewski P
FAU - Bedossa, Pierre
AU  - Bedossa P
FAU - Couvelard, Anne
AU  - Couvelard A
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Am J Surg Pathol
JT  - The American journal of surgical pathology
JID - 7707904
RN  - 0 (Antigens, CD34)
RN  - 0 (Antigens, Neoplasm)
RN  - 0 (Basic Helix-Loop-Helix Transcription Factors)
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (CCND1 protein, human)
RN  - 0 (Chromogranin A)
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Insulin)
RN  - 0 (VEGFA protein, human)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 136601-57-5 (Cyclin D1)
RN  - 1B37H0967P (endothelial PAS domain-containing protein 1)
RN  - 9007-92-5 (Glucagon)
RN  - EC 2.3.2.27 (Von Hippel-Lindau Tumor Suppressor Protein)
RN  - EC 4.2.1.1 (CA9 protein, human)
RN  - EC 4.2.1.1 (Carbonic Anhydrase IX)
RN  - EC 4.2.1.1 (Carbonic Anhydrases)
RN  - EC 6.3.2.- (VHL protein, human)
SB  - IM
MH  - Adenoma/*chemistry/genetics/surgery
MH  - Adult
MH  - Antigens, CD34/analysis
MH  - Antigens, Neoplasm/analysis
MH  - Basic Helix-Loop-Helix Transcription Factors/*analysis
MH  - Biomarkers, Tumor/*analysis
MH  - Carbonic Anhydrase IX
MH  - Carbonic Anhydrases/analysis
MH  - Chromogranin A/analysis
MH  - Cyclin D1/analysis
MH  - Female
MH  - Glucagon/analysis
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/*analysis
MH  - Immunohistochemistry
MH  - Insulin/analysis
MH  - Male
MH  - Middle Aged
MH  - Multiple Endocrine Neoplasia Type 1/chemistry/genetics
MH  - Mutation
MH  - Pancreas/*chemistry/surgery
MH  - Pancreatectomy
MH  - Pancreatic Neoplasms/*chemistry/genetics/surgery
MH  - Precancerous Conditions/*chemistry/genetics/surgery
MH  - Vascular Endothelial Growth Factor A/analysis
MH  - Von Hippel-Lindau Tumor Suppressor Protein/*genetics
MH  - von Hippel-Lindau Disease/genetics/*metabolism/surgery
EDAT- 2009/02/25 09:00
MHDA- 2009/05/08 09:00
CRDT- 2009/02/25 09:00
PHST- 2009/02/25 09:00 [entrez]
PHST- 2009/02/25 09:00 [pubmed]
PHST- 2009/05/08 09:00 [medline]
AID - 10.1097/PAS.0b013e3181967992 [doi]
PST - ppublish
SO  - Am J Surg Pathol. 2009 May;33(5):739-48. doi: 10.1097/PAS.0b013e3181967992.