Special ArticleThe Separation of Benign and Malignant Mesothelial Proliferations New Markers and How to Use ThemChurg, Andrew MD*,†; Naso, Julia R. MD, PhD*,†Author Information *Department of Pathology, Vancouver General Hospital †Department of Pathology, University of British Columbia, Vancouver, BC, Canada Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. Correspondence: Andrew Churg, MD, Department of Pathology, JPPN 1401 Vancouver General Hospital, 910 West 10th Avenue, Vancouver, BC, Canada V5Z 1M9 (e-mail: firstname.lastname@example.org). The American Journal of Surgical Pathology: November 2020 - Volume 44 - Issue 11 - p e100-e112 doi: 10.1097/PAS.0000000000001565 Buy Metrics Abstract The separation of benign from malignant mesothelial proliferations is an important clinical but often a difficult morphologic problem. Over the last roughly 10 years a variety of new markers that aid in this separation have been published and some older recommended markers reconsidered. Unlike previous, and largely unusable, empiric immunohistochemical (IHC) stains, these new markers, some using IHC and some using fluourescent in situ hybridization (FISH), are largely based on documented genomic abnormalities in malignant mesotheliomas. However, no marker works in all situations; rather, markers need to be chosen by the morphology of the process in question (epithelial vs. spindled) and the body cavity of interest (pleural vs. peritoneal). It is also important to be familiar with the exact pattern, for example nuclear versus cytoplasmic loss, that indicates a positive test. Furthermore, no single marker is 100% sensitive even with the optimal morphology/location, so that combinations of markers are essential. This review covers the various new markers in the literature, highlights their advantages and limitations, and suggests morphology/site specific combinations that can produce sensitivities in the 80% to 90% (and perhaps higher) range. At present only BRCA-1 related protein-1 and methylthioadenosine phosphorylase IHC, and cyclin-dependent kinase inhibitor 2A (p16) FISH have sufficient publications and reproducibility of results to be considered as established markers. 5-Hydroxymethyl cytosine, enhancer of zeste homolog 2, cyclin D1, and programmed death-ligand 1 IHC, and NF2 FISH are all potentially useful but need further study. The newly described entity of malignant mesothelioma in situ sits at the interface of benign and malignant mesothelial process; criteria for this diagnosis are reviewed. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.