{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T02:40:12Z","timestamp":1791945612363,"version":"4.3.4"},"reference-count":39,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,4,9]],"date-time":"2021-04-09T00:00:00Z","timestamp":1617926400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["por-journal.com"],"crossmark-restriction":true},"short-container-title":["Pathol. Oncol. Res."],"abstract":"<jats:p><jats:bold>Background:<\/jats:bold> Epithelioid mesothelioma (EM) is the commonest subtype of malignant pleural mesothelioma. Its histopathological discrimination from reactive mesothelial hyperplasia (RMH) could be challenging. Thus, an immunohistochemical panel is mandatory for better discrimination. BAP1 is a newly identified diagnostic marker whose loss is specific to malignant mesothelioma. EZH2 overexpression is reported in different cancers, but its relation to BAP1 in malignant mesothelioma has not been fully understood. Survivin expression is said to be significantly higher in EM than in non-neoplastic pleural tissue, but its diagnostic utility as an immunohistochemical marker has not been thoroughly investigated in this field. To the best of our knowledge, no previous studies have been conducted to assess the diagnostic accuracy of the combined use of these three nuclear markers (BAP1, EZH2 and Survivin) in discriminating pleural EM from RMH.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> This retrospective study includes two groups: 81 cases of pleural EM and 67 cases of RMH, retrieved from the archives of Pathology Department of Ain Shams University Hospitals and Ain-Shams University Specialized Hospital during the period from January 2016 to December 2019. An immunohistochemical study was performed using BAP1, EZH2 and Survivin antibodies.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> There were highly statistically significant relations between study groups as regards the studied markers (<jats:italic>p<\/jats:italic> = 0.001 for each). The specificity was 100% for all combinations of immunohistochemical markers. Sensitivity of any combination of the immunohistochemical markers used in this study was found to be higher than the sensitivity of any of these markers used individually. The combination of all three markers showed the highest diagnostic accuracy (95.9%) and the highest sensitivity (92.6%). However, the combination of Survivin and EZH2 yielded the same diagnostic accuracy and sensitivity.<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> Adding EZH2, Survivin and BAP1 to the diagnostic IHC panel for differentiating pleural EM and RMH could enhance diagnostic sensitivity. Moreover, Survivin is a potentially promising marker in this context, especially when combined with EZH2.<\/jats:p>","DOI":"10.3389\/pore.2021.600073","type":"journal-article","created":{"date-parts":[[2021,4,9]],"date-time":"2021-04-09T11:22:15Z","timestamp":1617967335000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":13,"title":["Diagnostic Utility of BAP1, EZH2 and Survivin in Differentiating Pleural Epithelioid Mesothelioma and Reactive Mesothelial Hyperplasia: Immunohistochemical Study"],"prefix":"10.3389","volume":"27","author":[{"given":"Sarah Adel","family":"Hakim","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hoda Hassan","family":"Abou Gabal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,4,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"318","DOI":"10.5858\/arpa.2015-0240-SA","article-title":"New markers for separating benign from malignant mesothelial proliferations: are we there yet?","volume":"140","author":"Churg","year":"2016","journal-title":"Arch Pathol Lab Med"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1022","DOI":"10.1038\/ng.912","article-title":"Germline BAP1 mutations predispose to malignant mesothelioma","volume":"43","author":"Testa","year":"2011","journal-title":"Nat Genet"},{"key":"B3","doi-asserted-by":"publisher","first-page":"668","DOI":"10.1038\/ng.855","article-title":"The nuclear deubiquitinase BAP1 is commonly inactivated by somatic mutations and 3p21.1 losses in malignant pleural mesothelioma","volume":"43","author":"Bott","year":"2011","journal-title":"Nat Genet"},{"key":"B4","doi-asserted-by":"publisher","first-page":"722","DOI":"10.1111\/his.13123","article-title":"Diagnostic utility of BAP1 and EZH2 expression in malignant mesothelioma","volume":"70","author":"Shinozaki-Ushiku","year":"2017","journal-title":"Histopathology"},{"key":"B5","doi-asserted-by":"publisher","first-page":"1344","DOI":"10.1038\/nm.3947","article-title":"Loss of BAP1 function leads to EZH2-dependent transformation","volume":"21","author":"LaFave","year":"2015","journal-title":"Nat Med"},{"key":"B6","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1038\/nm.4036","article-title":"Targeting EZH2 in cancer","volume":"22","author":"Kim","year":"2016","journal-title":"Nat Med"},{"key":"B7","doi-asserted-by":"publisher","first-page":"209","DOI":"10.4143\/crt.2014.46.3.209","article-title":"Regulation and role of EZH2 in cancer","volume":"46","author":"Yamaguchi","year":"2014","journal-title":"Cancer Res Treat"},{"key":"B8","doi-asserted-by":"publisher","first-page":"314","DOI":"10.7150\/jca.13332","article-title":"Survivin and tumorigenesis: molecular mechanisms and therapeutic strategies","volume":"7","author":"Chen","year":"2016","journal-title":"J Cancer"},{"key":"B9","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1159\/000442092","article-title":"Use of anti-noxa antibody for differential diagnosis between epithelioid mesothelioma and reactive mesothelial hyperplasia","volume":"83","author":"Kushitani","year":"2016","journal-title":"Pathobiology"},{"key":"B10","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/j.jtho.2019.08.2506","article-title":"EURACAN\/IASLC proposals for updating the histologic classification of pleural mesothelioma: towards a more multidisciplinary approach","volume":"15","author":"Nicholson","year":"2020","journal-title":"J Thorac Oncol"},{"key":"B11","doi-asserted-by":"publisher","first-page":"89","DOI":"10.5858\/arpa.2017-0124-RA","article-title":"Guidelines for pathologic diagnosis of malignant mesothelioma 2017 update of the consensus statement from the international mesothelioma interest group","volume":"142","author":"Husain","year":"2018","journal-title":"Arch Pathol Lab Med"},{"key":"B12","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1177\/29.4.6166661","article-title":"Use of avidin-biotin-peroxidase complex (ABC) in immunoperoxidase techniques: a comparison between ABC and unlabeled antibody (PAP) procedures","volume":"29","author":"Hsu","year":"1981","journal-title":"J Histochem Cytochem"},{"key":"B13","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1007\/s12308-009-0054-8","article-title":"Immunoexpression of Survivin in non-neoplastic lymphoid tissues and malignant lymphomas using a new monoclonal antibody reactive on paraffin sections","volume":"3","author":"Vassallo","year":"2010","journal-title":"J Hematop"},{"key":"B14","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1002\/cjp2.86","article-title":"Patterns of BAP1 protein expression provide insights into prognostic significance and the biology of uveal melanoma","volume":"4","author":"Farquhar","year":"2018","journal-title":"J Pathol Clin Res"},{"key":"B15","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1016\/j.lungcan.2019.02.004","article-title":"Highly expressed EZH2 in combination with BAP1 and MTAP loss, as detected by immunohistochemistry, is useful for differentiating malignant pleural mesothelioma from reactive mesothelial hyperplasia","volume":"130","author":"Yoshimura","year":"2019","journal-title":"Lung Cancer"},{"key":"B16","doi-asserted-by":"publisher","first-page":"3540","DOI":"10.3892\/ol.2018.7765","article-title":"Utility of survivin, BAP1, and ki-67 immunohistochemistry in distinguishing epithelioid mesothelioma from reactive mesothelial hyperplasia","volume":"15","author":"Kushitani","year":"2018","journal-title":"Oncol Lett"},{"key":"B17","doi-asserted-by":"publisher","first-page":"91","DOI":"10.3389\/fonc.2018.00091","article-title":"New perspectives on diagnosis and therapy of malignant pleural mesothelioma","volume":"8","author":"Rossini","year":"2018","journal-title":"Front Oncol"},{"key":"B18","doi-asserted-by":"publisher","first-page":"563","DOI":"10.1111\/pin.12453","article-title":"BAP1 immunohistochemistry and p16 FISH results in combination provide higher confidence in malignant pleural mesothelioma diagnosis: ROC analysis of the two tests","volume":"66","author":"Hida","year":"2016","journal-title":"Pathol Int"},{"key":"B19","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1097\/PAS.0000000000000529","article-title":"Utility of BAP1 immunohistochemistry and p16 (CDKN2A) FISH in the diagnosis of malignant mesothelioma in effusion cytology specimens","volume":"40","author":"Hwang","year":"2016","journal-title":"Am J Surg Pathol"},{"key":"B20","doi-asserted-by":"publisher","first-page":"1043","DOI":"10.1038\/modpathol.2015.65","article-title":"BAP1 (BRCA1-associated protein 1) is a highly specific marker for differentiating mesothelioma from reactive mesothelial proliferations","volume":"28","author":"Cigognetti","year":"2015","journal-title":"Mod Pathol"},{"key":"B21","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1159\/000501406","article-title":"Diagnostic value of the EZH2 immunomarker in malignant effusion cytology","volume":"64","author":"Ang","year":"2020","journal-title":"Acta Cytol"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1255","DOI":"10.1016\/j.molonc.2016.06.005","article-title":"Low merlin expression and high survivin labeling index are indicators for poor prognosis in patients with malignant pleural mesothelioma","volume":"10","author":"Meerang","year":"2016","journal-title":"Mol Oncol"},{"key":"B23","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1007\/s00428-013-1373-9","article-title":"Is survivin expression prognostic or predictive in malignant pleural mesothelioma?","volume":"462","author":"Hmeljak","year":"2013","journal-title":"Virchows Arch"},{"key":"B24","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1111\/his.14105","article-title":"Comparative analysis of prognostic histopathologic parameters in subtypes of epithelioid pleural mesothelioma","volume":"77","author":"Bilecz","year":"2020","journal-title":"Histopathology"},{"key":"B25","doi-asserted-by":"publisher","first-page":"376","DOI":"10.1038\/s41379-018-0159-7","article-title":"Immunohistochemical evaluation of nuclear 5-hydroxymethylcytosine (5-hmC) accurately distinguishes malignant pleural mesothelioma from benign mesothelial proliferations","volume":"32","author":"Chapel","year":"2019","journal-title":"Mod Pathol"},{"key":"B26","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1186\/1746-1596-5-47","article-title":"Re-evaluation of histological diagnoses of malignant mesothelioma by immunohistochemistry","volume":"5","author":"Sandeck","year":"2010","journal-title":"Diagn Pathol"},{"key":"B27","doi-asserted-by":"publisher","first-page":"1564","DOI":"10.5858\/arpa.2014-0074-RA","article-title":"Standardization of diagnostic immunohistochemistry: literature review and geisinger experience","volume":"138","author":"Lin","year":"2014","journal-title":"Arch Pathol Lab Med"},{"key":"B28","doi-asserted-by":"publisher","first-page":"557","DOI":"10.1016\/j.pathol.2017.03.008","article-title":"Loss of BAP1 expression is very rare in breast carcinoma","volume":"49","author":"Chui","year":"2017","journal-title":"Pathology"},{"key":"B29","doi-asserted-by":"publisher","first-page":"e0150338","DOI":"10.1371\/journal.pone.0150338","article-title":"Loss of BAP1 expression is very rare in pancreatic ductal adenocarcinoma","volume":"11","author":"Tayao","year":"2016","journal-title":"PLoS One"},{"key":"B30","doi-asserted-by":"publisher","first-page":"336","DOI":"10.1016\/j.pathol.2016.03.005","article-title":"Loss of expression of BAP1 is very rare in non-small cell lung carcinoma","volume":"48","author":"Andrici","year":"2016","journal-title":"Pathology"},{"key":"B31","doi-asserted-by":"publisher","first-page":"e91","DOI":"10.1097\/PAI.0000000000000506","article-title":"Loss of BAP1 expression occurs rarely to never in colorectal adenocarcinoma","volume":"26","author":"Chui","year":"2018","journal-title":"Appl Immunohistochem Mol Morphol"},{"key":"B32","doi-asserted-by":"publisher","first-page":"6556","DOI":"10.1158\/1078-0432.CCR-12-3946","article-title":"EZH2 protein expression associates with the early pathogenesis, tumor progression, and prognosis of non-small cell lung carcinoma","volume":"19","author":"Behrens","year":"2013","journal-title":"Clin Cancer Res"},{"key":"B33","doi-asserted-by":"publisher","first-page":"11194","DOI":"10.18632\/oncotarget.7156","article-title":"EZH2 promotes cell migration and invasion but not alters cell proliferation by suppressing E-cadherin, partly through association with MALAT-1 in pancreatic cancer","volume":"7","author":"Han","year":"2016","journal-title":"Oncotarget"},{"key":"B34","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1007\/s12029-019-00344-4","article-title":"Prognostic value of TWIST1 and EZH2 expression in colon cancer","volume":"52","author":"Abdel Raouf","year":"2019","journal-title":"J Gastrointest Cancer"},{"key":"B35","doi-asserted-by":"publisher","first-page":"53","DOI":"10.4048\/jbc.2016.19.1.53","article-title":"High EZH2 protein expression is associated with poor overall survival in patients with luminal A breast cancer","volume":"19","author":"Jang","year":"2016","journal-title":"J Breast Cancer"},{"key":"B36","first-page":"925","article-title":"Immunohistochemical analysis of survivin expression in primary breast cancers","volume":"103","author":"Chu","year":"2004","journal-title":"J Formos Med Assoc"},{"key":"B37","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1002\/1097-0142(20010715)92:2<271::aid-cncr1319>3.0.co;2-0","article-title":"Expression of survivin is correlated with cancer cell apoptosis and is involved in the development of human pancreatic duct cell tumors","volume":"92","author":"Satoh","year":"2001","journal-title":"Cancer"},{"key":"B38","doi-asserted-by":"publisher","first-page":"2220","DOI":"10.1016\/j.rmed.2006.02.031","article-title":"Correlation between survivin expression and prognosis in non-small cell lung cancer","volume":"100","author":"Atikcan","year":"2006","journal-title":"Respir Med"},{"key":"B39","doi-asserted-by":"publisher","first-page":"3591","DOI":"10.3892\/ol.2016.5075","article-title":"Immunohistochemical expression and serum level of survivin protein in colorectal cancer patients","volume":"12","author":"Jakubowska","year":"2016","journal-title":"Oncol Lett"}],"container-title":["Pathology and Oncology Research"],"original-title":[],"link":[{"URL":"https:\/\/www.por-journal.com\/articles\/10.3389\/pore.2021.600073\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,7,13]],"date-time":"2021-07-13T14:45:11Z","timestamp":1626187511000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.por-journal.com\/articles\/10.3389\/pore.2021.600073\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,9]]},"references-count":39,"alternative-id":["10.3389\/pore.2021.600073"],"URL":"https:\/\/doi.org\/10.3389\/pore.2021.600073","relation":{},"ISSN":["1532-2807"],"issn-type":[{"value":"1532-2807","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,9]]},"article-number":"600073"}}