Proliferative index using Ki-67 index in reactive mesothelial versus metastatic adenocarcinoma cells in serous fluid


1 Department of Pathology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran

2 Department of Gastroenterology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran


Background: The cytological diagnoses of serous effusions are usually made by routine cytomorphology with certainty. However, overlapping cases sometimes exist between reactive mesothelial and adenocarcinoma cells. We tried to evaluate the diagnostic utility of proliferative index using a Ki-67 monoclonal antibody in distinguishing between reactive mesothelial cells and adenocarcinoma in serous effusions.
Materials and Methods: Paraffin blocks and H and E stained slides of peritoneal and pleural fluid cell blocks were retrieved from cytology archive of Alzahra Hospital, Medical University of Isfahan, between 2006 and 2010, from among 1025 slides which were screened to ascertain their appropriate diagnoses. Among of these 80 paraffin-embedded cell blocks, 40 cases for each reactive and adenocarcinoma groups were selected. The proliferative index was calculated by using the Ki 67 monoclonal antibody against nuclear proteins.
Results: The mean ages of the patients in the reactive mesothelial and adenocarcinoma groups were 60.58 and 58.45 years, respectively. The gender distribution for the malignant group included 23 cases (%57.5) of females and 17 cases (42.5%) of males. This ratio for reactive group included 14 cases (35%) and 26 cases (65%). The mean of Ki-67 index in adenocarcinomatous cells was 17.15 (SD=15.11) and in reactive mesothelial cells was 3.58 (SD= 3.59) (P=0.001). We consider to using the proliferative marker of Ki-67 on benign and malignant lesions revealed 12% as cut off level. The means of Ki-67 index according to serousal spaces were included: Pleura: 10.56 (SD= 13.06) and peritoneum: 10.03 (SD= 12.78), (P=0.9).
Conclusion: Ki-67 index is useful immunostaining panel for differentiation of mesothelial and adenocarcinoma cells in malignancy like ovarian carcinoma that sometimes mimics mesothelial morphology.


1. Hong EK. The cytopathology of body cavity fluid. Korean J Cytopathol 2008;19:72-85.  Back to cited text no. 1
2. Naylor B. Pleural, peritoneal, and pericardial effusions. In: Bibbo M, Wilbur D, editors. Comprehensive cytopathology. 3 rd ed. Philadelphia: Saunders - Elevier; 2008. p. 515-65.  Back to cited text no. 2
3. Weinstein LJ, Cibas ES. Effusions (Pleural, Pericardial, and Peritoneal and Peritoneal Washing Cytopathology). In: Atkinson BF, editor. Atlas of diagnostic cytopathology. 2nd ed. Philadelphia: Saunders; 2003. p. 106-10.  Back to cited text no. 3
4. Sayed DM, el-Attar MM, Hussein AA. Evaluation of flow cytometric immunophenotyping and DNA analysis for detection of malignant cells in serosal cavity fluids. Diagn Cytopathol 2009;37:498-504.  Back to cited text no. 4
5. Fetsch PA, Abati A. Immunocytochemistry in effusion cytology. Cancer Cytopathol 2001;93:293-308.  Back to cited text no. 5
6. Rahmani A, Zahedi Dehghani M, Afshar Moghaddam N, Heidarian H, Tahririan R. HBME-1 immunostaining in reactive mesothelial versus metastatic adenocarcinoma cells in serous fluid. Indian J Pathol Microbiol 2011;54:460-3.  Back to cited text no. 6
[PUBMED]  Medknow Journal  
7. Gerdes J, Lemke H, Baisch H, Wacker HH, Schwab U, Stein H. Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67. J Immunol 1984;133:1710-5.  Back to cited text no. 7
8. Muñoz E, Gómez F, Paz JI, Casado I, Silva JM, Corcuera MT, et al. Ki-67 immunolabeling in pre-malignant lesions and carcinoma of the prostate. Histological correlation and prognostic evaluation. Eur J Histochem 2003;47:123-8.  Back to cited text no. 8
9. Radovanovic-Dinic B, Nagorni A, Katic V, Stamenkovic I, Zlatic A. An immunohistochemical study of Ki-67 in colorectal adenoma. Med Arch 2009;63:16-8.  Back to cited text no. 9
10. Preusser M, Heinzl H, Gelpi E, Höftberger R, Fischer I, Pipp I, et al. Ki67 index in intracranial ependymoma: A promising histopathological candidate biomarker. Histopathology 2008;53:39-47.  Back to cited text no. 10
11. Wiesner FG, Magener A, Fasching PA, Wesse J, Bani MR, Rauh C, et al. Ki 67 as a prognostic molecular marker in routine clinical use in breast cancer patients. Breast 2009;18:135-41.  Back to cited text no. 11
12. Cazzaniga M, Severi G, Casadio C, Chiapparini L, Veronesi U, Decensi A. Atypia and Ki-67 Expression from Ductal Lavage in Women at Different Risk for Breast Cancer. Cancer Epidemiol Biomarkers Prev 2006;15:1311-5.  Back to cited text no. 12
13. Dhall D, Mertens R, Bresee C, Parakh R, Wang HL, Li M, et al. Ki-67 proliferative index predicts progression-free survival of patients with well-differentiated ileal neuroendocrine tumors. Hum Pathol 2012;43:489-95.  Back to cited text no. 13
14. Shidham VB, Falzon M. Serous effusions. In: Gray W, Kocjan G, editors. Diagnostic cytopathology. 3rd ed. London: Churchill-Livingstone-Elsevier; 2010. p. 119.  Back to cited text no. 14
15. Cibas ES. Pleural, pericardial and peritoneal fluids. In: Cibas ES, Ducatman BS, editors. Cytology. 3rd ed. Philadelphia: Saunders -Elsevier; 2009. p. 131-2.  Back to cited text no. 15
16. Churg A, Cagle PT, Roggli VL: Separation of benign and malignant mesothelial proliferations. In: AFIP Atlas of tumor pathology. Series 4. Tumors of the serosal membrane. Silver Spring, Maryland: ARP Press; 2006. p. 83-101.  Back to cited text no. 16
17. Rosai J. Special techniques in surgical pathology. In: Rosai J .Rosai and Ackerman`s surgical pathology. USA: Mosby; 2011. p. 45-65.  Back to cited text no. 17
18. Loukas CG, Wilson GD, B. Vojnovic B, Linney A. An image analysis-based approach for automated counting of cancer cell nuclei in tissue sections. Cytometry Part A 2003;55:30-42.  Back to cited text no. 18
19. Gerdes J. Ki-67 and other proliferation markers useful for immunohistological diagnostic and prognostic evaluations in human malignancies. Semin Cancer Biol 1990;1:199-206.  Back to cited text no. 19
20. Haegens A, van der Vliet A, Butnor KJ, Heintz N, Taatjes D, Hemenway D, et al. Asbestos-induced lung inflammation and epithelial cell proliferation are altered in myeloperoxidase-null mice. Cancer Res 2005;65:9670-7.  Back to cited text no. 20
21. Bendary ME, Elalfy H, Zalata K. Predictors of hepatocyte proliferative activity in chronic hepatitis B and C vs. steatohepatitis as assessed by the monoclonal antibody MIB1-Ki-67. Arab J Gastroenterol 2011;12:119-24.  Back to cited text no. 21
22. Gerdes J, Li L, Schlueter C, Duchrow M, Wohlenberg C, Gerlach C, et al. Immunobiochemical and molecular biologic characterization of the cell proliferation-associated nuclear antigen that is defined by monoclonal antibody Ki-67. Am J Pathol 1991;138:867-73.  Back to cited text no. 22
23. Cattoretti G, Becker MH, Key G, Duchrow M, Schluter C, Galle J, et al. Monoclonal antibodies against recombinant parts of the Ki-67 antigen (MIB 1 and MIB 3) detect proliferating cells in microwave-processed formalin-fixed paraffin sections. J Pathol 1992;168:357-63.  Back to cited text no. 23
24. Sington JD, Morris LS, Nicholson AG, Coleman N. Assessment of cell cycle state may facilitate the histopathological diagnosis of malignant mesothelioma. Histopathology 2003;42:498-502.  Back to cited text no. 24
25. Schonherr A, Bayer M, Bocking A. Diagnostic and prognostic value of Ki67 proliferation fraction in serous effusions. Cell Oncol 2004;26:57-62.  Back to cited text no. 25
26. Mohammad Taheri Z, Mehrafza M, Mohammadi F, Khoddami M, Bahadori M. Proliferative marker in distinction between benign and malignant mesothelial proliferations. Tanaffos 2006;5:9-12.  Back to cited text no. 26
27. Terada T. Immunohistochemical profile of normal mesothelium and histiocytic/methothelial hyperplasia: A case report. Int J Clin Exp Pathol 2011;4:631-6.  Back to cited text no. 27
28. Schönherr A, Bayer M, Böcking A. Diagnostic and prognostic value of Ki67 proliferation fraction in serous effusions. Cell Oncol 2004;26:57-62.  Back to cited text no. 28
29. Kimura F, Kawamura J, Watanabe J, Kamoshida S, Kawai K, Okayasu L, et al. Significance of cell proliferation markers (Minichromosome maintenance protein 7, topoisomerase IIalpha and Ki-67) in cavital fluid cytology: Can we differentiate reactive mesothelial cells from malignant cells? Diagn Cytopathol 2010;38:161-7.  Back to cited text no. 29
30. Hasteh F, Lin GY, Weidner N, Michael CW. The use of immunohistochemistry to distinguish reactive mesothelial cells from malignant mesothelioma in cytologic effusions. Cancer Cytopathology 2010;118:90-6.  Back to cited text no. 30
31. Minato H, Nojima T, Kurose N, Kinoshita E. Adenomatoid tumor of the pleura. Pathol Int 2009;59:567-71.  Back to cited text no. 31