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Correlation of growth fraction by Ki-67 and proliferating cell nuclear antigen (PCNA) immunohistochemistry with histopathological parameters and prognosis in primary breast carcinomas

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Abstract

The immunoreactivity for Ki-67 and PCNA was investigated in 487 patients with primary breast carcinomas using MIB-1 (Immunotech, France) and PC-10 (DAKO, Denmark) as primary antibodies. Formalin-fixed and paraffin-embedded tissue sections were used. The immunoreactivity for Ki-67 and PCNA was found to be independent of the length of fixation if the sections were pretreated in a microwave oven in citrate buffer and distilled water, respectively. The immunostaining was evaluated semiquantitatively.

High Ki-67 score (more than 1% positive tumour cells) and PCNA over-expression (more than 25% positive tumour cells) were correlated with clinicopathological parameters such as large tumour size, high histological grade (poor differentiation), and absence of steroid hormone receptors, which are parameters of an aggressive phenotype of the tumour.

In univariate analysis of survival data, both Ki-67 and PCNA were parameters of a poor overall survival in both lymph node-positive and -negative patients.

In multivariate analysis using a Cox model stratified by nodal status, Ki-67 and PCNA failed to be of prognostic significance whereas classical histopathological parameters such as tumour size and histological grade turned out to be of independent prognostic significance in both lymph node-positive and -negative patients, while progesterone receptors were of independent prognostic significance only in lymph node-positive patients.

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References

  1. Ewertz M, Carstensen B: Trends in breast cancer incidence and mortality in Denmark, 1943–1982. Int J Cancer 41: 46–51, 1988

    PubMed  Google Scholar 

  2. Rosai J: Ackerman's surgical pathology. The C.V. Mosby Company, St. Louis, 1989

    Google Scholar 

  3. Meyer J, McDivitt R, Stone K, Prey M, Bauer W: Practical breast carcinoma cell kinetics: a review and update. Breast Cancer Res Treat 4: 79–88, 1984

    PubMed  Google Scholar 

  4. Meyer J, Province M: Proliferation index of breast carcinoma by thymidine labelling: prognostic power independent of stage, estrogen and progesterone receptor. Breast Cancer Res Treat 12: 191–204, 1988

    PubMed  Google Scholar 

  5. Tubiana M, Koscielny S: Cell kinetics, growth rate and the natural history of breast cancer. The Heuson memorial lecture. Eur J Cancer Clin Oncol 24: 9–14, 1988

    PubMed  Google Scholar 

  6. Tubiana M, Pejovic M, Koscielny S, Chvaudra N, Malaise E: Growth rate, kinetics of tumour cell proliferation and long-term outcome in human breast cancer. Int J Cancer 44: 17–22, 1989

    PubMed  Google Scholar 

  7. Tubiana M, Courdi A: Cell proliferation kinetics in human solid tumours: relation to probability of metastasis, dissemination, and long-term survival. Radiother Oncol 15: 1–18, 1989

    PubMed  Google Scholar 

  8. McGuire W, Tandon A, Allred DC, Chamness G, Clark G: How to use prognostic factors in axillary node-negative breast cancer patients. J Natl Cancer Inst 82:1006–1015,1990

    PubMed  Google Scholar 

  9. Graem N, Helweg-Larsen K: Mitotic activity and delay in fixation of tissues. Acta Pathol Microbiol Scand (A) 87: 375–379, 1979

    Google Scholar 

  10. Donhuijsen K, Schmidt U, Horche H, van Beuningen D, Budach V: Changes in mitotic rate and cell cycle fractions caused by delayed fixation. Hum Pathol 21: 709–714, 1990

    PubMed  Google Scholar 

  11. Clayton F: Pathologic correlates of survival in 378 lymph node-negative infiltrating ductal carcinomas: mitotic count is the best single predictor. Cancer 68: 1309–1317, 1991

    PubMed  Google Scholar 

  12. Gerdes J, Lemke H, Baisch H, Wacker H-H, Schwab U, Stein H: Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67. J Immunol 133: 1710–1715, 1984

    PubMed  Google Scholar 

  13. Gerdes J, Lelle R, Pickartz H, Heidenreich W, Schwarting R, Kurtsiefer L, Stauch G, Stein H: Growth fractions in breast cancers determined in situ with monoclonal antibody Ki-67. J Clin Pathol 39: 977–980, 1986

    PubMed  Google Scholar 

  14. Mathews M, Bernstein R, Franza B, Garrels J: Identity of the proliferating cell nuclear antigen and cyclin. Nature 303: 374–376, 1984

    Google Scholar 

  15. Celis J, Bravo R, Larsen P, Fey SJ: Cyclin: a nuclear protein whose level correlates with the proliferative state of normal as well as transformed cells. Leuk Res 8: 143–147, 1984

    PubMed  Google Scholar 

  16. Garcia R, Coltera M, Gown A: Analysis of proliferative grade using anti-PCNA/cyclin monoclonal antibodies in fixed, embedded tissues. Am J Pathol 134: 733–739, 1989

    PubMed  Google Scholar 

  17. Siitonen S, Kallioniemi O-P, Isola J: Proliferating cell nuclear antigen immunohistochemistry using monoclonal antibody 19A2 and a new antigen retrieval technique has prognostic impact in archival paraffin-embedded node-negative breast cancer. Am J Pathol 142: 1081–1089, 1993

    PubMed  Google Scholar 

  18. Battersby S, Andersson T: Correlation of proliferative activity in breast tissue using PCNA/cyclin. Hum Pathol 21: 781, 1990

    PubMed  Google Scholar 

  19. Haerslev T, Jacobsen GK: Proliferating cell nuclear antigen (PCNA) in breast carcinomas. An immunohistochemical study with correlation to histopathological features and prognostic factors. Virchow Archiv A 424: 39–46, 1994

    Google Scholar 

  20. Dervan P, Magee H, Buckley C, Carney D: Proliferating cell nuclear antigen counts in formalin-fixed paraffin-embedded tissue correlate with Ki-67 in fresh tissue. Am J Clin Pathol 97: S21-S28, 1992

    PubMed  Google Scholar 

  21. Andersen K, Mouridsen H, Castberg T, Fischerman K, Andersen J, Hou-Jensen K, Brincker H, Johansen H, Henriksen E, Rorth M, Rossing N: Organization of the Danish adjuvant trials in breast cancer. Danish Med Bull 28: 102–106, 1981

    PubMed  Google Scholar 

  22. World Health Organization: Histological typing of breast tumours. WHO, Geneva, 1968

    Google Scholar 

  23. Bloom HJG, Richardson WW: Histological grading and prognosis in breast cancer. Br J Cancer 11: 359–377, 1957

    PubMed  Google Scholar 

  24. Kaplan E, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53: 457–481, 1958

    Google Scholar 

  25. Cox D, Oakes D: Analysis of survival data. London, 1984

  26. Haerslev T, Jacobsen GK: Microwave processing for immunohistochemical demonstration of proliferating cell nuclear antigen (PCNA) in formalin-fixed and paraffin-embedded tissue. APMIS 102: 395–400, 1994

    PubMed  Google Scholar 

  27. Sabatti E, Gerdes J, Ghelinzoni F, Poggi S, Zucchini L, Melili G, Grigioni F, Del Vecchio M, Leoncini L, Falini B, Pileri S: Comparison between the monoclonal antibodies Ki-67 and PC-10 in 125 malignant lymphomas. J Pathol 169: 397–403, 1993

    PubMed  Google Scholar 

  28. Yu CC-W, Wilkinson N, Brito MJ, Buckley C, Fox H, Levison D: Patterns of immunohistochemical staining for proliferating nuclear antigen and p53 in benign and neoplastic human endometrium. Histopathology 23: 367–371, 1993

    PubMed  Google Scholar 

  29. Cattoretti G, Becker M, Key G, Duchrow M, Schlüter C, Galle J, Gerdes J: 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 168: 357–363, 1992

    PubMed  Google Scholar 

  30. Kurki P, Vanderlaan M, Dolbeare F, Gray J, Tan E: Expression of proliferating cell nuclear antigen (PCNA)/cyclin during the cell cycle. Exp Cell Res 166: 209–219, 1986

    PubMed  Google Scholar 

  31. Siitonen S, Isola J, Rantala I, Helin H: Intratumor variation in cell proliferation in breast carcinoma as determined by anti-PCNA monoclonal antibody and automated image analysis. Am J Clin Pathol 99: 226–231, 1993

    PubMed  Google Scholar 

  32. Suzuki K, Katoh R, Kawaoki A: Immunohistochemical demonstration of proliferating cell nuclear antigen (PCNA) in formalin-fixed, paraffin-embedded sections from rat and human tissues. Acta Histochem Cytochem 25: 13–21, 1992

    Google Scholar 

  33. Leong A-Y, Milios J, Tang S: Is immunolocalisation of proliferating cell nuclear antigen (PCNA) in paraffin sections a valid index of cell proliferation? Appl Immunohistochem 12: 127–135, 1993

    Google Scholar 

  34. He W, Meyer JS, Scrivner DL, Koehm S, Hughes J: Assessment of proliferating cell nuclear antigen (PCNA) in breast cancer using anti-PCNA PC10 and 19A2: correlation with 5-bromo-2′-deoxyuridine or tritiated thymidine labeling and flow cytometric analysis. Biotech & Histochem 69: 203–212, 1994

    Google Scholar 

  35. Barnard N, Hall P, Lemoine N, Kadar N: Proliferative index in breast carcinoma determined in situ by Ki-67 immunostaining and its relationship to clinical and pathological variables. J Pathol 152: 287–295, 1987

    PubMed  Google Scholar 

  36. Locker A, Birrell K, Bell J, Nicholson R, Elston C, Blamey R, Ellis I: Ki67 immunoreactivity in breast carcinoma: relationship to prognostic variables and short term survival. Eur J Surg Oncol 18: 224–229, 1992

    PubMed  Google Scholar 

  37. Vielh P, Chevillard S, Mosseri V, Donatini B, Magdelenat H: Ki67 index and S-phase fraction in human breast carcinomas. Comparison and correlations with prognostic factors. Am J Clin Pathol 94: 681–686, 1990

    PubMed  Google Scholar 

  38. Tahan S, Neuberg D, Dieffenbach A, Yacoub L: Prediction of early relapse and shortened survival in patients with breast cancer by proliferating cell nuclear antigen score. Cancer 71: 3552–3559, 1993

    PubMed  Google Scholar 

  39. Mango W, Hirchfield L, Bhuiya T, Harrison G, Mir R: Correlation of proliferating cell nuclear antigen (PCNA) and Ki-67 reactivity in primary breast carcinoma with hormone and disease-free survival. Conn Med 56: 667–669, 1992

    PubMed  Google Scholar 

  40. Linden MD, Ma CK, Kubus J, Brown RD, Zarbo RJ: Ki-67 and proliferating cell nuclear antigen, tumour proliferative indices in DNA diploid colorectal adenocarcinomas. Correlation with histopathologic characteristics and cell cycle analysis with two-color DNA flow cytometry. Am J Clin Pathol 100: 206–212, 1993

    PubMed  Google Scholar 

  41. Bravo R, MacDonald H: Existence of two populations of cyclins/proliferating cell nuclear antigen during the cell cycle: association with DNA replication sites. J Cell Biol 105: 1549–1554, 1987

    PubMed  Google Scholar 

  42. Aaltomaa S, Lipponen P, Eskelinen M, Kosma V-M, Marin S, Alhava E, Syrjänen K: Prognostic factors after 5 years follow-up in female breast cancer. Oncology 49: 49, 1993

    Google Scholar 

  43. Weikel W, Beck T, Mitze M, Knapstein P: Immunohistochemical evaluation of growth fractions in human breast cancers using monoclonal antibody Ki-67. Breast Cancer Res Treat 18: 149–154, 1991

    PubMed  Google Scholar 

  44. Gasparini S, Meli S, Pozza S, Cazzavilillan S, Beliacqua P: PC-10 antibody to proliferating cell nuclear antigen (PCNA) is not related to prognosis in human breast carcinomas. Growth Res 2: 145–150, 1992

    Google Scholar 

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Authors and Affiliations

  1. Department of Pathology, Gentofte Hospital, University of Copenhagen, Niels Andersensvej 65, DK-2900, Hellerup, Denmark

    Torben Haerslev & Grete Krag Jacobsen

  2. Danish Breast Cancer Cooperative Group (DBCG), Rigshospitalet, University of Copenhagen, Tagensvej 20, DK-2200, Copenhagen, Denmark

    Karin Zedeler

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  1. Torben Haerslev
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  2. Grete Krag Jacobsen
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  3. Karin Zedeler
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Haerslev, T., Jacobsen, G.K. & Zedeler, K. Correlation of growth fraction by Ki-67 and proliferating cell nuclear antigen (PCNA) immunohistochemistry with histopathological parameters and prognosis in primary breast carcinomas. Breast Cancer Res Tr 37, 101–113 (1996). https://doi.org/10.1007/BF01806492

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  • DOI: https://doi.org/10.1007/BF01806492

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