Objective: The aim of this study was to evaluate whether the immunocytochemical expression of cell proliferation markers, such as minichromosome maintenance protein 7 (MCM 7), geminin, topoisomerase II alpha (topo IIα) and Ki-67, which are different types of cell proliferation markers, could be useful for their differential diagnosis in reactive mesothelial cells and malignant mesothelioma cells obtained from body cavity fluids. Study Design: Samples diagnosed and later histologically confirmed as reactive mesothelial cells (39 cases) or malignant mesothelioma (32 cases) in body cavity fluids were examined. Immunocytochemical staining of MCM 7, geminin, topo IIα and Ki-67 was performed with the immunoperoxidase polymer method. Results: Labeling indices (LIs) of MCM 7 (cutoff value 20.0%; sensitivity 100%; specificity 100%), geminin (cutoff value 4.5%; sensitivity 88.0%; specificity 70.0%), topo IIα (cutoff value 11.0%; sensitivity 88.0%; specificity 92.0%) and Ki-67 (cutoff value 15.3%; sensitivity 78.0%; specificity 79.0%) of malignant mesothelioma cells were significantly higher than those of reactive mesothelial cells. Conclusion: LIs of MCM 7, geminin and topo IIα can be reliable tools for the differential diagnosis of reactive mesothelial cells and malignant mesothelioma cells.

1.
Sterman DH, Albelda SM: Advances in the diagnosis, evaluation, and management of malignant pleural mesothelioma. Respirology 2005;10:266-283.
2.
Robinson BW, Lake RA: Advances in malignant mesothelioma. N Engl J Med 2005;353:1591-1603.
3.
Nasser H, Kuntzman TJ: Pleural effusion in women with a known adenocarcinoma: the role of immunostains in uncovering another hidden primary tumor. Acta Cytol 2011;55:438-444.
4.
Spieler P, Gloor F: Identification of types and primary sites of malignant tumors by examination of exfoliated tumor cells in serous fluids: comparison with the diagnostic accuracy on small histologic biopsies. Acta Cytol 1985;29:753-767.
5.
Bottles K, Reznicek MJ, Holly EA, Ahn DK, Layfield LJ, Cohen MB: Cytologic criteria used to diagnose adenocarcinoma in pleural effusions. Mod Pathol 1991;4:677-681.
6.
Rakha EA, Patil S, Abdulla K, Abdulkader M, Chaudry Z, Soomro IN: The sensitivity of cytologic evaluation of pleural fluid in the diagnosis of malignant mesothelioma. Diagn Cytopathol 2010;38:874-879.
7.
Granados R, Cibas ES, Fletcher JA: Cytogenetic analysis of effusions from malignant mesothelioma: a diagnostic adjunct to cytology. Acta Cytol 1994;38:711-717.
8.
Husain AN, Colby T, Ordonez N, Krausz T, Attanoos R, Beasley MB, Borczuk AC, Butnor K, Cagle PT, Chirieac LR, Churg A, Dacic S, Fraire A, Galateau-Salle F, Gibbs A, Gown A, Hammar S, Litzky L, Marchevsky AM, Nicholson A, Roggli V, Travis WD, Wick M: Guidelines for pathologic diagnosis of malignant mesothelioma: 2012 update of the Consensus Statement from the International Mesothelioma Interest Group. Arch Pathol Lab Med 2012;136:1-21.
9.
Kimura F, Kawamura J, Watanabe J, Kamoshida S, Kawai K, Okayasu I, Kuwao S: Significance of cell proliferation markers (minichromosome maintenance protein 7, topoisomerase II alpha and Ki-67) in cavital fluid cytology - can we differentiate reactive mesothelial cells from malignant cells? Diagn Cytopathol 2010;38:161-167.
10.
McGarry TJ, Kirschner MW: Geminin, an inhibitor of DNA replication, is degraded during mitosis. Cell 1998;93:1043-1053.
11.
Wohlschlegel JA, Dwyer BT, Dhar SK, Cvetic C, Walter JC, Dutta A: Inhibition of eukaryotic DNA replication by geminin binding to Cdt1. Science 2000;290:2309-2312.
12.
Lygerou Z, Nurse P: Cell cycle: license withheld - geminin blocks DNA replication. Science 2000;290:2271-2273.
13.
Shrestha P, Saito T, Hama S, Arifin MT, Kajiwara Y, Yamasaki F, Hidaka T, Sugiyama K, Kurisu K: Geminin: a good prognostic factor in high-grade astrocytic brain tumors. Cancer 2007;109:949-956.
14.
Gonzalez MA, Tachibana KE, Chin SF, Callagy G, Madine MA, Vowler SL, Pinder SE, Laskey RA, Coleman N: Geminin predicts adverse clinical outcome in breast cancer by reflecting cell-cycle progression. J Pathol 2004;204:121-130.
15.
Yoshida K, Oyaizu N, Dutta A, Inoue I: The destruction box of human Geminin is critical for proliferation and tumor growth in human colon cancer cells. Oncogene 2004;23:58-70.
16.
Sherman ME, Jimenez-Joseph D, Gangi MD, Rojas-Corona RR: Immunostaining of small cytologic specimens: facilitation with cell transfer. Acta Cytol 1994;38:18-22.
17.
Akobeng AK: Understanding diagnostic tests 3: receiver operating characteristic curves. Acta Paediatr 2007;96:644-647.
18.
Sato A, Torii I, Okamura Y, Yamamoto T, Nishigami T, Kataoka TR, Song M, Hasegawa S, Nakano T, Kamei T, Tsujimura T: Immunocytochemistry of CD146 is useful to discriminate between malignant pleural mesothelioma and reactive mesothelium. Mod Pathol 2010;23:1458-1466.
19.
Shomori K, Nishihara K, Tamura T, Tatebe S, Horie Y, Nosaka K, Haruki T, Hamamoto Y, Shiomi T, Nakabayashi M, Ito H: Geminin, Ki67, and minichromosome maintenance 2 in gastric hyperplastic polyps, adenomas, and intestinal-type carcinomas: pathobiological significance. Gastric Cancer 2010;13:177-185.
20.
Ito K, Sasano H, Yabuki N, Matsunaga G, Sato S, Kikuchi A, Yajima A, Nagura H: Immunohistochemical study of Ki-67 and DNA topoisomerase II in human endometrium. Mod Pathol 1997;10:289-294.
21.
Yabuki N, Sasano H, Kato K, Ohara S, Toyota T, Nagura H, Miyaike M, Nozaki N, Kikuchi A: Immunohistochemical study of DNA topoisomerase II in human gastric disorders. Am J Pathol 1996;149:997-1006.
22.
Taheri ZM, Mehrafza M, Mohammadi F, Khoddami M, Bahadori M, Masjedi MR: The diagnostic value of Ki-67 and repp86 in distinguishing between benign and malignant mesothelial proliferations. Arch Pathol Lab Med 2008;132:694-697.
23.
Hasteh F, Lin GY, Weidner N, Michael CW: The use of immunohistochemistry to distinguish reactive mesothelial cells from malignant mesothelioma in cytologic effusions. Cancer Cytopathol 2010;118:90-96.
24.
Chen G, Bhojani MS, Heaford AC, Chang DC, Laxman B, Thomas DG, Griffin LB, Yu J, Coppola JM, Giordano TJ, Lin L, Adams D, Orringer MB, Ross BD, Beer DG, Rehemtulla A: Phosphorylated FADD induces NF-κB, perturbs cell cycle, and is associated with poor outcome in lung adenocarcinomas. Proc Natl Acad Sci USA 2005;102:12507-12512.
25.
Spugnini EP, Campioni M, D'Avino A, Caruso G, Citro G, Baldi A: Cell-cycle molecules in mesothelioma: an overview. J Exp Clin Cancer Res 2007;26:443-449.
26.
Tachibana KE, Gonzalez MA, Coleman N: Cell-cycle-dependent regulation of DNA replication and its relevance to cancer pathology. J Pathol 2005;205:123-129.
27.
Heck MM, Hittelman WN, Earnshaw WC: Differential expression of DNA topoisomerase I and II during the eukaryotic cell cycle. Proc Natl Acad Sci USA 1988;85:1086-1090.
28.
Tani EM, Christensson B, Porwit A, Skoog L: Immunocytochemical analysis and cytomorphologic diagnosis on fine needle aspirates of lymphoproliferative disease. Acta Cytol 1988;32:209-215.
29.
Cakir E, Demirag F, Aydin M, Unsal E: Cytopathologic differential diagnosis of malignant mesothelioma, adenocarcinoma and reactive mesothelial cells: a logistic regression analysis. Diagn Cytopathol 2009;37:4-10.
30.
Sakuma N, Kamei T, Ishihara T: Ultrastructure of pleural mesothelioma and pulmonary adenocarcinoma in malignant effusions as compared with reactive mesothelial cells. Acta Cytol 1999;43:777-785.
31.
Bedrossian CW: Special stains, the old and the new: the impact of immunocytochemistry in effusion cytology. Diagn Cytopathol 1998;18:141-149.
32.
Pu RT, Pang Y, Michael CW: Utility of WT-1, p63, MOC31, mesothelin, and cytokeratin (K903 and CK5/6) immunostains in differentiating adenocarcinoma, squamous cell carcinoma, and malignant mesothelioma in effusions. Diagn Cytopathol 2008;36:20-25.
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