Malignant mesothelioma (MM) is a rare and aggressive tumor arising from mesothelial cells that line the pleura, peritoneal cavity, pericardium, and tunica vaginalis in the testis [1]. Most cases occur in the pleura, while peritoneal is rare, accounting for 10–15% of new MM cases [1], [2]. Malignant pleural mesothelioma (MPM) occurs more frequently with a unilateral recurrent pleural effusion and arises in older men [3]. MPM is divided into three histological subtypes: epithelioid malignant mesothelioma (EMM), biphasic malignant mesothelioma (BMM), and sarcomatoid malignant mesothelioma (SMM). The median survival is 9–12 months, with a 5-year survival of 5%. It is observed that EMM has a better prognosis compared with BMM and SMM [4]. More recently, it has been recognized that the clinical prognosis may also change in specific histologic subtypes and grading of EMM [1].

One of the most significant challenges in the cytopathological and histopathological diagnosis is the separation between reactive mesothelial cells and MPM. Reactive mesothelial hyperplasia may have atypical cells and mimic MPM, particularly in the context of infections, collagen vascular disease, pulmonary embolism, and pulmonary infarction [5]. The diagnosis may become more difficult for pathologists in cases with unusual variants since several morphologic changes have been described, such as deciduoid, clear cell, small cell, signet ring cell, pleomorphic, adenomatoid-like, and lymphohistiocytoid appearances [6]. Another challenge is the distinction between reactive stromal changes and SMM. In reactive conditions, the densest proliferation of cells is close to the surface; in contrast, SMM is more uniformly cellular through the thickness of the pleura [7].

Ancillary studies are useful mainly in small biopsies and cytology. The combination of a large panel of biomarkers has been evaluated through immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), enzyme-linked immunosorbent assays, and chemiluminescent enzyme immunoassays [8], [9]. The main ancillary study used by the pathologist is the IHC due to its cost-effectiveness and simplicity. Several IHC markers as mesothelial markers (CKAE1/AE3, calretinin, CK5/6, WT1, D2–40, HEG1) and epithelial markers (MOC-31, BerEP4, claudin-4) have been used to distinguish MPM, reactive hyperplasia or metastatic tumor [10]. However, these have not proven to be a specific biomarker to discriminate between benign and malignant cells. In recent years, new markers evaluated by IHC and FISH have shown high sensitivity and specificity, and some of them have been associated with prognosis [2]. Among the new markers are BAP1, MTAP, MET, 5-hmC, EZH2, HEG1, and GLUT1 [2], [11]. In line with the preceding discussion, this systematic review aims to assess the diagnostic efficacy of IHC markers commonly utilized to identify malignant pleural mesothelioma (MPM) and its subtypes, particularly regarding sensitivity and specificity.