Immunohistochemical markers of the hypoxic response can identify malignancy in phaeochromocytomas and paragangliomas and optimize the detection of tumours with VHL germline mutations

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...

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Veröffentlicht in:British journal of cancer 2013-02, Vol.108 (2), p.429-437
Hauptverfasser: Pinato, D J, Ramachandran, R, Toussi, S T K, Vergine, M, Ngo, N, Sharma, R, Lloyd, T, Meeran, K, Palazzo, F, Martin, N, Khoo, B, Dina, R, Tan, T M
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container_issue 2
container_start_page 429
container_title British journal of cancer
container_volume 108
creator Pinato, D J
Ramachandran, R
Toussi, S T K
Vergine, M
Ngo, N
Sharma, R
Lloyd, T
Meeran, K
Palazzo, F
Martin, N
Khoo, B
Dina, R
Tan, T M
description 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 1 α (Hif-1 α ), 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-1 α overexpression, tumour necrosis, size >5 cm, capsular and vascular invasion to be predictors of metastasis. In multivariate analysis, Hif-1 α , necrosis and vascular invasion remained as independent predictors of metastasis. Hif-1 α 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-1 α 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.
doi_str_mv 10.1038/bjc.2012.538
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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 1 α (Hif-1 α ), 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-1 α overexpression, tumour necrosis, size &gt;5 cm, capsular and vascular invasion to be predictors of metastasis. In multivariate analysis, Hif-1 α , necrosis and vascular invasion remained as independent predictors of metastasis. Hif-1 α 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-1 α 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.</description><identifier>ISSN: 0007-0920</identifier><identifier>EISSN: 1532-1827</identifier><identifier>DOI: 10.1038/bjc.2012.538</identifier><identifier>PMID: 23257898</identifier><identifier>CODEN: BJCAAI</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>631/208/737 ; 631/67/1857 ; 692/699/67/1459/1963 ; Adrenal Gland Neoplasms - diagnosis ; Adrenal Gland Neoplasms - genetics ; Adrenal Gland Neoplasms - immunology ; Adrenals. Adrenal axis. 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Benign neoplasms ; Oncology ; Paraganglioma - chemistry ; Paraganglioma - diagnosis ; Paraganglioma - genetics ; Pheochromocytoma - chemistry ; Pheochromocytoma - diagnosis ; Pheochromocytoma - genetics ; Proto-Oncogene Proteins c-akt - analysis ; Proto-Oncogene Proteins c-akt - immunology ; Tissue Array Analysis ; TOR Serine-Threonine Kinases - analysis ; TOR Serine-Threonine Kinases - immunology ; Tumors ; Vascular endothelial growth factor ; Vascular Endothelial Growth Factor A - analysis ; Vascular Endothelial Growth Factor A - immunology ; von Hippel-Lindau Disease - diagnosis ; von Hippel-Lindau Disease - genetics ; Von Hippel-Lindau Tumor Suppressor Protein - genetics</subject><ispartof>British journal of cancer, 2013-02, Vol.108 (2), p.429-437</ispartof><rights>The Author(s) 2013</rights><rights>2014 INIST-CNRS</rights><rights>Copyright Nature Publishing Group Feb 5, 2013</rights><rights>Copyright © 2013 Cancer Research UK 2013 Cancer Research UK</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c480t-d3bc03a8ab1dbd89de6c786fa301ae9550982b8e9b78ea00e0e86cf4a2fee2df3</citedby><cites>FETCH-LOGICAL-c480t-d3bc03a8ab1dbd89de6c786fa301ae9550982b8e9b78ea00e0e86cf4a2fee2df3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3566818/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3566818/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&amp;idt=27104629$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23257898$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Pinato, D J</creatorcontrib><creatorcontrib>Ramachandran, R</creatorcontrib><creatorcontrib>Toussi, S T K</creatorcontrib><creatorcontrib>Vergine, M</creatorcontrib><creatorcontrib>Ngo, N</creatorcontrib><creatorcontrib>Sharma, R</creatorcontrib><creatorcontrib>Lloyd, T</creatorcontrib><creatorcontrib>Meeran, K</creatorcontrib><creatorcontrib>Palazzo, F</creatorcontrib><creatorcontrib>Martin, N</creatorcontrib><creatorcontrib>Khoo, B</creatorcontrib><creatorcontrib>Dina, R</creatorcontrib><creatorcontrib>Tan, T M</creatorcontrib><title>Immunohistochemical markers of the hypoxic response can identify malignancy in phaeochromocytomas and paragangliomas and optimize the detection of tumours with VHL germline mutations</title><title>British journal of cancer</title><addtitle>Br J Cancer</addtitle><addtitle>Br J Cancer</addtitle><description>Background: There are no reliable markers of malignancy in phaeochromocytomas (PCC) and paragangliomas (PGL). 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Hif-1 α 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-1 α 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.</description><subject>631/208/737</subject><subject>631/67/1857</subject><subject>692/699/67/1459/1963</subject><subject>Adrenal Gland Neoplasms - diagnosis</subject><subject>Adrenal Gland Neoplasms - genetics</subject><subject>Adrenal Gland Neoplasms - immunology</subject><subject>Adrenals. Adrenal axis. Renin-angiotensin system (diseases)</subject><subject>Adult</subject><subject>Antigens, Neoplasm - analysis</subject><subject>Antigens, Neoplasm - immunology</subject><subject>Biological and medical sciences</subject><subject>Biomarkers</subject><subject>Biomarkers, Tumor - analysis</subject><subject>Biomarkers, Tumor - genetics</subject><subject>Biomarkers, Tumor - immunology</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Cancer</subject><subject>Cancer Research</subject><subject>Carbonic Anhydrase IX</subject><subject>Carbonic Anhydrases - analysis</subject><subject>Carbonic Anhydrases - immunology</subject><subject>Catecholamines</subject><subject>Cell Hypoxia</subject><subject>Drug Resistance</subject><subject>Endocrinopathies</subject><subject>Epidemiology</subject><subject>Female</subject><subject>Germ-Line Mutation</subject><subject>Hospitals</subject><subject>Humans</subject><subject>Hypoxia</subject><subject>Hypoxia-Inducible Factor 1, alpha Subunit - analysis</subject><subject>Hypoxia-Inducible Factor 1, alpha Subunit - immunology</subject><subject>Immunohistochemistry</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Metastasis</subject><subject>Molecular Diagnostics</subject><subject>Molecular Medicine</subject><subject>Mutation</subject><subject>Neoplasm Metastasis</subject><subject>Non tumoral diseases. 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Hif-1 α 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-1 α 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.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>23257898</pmid><doi>10.1038/bjc.2012.538</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record>
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subjects 631/208/737
631/67/1857
692/699/67/1459/1963
Adrenal Gland Neoplasms - diagnosis
Adrenal Gland Neoplasms - genetics
Adrenal Gland Neoplasms - immunology
Adrenals. Adrenal axis. Renin-angiotensin system (diseases)
Adult
Antigens, Neoplasm - analysis
Antigens, Neoplasm - immunology
Biological and medical sciences
Biomarkers
Biomarkers, Tumor - analysis
Biomarkers, Tumor - genetics
Biomarkers, Tumor - immunology
Biomedical and Life Sciences
Biomedicine
Cancer
Cancer Research
Carbonic Anhydrase IX
Carbonic Anhydrases - analysis
Carbonic Anhydrases - immunology
Catecholamines
Cell Hypoxia
Drug Resistance
Endocrinopathies
Epidemiology
Female
Germ-Line Mutation
Hospitals
Humans
Hypoxia
Hypoxia-Inducible Factor 1, alpha Subunit - analysis
Hypoxia-Inducible Factor 1, alpha Subunit - immunology
Immunohistochemistry
Male
Medical sciences
Metastasis
Molecular Diagnostics
Molecular Medicine
Mutation
Neoplasm Metastasis
Non tumoral diseases. Target tissue resistance. Benign neoplasms
Oncology
Paraganglioma - chemistry
Paraganglioma - diagnosis
Paraganglioma - genetics
Pheochromocytoma - chemistry
Pheochromocytoma - diagnosis
Pheochromocytoma - genetics
Proto-Oncogene Proteins c-akt - analysis
Proto-Oncogene Proteins c-akt - immunology
Tissue Array Analysis
TOR Serine-Threonine Kinases - analysis
TOR Serine-Threonine Kinases - immunology
Tumors
Vascular endothelial growth factor
Vascular Endothelial Growth Factor A - analysis
Vascular Endothelial Growth Factor A - immunology
von Hippel-Lindau Disease - diagnosis
von Hippel-Lindau Disease - genetics
Von Hippel-Lindau Tumor Suppressor Protein - genetics
title Immunohistochemical markers of the hypoxic response can identify malignancy in phaeochromocytomas and paragangliomas and optimize the detection of tumours with VHL germline mutations
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