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Immunohistochemical Evaluation of Minichromosome Maintenance Protein 7 (MCM7), Topoisomerase IIα, and Ki-67 in Diffuse Malignant Peritoneal Mesothelioma Patients Using Tissue Microarray

  • Colorectal Cancer
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Purpose

Immunohistochemistry and tissue microarray (TMA) were used to perform a prognostic analysis of markers related to cell proliferation in diffuse malignant peritoneal mesothelioma (DMPM).

Methods

Clinicopathologic data were extracted from a prospectively collected database containing cases of peritoneal mesothelioma treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in the National Cancer Institute of Milan from 1995 to 2013. Eighty-one DMPM patients were recruited and their tissue samples were used to construct TMAs. We evaluated the immunoexpressions of markers related to cell proliferation—topoisomerase IIα, minichromosome maintenance protein 7 (MCM7), and Ki-67—and then conducted a multivariate Cox model to identify the predictors of overall survival (OS) and progression-free survival (PFS) among the following parameters: age, sex, Eastern Cooperative Oncology Group (ECOG) performance status, baseline serum albumin, Charlson Comorbidity Index, previous systemic chemotherapy, histological subtype (epithelioid vs. biphasic/sarcomatoid), peritoneal cancer index, completeness of cytoreduction (CC), and proliferative biological markers.

Results

The rates of high/intermediate immunoreactivity were 95 % for topoisomerase IIα and 90 % for MCM7, and the median Ki-67 labeling index was 5 %. The independent predictors of OS were baseline serum albumin >3.5 g/dl, CC, and Ki-67 >5 %, whereas those for PFS were an ECOG performance status of 0, baseline serum albumin >3.5 g/dl, Charlson Comorbidity Index >3, previous systemic chemotherapy, morbidity G3–5, and Ki-67 >5 %. The remaining biological markers were not associated with outcome.

Conclusions

Ki-67 was found to be a new powerful determinant of outcome. Patients with a Ki-67 labeling index >5 % carry a very poor prognosis and do not benefit from the combined procedure. Further studies should be conducted to confirm the present data.

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References

  1. Peto J, Decarli A, La Vecchia C, Levi F, Negri E. The European mesothelioma epidemic. Br J Cancer. 1999;79(3–4):666–72.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. DeVita V, Hellman S, Rosenberg S. Cancer: principles and practice of oncology. 7th ed. Philadelphia (PA): Lippincott Williams &Wilkins; 2004.

    Google Scholar 

  3. Loggie BW, Fleming RA, McQuellon RP, Russell GB, Geisinger KR, Levine EA. Prospective trial for the treatment of malignant peritoneal mesothelioma. Am Surg. 2001;67(10):999–1003.

    CAS  PubMed  Google Scholar 

  4. Yan TD, Deraco M, Baratti D, Kusamura S, Elias D, Glehen O, et al. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for malignant peritoneal mesothelioma: multi-institutional experience. J Clin Oncol. 2009;27(36):6237–42.

    Article  PubMed  Google Scholar 

  5. Zaffaroni N, Costa A, Pennati M, et al. Survivin is highly expressed and promotes cell survival in malignant peritoneal mesothelioma. Cell Oncol. 2007;29:453–466.

    CAS  PubMed  Google Scholar 

  6. Villa R, Daidone MG, Motta R, Venturini L, De Marco C, Vannelli A, et al. Multiple mechanisms of telomere maintenance exist and differentially affect clinical outcome in diffuse malignant peritoneal mesothelioma. Clin Cancer Res. 2008;14(13):4134–40.

    Article  CAS  PubMed  Google Scholar 

  7. Tuteja N, Tuteja R. Prokaryotic and eukaryotic DNA helicases. Eur J Biochem. 2004;271:1835–1848.

    Article  CAS  PubMed  Google Scholar 

  8. Pucci B, De Felice M, Rossi M, Onesti S, Pisani FM. Amino acids of the Sulfolobus solfataricus mini–chromosome maintenance-like DNA helicase involved in DNA binding/remodeling. J Biol Chem. 2004;279:49222–49228.

    Article  CAS  PubMed  Google Scholar 

  9. Tye BK. MCM proteins in DNA replication. Annu Rev Biochem. 1999;68:649–686.

    Article  CAS  PubMed  Google Scholar 

  10. Li SS, Xue WC, Khoo US, et al. Replicative MCM7 protein as a proliferation marker in endometrial carcinoma: a tissue microarray and clinicopathological analysis. Histopathology. 2005;46:307–313.

    Article  CAS  PubMed  Google Scholar 

  11. Nishihara K, Shomori K, Fujioka S, et al. Minichromosome maintenance protein 7 in colorectal cancer: implication of prognostic significance. Int J Oncol. 2008;33:245–51.

    CAS  PubMed  Google Scholar 

  12. Fujioka S, Shomori K, Nishihara K, et al. Expression of minichromosome maintenance 7 (MCM 7) in small lung adenocarcinomas (pT1): prognostic implication. Lung Cancer. 2009;65(2):223–9.

    Article  PubMed  Google Scholar 

  13. Bechert T, Diekman S, Arndt-Jovin DJ. Human 170 kDa and 180 kDa topoisomerase II bind preferentially to curved and left handed linear DNA. J Biomol Struct Dyn. 1994;12:605–623.

    Article  CAS  PubMed  Google Scholar 

  14. Wang JC. Cellular roles of DNA topoisomerases: a molecular perspective. Nat Rev Mol Cell Biol. 2002;3:430–440.

    Article  CAS  PubMed  Google Scholar 

  15. Ito K, Sasano H, Yabuki N, et al. Immunohistochemical study of Ki-67 and DNA topoisomerase II in human endometrium. Mod Pathol. 1997;10:289–294.

    CAS  PubMed  Google Scholar 

  16. Yabuki N, Sasano H, Kato K, et al. Immunohistochemical study of DNA topoisomerase II in human gastric disorders. Am J Pathol. 1996;149:997–1006.

    PubMed Central  CAS  PubMed  Google Scholar 

  17. Brown DC, Gatter KC. Monoclonal antibody Ki-67: its use in histopathology. Histopathology. 1990;17:489–503.

    Article  CAS  PubMed  Google Scholar 

  18. Scholzen T, Gerdes J. The Ki-67 proten: from the known and the unknown. J Cell Physiol. 2000;182:311–322.

    Article  CAS  PubMed  Google Scholar 

  19. Kononen J, Bubendorf L, Kallioniemi A, et al. Tissue microarray for high-throughput molecular profiling of tumor specimens. Nat Med. 1998;4;844–847.

    Article  CAS  PubMed  Google Scholar 

  20. Deraco M, Baratti D, Kusamura S, et al. Surgical technique of parietal and visceral peritonectomy for peritoneal surface malignancies. J Surg Oncol. 2009;100:321-8.

    Article  PubMed  Google Scholar 

  21. Rossi CR, Foletto M, Mocellin S, et al. Hyperthermic intraoperative intraperitoneal chemotherapy with cisplatin and doxorubicin in patients who undergo cytoreductive surgery for peritoneal carcinomatosis and sarcomatosis: phase I study. Cancer. 2002;94:492–499.

    Article  CAS  PubMed  Google Scholar 

  22. Hinterberger M, Reineke T, Storz M, Weder W, Vogt P, Moch H. D2-40 and calretinin: a tissue microarray analysis of 341 malignant mesotheliomas with emphasis on sarcomatoid differentiation. Mod Pathol. 2007;20:248–55.

    Article  CAS  PubMed  Google Scholar 

  23. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chron Dis. 1987;40:373–383.

    Article  CAS  PubMed  Google Scholar 

  24. Sugarbaker PH. Results of treatment of 385 patients with peritoneal surface spread of appendiceal malignancy. Ann Surg Oncol. 1999;6:727-731.

    Article  CAS  PubMed  Google Scholar 

  25. Kusamura S, Baratti D, Deraco M. Multidimensional analysis of the learning curve for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in peritoneal surface malignancies. Ann Surg. 2012;255(2):348–56.

    Article  PubMed  Google Scholar 

  26. Jacquet P, Sugarbaker PH. Current methodologies for clinical assessment of patients with peritoneal carcinomatosis. J Exp Clin Cancer Res. 1996;15:49–58.

    Google Scholar 

  27. Younan R, Kusamura S, Baratti D, et al. Morbidity, toxicity, and mortality classification systems in the local regional treatment of peritoneal surface malignancy. J Surg Oncol. 2008;98:253–7.

    Article  PubMed  Google Scholar 

  28. Gupta D, Lis CG. Pretreatment serum albumin as a predictor of cancer survival: a systematic review of the epidemiological literature. Nutr J. 2010;9:69.

    Article  PubMed Central  PubMed  Google Scholar 

  29. Harrell FE Jr, Lee KL, Mark DB. Multivariable prognostic models: Issues in developing models, evaluating assumptions and adequacy, and measuring and reducing errors. Stat Med. 1996;15:361–387.

    Article  PubMed  Google Scholar 

  30. Efron B, Tibshirani RJ. An introduction to the bootstrap. New York: Chapman and Hall; 1993.

    Book  Google Scholar 

  31. Nonaka D, Kusamura S, Baratti D, Casali P, Cabras AD, Younan R, et al. Diffuse malignant mesothelioma of the peritoneum: a clinicopathological study of 35 patients treated locoregionally at a single institution. Cancer. 2005;104(10):2181–8.

    Article  PubMed  Google Scholar 

  32. Schaarschmidt D, Landenburger EM, Keller C, Knippers R. Human Mcm proteins at a replication origin during to G1 to S phase transition. Nucleic Acids Res. 2002;30:4176–4185.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Morgarete M, Heck S, Hittelman WN, Earnshaw WC. Differential expression of DNA topoisomerase I and II during the eukaryotic cell cycle. Proc Natl Acad Sci U S A. 1988;85:1086–1090.

    Article  Google Scholar 

  34. Kimura F, Okayasu I, Kakinuma H, Satoh Y, Kuwao S, Saegusa M, et al. Differential diagnosis of reactive mesothelial cells and malignant mesothelioma cells using the cell proliferation markers minichromosome maintenance protein 7, geminin, topoisomerase II alpha and Ki-67. Acta Cytol. 2013;57(4):384–90.

    Article  CAS  PubMed  Google Scholar 

  35. Kritpracha K, Hanprasertpong J, Chandeying V, Dechsukhum C, Geater A. Survival analysis in advanced epithelial ovarian carcinoma in relation to proliferative index of MIB-1 immunostaining. J Obstet Gynaecol Res. 2005;31(3):268–76.

    Article  PubMed  Google Scholar 

  36. Salminen E, Palmu S, Vahlberg T, Roberts PJ, Söderström KO. Increased proliferation activity measured by immunoreactive Ki67 is associated with survival improvement in rectal/recto sigmoid cancer. World J Gastroenterol. 2005;11(21):3245–9.

    Article  PubMed Central  PubMed  Google Scholar 

  37. Pathmanathan N, Balleine RL. Ki67 and proliferation in breast cancer. J Clin Pathol. 2013;66(6):512–6.

    Article  CAS  PubMed  Google Scholar 

  38. Pillai K, Pourgholami MH, Chua TC, Morris DL. Ki67-BCL2 index in prognosis of malignant peritoneal mesothelioma. Am J Cancer Res. 2013;3(4):411–23.

    PubMed Central  PubMed  Google Scholar 

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Conflict of interest

Marcello Deraco, Antonello Cabras, Dario Baratti, and Shigeki Kusamura declare they have no conflicts of interest.

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Authors and Affiliations

  1. Peritoneal Surface Malignancy Program, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy

    Marcello Deraco MD, Dario Baratti MD & Shigeki Kusamura MD, PhD

  2. Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy

    Antonello Cabras MD

Authors
  1. Marcello Deraco MD
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  2. Antonello Cabras MD
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  3. Dario Baratti MD
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  4. Shigeki Kusamura MD, PhD
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Correspondence to Marcello Deraco MD.

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Deraco, M., Cabras, A., Baratti, D. et al. Immunohistochemical Evaluation of Minichromosome Maintenance Protein 7 (MCM7), Topoisomerase IIα, and Ki-67 in Diffuse Malignant Peritoneal Mesothelioma Patients Using Tissue Microarray. Ann Surg Oncol 22, 4344–4351 (2015). https://doi.org/10.1245/s10434-015-4498-z

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  • DOI: https://doi.org/10.1245/s10434-015-4498-z

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