Objective: Claudin-3 and claudin-4 have recently been reported as promising targets for the detection and diagnosis of cancer. This study was designed to evaluate the diagnostic value of claudin-3 and claudin-4 immunoreactivity to distinguish metastatic adenocarcinoma cells (MAC) from reactive mesothelial cells (RMC) in effusions. Study Design: Claudin-3 and claudin-4 immunocytochemical staining was performed on 234 cell block specimens, including 194 malignant effusions with MAC and 40 benign effusions with RMC. Any degree of membranous staining was considered positive. Results: Claudin-3 was positive in 190 (97.9%) out of 194 cases with MAC and in 3 (7.5%) out of 40 cases with RMC. Claudin-4 immunoreactivity was seen in all 194 (100%) cases with MAC and in 11 (27.5%) out of 40 cases with RMC. In all claudin-3- or claudin-4-positive RMC samples, the area of positive staining was <25% of the cells. Claudin-3 and claudin-4 efficiently discriminated between MAC and RMC (p < 0.001 for both), and claudin-3 was more specific than claudin-4 in differentiating between MAC and RMC (p < 0.05). Conclusion: These results suggest that claudin-3 and claudin-4 are good candidates to be included as MAC markers in the panel of antibodies to distinguish MAC from RMC in effusion specimens.

Koss LG, Melamed MR: Effusions in the presence of cancer; in Koss LG, Melamed MR (eds): Koss' Diagnostic Cytology and Its Histopathological Bases. Philadelphia, Lippincott Williams and Wilkins, 2006, pp 919-948.
Pereira TC, Saad RS, Liu Y, Silverman JF: The diagnosis of malignancy in effusion cytology: a pattern recognition approach. Adv Anat Pathol 2006;13:174-184.
Mohanty SK, Dey P: Serous effusions: diagnosis of malignancy beyond cytomorphology: an analytic review. Postgrad Med J 2003;79:569-574.
Chowdhuri SR, Fetsch P, Squires J, Kohn E, Filie AC: Adenocarcinoma cells in effusion cytology as a diagnostic pitfall with potential impact on clinical management: a case report with brief review of immunomarkers. Diagn Cytopathol 2014;42:253-258.
Choi SJ, Choi YI, Kim L, Park IS, Han JY, Kim JM, Chu YC: Preparation of compact agarose cell blocks from the residues of liquid-based cytology samples. Korean J Pathol 2014;48:351-360.
Saleh HA, El-Fakharany M, Makki H, Kadhim A, Masood S: Differentiating reactive mesothelial cells from metastatic adenocarcinoma in serous effusions: the utility of immunocytochemical panel in the differential diagnosis. Diagn Cytopathol 2009;37:324-332.
Ikeda K, Tate G, Suzuki T, Kitamura T, Mitsuya T: Diagnostic usefulness of EMA, IMP3, and GLUT-1 for the immunocytochemical distinction of malignant cells from reactive mesothelial cells in effusion cytology using cytospin preparations. Diagn Cytopathol 2011;39:395-401.
Su XY, Li GD, Liu WP, Xie B, Jiang YH: Cytological differential diagnosis among adenocarcinoma, epithelial mesothelioma, and reactive mesothelial cells in serous effusions by immunocytochemistry. Diagn Cytopathol 2011;39:900-908.
Hjerpe A, Ascoli V, Bedrossian C, Boon M, Creaney J, Davidson B, Dejmek A, Dobra K, Fassina A, Field A, Firat P, Kamei T, Kobayashi T, Michael CW, Önder S, Segal A, Vielh P: Guidelines for cytopathologic diagnosis of epithelioid and mixed type malignant mesothelioma. Complementary statement from the International Mesothelioma Interest Group, also endorsed by the International Academy of Cytology and the Papanicolaou Society of Cytopathology. Cytojournal 2015;12:26.
Tsukita S, Furuse M, Itoh M: Multifunctional strands in tight junctions. Nat Rev Mol Cell Biol 2001;2:285-293.
Schneeberger EE, Lynch RD: The tight junction: a multifunctional complex. Am J Physiol Cell Physiol 2004;286:C1213-C1228.
Krause G, Winkler L, Mueller SL, Haseloff RF, Piontek J, Blasig IE: Structure and function of claudins. Biochim Biophys Acta 2008;1778:631-645.
Hewitt KJ, Agarwal R, Morin PJ: The claudin gene family: expression in normal and neoplastic tissues. BMC Cancer 2006;6:186.
Furuse M, Sasaki H, Tsukita S: Manner of interaction of heterogeneous claudin species within and between tight junction strands. J Cell Biol 1999;147:891-903.
Morin PJ: Claudin proteins in human cancer: promising new targets for diagnosis and therapy. Cancer Res 2005;65:9603-9606.
Ouban A, Ahmed AA: Claudins in human cancer: a review. Histol Histopathol 2010;25:83-90.
Ding L, Lu Z, Lu Q, Chen YH: The claudin family of proteins in human malignancy: a clinical perspective. Cancer Manag Res 2013;5:367-375.
Soini Y, Kinnula V, Kahlos K, Pääkkö P: Claudins in differential diagnosis between mesothelioma and metastatic adenocarcinoma of the pleura. J Clin Pathol 2006;59:250-254.
Facchetti F, Lonardi S, Gentili F, Bercich L, Falchetti M, Tardanico R, Baronchelli C, Lucini L, Santin A, Murer B: Claudin 4 identifies a wide spectrum of epithelial neoplasms and represents a very useful marker for carcinoma versus mesothelioma diagnosis in pleural and peritoneal biopsies and effusions. Virchows Arch 2007;451:669-680.
Ordóñez NG: Value of claudin-4 immunostaining in the diagnosis of mesothelioma. Am J Clin Pathol 2013;139:611-619.
Ordóñez NG: Value of PAX8, PAX2, claudin-4, and h-caldesmon immunostaining in distinguishing peritoneal epithelioid mesotheliomas from serous carcinomas. Mod Pathol 2013;26:553-562.
Mohamed F, Vincent N, Cottier M, Peoc'h M, Merrouche Y, Patouillard B, Paul S, Genin C: Improvement of malignant serous effusions diagnosis by quantitative analysis of molecular claudin 4 expression. Biomarkers 2010;15:315-324.
Lonardi S, Manera C, Marucci R, Santoro A, Lorenzi L, Facchetti F: Usefulness of claudin 4 in the cytological diagnosis of serosal effusions. Diagn Cytopathol 2011;39:313-317.
Afshar-Moghaddam N, Heidarpour M, Dashti S: Diagnostic value of claudin-4 marker in pleural and peritoneal effusion cytology: does it differentiate between metastatic adenocarcinoma and reactive mesothelial cells? Adv Biomed Res 2014;3:161.
Jo VY, Cibas ES, Pinkus GS: Claudin-4 immunohistochemistry is highly effective in distinguishing adenocarcinoma from malignant mesothelioma in effusion cytology. Cancer Cytopathol 2014;122:299-306.
Kleinberg L, Holth A, Fridman E, Schwartz I, Shih IeM, Davidson B: The diagnostic role of claudins in serous effusions. Am J Clin Pathol 2007;127:928-937.
Kim JH, Kim GE, Choi YD, Lee JS, Lee JH, Nam JH, Choi C: Immunocytochemical panel for distinguishing between adenocarcinomas and reactive mesothelial cells in effusion cell blocks. Diagn Cytopathol 2009;37:258-261.
Cho JS, Kim GE, Lee JS, Lee JH, Nam JH, Choi C: Diagnostic usefulness of MUC1 and MUC4 for distinguishing between metastatic adenocarcinoma cells and reactive mesothelial cells in effusion cell blocks. Acta Cytol 2013;57:377-383.
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