Original Articles Differential Diagnosis of Epithelioid Malignant Mesothelioma With Lung and Breast Pleural Metastasis A Systematic Review Compared With a Standardized Panel of Antibodies—A New Proposal That May Influence Pathologic Practice Nolwenn Le Stang, MSc; Louise Burke, MD; Gaetane Blaizot, MSc; Allen R. Gibbs, MD; Pierre Lebailly, PhD; B´ en ´ edicte Clin, MD, PhD; Nicolas Girard, MD, PhD; Fran ¸ coise Galateau-Sall ´ e, MD, PhD; for the MESOPATH and EURACAN networks  Context.—Pleural mesothelioma is a rare cancer with an often-challenging diagnosis because of its potential to be a great mimicker of many other tumors. Among them, primary lung and breast cancers are the 2 main causes of pleural metastasis. The development and application of targeted therapeutic agents have made it even more important to achieve an accurate diagnosis. In this setting, international guidelines have recommended the use of 2 positive and 2 negative immunohistochemical biomarkers. Objectives.—To define the most highly specific and sensitive minimum set of antibodies for routine practice to use for the separation of epithelioid malignant mesotheli- oma from lung and breast metastasis and to determine the most relevant expression cutoff. Design.—To provide information at different levels of expression of 16 mesothelial and epithelial biomarkers, we performed a systematic review of articles published between 1979 and 2017, and we compared those data to results from the Mesothelioma Telepathology Network (MESOPATH) of the standardized panel used in routine practice database since 1998. Results.—Our results indicate that the following panel of markers—calretinin (poly)/thyroid transcription factor 1 (TTF-1; clone 8G7G3/1) and calretinin (poly)/estrogen receptor-a (ER-a; clone EP1)—should be recommended; ultimately, based on the MESOPATH database, we highlight their relevance which are the most sensitive and specific panel useful to the differential diagnosis at 10% cutoff. Conclusions.—Highlighted by their relevance in the large cohort reported, we recommend 2 useful panels to the differential diagnosis at 10% cutoff. (Arch Pathol Lab Med. 2020;144:446–456; doi: 10.5858/ arpa.2018-0457-OA) M esothelioma is a rare cancer derived from the transformation of mesothelial cells that line the serosal surfaces. It represents 0.2% of all cancers and has a dismal prognosis with limited therapeutic options. 1 Mesothelioma is related to asbestos exposure in up to 90% of cases in men 2 and is located to the pleura in 90%, the peritoneum in nearly 10%, and rarely in the tunica vaginalis testis and pericardium. 3 Diagnosis is based on biopsy tissue samples according to the 2015 World Health Organization classification. The diagnosis is often challeng- ing because of mesothelioma tumor heterogeneity and to the potential of this tumor to be a great mimicker of many other tumors in the setting of small biopsies. Among them, primary lung and breast carcinomas are the 2 main causes of pleural metastasis that mimic mesothelioma, accounting for more than 150 000 cases a year in the United States, with 11% (n ¼ 16 500) from lung and 14% (n ¼ 21 000) from breast carcinomas. 4 The development and application of drugs that target specific molecules expressed in breast and lung carcinomas have made it even more important to Accepted for publication May 7, 2019. Published online August 7, 2019. From the Pleural Mesothelioma National Multicentric Registry (MESONAT), MESOPATH National Network on Mesothelioma (Ms Le Stang and Dr Galateau-Sall´ e), the EURACAN network (Dr Girard), and MESOBANK Clinicobiological Database and National Frozen Tissue Bank (Dr Galateau-Sall´ e), L´ eon B´ erard Cancer Center, Lyon, France; the Department of Pathology, Cork University Hospital, Cork, Ireland (Dr Burke); the Frozen Tissue Bank InnovaBio, CHU de Caen, France (Ms Blaizot); the Department of Pathology, University Hospital Llandough, Cardiff, England (Dr Gibbs); INSERM U1086, ANTICIPE, Caen University, Caen, France (Drs Lebailly and Clin); the Department of Occupational Diseases, University Hospital, Caen, France (Dr Clin); the University of Lyon, Lyon, France (Dr Girard); and the Curie Montsouris Thorax Institute, Curie Institut, Paris, France (Dr Girard). The following are past or current members of MESOPATH network: I. Abd Alsamad, H. Begueret, E. Brambilla, F. Capron, A. Caz` es, M. C. Copin, D. Damotte, C. Danel, P. Dartigues, A. Y. De Lajartre, A. Foulet-Rog´ e, F. Galateau-Sall´ e, L. Garbe, S. Giusiano, O. Groussard, V. Hofman, S. Isaac, S. Lantuejoul, J. M. Picquenot, G. Planchard, E. Mery, I. Rouquette, C. Sagan, F. Thivolet-Bejui, S. Valmary-Degano, and J. M. Vignaud. The following are current members of EURACAN network: J. Y. Blay and N. Girard. This work was supported by the Brazilian National Cancer Institute (INCA) core grant and by Sant´ e Publique France. The authors have no relevant financial interest in the products or companies described in this article. Corresponding author: Fran¸ coise Galateau-Sall´ e, MD, PhD, MESONAT Registry Biopathology, MESOPATH National Network on Mesothelioma, 28 Rue Laennec 69008 Lyon, France (email: francoise.galateau@lyon.unicancer.fr). 446 Arch Pathol Lab Med—Vol 144, April 2020 Systematic Review and MESOPATH Experience—Le Stang et al