*3.3.3.1 Carcinoembryonic antigen (CEA)*

CEA is a recommended marker for discriminating between mesothelioma and adenocarcinoma in effusions [54] (**Figure 2F**). It has a high reported specificity (90%−100%) and variable sensitivity (43%−100%) [54, 55] in detecting adenocarcinoma in effusions and exhibits a strong membranous staining pattern [55]. Monoclonal CEA antibody is more commonly used in effusions and generally preferred over polyclonal antibody to avoid the nonspecific staining in background inflammatory cells [8]. CEA is less specific in tissue sections as carcinomas of various origins and well-differentiated neuroendocrine tumors are negative with monoclonal CEA antibodies on tissue sections [56].

### *3.3.3.2 Claudin-4 (CL-4)*

CL-4 belongs to a family of tight junction-associated proteins expressed in most epithelial cells but absent in mesothelial cells. CL-4 is a useful pan-carcinoma marker for serous effusion specimen, showing strong diffuse membranous expression pattern in 84%−96% adenocarcinomas and being negative in most mesotheliomas [57, 58]. CL-4 is useful also in tissue sections, where it has been expressed in 91% of carcinomas of different types and negative in mesothelioma [57]. CL-4 has a sensitivity of 85%−99% and specificity of 99%−100% in distinguishing carcinoma versus mesothelioma [57–61]. CL-4 is also very useful in detecting single tumor cells dispersed among heavy inflammatory reactions [61] or metastatic epithelial cells in serous effusions [8, 57, 61].

### *3.3.3.3 Ber-EP4*

Ber-EP4 is an epithelial cell adhesion molecule (TACSTD1) that shows a predominantly membranous pattern [55]. Mesothelial cells are shown negative for Ber-EP4 in most studies (**Figure 2G**) [8]. Ber-EP4 has a sensitivity of 76%−94%, and specificity of 84%−100% in detecting adenocarcinoma [8, 51, 54, 55]. It is also reportedly positive in 87%−100% of SCC cases [8, 32].

### *3.3.4 Additional markers for organ/differentiation specific differentiation*

In addition to general carcinoma markers, many antibodies can be helpful for detecting specific differentiation of cells and distinguishing mesothelioma from other malignancies in specific settings. **Table 2** summarizes some of their most common applications [7, 8, 62].


#### **Table 2.**

*Additional immunostains used for organ-specific differentiation of epithelioid mesothelioma.*
