PMID- 23257898
OWN - NLM
STAT- MEDLINE
DCOM- 20130402
LR  - 20211203
IS  - 1532-1827 (Electronic)
IS  - 0007-0920 (Print)
IS  - 0007-0920 (Linking)
VI  - 108
IP  - 2
DP  - 2013 Feb 5
TI  - Immunohistochemical markers of the hypoxic response can identify malignancy in 
      phaeochromocytomas and paragangliomas and optimize the detection of tumours with 
      VHL germline mutations.
PG  - 429-37
LID - 10.1038/bjc.2012.538 [doi]
AB  - BACKGROUND: There are no reliable markers of malignancy in phaeochromocytomas 
      (PCC) and paragangliomas (PGL). We investigated the relevance of the mammalian 
      target of rapamycin (mTOR)/AKT and hypoxic pathways as novel immunohistochemical 
      markers of malignancy. METHODS: Tissue microarray blocks were constructed with a 
      total of 100 tumours (10 metastatic) and 20 normal adrenomedullary samples. 
      Sections were immunostained for hypoxia-inducible factor 1alpha (Hif-1alpha), vascular 
      endothelial growth factor A (VEGF-A), mTOR, carbonic anhydrase IX (CaIX) and AKT. 
      The predictive performance of these markers was studied using univariate, 
      multivariate and receiver operating characteristic analyses. RESULTS: In all, 100 
      consecutive patients, 64% PCC, 29% familial with a median tumour size of 4.7 cm 
      (range 1-14) were included. Univariate analyses showed Hif-1alpha overexpression, 
      tumour necrosis, size >5 cm, capsular and vascular invasion to be predictors of 
      metastasis. In multivariate analysis, Hif-1alpha, necrosis and vascular invasion 
      remained as independent predictors of metastasis. Hif-1alpha was the most 
      discriminatory biomarker for the presence of metastatic diffusion. Strong 
      membranous CaIX expression was seen in von Hippel-Lindau (VHL) PCC as opposed to 
      other subtypes. CONCLUSION: Lack of vascular invasion, tumour necrosis and low 
      Hif-1alpha expression identify tumours with lower risk of malignancy. We propose 
      membranous CaIX expression as a potential marker for VHL disease in patients 
      presenting with PCC.
FAU - Pinato, D J
AU  - Pinato DJ
AD  - Department of Investigative Medicine, Imperial College London, Hammersmith 
      Hospital Campus, Du Cane Road, London W12 0NN, UK.
FAU - Ramachandran, R
AU  - Ramachandran R
FAU - Toussi, S T K
AU  - Toussi ST
FAU - Vergine, M
AU  - Vergine M
FAU - Ngo, N
AU  - Ngo N
FAU - Sharma, R
AU  - Sharma R
FAU - Lloyd, T
AU  - Lloyd T
FAU - Meeran, K
AU  - Meeran K
FAU - Palazzo, F
AU  - Palazzo F
FAU - Martin, N
AU  - Martin N
FAU - Khoo, B
AU  - Khoo B
FAU - Dina, R
AU  - Dina R
FAU - Tan, T M
AU  - Tan TM
LA  - eng
PT  - Journal Article
DEP - 20121220
PL  - England
TA  - Br J Cancer
JT  - British journal of cancer
JID - 0370635
RN  - 0 (Antigens, Neoplasm)
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - EC 2.3.2.27 (Von Hippel-Lindau Tumor Suppressor Protein)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
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)
SB  - IM
MH  - Adrenal Gland Neoplasms/diagnosis/genetics/immunology
MH  - Adult
MH  - Antigens, Neoplasm/*analysis/immunology
MH  - Biomarkers, Tumor/analysis/genetics/immunology
MH  - Carbonic Anhydrase IX
MH  - Carbonic Anhydrases/*analysis/immunology
MH  - Cell Hypoxia
MH  - Female
MH  - Germ-Line Mutation
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/*analysis/immunology
MH  - Immunohistochemistry
MH  - Male
MH  - Neoplasm Metastasis
MH  - Paraganglioma/*chemistry/diagnosis/*genetics
MH  - Pheochromocytoma/*chemistry/diagnosis/*genetics
MH  - Proto-Oncogene Proteins c-akt/analysis/immunology
MH  - TOR Serine-Threonine Kinases/analysis/immunology
MH  - Tissue Array Analysis
MH  - Vascular Endothelial Growth Factor A/analysis/immunology
MH  - Von Hippel-Lindau Tumor Suppressor Protein/*genetics
MH  - von Hippel-Lindau Disease/diagnosis/genetics
PMC - PMC3566818
EDAT- 2012/12/22 06:00
MHDA- 2013/04/03 06:00
PMCR- 2014/02/05
CRDT- 2012/12/22 06:00
PHST- 2012/12/22 06:00 [entrez]
PHST- 2012/12/22 06:00 [pubmed]
PHST- 2013/04/03 06:00 [medline]
PHST- 2014/02/05 00:00 [pmc-release]
AID - bjc2012538 [pii]
AID - 10.1038/bjc.2012.538 [doi]
PST - ppublish
SO  - Br J Cancer. 2013 Feb 5;108(2):429-37. doi: 10.1038/bjc.2012.538. Epub 2012 Dec 
      20.