Journal of Cancer Research and Clinical Oncology

, Volume 122, Issue 11, pp 687–692 | Cite as

The important prognostic value of Ki-67 expression as determined by image analysis in breast cancer

  • T. Pietiläinen
  • P. Lipponen
  • S. Aaltomaa
  • M. Eskelinen
  • V-M. Kosma
  • K. Syrjänen
Original Paper Clinical Oncology


A series of 191 female breast carcinomas (with long-term follow-up) were analysed immunohistochemically (with a monoclonal MIB1 antibody) for Ki-67 (a proliferation marker) expression with special reference to well-established prognostic factors and patient survival. Expression of Ki-67 was directly related to the S-phase fraction (P<0.0001), the volume-corrected mitotic index (P<0.0001), histological grade (P<0.0001), the apoptotic index (P<0.0001), oestrogen and progesterose receptor content (P<0.0001 for both) and p53 accumulation (P=0.001). No correlation was found between Ki-67 expression and lymph node status (P=0.25), metastasis at operation (n=0.81) or tumour size (n=0.38). The proliferation rate, as measured by image analysis of Ki-67 expression, predicted survival in the entire cohort (P=0.001) and in axillary-lymph-node-negative (ANN) patients (P=0.003). The difference in recurrence-free survival between the high- and low-expression groups was greatest in ANN tumours, 40% (P=0.008). In axillary-lymph-node-positive tumours, the Ki-67 expression was not significantly related to recurrence-free survival (P=0.723). The results of multivariate survival analysis showed that tumour size, axillary lymph node status, and mitotic index were independent prognostic factors in the entire series whereas, in ANN cases, tumour size and Ki-67 labelling were independent prognostic factors. These findings imply that Ki-67 expression could be an important prognostic determinant in breast cancer. Because of the evident loss of the predictive power of tumour size in the 1990s, the prognostic value of Ki-67 expression may even be accentuated in the currently diagnosed small breast carcinomas.

Key words

Cell proliferation Breast cancer Image analysis Ki-67. Prognosis 



index the volume-corrected mitotic index


axillary lymph node negative


axillary lymph node positive


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Aaltomaa S, Lipponen P, Eskelimen M, Kosma VM, Marin S, Alhava E, Syrjanen K (1991) Prognostic scores combining clinical, histological and morphometric variables in assessment of the disease outcome in female breast cancer. Int J Cancer 49:886–892PubMedGoogle Scholar
  2. Aaltomaa S, Lipponen P, Eskelinen M, Kosma VM, Marin S, Alhava E Syrjanen K (1992) Mitotic indexes as prognostic predictors in female breast cancer. J Cancer Res Clin Oncol 118:75–81PubMedGoogle Scholar
  3. Beck T, Weller EE, Brumm C, Wilkens C, Knapstein PG (1995) Usefullness of immunohistochemical staining for p53 in the prognosis of breast carcinomas: correlations with established prognostic parameters and with the proliferation marker, MIB-1. Gynecol Oncol 57:96–104.PubMedGoogle Scholar
  4. Bloom HJG, Richardson WW (1957) Histological grading and prognosis in breast cancer. Br J Cancer 11:359–377PubMedGoogle Scholar
  5. Bouzubar N, Walker KJ, Griffiths K, Ellis IO, Elston CW, Robertson JF, Blamey RW, Nicholson RI (1989) Ki67 immunostaining in primary breast cancer: pathological and clinical associations. Br J Cancer 59:943–947PubMedGoogle Scholar
  6. Brown DC, Gatter KC (1990) Monoclonal antibody Ki-67: its use in histopathology. Histopathology 17:489–503Google Scholar
  7. Cattoretti G, Becker MH, Key G, Duchrow M, Schluter C, Galle J, Gerdes J (1992) 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 168:357–363PubMedGoogle Scholar
  8. Chauvel P, Courdi A, Gioanni J, Vallicinoi J, Santini J, Demard F (1989) The labelling index: a prognostic factor in head and neck carcinoma. Radiother Oncol 14:231–237PubMedGoogle Scholar
  9. Eskelinen M, Lipponen P, Papinaho S, Aaltomaa S, Kosma VM, Klemi P, Syrjanen K (1992) DNA flow cytometry, nuclear morphometry, mitotic indices and steroid receptors as independent prognostic factors in female breast cancer. Int J Cancer 51:555–561PubMedGoogle Scholar
  10. Gasparini G, Boracchi P, Verderio P, Bevilacqua P (1994) Cell kinetics in human brest cancer: comparison between the prognostic value of the cytofluorimetric S-phase fraction and that of the antibodies to Ki-67 and PCNA antigens detected by immunocytochemistry. Int J Cancer 57:822–829PubMedGoogle Scholar
  11. Gavrieli Y, Sherman Y, Ben-Sasson SA (1992) Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J Cell Biol 119:493–501PubMedGoogle Scholar
  12. Huovinen R, Collany (1994) Cell loss in dimethylbenz(a)anthraceneinduced rat mammary carcinoma treated with toremifene and ovariectomy. Tumor Biol 15:345–353Google Scholar
  13. Isola J, Visakorpi T, Holli K, Kallioniemi OP (1992) Association of overexpression of tumour suppressor protein p53 with rapid cell proliferation and poor prognosis in node-negative breast cancer patients. J Natl Cancer Inst 84:1109–1114PubMedGoogle Scholar
  14. Jensen EV (1991) Steroid hormone receptors. Curr Top Pathol 83:365–431PubMedGoogle Scholar
  15. Kennedy JC, Badawy N, el, DeRose PB, Cohen C (1992) Comparison of cell prolifration in breast carcinoma using image analysis (Ki-67) and flow cytometric systems. Anal Quant Cytol Histol 14:304–311PubMedGoogle Scholar
  16. Kerr JF, Winterford CM, Harmon BV (1994) Apoptosis. Its significance in cancer and cancer therapy. Cancer 73:2013–2026PubMedGoogle Scholar
  17. Lee E, Lesu M (1972) A computer program for comparing k samples with right censored data. Comput Prog Biomed 2:315–320Google Scholar
  18. Liotta LA (1992) Cancer cell invasion and metastasis. Sci Am 266:54–59, 62–63Google Scholar
  19. Martinazzi M, Crivelli F, Zampatti C, Martinazzi S (1993) Relationship between p53 expression and other progonostic factors in human breast carcinoma. An immunohistochemical study. Am J Clin Pathol 100:213–217PubMedGoogle Scholar
  20. Pavelic ZP, Pavelic L, Lower EE, Gapany M, Gapany S, Barker EA Preisler HD (1992)c-myc, c-erb B-2, and Ki-67 expression in normal breast tissue and in invasive and noninvassive breast carcinoma. Cancer Res 52:2597–2602PubMedGoogle Scholar
  21. Pietiläinen T, Lipponen P, Aaltomaa S, Eskelinen M, Kosma VM, Syrjanen K (1995) Expression of p53 protein has no independent prognostic value in breast cancer. J Pathol 177:225–232PubMedGoogle Scholar
  22. Pinder SE, Wencyk P, Sibbering DM, Bell JA, Elston CW, Nicholson R, Robertson JF, Blamey RW Ellis IO (1995) Assessment of the new proliferation marker MIBI in breast carcinoma using image analysis: associations with other prognostic factors and survival. Br J Cancer 71:146–149PubMedGoogle Scholar
  23. Railo M, Nordling S, von Boguslawsky K, Leivonen M, Kyllonen L, von Smitten K (1993) Prognostic value of Ki-67 immunolabelling in primary operable breast cancer. Br J Cancer 68:579–583PubMedGoogle Scholar
  24. Rudas M, Gnant MF, Mittlbock M, Neumayer R, Kummer A, Jakesz R, Reiner G, Reiner A (1994) Thymidine labeling index and Ki-67 growth fraction in breast cancer: comparison and correlation with prognosis. Breast Cancer Res Treat 32:165–175PubMedGoogle Scholar
  25. Schulte Hermann R, Grasl Kraupp B, Bursch W (1994) Tumour development and apoptosis. Int Arch Allergy Immunol 105:363–367PubMedGoogle Scholar
  26. Silvestrini R, Benini E, Daidone MG, Veneroni S, Boracchi P, Cappelletti V, Di Fronzo G, Veronesi U (1993) p53 as an independent prognostic marker in lymph node-negative breast cancer patients. J Natl Cancer Inst 85:965–970PubMedGoogle Scholar
  27. Steller H (1995) Mechanisms and genes of cellular suicide. Science 267:1145–1449Google Scholar
  28. Vihko R, Jänne O, Kontula K, Syrjälä P (1980) Female sex steroid reseptor status in primary and metastatic breast carcinoma and its relationship to serum steroid and peptide hormone levels. Int J Can 26:13–21Google Scholar
  29. Walker NI, Harmon BV, Gobe GC, Kerr JFR (1988) Patterns of cell death. Methods Achiev Exp Pathol 13:18–54PubMedGoogle Scholar
  30. Weinder N, Moore DHI, Vartarian R (1994) Correlation of Ki-67 antigen expression with mitotic figure index and tumour grade in breast carcinoma using the novel “paraffin”-reactive MIBI antibody. Hum Pathol 25:337–342PubMedGoogle Scholar
  31. WHO (1981) Histological typing of breast tumours. In: International histological classification of tumours. 2, 2nd ed. World Health Organization, GenevaGoogle Scholar

Copyright information

© Springer-Verlag 1996

Authors and Affiliations

  • T. Pietiläinen
    • 1
  • P. Lipponen
    • 1
  • S. Aaltomaa
    • 2
  • M. Eskelinen
    • 2
  • V-M. Kosma
    • 1
  • K. Syrjänen
    • 1
  1. 1.Department of Pathology and Forensic MedicineUniversity of KuopioKuopioFinland
  2. 2.Department SurgeryUniversity of KuopioKuopioFinland

Personalised recommendations