ES03.01 Diagnosis of Mesothelioma Based on Cytology Alone

Abstract

Historically, the diagnosis of malignant mesothelioma in cytology specimens has been controversial. It is difficult, and some would argue impossible, to make the diagnosis of malignant mesothelioma in cytology specimens since the presence of atypia in mesothelial cells is not specific for malignancy and the lack of architecture inherent in cytology specimens precludes assessment of invasion, which is an important diagnostic feature of malignant mesothelioma. However, relatively recent developments in ancillary tests that aid in the diagnosis of malignancy in mesothelial proliferations have improved our ability to diagnose malignant mesothelioma in cytology specimens. Loss of BAP1 protein expression by immunohistochemistry (IHC) and homozygous deletion of p16/CDKN2a by FISH are specific but not sensitive for malignant mesothelioma (1–4). Recent studies have demonstrated that the combination of both increases the sensitivity for malignant mesothelioma (3–5). Homozygous co-deletion of methylthioadenosine physphorylase (MTAP) occurs in the majority of malignant mesotheliomas with p16/CDKN2A deletions (6-8). MTAP protein expression detected by IHC has advantages over FISH (e.g. not all laboratories perform FISH; truncation artifact can occur with FISH; and IHC requires less time). These ancillary studies, particularly BAP1 IHC and p16/CDKN2A FISH, have become useful in clinical practice for facilitating the diagnosis of malignant mesothelioma in limited samples. Despite these advances, the diagnosis of malignant mesothelioma based on cytology alone remains challenging and there are many cases in which a definitive diagnosis cannot be rendered. 1. Churg A, Sheffield BS, Galateau-Salle F. New Markers for Separating Benign From Malignant Mesothelial Proliferations: Are We There Yet? Arch Pathol Lab Med. 2015 Aug 19;140(4):318–21. 2. Cigognetti M, Lonardi S, Fisogni S, Balzarini P, Pellegrini V, Tironi A, et al. BAP1 (BRCA1-associated protein 1) is a highly specific marker for differentiating mesothelioma from reactive mesothelial proliferations. Mod Pathol. 2015 Aug;28(8):1043–57. 3. Hwang HC, Sheffield BS, Rodriguez S, Thompson K, Tse CH, Gown AM, et al. Utility of Bap1 Immunohistochemistry and p16 (cdkn2a) Fish in the Diagnosis of Malignant Mesothelioma in Effusion Cytology Specimens. Am J Surg Pathol. 2016 Jan 1;40(1):120–6. 4. Walts AE, Hiroshima K, McGregor SM, Wu D, Husain AN, Marchevsky AM. BAP1 Immunostain and CDKN2A (p16) FISH Analysis. Diagn Cytopathol. 2016 Jul 1;44(7):599–606. 5. Hwang HC, Pyott S, Rodriguez S, Cindric A, Carr A, Michelsen C, et al. BAP1 Immunohistochemistry and p16 FISH in the Diagnosis of Sarcomatous and Desmoplastic Mesotheliomas. Am J Surg Pathol. 2016 May;40(5):714–8. 6. Illei PB, Rusch VW, Zakowski MF, Ladanyi M. Homozygous Deletion of CDKN2A and Codeletion of the Methylthioadenosine Phosphorylase Gene in the Majority of Pleural Mesotheliomas. Clin Cancer Res. 2003 Jun 1;9(6):2108–13. 7. Krasinskas AM, Bartlett DL, Cieply K, Dacic S. CDKN2A and MTAP deletions in peritoneal mesotheliomas are correlated with loss of p16 protein expression and poor survival. Mod Pathol. 2010 Apr;23(4):531–8. 8. Hida T, Hamasaki M, Matsumoto S, Sato A, Tsujimura T, Kawahara K, et al. Immunohistochemical detection of MTAP and BAP1 protein loss for mesothelioma diagnosis: Comparison with 9p21 FISH and BAP1 immunohistochemistry. Lung Cancer Amst Neth. 2017 Feb;104:98–105. Mesothelioma, BAP1, cytology