{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:38:44Z","timestamp":1787027924829,"version":"build-2736575974"},"reference-count":47,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2022,11,22]],"date-time":"2022-11-22T00:00:00Z","timestamp":1669075200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diagnostics"],"abstract":"<jats:p>The 2021 WHO Classification of Tumors of the Pleura has introduced significant changes in mesothelioma codification beyond the three current histological subtypes\u2014epithelioid, sarcomatoid and biphasic. Major advances since the 2015 WHO classification include nuclear grading and the introduction of architectural patterns, cytological and stromal features for epithelioid diffuse mesothelioma. Mesothelioma in situ has been recognized as a diagnostic category. Demonstration of loss of BAP1 or MTAP by immunohistochemistry, or CDKN2A homozygous deletion by FISH, is valuable in establishing the diagnosis of epithelioid mesothelioma. Recent emerging data proved that grading and histological subtypes have prognostic implications and may be helpful to patient risk stratification and clinical management. Nevertheless, the latest mesothelioma classification increases the already non-negligible diagnostic pitfalls, especially concerning differential diagnosis of pre-invasive tumors. In this review, recent changes in histologic classification of mesothelioma and advances in molecular markers are presented and their relation to diagnostic challenges and prognostic implications is discussed.<\/jats:p>","DOI":"10.3390\/diagnostics12122905","type":"journal-article","created":{"date-parts":[[2022,11,23]],"date-time":"2022-11-23T02:55:51Z","timestamp":1669172151000},"page":"2905","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["New Insights in Pleural Mesothelioma Classification Update: Diagnostic Traps and Prognostic Implications"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9291-5619","authenticated-orcid":false,"given":"Maria Giovanna","family":"Mastromarino","sequence":"first","affiliation":[{"name":"Department of Cardiology, Thoracic and Vascular Medicine, Division of Thoracic Surgery, Pisa University Hospital, 56124 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Lenzini","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Thoracic and Vascular Medicine, Division of Thoracic Surgery, Pisa University Hospital, 56124 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vittorio","family":"Aprile","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Thoracic and Vascular Medicine, Division of Thoracic Surgery, Pisa University Hospital, 56124 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Greta","family":"Al\u00ec","sequence":"additional","affiliation":[{"name":"Anatomic Pathology Section, Department of Surgical, Medical, Molecular Pathology and Critical Area, University di Pisa, 56124 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5706-0974","authenticated-orcid":false,"given":"Diana","family":"Bacchin","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Thoracic and Vascular Medicine, Division of Thoracic Surgery, Pisa University Hospital, 56124 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8818-6553","authenticated-orcid":false,"given":"Stylianos","family":"Korasidis","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Thoracic and Vascular Medicine, Division of Thoracic Surgery, Pisa University Hospital, 56124 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcello Carlo","family":"Ambrogi","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Thoracic and Vascular Medicine, Division of Thoracic Surgery, Pisa University Hospital, 56124 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9909-6820","authenticated-orcid":false,"given":"Marco","family":"Lucchi","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Thoracic and Vascular Medicine, Division of Thoracic Surgery, Pisa University Hospital, 56124 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1655","DOI":"10.1016\/j.jtho.2018.08.2036","article-title":"Current and future management of malignant mesothelioma: A consensus report from the National Cancer Institute Thoracic Malignancy Steering Committee, International Association for the Study of Lung Cancer, and Mesothelioma Applied Research Foundation","volume":"13","author":"Tsao","year":"2018","journal-title":"J. Thorac. Oncol."},{"key":"ref_2","unstructured":"WHO (2015). Classification of Tumours of the Lung, Pleura, Thymus and Heart, International Agency for Research on Cancer (IARC)."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"747","DOI":"10.5858\/arpa.2017-0295-OA","article-title":"Reproducibility of malignant pleural mesothelioma histopathologic subtyping","volume":"142","author":"Brcic","year":"2018","journal-title":"Arch. Pathol. Lab. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1097\/JTO.0b013e318211127a","article-title":"Pleomorphic epithelioid diffuse malignant pleural mesothelioma: A clinicopathological review and conceptual proposal to reclassify as biphasic or sarcomatoid mesothelioma","volume":"6","author":"Kadota","year":"2011","journal-title":"J. Thorac. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1038\/modpathol.2011.146","article-title":"A nuclear grading system is a strong predictor of survival in epitheloid diffuse malignant pleural mesothelioma","volume":"25","author":"Kadota","year":"2012","journal-title":"Mod. Pathol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1750","DOI":"10.1016\/j.jtho.2018.07.002","article-title":"Pathologic grading of malignant pleural mesothelioma: An evidence-based proposal","volume":"13","author":"Pelosi","year":"2018","journal-title":"J. Thorac. Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1038\/modpathol.2017.170","article-title":"Nuclear grade and necrosis predict prognosis in malignant epithelioid pleural mesothelioma: A multi-institutional study","volume":"31","author":"Rosen","year":"2018","journal-title":"Mod. Pathol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1097\/PAS.0000000000001416","article-title":"Utility of nuclear grading system in epithelioid malignant pleural mesothelioma in biopsy-heavy setting: An external validation study of 563 cases","volume":"44","author":"Zhang","year":"2020","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_9","doi-asserted-by":"crossref","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":"ref_10","unstructured":"WHO (2021). Classification of Tumours Editorial Board. WHO Classification of Tumours: Thoracic Tumours, International Agency for Research on Cancer. [5th ed.]."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1304","DOI":"10.1097\/00000478-200110000-00012","article-title":"Well-differentiated papillary mesothelioma","volume":"25","author":"Butnor","year":"2001","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1097\/00000478-200404000-00013","article-title":"Mesopath group. Well-differentiated papillary mesothelioma of the pleura: A series of 24 cases","volume":"28","author":"Vignaud","year":"2004","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1038\/s41379-019-0347-0","article-title":"Malignant mesothelioma in situ: Morphologic features and clinical outcome","volume":"33","author":"Churg","year":"2020","journal-title":"Mod. Pathol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1111\/his.13468","article-title":"Malignant mesothelioma in situ","volume":"72","author":"Churg","year":"2018","journal-title":"Histopathology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1007\/s00428-019-02674-x","article-title":"Malignant mesothelioma in situ diagnosed by methylthioadenosine phosphorylase loss and homozygous deletion of CDKN2A: A case report","volume":"476","author":"Minami","year":"2020","journal-title":"Virchows Arch."},{"key":"ref_16","doi-asserted-by":"crossref","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":"ref_17","doi-asserted-by":"crossref","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":"ref_18","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.humpath.2020.02.007","article-title":"Histopathological features of epithelioid malignant pleural mesotheliomas in patients with extended survival","volume":"98","author":"Paajanen","year":"2020","journal-title":"Hum. Pathol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1016\/j.pathol.2021.01.010","article-title":"Histopathological typing in diffuse malignant epithelioid mesothelioma: Implication for prognosis and molecular basis","volume":"53","author":"Forest","year":"2021","journal-title":"Pathology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/j.humpath.2018.05.001","article-title":"BAP1 loss is unusual in well-differentiated papillary mesothelioma and may predict development of malignant mesothelioma","volume":"79","author":"Lee","year":"2018","journal-title":"Hum. Pathol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.anndiagpath.2018.10.012","article-title":"Well-differentiated papillary mesothelioma: A 17-year single institution experience with a series of 75 cases","volume":"38","author":"Sun","year":"2019","journal-title":"Ann Diagn Pathol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.humpath.2017.10.036","article-title":"Aberrant Pax-8 expression in well-differentiated papillary mesothelioma and malignant mesothelioma of the peritoneum: A clinicopathologic study","volume":"72","author":"Xing","year":"2018","journal-title":"Hum. Pathol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1675","DOI":"10.1097\/PAS.0000000000000935","article-title":"PAX8 Expression in a subset of malignant peritoneal mesotheliomas and benign mesothelium has diagnostic implications in the differential diagnosis of ovarian serous carcinoma","volume":"41","author":"Chapel","year":"2017","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1038\/s41379-021-00895-7","article-title":"Pleural mesothelioma classification-update and challenges","volume":"35","author":"Dacic","year":"2022","journal-title":"Mod. Pathol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1002\/cncr.10923","article-title":"The use of CDKN2A deletion as a diagnostic marker for malignant mesothelioma in body cavity effusions","volume":"99","author":"Illei","year":"2003","journal-title":"Cancer"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1549","DOI":"10.5858\/arpa.2018-0273-OA","article-title":"Utility of methylthioadenosine phosphorylase compared with BAP1 immunohistochemistry, and CDKN2A and NF2 fluorescence in situ hybridization in separating reactive mesothelial proliferations from epithelioid malignant mesotheliomas","volume":"142","author":"Berg","year":"2018","journal-title":"Arch. Pathol. Lab. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.lungcan.2016.12.017","article-title":"Immunohistochemical detection of MTAP and BAP1 protein loss for mesothelioma diagnosis: Comparison with 9p21 FISH and BAP1 immunohistochemistry","volume":"104","author":"Hida","year":"2017","journal-title":"Lung Cancer"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.lungcan.2020.09.002","article-title":"Whole exome sequencing reveals BAP1 somatic abnormalities in mesothelioma in situ","volume":"149","author":"Dacic","year":"2020","journal-title":"Lung Cancer"},{"key":"ref_29","doi-asserted-by":"crossref","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":"ref_30","doi-asserted-by":"crossref","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":"ref_31","doi-asserted-by":"crossref","first-page":"1217","DOI":"10.5858\/arpa.2012-0112-RA","article-title":"The separation of benign and malignant mesothelial proliferations","volume":"136","author":"Churg","year":"2012","journal-title":"Arch. Pathol. Lab. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1097\/PAS.0000000000000616","article-title":"BAP1 Immunohistochemistry and p16 FISH in the diagnosis of sarcomatous and desmoplastic mesotheliomas","volume":"40","author":"Hwang","year":"2016","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1309\/AJCPP5R2ZJZKCLWN","article-title":"The diagnostic utility of p16 FISH and GLUT-1 immunohistochemical analysis in mesothelial proliferations","volume":"135","author":"Monaco","year":"2011","journal-title":"Am. J. Clin. Pathol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1111\/his.13123","article-title":"Diagnostic utility of BAP1 and EZH2 expression in malignant mesothelioma","volume":"70","author":"Ushiku","year":"2017","journal-title":"Histopathology"},{"key":"ref_35","doi-asserted-by":"crossref","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":"ref_36","doi-asserted-by":"crossref","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":"ref_37","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1200\/JCO.1998.16.1.145","article-title":"Prognostic factors in patients with pleural mesothelioma: The European Organization for Research and Treatment of Cancer experience","volume":"16","author":"Curran","year":"1998","journal-title":"J. Clin. Oncol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.jss.2015.01.043","article-title":"Impact of mesothelioma histologic subtype on outcomes in the Surveillance, Epidemiology, and End Results database","volume":"196","author":"Meyerhoff","year":"2015","journal-title":"J. Surg. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1007\/s00428-021-03031-7","article-title":"Pleural mesothelioma classification update","volume":"478","author":"Beasley","year":"2021","journal-title":"Virchows Arch."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"924","DOI":"10.21037\/tlcr.2020.03.38","article-title":"Clinical significance of histologic subtyping of malignant pleural mesothelioma","volume":"9","author":"Brcic","year":"2020","journal-title":"Transl. Lung Cancer Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1136\/jclinpath-2016-203993","article-title":"Myxoid variant epithelioid pleural mesothelioma defines a favourable prognosis group: An analysis of 191 patients with pleural malignant mesothelioma","volume":"70","author":"Alchami","year":"2017","journal-title":"J. Clin. Pathol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1038\/modpathol.3800543","article-title":"Mesothelioma with rhabdoid features: An ultrastructural and immunohistochemical study of 10 cases","volume":"19","year":"2006","journal-title":"Mod. Pathol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"4164","DOI":"10.1002\/cncr.32416","article-title":"Diagnostic value of biopsy sampling in predicting histology in patients with diffuse malignant pleural mesothelioma","volume":"125","author":"Chirieac","year":"2019","journal-title":"Cancer"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1510\/icvts.2010.255893","article-title":"What is the best way to diagnose and stage malignant pleural mesothelioma?","volume":"12","author":"Zahid","year":"2011","journal-title":"Interact. Cardiovasc. Thorac. Surg."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1900953","DOI":"10.1183\/13993003.00953-2019","article-title":"ERS\/ESTS\/EACTS\/ESTRO guidelines for the management of malignant pleural mesothelioma","volume":"55","author":"Scherpereel","year":"2020","journal-title":"Eur. Respir. J."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1638","DOI":"10.1016\/j.jtho.2018.08.001","article-title":"Surgery in malignant pleural mesothelioma","volume":"13","author":"Bueno","year":"2018","journal-title":"J. Thorac. Oncol."},{"key":"ref_47","first-page":"MC01","article-title":"Medical thoracoscopy vs closed pleural biopsy in pleural effusions: A randomized controlled study","volume":"8","author":"Haridas","year":"2014","journal-title":"J. Clin. Diagn. Res."}],"container-title":["Diagnostics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4418\/12\/12\/2905\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:24:30Z","timestamp":1760145870000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4418\/12\/12\/2905"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,22]]},"references-count":47,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["diagnostics12122905"],"URL":"https:\/\/doi.org\/10.3390\/diagnostics12122905","relation":{},"ISSN":["2075-4418"],"issn-type":[{"value":"2075-4418","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,22]]}}}