All mesothelial tumors are positive for pan-cytokeratin and the cytokeratins 5/6/7/8/10/14/18 but typically lack the expression of cytokeratin 20. Consequently, the cytokeratin profile alone cannot discriminate between mesotheliomas and metastatic carcinomas. It is important to consider that submesothelial fibroblasts are usually positive for pan-cytokeratin and other keratins that maybe a source of misinterpretation.

Calretinin is an intracellular neuron-specific calcium-binding vitamin D-dependent protein expressed in various epithelial, mesenchymal, and central and peripheral neurogenic tissue types. Calretinin is strongly expressed in normal and neoplastic mesothelial cells and considered as an important mesothelioma marker (Fig. 15.1). Calretinin is also a marker for mast cells and steroid-producing cells and tumors derived from these cells, namely, sex cord-stromal tumors including granulosa cell tumor, Sertoli and Leydig cell tumors, gonadoblastoma, and gynandroblastoma in addition to adrenocortical tumors. About one third of squamous cell carcinomas shows also different calretinin expression intensity. Calretinin is also widely expressed in different soft tissue tumors such as synovial sarcoma, chondrosarcoma, desmoplastic small round cell tumor, lipoma, and liposarcoma [4, 5]. Moreover, calretinin is an optimal marker to highlight ganglion cells in colonic biopsies for the diagnosis of Hirschsprung disease.

Calretinin has a wide expression spectrum, and the calretinin positivity alone is not enough for the diagnosis of mesothelioma.

Thrombomodulin (also known as endothelial anticoagulant protein, clustered as CD141) is a transmembrane glycoprotein expressed on the surface of endothelial cells and taking part in the regulation of intravascular coagulation. The expression of thrombomodulin is characteristic for other cell and tissue types including mesothelial cells, squamous epithelial cells, and transitional epithelium of the urinary tract. Thrombomodulin is a useful screening antibody for mesothelioma, transitional cell carcinoma, and squamous cell carcinoma in addition to vascular tumors (Fig. 15.2). Thrombomodulin is usually negative in sarcomatoid mesothelioma. To discriminate between thrombomodulin-positive tumors, it is important to use other more specific markers. Thrombomodulin is constantly negative in renal cell carcinoma, prostatic carcinoma, gastrointestinal adenocarcinoma, and endometrioid carcinoma.

Mesothelin is a glycoprotein located on the cell surface of mesothelial cells in addition of some other types of epithelial cells.

Mesothelin labels mesothelioma in addition to other carcinoma types including ovarian, pancreatic, and pulmonary carcinoma and adenocarcinomas. Generally, mesothelin is a screening antibody and cannot be considered as a specific mesothelioma marker. Sarcomatoid mesothelioma is negative for mesothelin.

WT-1 is one of the important mesothelioma markers discussed in a previous chapter. In mesothelioma cells, WT-1 has a nuclear expression pattern and can be used as the double stain in combination with other markers exhibiting membranous stain.

Podoplanin (also known as D2-40) is a mucoprotein expressed on the membrane of lymphatic endothelium discussed in the chapter of vascular tumors. Podoplanin is not specific for lymphatic endothelium but also expressed in other cell and tumor types such as meningeal cells, germ cells and germ cell tumors, mesothelial cells and mesothelioma in addition to many other mesenchymal tumors (Fig. 15.3) [6, 7].

Glucose transporter 1 (GLUT1) is a member of the GLUT transporter family and a membrane-associated erythrocyte glucose transport protein maintaining the basal glucose transport in most cell types. GLUT1 is not a tissue-specific marker but expressed in a wide range of epithelial and non-epithelial tumors. In diagnostic histopathology, GLUT1 is a potential marker for malignant transformation as it is overexpressed in many types of malignant epithelial and non-epithelial tumors. It is helpful marker to discriminate between malignant mesothelioma and reactive proliferation of mesothelial cells. GLUT1 is a helpful marker to distinguish between hemangioma usually positive for GLUT1 and vascular malformation, pyogenic granuloma, and granulation tissue lacking the expression of GLUT1.

GLUT1 is a hypoxia-inducible factor (HIF) target gene which is also induced by the hypoxia-inducible factor 1α (HIF-1α) [8]. Consequently, hypoxic areas will also overexpress GLUT1.

IMP3 is a cytoplasmic oncofetal protein mediating RNA trafficking and cell growth expressed in fetal tissue and different premalignant and malignant lesions. Benign adult tissue usually lacks the expression of IMP3 with the exception of the ovarian and testicular tissue, placenta, endocrine cells, and brain. In routine immunohistochemistry, IMP3 is used to discriminate between malignant and reactive proliferative lesions. Similar to GLUT1, IMP3 is a helpful marker to discriminate between mesothelioma and reactive mesothelial proliferation, as the majority of benign mesothelial cells are negative for IMP3 (Fig. 15.4) [9].

IMP3 is also a selective marker for Hodgkin cells; however, it can be also found some extrafollicular blasts or cells of B-cell lymphoma. Furthermore, IMP3 is a helpful marker to discriminate between serous endometrial carcinoma positive for IMP3 and endometrioid carcinoma negative for IMP3 [10].