Evidence map›Paper›PMID 25720320›Full record

ArticleModern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc2015

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).

Thomas G Papathomas, Lindsey Oudijk, Alexandre Persu, Anthony J Gill, Francien van Nederveen, Arthur S Tischler, Frédérique Tissier, Marco Volante, Xavier Matias-Guiu, Marcel Smid and 28 more

Open access · bronzeAbstract readMulticenter Study
PubMed Publisher
In one paragraph

Article in Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 115 papers, 2 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
115citing papers in PubMed, 2 pooled it
18.9field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

115 citing papers in PubMed, 2 syntheses or guidelines pooled it, 224 citations in OpenAlex.

  1. Multidisciplinary practice guidelines for the diagnosis, genetic counseling and treatment of pheochromocytomas and paragangliomas.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2021
    Guideline
  2. Pooled it
  3. Immunohistochemistry and Mutation Analysis ofInternational journal of molecular sciences · 2020
    Trial
  4. Review
  5. Review
  6. Article
  7. Article
  8. The evolving roles of pathologists in paragangliomas and pheochromocytomas.Virchows Archiv : an international journal of pathology · 2026
    Review
  9. Article
  10. Article
  11. Article
  12. Article
  13. Paraganglioma in Pregnancy with Recurrent Pregnancy Loss: A Case Report.Journal of the ASEAN Federation of Endocrine Societies · 2025
    Article
  14. Article
  15. Review
  16. A Novel Human SDHA-Knockout Cell Line Model for the Functional Analysis of Clinically Relevant SDHA Variants.Clinical cancer research : an official journal of the American Association for Cancer Research · 2024
    Article
  17. Non-Susceptibility Gene Variants in Head and Neck Paragangliomas.International journal of molecular sciences · 2024
    Article
  18. Article
  19. Review
  20. Article

55 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

38 authors at 19 institutions in 10 countries.

Thomas G Papathomas1] Department of Histopathology, King's College Hospital, London, UK [2] Department of Pathology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Lindsey OudijkDepartment of Pathology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Alexandre PersuPole of Cardiovascular Research, Institut de Recherche Expérimentale et Clinique and Division of Cardiology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.
Anthony J Gill1] 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.
Francien van NederveenLaboratory for Pathology, PAL Dordrecht, Dordrecht, The Netherlands.
Arthur S TischlerDepartment of Pathology and Laboratory Medicine, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA.
Frédérique Tissier1] 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.
Marco VolanteDepartment of Oncology, University of Turin at San Luigi Hospital, Turin, Italy.
Xavier Matias-GuiuDepartment of Pathology and Molecular Genetics and Research Laboratory, Hospital Universitari Arnau de Vilanova, IRBLLEIDA, University of Lleida, Lleida, Spain.
Marcel SmidDepartment of Medical Oncology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Judith Favier1] 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.
Elena RapizziEndocrinology Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.
Rosella LibeInstitut 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.
Maria Currás-FreixesHereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Selda AydinDepartment of Pathology, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Institut de Recherche Expérimentale et Clinique, Brussels, Belgium.
Thanh HuynhProgram in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
Urs LichtenauerEndocrine Research Unit, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany.
Anouk van BerkelDepartment of Internal Medicine, Section of Endocrinology, Radboud University Medical Centre, Nijmegen, The Netherlands.
Letizia CanuEndocrinology Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.
Rita DominguesUnidade de Investigação em Patobiologia Molecular (UIPM), Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisbon, Portugal.
Roderick J Clifton-BlighCancer Genetics, Kolling Institute of Medical Research, Royal North Shore Hospital, University of Sydney, Sydney, NSW, Australia.
Magdalena BialasDepartment of Pathomorphology, Jagiellonian University Medical College, Krakow, Poland.
Miikka VikkulaLaboratory of Human Molecular Genetics, de Duve Institute, Université Catholique de Louvain, Brussels, Belgium.
Gustavo BarettonDepartment of Pathology, Technische Universität Dresden, Dresden, Germany.
Mauro PapottiDepartment of Oncology, University of Turin at San Luigi Hospital, Turin, Italy.
Gabriella NesiDivision of Pathological Anatomy, University of Florence, Florence, Italy.
Cécile Badoual1] 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.
Karel PacakProgram in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
Graeme EisenhoferInstitute of Clinical Chemistry and Laboratory Medicine and Department of Medicine III, University Hospital, Technische Universität Dresden, Dresden, Germany.
Henri J TimmersDepartment of Internal Medicine, Section of Endocrinology, Radboud University Medical Centre, Nijmegen, The Netherlands.
Felix BeuschleinEndocrine Research Unit, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany.ORCID 0000000178263984
Jérôme Bertherat1] 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.
Massimo Mannelli1] Endocrinology Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy [2] Istituto Toscano Tumori (ITT), Florence, Italy.
Mercedes Robledo1] Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain [2] Centre for Biomedical Network Research on Rare Diseases (CIBERER), Madrid, Spain.
Anne-Paule Gimenez-Roqueplo1] 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.
Winand Nm DinjensDepartment of Pathology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Esther KorpershoekDepartment of Pathology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Ronald R de Krijger1] 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.
Erasmus MC Cancer Institute · NLDélégation Paris 5 · FRUniversity of Florence · ITCliniques Universitaires Saint-Luc · BELMU Klinikum · DENational Institutes of Health · USRadboud University Nijmegen · NLSpanish National Cancer Research Centre · ESTechnische Universität Dresden · DEThe University of Sydney · AUUniversité Paris Cité · FRUniversity of Turin · ITCentre National de la Recherche Scientifique · FRde Duve Institute · BEErasmus MC · NLJagiellonian University · PLTufts University · USTumour Institute of Tuscany · ITUniversitat de Lleida · ES

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

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.

Indexed as

Adrenal Gland NeoplasmsBiomarkers, TumorElectron Transport Complex IIHumansImmunohistochemistryMicroscopyMutationObserver VariationParagangliomaPheochromocytomaSuccinate DehydrogenaseTelepathologyBiomarkers, TumorElectron Transport Complex IISDHA protein, humanSDHB protein, humanSuccinate Dehydrogenase

Identifiers

PMID25720320
OpenAlexW1982640657

What Socratic holds

Textmetadata
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Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.