AustralieFrV1, Main, Exploration, bibRecord, 002858

SDHB/SDHA immunohistochemistry in pheochromocytomas and paragangliomas: a multicenter interobserver variation analysis using virtual microscopy: a Multinational Study of the European Network for the Study of Adrenal Tumors (ENS@T).

Identifieur interne : 002858 ( Main/Exploration ); précédent : 002857; suivant : 002859

SDHB/SDHA immunohistochemistry in pheochromocytomas and paragangliomas: a multicenter interobserver variation analysis using virtual microscopy: a Multinational Study of the European Network for the Study of Adrenal Tumors (ENS@T).

Auteurs : Thomas G. Papathomas [Pays-Bas] ; Lindsey Oudijk [Pays-Bas] ; Alexandre Persu [Belgique] ; Anthony J. Gill [Australie] ; Francien Van Nederveen [Pays-Bas] ; Arthur S. Tischler [États-Unis] ; Frédérique Tissier [France] ; Marco Volante [Italie] ; Xavier Matias-Guiu [Espagne] ; Marcel Smid [Pays-Bas] ; Judith Favier [France] ; Elena Rapizzi [Italie] ; Rosella Libe [France] ; Maria Currás-Freixes [Espagne] ; Selda Aydin [Belgique] ; Thanh Huynh [États-Unis] ; Urs Lichtenauer [Allemagne] ; Anouk Van Berkel [Pays-Bas] ; Letizia Canu [Italie] ; Rita Domingues [Portugal] ; Roderick J. Clifton-Bligh [Australie] ; Magdalena Bialas [Pologne] ; Miikka Vikkula [Belgique] ; Gustavo Baretton [Allemagne] ; Mauro Papotti [Italie] ; Gabriella Nesi [Italie] ; Cécile Badoual [France] ; Karel Pacak [États-Unis] ; Graeme Eisenhofer [Allemagne] ; Henri J. Timmers [Pays-Bas] ; Felix Beuschlein [Allemagne] ; Jérôme Bertherat [France] ; Massimo Mannelli [Italie] ; Mercedes Robledo [Espagne] ; Anne-Paule Gimenez-Roqueplo [France] ; Winand Nm Dinjens [Pays-Bas] ; Esther Korpershoek [Pays-Bas] ; Ronald R. De Krijger [Pays-Bas]

Source :

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc [ 1530-0285 ] ; 2015.

RBID : pubmed:25720320

Descripteurs français

English descriptors

KwdEn :
- Adrenal Gland Neoplasms (genetics), Biomarkers, Tumor (analysis), Biomarkers, Tumor (genetics), Electron Transport Complex II (analysis), Electron Transport Complex II (genetics), Humans, Immunohistochemistry (standards), Microscopy (methods), Mutation, Observer Variation, Paraganglioma (genetics), Pheochromocytoma (genetics), Succinate Dehydrogenase (analysis), Succinate Dehydrogenase (genetics), Telepathology (methods).
MESH :
- chemical , analysis : Biomarkers, Tumor, Electron Transport Complex II, Succinate Dehydrogenase.
- genetics : Adrenal Gland Neoplasms, Biomarkers, Tumor, Electron Transport Complex II, Paraganglioma, Pheochromocytoma, Succinate Dehydrogenase.
- methods : Microscopy, Telepathology.
- standards : Immunohistochemistry.
- Humans, Mutation, Observer Variation.

Abstract

Despite the established role of SDHB/SDHA immunohistochemistry as a valuable tool to identify patients at risk for familial succinate dehydrogenase-related pheochromocytoma/paraganglioma syndromes, the reproducibility of the assessment methods has not as yet been determined. The aim of this study was to investigate interobserver variability among seven expert endocrine pathologists using a web-based virtual microscopy approach in a large multicenter pheochromocytoma/paraganglioma cohort (n=351): (1) 73 SDH mutated, (2) 105 non-SDH mutated, (3) 128 samples without identified SDH-x mutations, and (4) 45 with incomplete SDH molecular genetic analysis. Substantial agreement among all the reviewers was observed either with a two-tiered classification (SDHB κ=0.7338; SDHA κ=0.6707) or a three-tiered classification approach (SDHB κ=0.6543; SDHA κ=0.7516). Consensus was achieved in 315 cases (89.74%) for SDHB immunohistochemistry and in 348 cases (99.15%) for SDHA immunohistochemistry. Among the concordant cases, 62 of 69 (~90%) SDHB-/C-/D-/AF2-mutated cases displayed SDHB immunonegativity and SDHA immunopositivity, 3 of 4 (75%) with SDHA mutations showed loss of SDHA/SDHB protein expression, whereas 98 of 105 (93%) non-SDH-x-mutated counterparts demonstrated retention of SDHA/SDHB protein expression. Two SDHD-mutated extra-adrenal paragangliomas were scored as SDHB immunopositive, whereas 9 of 128 (7%) tumors without identified SDH-x mutations, 6 of 37 (~16%) VHL-mutated, as well as 1 of 21 (~5%) NF1-mutated tumors were evaluated as SDHB immunonegative. Although 14 out of those 16 SDHB-immunonegative cases were nonmetastatic, an overall significant correlation between SDHB immunonegativity and malignancy was observed (P=0.00019). We conclude that SDHB/SDHA immunohistochemistry is a reliable tool to identify patients with SDH-x mutations with an additional value in the assessment of genetic variants of unknown significance. If SDH molecular genetic analysis fails to detect a mutation in SDHB-immunonegative tumor, SDHC promoter methylation and/or VHL/NF1 testing with the use of targeted next-generation sequencing is advisable.

DOI: 10.1038/modpathol.2015.41
PubMed: 25720320

Affiliations:

Le document en format XML

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<author><name sortKey="Tissier, Frederique" sort="Tissier, Frederique" uniqKey="Tissier F" first="Frédérique" last="Tissier">Frédérique Tissier</name>
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<wicri:regionArea>1] Institut National de la Santé et de la Recherche Médicale U1016, Institut Cochin, Centre National de la Recherche Scientifique UMR8104, Université Paris Descartes, Sorbonne Paris Cité, Rare Adrenal Cancer Network COMETE, Paris, France [2] Department of Pathology, Hôpital Pitié-Salpêtrière, Université Pierre et Marie Curie, Paris</wicri:regionArea>
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<country xml:lang="fr">Espagne</country>
<wicri:regionArea>Department of Pathology and Molecular Genetics and Research Laboratory, Hospital Universitari Arnau de Vilanova, IRBLLEIDA, University of Lleida, Lleida</wicri:regionArea>
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</affiliation>
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<author><name sortKey="Smid, Marcel" sort="Smid, Marcel" uniqKey="Smid M" first="Marcel" last="Smid">Marcel Smid</name>
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<country xml:lang="fr">Pays-Bas</country>
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<author><name sortKey="Favier, Judith" sort="Favier, Judith" uniqKey="Favier J" first="Judith" last="Favier">Judith Favier</name>
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<wicri:regionArea>1] Paris-Centre de Recherche Cardiovasculaire (PARCC), Inserm UMR970, Hôpital Européen Georges Pompidou, Paris, France [2] Université Paris Descartes, Faculté de Médecine, Paris Cité Sorbonne</wicri:regionArea>
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<author><name sortKey="Rapizzi, Elena" sort="Rapizzi, Elena" uniqKey="Rapizzi E" first="Elena" last="Rapizzi">Elena Rapizzi</name>
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<author><name sortKey="Libe, Rosella" sort="Libe, Rosella" uniqKey="Libe R" first="Rosella" last="Libe">Rosella Libe</name>
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<country xml:lang="fr">France</country>
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<author><name sortKey="Curras Freixes, Maria" sort="Curras Freixes, Maria" uniqKey="Curras Freixes M" first="Maria" last="Currás-Freixes">Maria Currás-Freixes</name>
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<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Department of Pathology, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Institut de Recherche Expérimentale et Clinique, Brussels</wicri:regionArea>
<placeName><settlement type="city">Bruxelles</settlement>
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<author><name sortKey="Huynh, Thanh" sort="Huynh, Thanh" uniqKey="Huynh T" first="Thanh" last="Huynh">Thanh Huynh</name>
<affiliation wicri:level="2"><nlm:affiliation>Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD</wicri:regionArea>
<placeName><region type="state">Maryland</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Lichtenauer, Urs" sort="Lichtenauer, Urs" uniqKey="Lichtenauer U" first="Urs" last="Lichtenauer">Urs Lichtenauer</name>
<affiliation wicri:level="4"><nlm:affiliation>Endocrine Research Unit, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany.</nlm:affiliation>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Endocrine Research Unit, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich</wicri:regionArea>
<placeName><region type="land" nuts="1">Bavière</region>
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</placeName>
<orgName type="university">Université Louis-et-Maximilien de Munich</orgName>
</affiliation>
</author>
<author><name sortKey="Van Berkel, Anouk" sort="Van Berkel, Anouk" uniqKey="Van Berkel A" first="Anouk" last="Van Berkel">Anouk Van Berkel</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Internal Medicine, Section of Endocrinology, Radboud University Medical Centre, Nijmegen, The Netherlands.</nlm:affiliation>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>Department of Internal Medicine, Section of Endocrinology, Radboud University Medical Centre, Nijmegen</wicri:regionArea>
<placeName><settlement type="city">Nimègue</settlement>
<region type="province" nuts="2">Gueldre</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Canu, Letizia" sort="Canu, Letizia" uniqKey="Canu L" first="Letizia" last="Canu">Letizia Canu</name>
<affiliation wicri:level="1"><nlm:affiliation>Endocrinology Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.</nlm:affiliation>
<country xml:lang="fr">Italie</country>
<wicri:regionArea>Endocrinology Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence</wicri:regionArea>
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</affiliation>
</author>
<author><name sortKey="Domingues, Rita" sort="Domingues, Rita" uniqKey="Domingues R" first="Rita" last="Domingues">Rita Domingues</name>
<affiliation wicri:level="1"><nlm:affiliation>Unidade de Investigação em Patobiologia Molecular (UIPM), Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisbon, Portugal.</nlm:affiliation>
<country xml:lang="fr">Portugal</country>
<wicri:regionArea>Unidade de Investigação em Patobiologia Molecular (UIPM), Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisbon</wicri:regionArea>
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</affiliation>
</author>
<author><name sortKey="Clifton Bligh, Roderick J" sort="Clifton Bligh, Roderick J" uniqKey="Clifton Bligh R" first="Roderick J" last="Clifton-Bligh">Roderick J. Clifton-Bligh</name>
<affiliation wicri:level="4"><nlm:affiliation>Cancer Genetics, Kolling Institute of Medical Research, Royal North Shore Hospital, University of Sydney, Sydney, NSW, Australia.</nlm:affiliation>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Cancer Genetics, Kolling Institute of Medical Research, Royal North Shore Hospital, University of Sydney, Sydney, NSW</wicri:regionArea>
<orgName type="university">Université de Sydney</orgName>
<placeName><settlement type="city">Sydney</settlement>
<region type="état">Nouvelle-Galles du Sud</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Bialas, Magdalena" sort="Bialas, Magdalena" uniqKey="Bialas M" first="Magdalena" last="Bialas">Magdalena Bialas</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Pathomorphology, Jagiellonian University Medical College, Krakow, Poland.</nlm:affiliation>
<country xml:lang="fr">Pologne</country>
<wicri:regionArea>Department of Pathomorphology, Jagiellonian University Medical College, Krakow</wicri:regionArea>
<wicri:noRegion>Krakow</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Vikkula, Miikka" sort="Vikkula, Miikka" uniqKey="Vikkula M" first="Miikka" last="Vikkula">Miikka Vikkula</name>
<affiliation wicri:level="4"><nlm:affiliation>Laboratory of Human Molecular Genetics, de Duve Institute, Université Catholique de Louvain, Brussels, Belgium.</nlm:affiliation>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Laboratory of Human Molecular Genetics, de Duve Institute, Université Catholique de Louvain, Brussels</wicri:regionArea>
<placeName><settlement type="city">Bruxelles</settlement>
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</author>
<author><name sortKey="Baretton, Gustavo" sort="Baretton, Gustavo" uniqKey="Baretton G" first="Gustavo" last="Baretton">Gustavo Baretton</name>
<affiliation wicri:level="4"><nlm:affiliation>Department of Pathology, Technische Universität Dresden, Dresden, Germany.</nlm:affiliation>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Department of Pathology, Technische Universität Dresden, Dresden</wicri:regionArea>
<placeName><region type="land" nuts="1">Saxe (Land)</region>
<region type="district" nuts="2">District de Dresde</region>
<settlement type="city">Dresde</settlement>
<settlement type="city">Dresde</settlement>
</placeName>
<orgName type="university">Université technique de Dresde</orgName>
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</author>
<author><name sortKey="Papotti, Mauro" sort="Papotti, Mauro" uniqKey="Papotti M" first="Mauro" last="Papotti">Mauro Papotti</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Oncology, University of Turin at San Luigi Hospital, Turin, Italy.</nlm:affiliation>
<country xml:lang="fr">Italie</country>
<wicri:regionArea>Department of Oncology, University of Turin at San Luigi Hospital, Turin</wicri:regionArea>
<placeName><settlement type="city">Turin</settlement>
<region type="région" nuts="2">Piémont</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Nesi, Gabriella" sort="Nesi, Gabriella" uniqKey="Nesi G" first="Gabriella" last="Nesi">Gabriella Nesi</name>
<affiliation wicri:level="1"><nlm:affiliation>Division of Pathological Anatomy, University of Florence, Florence, Italy.</nlm:affiliation>
<country xml:lang="fr">Italie</country>
<wicri:regionArea>Division of Pathological Anatomy, University of Florence, Florence</wicri:regionArea>
<wicri:noRegion>Florence</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Badoual, Cecile" sort="Badoual, Cecile" uniqKey="Badoual C" first="Cécile" last="Badoual">Cécile Badoual</name>
<affiliation wicri:level="4"><nlm:affiliation>1] Paris-Centre de Recherche Cardiovasculaire (PARCC), Inserm UMR970, Hôpital Européen Georges Pompidou, Paris, France [2] Université Paris Descartes, Faculté de Médecine, Paris Cité Sorbonne, France [3] Service d'Anatomie Pathologique, Hôpital Européen Georges-Pompidou, Assistance Publique Hôpitaux de Paris (AP-HP), Paris, France.</nlm:affiliation>
<country xml:lang="fr">France</country>
<wicri:regionArea>1] Paris-Centre de Recherche Cardiovasculaire (PARCC), Inserm UMR970, Hôpital Européen Georges Pompidou, Paris, France [2] Université Paris Descartes, Faculté de Médecine, Paris Cité Sorbonne, France [3] Service d'Anatomie Pathologique, Hôpital Européen Georges-Pompidou, Assistance Publique Hôpitaux de Paris (AP-HP), Paris</wicri:regionArea>
<placeName><region type="region">Île-de-France</region>
<region type="old region">Île-de-France</region>
<settlement type="city">Paris</settlement>
<settlement type="city">Paris</settlement>
</placeName>
<orgName type="university">Université Paris-Descartes</orgName>
</affiliation>
</author>
<author><name sortKey="Pacak, Karel" sort="Pacak, Karel" uniqKey="Pacak K" first="Karel" last="Pacak">Karel Pacak</name>
<affiliation wicri:level="2"><nlm:affiliation>Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD</wicri:regionArea>
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</placeName>
</affiliation>
</author>
<author><name sortKey="Eisenhofer, Graeme" sort="Eisenhofer, Graeme" uniqKey="Eisenhofer G" first="Graeme" last="Eisenhofer">Graeme Eisenhofer</name>
<affiliation wicri:level="3"><nlm:affiliation>Institute of Clinical Chemistry and Laboratory Medicine and Department of Medicine III, University Hospital, Technische Universität Dresden, Dresden, Germany.</nlm:affiliation>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Institute of Clinical Chemistry and Laboratory Medicine and Department of Medicine III, University Hospital, Technische Universität Dresden, Dresden</wicri:regionArea>
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<settlement type="city">Dresde</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Timmers, Henri J" sort="Timmers, Henri J" uniqKey="Timmers H" first="Henri J" last="Timmers">Henri J. Timmers</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Internal Medicine, Section of Endocrinology, Radboud University Medical Centre, Nijmegen, The Netherlands.</nlm:affiliation>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>Department of Internal Medicine, Section of Endocrinology, Radboud University Medical Centre, Nijmegen</wicri:regionArea>
<placeName><settlement type="city">Nimègue</settlement>
<region type="province" nuts="2">Gueldre</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Beuschlein, Felix" sort="Beuschlein, Felix" uniqKey="Beuschlein F" first="Felix" last="Beuschlein">Felix Beuschlein</name>
<affiliation wicri:level="4"><nlm:affiliation>Endocrine Research Unit, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany.</nlm:affiliation>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Endocrine Research Unit, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich</wicri:regionArea>
<placeName><region type="land" nuts="1">Bavière</region>
<region type="district" nuts="2">District de Haute-Bavière</region>
<settlement type="city">Munich</settlement>
<settlement type="city">Munich</settlement>
</placeName>
<orgName type="university">Université Louis-et-Maximilien de Munich</orgName>
</affiliation>
</author>
<author><name sortKey="Bertherat, Jerome" sort="Bertherat, Jerome" uniqKey="Bertherat J" first="Jérôme" last="Bertherat">Jérôme Bertherat</name>
<affiliation wicri:level="4"><nlm:affiliation>1] Institut Cochin, Université Paris Descartes, INSERM U1016, CNRS UMR8104, Paris, France [2] Department of Endocrinology, Referral Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France.</nlm:affiliation>
<country xml:lang="fr">France</country>
<wicri:regionArea>1] Institut Cochin, Université Paris Descartes, INSERM U1016, CNRS UMR8104, Paris, France [2] Department of Endocrinology, Referral Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris</wicri:regionArea>
<placeName><region type="region">Île-de-France</region>
<region type="old region">Île-de-France</region>
<settlement type="city">Paris</settlement>
<settlement type="city">Paris</settlement>
</placeName>
<orgName type="university">Université Paris-Descartes</orgName>
</affiliation>
</author>
<author><name sortKey="Mannelli, Massimo" sort="Mannelli, Massimo" uniqKey="Mannelli M" first="Massimo" last="Mannelli">Massimo Mannelli</name>
<affiliation wicri:level="1"><nlm:affiliation>1] Endocrinology Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy [2] Istituto Toscano Tumori (ITT), Florence, Italy.</nlm:affiliation>
<country xml:lang="fr">Italie</country>
<wicri:regionArea>1] Endocrinology Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy [2] Istituto Toscano Tumori (ITT), Florence</wicri:regionArea>
<wicri:noRegion>Florence</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Robledo, Mercedes" sort="Robledo, Mercedes" uniqKey="Robledo M" first="Mercedes" last="Robledo">Mercedes Robledo</name>
<affiliation wicri:level="3"><nlm:affiliation>1] Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain [2] Centre for Biomedical Network Research on Rare Diseases (CIBERER), Madrid, Spain.</nlm:affiliation>
<country xml:lang="fr">Espagne</country>
<wicri:regionArea>1] Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain [2] Centre for Biomedical Network Research on Rare Diseases (CIBERER), Madrid</wicri:regionArea>
<placeName><settlement type="city">Madrid</settlement>
<region nuts="2" type="region">Communauté de Madrid</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Gimenez Roqueplo, Anne Paule" sort="Gimenez Roqueplo, Anne Paule" uniqKey="Gimenez Roqueplo A" first="Anne-Paule" last="Gimenez-Roqueplo">Anne-Paule Gimenez-Roqueplo</name>
<affiliation wicri:level="4"><nlm:affiliation>1] Paris-Centre de Recherche Cardiovasculaire (PARCC), Inserm UMR970, Hôpital Européen Georges Pompidou, Paris, France [2] Université Paris Descartes, Faculté de Médecine, Paris Cité Sorbonne, France.</nlm:affiliation>
<country xml:lang="fr">France</country>
<wicri:regionArea>1] Paris-Centre de Recherche Cardiovasculaire (PARCC), Inserm UMR970, Hôpital Européen Georges Pompidou, Paris, France [2] Université Paris Descartes, Faculté de Médecine, Paris Cité Sorbonne</wicri:regionArea>
<wicri:noRegion>Paris Cité Sorbonne</wicri:noRegion>
<orgName type="university">Université Paris-Descartes</orgName>
<placeName><settlement type="city">Paris</settlement>
<region type="region" nuts="2">Île-de-France</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Dinjens, Winand Nm" sort="Dinjens, Winand Nm" uniqKey="Dinjens W" first="Winand Nm" last="Dinjens">Winand Nm Dinjens</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Pathology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands.</nlm:affiliation>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>Department of Pathology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam</wicri:regionArea>
<placeName><settlement type="city">Rotterdam</settlement>
<region nuts="2" type="province">Hollande-Méridionale</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Korpershoek, Esther" sort="Korpershoek, Esther" uniqKey="Korpershoek E" first="Esther" last="Korpershoek">Esther Korpershoek</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Pathology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands.</nlm:affiliation>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>Department of Pathology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam</wicri:regionArea>
<placeName><settlement type="city">Rotterdam</settlement>
<region nuts="2" type="province">Hollande-Méridionale</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="De Krijger, Ronald R" sort="De Krijger, Ronald R" uniqKey="De Krijger R" first="Ronald R" last="De Krijger">Ronald R. De Krijger</name>
<affiliation wicri:level="3"><nlm:affiliation>1] Department of Pathology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands [2] Department of Pathology, Reinier de Graaf Hospital, Delft, The Netherlands [3] Department of Pathology, University Medical Center Utrecht, Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands.</nlm:affiliation>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>1] Department of Pathology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands [2] Department of Pathology, Reinier de Graaf Hospital, Delft, The Netherlands [3] Department of Pathology, University Medical Center Utrecht, Princess Maxima Center for Pediatric Oncology, Utrecht</wicri:regionArea>
<placeName><settlement type="city">Utrecht</settlement>
<region nuts="2" type="province">Utrecht (province)</region>
</placeName>
</affiliation>
</author>
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<sourceDesc><biblStruct><analytic><title xml:lang="en">SDHB/SDHA immunohistochemistry in pheochromocytomas and paragangliomas: a multicenter interobserver variation analysis using virtual microscopy: a Multinational Study of the European Network for the Study of Adrenal Tumors (ENS@T).</title>
<author><name sortKey="Papathomas, Thomas G" sort="Papathomas, Thomas G" uniqKey="Papathomas T" first="Thomas G" last="Papathomas">Thomas G. Papathomas</name>
<affiliation wicri:level="3"><nlm:affiliation>1] Department of Histopathology, King's College Hospital, London, UK [2] Department of Pathology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands.</nlm:affiliation>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>1] Department of Histopathology, King's College Hospital, London, UK [2] Department of Pathology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam</wicri:regionArea>
<placeName><settlement type="city">Rotterdam</settlement>
<region nuts="2" type="province">Hollande-Méridionale</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Oudijk, Lindsey" sort="Oudijk, Lindsey" uniqKey="Oudijk L" first="Lindsey" last="Oudijk">Lindsey Oudijk</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Pathology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands.</nlm:affiliation>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>Department of Pathology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam</wicri:regionArea>
<placeName><settlement type="city">Rotterdam</settlement>
<region nuts="2" type="province">Hollande-Méridionale</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Persu, Alexandre" sort="Persu, Alexandre" uniqKey="Persu A" first="Alexandre" last="Persu">Alexandre Persu</name>
<affiliation wicri:level="3"><nlm:affiliation>Pole of Cardiovascular Research, Institut de Recherche Expérimentale et Clinique and Division of Cardiology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.</nlm:affiliation>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Pole of Cardiovascular Research, Institut de Recherche Expérimentale et Clinique and Division of Cardiology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels</wicri:regionArea>
<placeName><settlement type="city">Bruxelles</settlement>
<region nuts="2">Région de Bruxelles-Capitale</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Gill, Anthony J" sort="Gill, Anthony J" uniqKey="Gill A" first="Anthony J" last="Gill">Anthony J. Gill</name>
<affiliation wicri:level="4"><nlm:affiliation>1] Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards, NSW, Australia [2] Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, University of Sydney, Sydney, NSW, Australia.</nlm:affiliation>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>1] Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards, NSW, Australia [2] Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, University of Sydney, Sydney, NSW</wicri:regionArea>
<orgName type="university">Université de Sydney</orgName>
<placeName><settlement type="city">Sydney</settlement>
<region type="état">Nouvelle-Galles du Sud</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Van Nederveen, Francien" sort="Van Nederveen, Francien" uniqKey="Van Nederveen F" first="Francien" last="Van Nederveen">Francien Van Nederveen</name>
<affiliation wicri:level="1"><nlm:affiliation>Laboratory for Pathology, PAL Dordrecht, Dordrecht, The Netherlands.</nlm:affiliation>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>Laboratory for Pathology, PAL Dordrecht, Dordrecht</wicri:regionArea>
<wicri:noRegion>Dordrecht</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Tischler, Arthur S" sort="Tischler, Arthur S" uniqKey="Tischler A" first="Arthur S" last="Tischler">Arthur S. Tischler</name>
<affiliation wicri:level="2"><nlm:affiliation>Department of Pathology and Laboratory Medicine, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Pathology and Laboratory Medicine, Tufts Medical Center, Tufts University School of Medicine, Boston, MA</wicri:regionArea>
<placeName><region type="state">Massachusetts</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Tissier, Frederique" sort="Tissier, Frederique" uniqKey="Tissier F" first="Frédérique" last="Tissier">Frédérique Tissier</name>
<affiliation wicri:level="4"><nlm:affiliation>1] Institut National de la Santé et de la Recherche Médicale U1016, Institut Cochin, Centre National de la Recherche Scientifique UMR8104, Université Paris Descartes, Sorbonne Paris Cité, Rare Adrenal Cancer Network COMETE, Paris, France [2] Department of Pathology, Hôpital Pitié-Salpêtrière, Université Pierre et Marie Curie, Paris, France.</nlm:affiliation>
<country xml:lang="fr">France</country>
<wicri:regionArea>1] Institut National de la Santé et de la Recherche Médicale U1016, Institut Cochin, Centre National de la Recherche Scientifique UMR8104, Université Paris Descartes, Sorbonne Paris Cité, Rare Adrenal Cancer Network COMETE, Paris, France [2] Department of Pathology, Hôpital Pitié-Salpêtrière, Université Pierre et Marie Curie, Paris</wicri:regionArea>
<placeName><region type="region">Île-de-France</region>
<region type="old region">Île-de-France</region>
<settlement type="city">Paris</settlement>
<settlement type="city">Paris</settlement>
</placeName>
<orgName type="university">Université Paris-Descartes</orgName>
</affiliation>
</author>
<author><name sortKey="Volante, Marco" sort="Volante, Marco" uniqKey="Volante M" first="Marco" last="Volante">Marco Volante</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Oncology, University of Turin at San Luigi Hospital, Turin, Italy.</nlm:affiliation>
<country xml:lang="fr">Italie</country>
<wicri:regionArea>Department of Oncology, University of Turin at San Luigi Hospital, Turin</wicri:regionArea>
<placeName><settlement type="city">Turin</settlement>
<region type="région" nuts="2">Piémont</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Matias Guiu, Xavier" sort="Matias Guiu, Xavier" uniqKey="Matias Guiu X" first="Xavier" last="Matias-Guiu">Xavier Matias-Guiu</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Pathology and Molecular Genetics and Research Laboratory, Hospital Universitari Arnau de Vilanova, IRBLLEIDA, University of Lleida, Lleida, Spain.</nlm:affiliation>
<country xml:lang="fr">Espagne</country>
<wicri:regionArea>Department of Pathology and Molecular Genetics and Research Laboratory, Hospital Universitari Arnau de Vilanova, IRBLLEIDA, University of Lleida, Lleida</wicri:regionArea>
<wicri:noRegion>Lleida</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Smid, Marcel" sort="Smid, Marcel" uniqKey="Smid M" first="Marcel" last="Smid">Marcel Smid</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands.</nlm:affiliation>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam</wicri:regionArea>
<placeName><settlement type="city">Rotterdam</settlement>
<region nuts="2" type="province">Hollande-Méridionale</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Favier, Judith" sort="Favier, Judith" uniqKey="Favier J" first="Judith" last="Favier">Judith Favier</name>
<affiliation wicri:level="4"><nlm:affiliation>1] Paris-Centre de Recherche Cardiovasculaire (PARCC), Inserm UMR970, Hôpital Européen Georges Pompidou, Paris, France [2] Université Paris Descartes, Faculté de Médecine, Paris Cité Sorbonne, France.</nlm:affiliation>
<country xml:lang="fr">France</country>
<wicri:regionArea>1] Paris-Centre de Recherche Cardiovasculaire (PARCC), Inserm UMR970, Hôpital Européen Georges Pompidou, Paris, France [2] Université Paris Descartes, Faculté de Médecine, Paris Cité Sorbonne</wicri:regionArea>
<wicri:noRegion>Paris Cité Sorbonne</wicri:noRegion>
<orgName type="university">Université Paris-Descartes</orgName>
<placeName><settlement type="city">Paris</settlement>
<region type="region" nuts="2">Île-de-France</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Rapizzi, Elena" sort="Rapizzi, Elena" uniqKey="Rapizzi E" first="Elena" last="Rapizzi">Elena Rapizzi</name>
<affiliation wicri:level="1"><nlm:affiliation>Endocrinology Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.</nlm:affiliation>
<country xml:lang="fr">Italie</country>
<wicri:regionArea>Endocrinology Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence</wicri:regionArea>
<wicri:noRegion>Florence</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Libe, Rosella" sort="Libe, Rosella" uniqKey="Libe R" first="Rosella" last="Libe">Rosella Libe</name>
<affiliation wicri:level="4"><nlm:affiliation>Institut National de la Santé et de la Recherche Médicale U1016, Institut Cochin, Centre National de la Recherche Scientifique UMR8104, Université Paris Descartes, Sorbonne Paris Cité, Rare Adrenal Cancer Network COMETE, Paris, France.</nlm:affiliation>
<country xml:lang="fr">France</country>
<wicri:regionArea>Institut National de la Santé et de la Recherche Médicale U1016, Institut Cochin, Centre National de la Recherche Scientifique UMR8104, Université Paris Descartes, Sorbonne Paris Cité, Rare Adrenal Cancer Network COMETE, Paris</wicri:regionArea>
<placeName><region type="region">Île-de-France</region>
<region type="old region">Île-de-France</region>
<settlement type="city">Paris</settlement>
<settlement type="city">Paris</settlement>
</placeName>
<orgName type="university">Université Paris-Descartes</orgName>
</affiliation>
</author>
<author><name sortKey="Curras Freixes, Maria" sort="Curras Freixes, Maria" uniqKey="Curras Freixes M" first="Maria" last="Currás-Freixes">Maria Currás-Freixes</name>
<affiliation wicri:level="3"><nlm:affiliation>Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.</nlm:affiliation>
<country xml:lang="fr">Espagne</country>
<wicri:regionArea>Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid</wicri:regionArea>
<placeName><settlement type="city">Madrid</settlement>
<region nuts="2" type="region">Communauté de Madrid</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Aydin, Selda" sort="Aydin, Selda" uniqKey="Aydin S" first="Selda" last="Aydin">Selda Aydin</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Pathology, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Institut de Recherche Expérimentale et Clinique, Brussels, Belgium.</nlm:affiliation>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Department of Pathology, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Institut de Recherche Expérimentale et Clinique, Brussels</wicri:regionArea>
<placeName><settlement type="city">Bruxelles</settlement>
<region nuts="2">Région de Bruxelles-Capitale</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Huynh, Thanh" sort="Huynh, Thanh" uniqKey="Huynh T" first="Thanh" last="Huynh">Thanh Huynh</name>
<affiliation wicri:level="2"><nlm:affiliation>Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD</wicri:regionArea>
<placeName><region type="state">Maryland</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Lichtenauer, Urs" sort="Lichtenauer, Urs" uniqKey="Lichtenauer U" first="Urs" last="Lichtenauer">Urs Lichtenauer</name>
<affiliation wicri:level="4"><nlm:affiliation>Endocrine Research Unit, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany.</nlm:affiliation>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Endocrine Research Unit, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich</wicri:regionArea>
<placeName><region type="land" nuts="1">Bavière</region>
<region type="district" nuts="2">District de Haute-Bavière</region>
<settlement type="city">Munich</settlement>
<settlement type="city">Munich</settlement>
</placeName>
<orgName type="university">Université Louis-et-Maximilien de Munich</orgName>
</affiliation>
</author>
<author><name sortKey="Van Berkel, Anouk" sort="Van Berkel, Anouk" uniqKey="Van Berkel A" first="Anouk" last="Van Berkel">Anouk Van Berkel</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Internal Medicine, Section of Endocrinology, Radboud University Medical Centre, Nijmegen, The Netherlands.</nlm:affiliation>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>Department of Internal Medicine, Section of Endocrinology, Radboud University Medical Centre, Nijmegen</wicri:regionArea>
<placeName><settlement type="city">Nimègue</settlement>
<region type="province" nuts="2">Gueldre</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Canu, Letizia" sort="Canu, Letizia" uniqKey="Canu L" first="Letizia" last="Canu">Letizia Canu</name>
<affiliation wicri:level="1"><nlm:affiliation>Endocrinology Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.</nlm:affiliation>
<country xml:lang="fr">Italie</country>
<wicri:regionArea>Endocrinology Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence</wicri:regionArea>
<wicri:noRegion>Florence</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Domingues, Rita" sort="Domingues, Rita" uniqKey="Domingues R" first="Rita" last="Domingues">Rita Domingues</name>
<affiliation wicri:level="1"><nlm:affiliation>Unidade de Investigação em Patobiologia Molecular (UIPM), Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisbon, Portugal.</nlm:affiliation>
<country xml:lang="fr">Portugal</country>
<wicri:regionArea>Unidade de Investigação em Patobiologia Molecular (UIPM), Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisbon</wicri:regionArea>
<wicri:noRegion>Lisbon</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Clifton Bligh, Roderick J" sort="Clifton Bligh, Roderick J" uniqKey="Clifton Bligh R" first="Roderick J" last="Clifton-Bligh">Roderick J. Clifton-Bligh</name>
<affiliation wicri:level="4"><nlm:affiliation>Cancer Genetics, Kolling Institute of Medical Research, Royal North Shore Hospital, University of Sydney, Sydney, NSW, Australia.</nlm:affiliation>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Cancer Genetics, Kolling Institute of Medical Research, Royal North Shore Hospital, University of Sydney, Sydney, NSW</wicri:regionArea>
<orgName type="university">Université de Sydney</orgName>
<placeName><settlement type="city">Sydney</settlement>
<region type="état">Nouvelle-Galles du Sud</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Bialas, Magdalena" sort="Bialas, Magdalena" uniqKey="Bialas M" first="Magdalena" last="Bialas">Magdalena Bialas</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Pathomorphology, Jagiellonian University Medical College, Krakow, Poland.</nlm:affiliation>
<country xml:lang="fr">Pologne</country>
<wicri:regionArea>Department of Pathomorphology, Jagiellonian University Medical College, Krakow</wicri:regionArea>
<wicri:noRegion>Krakow</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Vikkula, Miikka" sort="Vikkula, Miikka" uniqKey="Vikkula M" first="Miikka" last="Vikkula">Miikka Vikkula</name>
<affiliation wicri:level="4"><nlm:affiliation>Laboratory of Human Molecular Genetics, de Duve Institute, Université Catholique de Louvain, Brussels, Belgium.</nlm:affiliation>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Laboratory of Human Molecular Genetics, de Duve Institute, Université Catholique de Louvain, Brussels</wicri:regionArea>
<placeName><settlement type="city">Bruxelles</settlement>
<region nuts="2">Région de Bruxelles-Capitale</region>
<settlement type="city">Louvain-la-Neuve</settlement>
</placeName>
<orgName type="university">Université catholique de Louvain</orgName>
</affiliation>
</author>
<author><name sortKey="Baretton, Gustavo" sort="Baretton, Gustavo" uniqKey="Baretton G" first="Gustavo" last="Baretton">Gustavo Baretton</name>
<affiliation wicri:level="4"><nlm:affiliation>Department of Pathology, Technische Universität Dresden, Dresden, Germany.</nlm:affiliation>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Department of Pathology, Technische Universität Dresden, Dresden</wicri:regionArea>
<placeName><region type="land" nuts="1">Saxe (Land)</region>
<region type="district" nuts="2">District de Dresde</region>
<settlement type="city">Dresde</settlement>
<settlement type="city">Dresde</settlement>
</placeName>
<orgName type="university">Université technique de Dresde</orgName>
</affiliation>
</author>
<author><name sortKey="Papotti, Mauro" sort="Papotti, Mauro" uniqKey="Papotti M" first="Mauro" last="Papotti">Mauro Papotti</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Oncology, University of Turin at San Luigi Hospital, Turin, Italy.</nlm:affiliation>
<country xml:lang="fr">Italie</country>
<wicri:regionArea>Department of Oncology, University of Turin at San Luigi Hospital, Turin</wicri:regionArea>
<placeName><settlement type="city">Turin</settlement>
<region type="région" nuts="2">Piémont</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Nesi, Gabriella" sort="Nesi, Gabriella" uniqKey="Nesi G" first="Gabriella" last="Nesi">Gabriella Nesi</name>
<affiliation wicri:level="1"><nlm:affiliation>Division of Pathological Anatomy, University of Florence, Florence, Italy.</nlm:affiliation>
<country xml:lang="fr">Italie</country>
<wicri:regionArea>Division of Pathological Anatomy, University of Florence, Florence</wicri:regionArea>
<wicri:noRegion>Florence</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Badoual, Cecile" sort="Badoual, Cecile" uniqKey="Badoual C" first="Cécile" last="Badoual">Cécile Badoual</name>
<affiliation wicri:level="4"><nlm:affiliation>1] Paris-Centre de Recherche Cardiovasculaire (PARCC), Inserm UMR970, Hôpital Européen Georges Pompidou, Paris, France [2] Université Paris Descartes, Faculté de Médecine, Paris Cité Sorbonne, France [3] Service d'Anatomie Pathologique, Hôpital Européen Georges-Pompidou, Assistance Publique Hôpitaux de Paris (AP-HP), Paris, France.</nlm:affiliation>
<country xml:lang="fr">France</country>
<wicri:regionArea>1] Paris-Centre de Recherche Cardiovasculaire (PARCC), Inserm UMR970, Hôpital Européen Georges Pompidou, Paris, France [2] Université Paris Descartes, Faculté de Médecine, Paris Cité Sorbonne, France [3] Service d'Anatomie Pathologique, Hôpital Européen Georges-Pompidou, Assistance Publique Hôpitaux de Paris (AP-HP), Paris</wicri:regionArea>
<placeName><region type="region">Île-de-France</region>
<region type="old region">Île-de-France</region>
<settlement type="city">Paris</settlement>
<settlement type="city">Paris</settlement>
</placeName>
<orgName type="university">Université Paris-Descartes</orgName>
</affiliation>
</author>
<author><name sortKey="Pacak, Karel" sort="Pacak, Karel" uniqKey="Pacak K" first="Karel" last="Pacak">Karel Pacak</name>
<affiliation wicri:level="2"><nlm:affiliation>Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD</wicri:regionArea>
<placeName><region type="state">Maryland</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Eisenhofer, Graeme" sort="Eisenhofer, Graeme" uniqKey="Eisenhofer G" first="Graeme" last="Eisenhofer">Graeme Eisenhofer</name>
<affiliation wicri:level="3"><nlm:affiliation>Institute of Clinical Chemistry and Laboratory Medicine and Department of Medicine III, University Hospital, Technische Universität Dresden, Dresden, Germany.</nlm:affiliation>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Institute of Clinical Chemistry and Laboratory Medicine and Department of Medicine III, University Hospital, Technische Universität Dresden, Dresden</wicri:regionArea>
<placeName><region type="land" nuts="1">Saxe (Land)</region>
<region type="district" nuts="2">District de Dresde</region>
<settlement type="city">Dresde</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Timmers, Henri J" sort="Timmers, Henri J" uniqKey="Timmers H" first="Henri J" last="Timmers">Henri J. Timmers</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Internal Medicine, Section of Endocrinology, Radboud University Medical Centre, Nijmegen, The Netherlands.</nlm:affiliation>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>Department of Internal Medicine, Section of Endocrinology, Radboud University Medical Centre, Nijmegen</wicri:regionArea>
<placeName><settlement type="city">Nimègue</settlement>
<region type="province" nuts="2">Gueldre</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Beuschlein, Felix" sort="Beuschlein, Felix" uniqKey="Beuschlein F" first="Felix" last="Beuschlein">Felix Beuschlein</name>
<affiliation wicri:level="4"><nlm:affiliation>Endocrine Research Unit, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany.</nlm:affiliation>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Endocrine Research Unit, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich</wicri:regionArea>
<placeName><region type="land" nuts="1">Bavière</region>
<region type="district" nuts="2">District de Haute-Bavière</region>
<settlement type="city">Munich</settlement>
<settlement type="city">Munich</settlement>
</placeName>
<orgName type="university">Université Louis-et-Maximilien de Munich</orgName>
</affiliation>
</author>
<author><name sortKey="Bertherat, Jerome" sort="Bertherat, Jerome" uniqKey="Bertherat J" first="Jérôme" last="Bertherat">Jérôme Bertherat</name>
<affiliation wicri:level="4"><nlm:affiliation>1] Institut Cochin, Université Paris Descartes, INSERM U1016, CNRS UMR8104, Paris, France [2] Department of Endocrinology, Referral Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France.</nlm:affiliation>
<country xml:lang="fr">France</country>
<wicri:regionArea>1] Institut Cochin, Université Paris Descartes, INSERM U1016, CNRS UMR8104, Paris, France [2] Department of Endocrinology, Referral Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris</wicri:regionArea>
<placeName><region type="region">Île-de-France</region>
<region type="old region">Île-de-France</region>
<settlement type="city">Paris</settlement>
<settlement type="city">Paris</settlement>
</placeName>
<orgName type="university">Université Paris-Descartes</orgName>
</affiliation>
</author>
<author><name sortKey="Mannelli, Massimo" sort="Mannelli, Massimo" uniqKey="Mannelli M" first="Massimo" last="Mannelli">Massimo Mannelli</name>
<affiliation wicri:level="1"><nlm:affiliation>1] Endocrinology Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy [2] Istituto Toscano Tumori (ITT), Florence, Italy.</nlm:affiliation>
<country xml:lang="fr">Italie</country>
<wicri:regionArea>1] Endocrinology Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy [2] Istituto Toscano Tumori (ITT), Florence</wicri:regionArea>
<wicri:noRegion>Florence</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Robledo, Mercedes" sort="Robledo, Mercedes" uniqKey="Robledo M" first="Mercedes" last="Robledo">Mercedes Robledo</name>
<affiliation wicri:level="3"><nlm:affiliation>1] Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain [2] Centre for Biomedical Network Research on Rare Diseases (CIBERER), Madrid, Spain.</nlm:affiliation>
<country xml:lang="fr">Espagne</country>
<wicri:regionArea>1] Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain [2] Centre for Biomedical Network Research on Rare Diseases (CIBERER), Madrid</wicri:regionArea>
<placeName><settlement type="city">Madrid</settlement>
<region nuts="2" type="region">Communauté de Madrid</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Gimenez Roqueplo, Anne Paule" sort="Gimenez Roqueplo, Anne Paule" uniqKey="Gimenez Roqueplo A" first="Anne-Paule" last="Gimenez-Roqueplo">Anne-Paule Gimenez-Roqueplo</name>
<affiliation wicri:level="4"><nlm:affiliation>1] Paris-Centre de Recherche Cardiovasculaire (PARCC), Inserm UMR970, Hôpital Européen Georges Pompidou, Paris, France [2] Université Paris Descartes, Faculté de Médecine, Paris Cité Sorbonne, France.</nlm:affiliation>
<country xml:lang="fr">France</country>
<wicri:regionArea>1] Paris-Centre de Recherche Cardiovasculaire (PARCC), Inserm UMR970, Hôpital Européen Georges Pompidou, Paris, France [2] Université Paris Descartes, Faculté de Médecine, Paris Cité Sorbonne</wicri:regionArea>
<wicri:noRegion>Paris Cité Sorbonne</wicri:noRegion>
<orgName type="university">Université Paris-Descartes</orgName>
<placeName><settlement type="city">Paris</settlement>
<region type="region" nuts="2">Île-de-France</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Dinjens, Winand Nm" sort="Dinjens, Winand Nm" uniqKey="Dinjens W" first="Winand Nm" last="Dinjens">Winand Nm Dinjens</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Pathology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands.</nlm:affiliation>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>Department of Pathology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam</wicri:regionArea>
<placeName><settlement type="city">Rotterdam</settlement>
<region nuts="2" type="province">Hollande-Méridionale</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Korpershoek, Esther" sort="Korpershoek, Esther" uniqKey="Korpershoek E" first="Esther" last="Korpershoek">Esther Korpershoek</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Pathology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands.</nlm:affiliation>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>Department of Pathology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam</wicri:regionArea>
<placeName><settlement type="city">Rotterdam</settlement>
<region nuts="2" type="province">Hollande-Méridionale</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="De Krijger, Ronald R" sort="De Krijger, Ronald R" uniqKey="De Krijger R" first="Ronald R" last="De Krijger">Ronald R. De Krijger</name>
<affiliation wicri:level="3"><nlm:affiliation>1] Department of Pathology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands [2] Department of Pathology, Reinier de Graaf Hospital, Delft, The Netherlands [3] Department of Pathology, University Medical Center Utrecht, Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands.</nlm:affiliation>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>1] Department of Pathology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands [2] Department of Pathology, Reinier de Graaf Hospital, Delft, The Netherlands [3] Department of Pathology, University Medical Center Utrecht, Princess Maxima Center for Pediatric Oncology, Utrecht</wicri:regionArea>
<placeName><settlement type="city">Utrecht</settlement>
<region nuts="2" type="province">Utrecht (province)</region>
</placeName>
</affiliation>
</author>
</analytic>
<series><title level="j">Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc</title>
<idno type="eISSN">1530-0285</idno>
<imprint><date when="2015" type="published">2015</date>
</imprint>
</series>
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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Adrenal Gland Neoplasms (genetics)</term>
<term>Biomarkers, Tumor (analysis)</term>
<term>Biomarkers, Tumor (genetics)</term>
<term>Electron Transport Complex II (analysis)</term>
<term>Electron Transport Complex II (genetics)</term>
<term>Humans</term>
<term>Immunohistochemistry (standards)</term>
<term>Microscopy (methods)</term>
<term>Mutation</term>
<term>Observer Variation</term>
<term>Paraganglioma (genetics)</term>
<term>Pheochromocytoma (genetics)</term>
<term>Succinate Dehydrogenase (analysis)</term>
<term>Succinate Dehydrogenase (genetics)</term>
<term>Telepathology (methods)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Biais de l'observateur</term>
<term>Complexe II de la chaîne respiratoire (analyse)</term>
<term>Complexe II de la chaîne respiratoire (génétique)</term>
<term>Humains</term>
<term>Immunohistochimie (normes)</term>
<term>Marqueurs biologiques tumoraux (analyse)</term>
<term>Marqueurs biologiques tumoraux (génétique)</term>
<term>Microscopie ()</term>
<term>Mutation</term>
<term>Paragangliome (génétique)</term>
<term>Phéochromocytome (génétique)</term>
<term>Succinate Dehydrogenase (analyse)</term>
<term>Succinate Dehydrogenase (génétique)</term>
<term>Tumeurs de la surrénale (génétique)</term>
<term>Télé-anatomopathologie ()</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="analysis" xml:lang="en"><term>Biomarkers, Tumor</term>
<term>Electron Transport Complex II</term>
<term>Succinate Dehydrogenase</term>
</keywords>
<keywords scheme="MESH" qualifier="analyse" xml:lang="fr"><term>Complexe II de la chaîne respiratoire</term>
<term>Marqueurs biologiques tumoraux</term>
<term>Succinate Dehydrogenase</term>
</keywords>
<keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Adrenal Gland Neoplasms</term>
<term>Biomarkers, Tumor</term>
<term>Electron Transport Complex II</term>
<term>Paraganglioma</term>
<term>Pheochromocytoma</term>
<term>Succinate Dehydrogenase</term>
</keywords>
<keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Complexe II de la chaîne respiratoire</term>
<term>Marqueurs biologiques tumoraux</term>
<term>Paragangliome</term>
<term>Phéochromocytome</term>
<term>Succinate Dehydrogenase</term>
<term>Tumeurs de la surrénale</term>
</keywords>
<keywords scheme="MESH" qualifier="methods" xml:lang="en"><term>Microscopy</term>
<term>Telepathology</term>
</keywords>
<keywords scheme="MESH" qualifier="normes" xml:lang="fr"><term>Immunohistochimie</term>
</keywords>
<keywords scheme="MESH" qualifier="standards" xml:lang="en"><term>Immunohistochemistry</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Humans</term>
<term>Mutation</term>
<term>Observer Variation</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Biais de l'observateur</term>
<term>Humains</term>
<term>Microscopie</term>
<term>Mutation</term>
<term>Télé-anatomopathologie</term>
</keywords>
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<front><div type="abstract" xml:lang="en">Despite the established role of SDHB/SDHA immunohistochemistry as a valuable tool to identify patients at risk for familial succinate dehydrogenase-related pheochromocytoma/paraganglioma syndromes, the reproducibility of the assessment methods has not as yet been determined. The aim of this study was to investigate interobserver variability among seven expert endocrine pathologists using a web-based virtual microscopy approach in a large multicenter pheochromocytoma/paraganglioma cohort (n=351): (1) 73 SDH mutated, (2) 105 non-SDH mutated, (3) 128 samples without identified SDH-x mutations, and (4) 45 with incomplete SDH molecular genetic analysis. Substantial agreement among all the reviewers was observed either with a two-tiered classification (SDHB κ=0.7338; SDHA κ=0.6707) or a three-tiered classification approach (SDHB κ=0.6543; SDHA κ=0.7516). Consensus was achieved in 315 cases (89.74%) for SDHB immunohistochemistry and in 348 cases (99.15%) for SDHA immunohistochemistry. Among the concordant cases, 62 of 69 (~90%) SDHB-/C-/D-/AF2-mutated cases displayed SDHB immunonegativity and SDHA immunopositivity, 3 of 4 (75%) with SDHA mutations showed loss of SDHA/SDHB protein expression, whereas 98 of 105 (93%) non-SDH-x-mutated counterparts demonstrated retention of SDHA/SDHB protein expression. Two SDHD-mutated extra-adrenal paragangliomas were scored as SDHB immunopositive, whereas 9 of 128 (7%) tumors without identified SDH-x mutations, 6 of 37 (~16%) VHL-mutated, as well as 1 of 21 (~5%) NF1-mutated tumors were evaluated as SDHB immunonegative. Although 14 out of those 16 SDHB-immunonegative cases were nonmetastatic, an overall significant correlation between SDHB immunonegativity and malignancy was observed (P=0.00019). We conclude that SDHB/SDHA immunohistochemistry is a reliable tool to identify patients with SDH-x mutations with an additional value in the assessment of genetic variants of unknown significance. If SDH molecular genetic analysis fails to detect a mutation in SDHB-immunonegative tumor, SDHC promoter methylation and/or VHL/NF1 testing with the use of targeted next-generation sequencing is advisable.</div>
</front>
</TEI>
<affiliations><list><country><li>Allemagne</li>
<li>Australie</li>
<li>Belgique</li>
<li>Espagne</li>
<li>France</li>
<li>Italie</li>
<li>Pays-Bas</li>
<li>Pologne</li>
<li>Portugal</li>
<li>États-Unis</li>
</country>
<region><li>Bavière</li>
<li>Communauté de Madrid</li>
<li>District de Dresde</li>
<li>District de Haute-Bavière</li>
<li>Gueldre</li>
<li>Hollande-Méridionale</li>
<li>Maryland</li>
<li>Massachusetts</li>
<li>Nouvelle-Galles du Sud</li>
<li>Piémont</li>
<li>Région de Bruxelles-Capitale</li>
<li>Saxe (Land)</li>
<li>Utrecht (province)</li>
<li>Île-de-France</li>
</region>
<settlement><li>Bruxelles</li>
<li>Dresde</li>
<li>Louvain-la-Neuve</li>
<li>Madrid</li>
<li>Munich</li>
<li>Nimègue</li>
<li>Paris</li>
<li>Rotterdam</li>
<li>Sydney</li>
<li>Turin</li>
<li>Utrecht</li>
</settlement>
<orgName><li>Université Louis-et-Maximilien de Munich</li>
<li>Université Paris-Descartes</li>
<li>Université catholique de Louvain</li>
<li>Université de Sydney</li>
<li>Université technique de Dresde</li>
</orgName>
</list>
<tree><country name="Pays-Bas"><region name="Hollande-Méridionale"><name sortKey="Papathomas, Thomas G" sort="Papathomas, Thomas G" uniqKey="Papathomas T" first="Thomas G" last="Papathomas">Thomas G. Papathomas</name>
</region>
<name sortKey="De Krijger, Ronald R" sort="De Krijger, Ronald R" uniqKey="De Krijger R" first="Ronald R" last="De Krijger">Ronald R. De Krijger</name>
<name sortKey="Dinjens, Winand Nm" sort="Dinjens, Winand Nm" uniqKey="Dinjens W" first="Winand Nm" last="Dinjens">Winand Nm Dinjens</name>
<name sortKey="Korpershoek, Esther" sort="Korpershoek, Esther" uniqKey="Korpershoek E" first="Esther" last="Korpershoek">Esther Korpershoek</name>
<name sortKey="Oudijk, Lindsey" sort="Oudijk, Lindsey" uniqKey="Oudijk L" first="Lindsey" last="Oudijk">Lindsey Oudijk</name>
<name sortKey="Smid, Marcel" sort="Smid, Marcel" uniqKey="Smid M" first="Marcel" last="Smid">Marcel Smid</name>
<name sortKey="Timmers, Henri J" sort="Timmers, Henri J" uniqKey="Timmers H" first="Henri J" last="Timmers">Henri J. Timmers</name>
<name sortKey="Van Berkel, Anouk" sort="Van Berkel, Anouk" uniqKey="Van Berkel A" first="Anouk" last="Van Berkel">Anouk Van Berkel</name>
<name sortKey="Van Nederveen, Francien" sort="Van Nederveen, Francien" uniqKey="Van Nederveen F" first="Francien" last="Van Nederveen">Francien Van Nederveen</name>
</country>
<country name="Belgique"><region name="Région de Bruxelles-Capitale"><name sortKey="Persu, Alexandre" sort="Persu, Alexandre" uniqKey="Persu A" first="Alexandre" last="Persu">Alexandre Persu</name>
</region>
<name sortKey="Aydin, Selda" sort="Aydin, Selda" uniqKey="Aydin S" first="Selda" last="Aydin">Selda Aydin</name>
<name sortKey="Vikkula, Miikka" sort="Vikkula, Miikka" uniqKey="Vikkula M" first="Miikka" last="Vikkula">Miikka Vikkula</name>
</country>
<country name="Australie"><region name="Nouvelle-Galles du Sud"><name sortKey="Gill, Anthony J" sort="Gill, Anthony J" uniqKey="Gill A" first="Anthony J" last="Gill">Anthony J. Gill</name>
</region>
<name sortKey="Clifton Bligh, Roderick J" sort="Clifton Bligh, Roderick J" uniqKey="Clifton Bligh R" first="Roderick J" last="Clifton-Bligh">Roderick J. Clifton-Bligh</name>
</country>
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   |texte=   SDHB/SDHA immunohistochemistry in pheochromocytomas and paragangliomas: a multicenter interobserver variation analysis using virtual microscopy: a Multinational Study of the European Network for the Study of Adrenal Tumors (ENS@T).
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Serveur d'exploration sur les relations entre la France et l'Australie

SDHB/SDHA immunohistochemistry in pheochromocytomas and paragangliomas: a multicenter interobserver variation analysis using virtual microscopy: a Multinational Study of the European Network for the Study of Adrenal Tumors (ENS@T).

SDHB/SDHA immunohistochemistry in pheochromocytomas and paragangliomas: a multicenter interobserver variation analysis using virtual microscopy: a Multinational Study of the European Network for the Study of Adrenal Tumors (ENS@T).

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	Serveur d'exploration sur les relations entre la France et l'Australie
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