Skip to main content
SpringerLink
Log in

Ki67-Tumorheterogenität vs. Assayheterogenität

Ki67: biological intertumor variance versus variance of assay

  • Hauptreferate: Tumorheterogenität
  • Published:
Der Pathologe Aims and scope Submit manuscript

Zusammenfassung

Seit der Erstbeschreibung in der Kieler Pathologie vor nunmehr 34 Jahren wurde die prognostische Aussagefähigkeit des immunhistochemischen Proliferationsmarkers Ki67 in zahlreichen retrospektiven und auch einigen prospektiven Studien bei Tumoren unterschiedlicher Histogenese demonstriert. Fehlende Standardisierung in der Auswertung hinsichtlich Feldauswahl, der zu analysierenden Mindestzellzahl, einer quantitativen oder semiquantitativen Zählweise stellen potentielle Quellen einer Assayheterogenität bei Ki67 dar. Hinzu kommen Varianzen in der immunhistochemischen Aufarbeitung und Darstellung. Ferner ist die Interpretation uneinheitlich, insbesondere, was die Grenzwerte zwischen hoher und niedriger Proliferation angeht. Wegen dieser vielzähligen methodischen Einschränkungen wurde Ki67 außerhalb Deutschlands und außerhalb der Pathologie als prognostischer Marker lange Zeit nicht ernst genommen. Hier hat in den letzten Jahren ein Meinungswandel eingesetzt. Trotz der die eigentlich darzustellende biologische Unterschiedlichkeit überlagernden potentiellen Assayheterogenität nimmt Ki67 mittlerweile beim Grading einiger Neoplasien, wie dem Mammakarzinom, den malignen Lymphomen und neuroendokrinen Tumoren eine wichtige Auxiliarfunktion wahr und wird in der klinischen Routine und in Studien zur Stratifizierung eingesetzt. Gerade wegen dieses weit verbreiteten Einsatzes erscheint es aber notwendig, die möglichen methodischen Limitationen ins Bewusstsein zu rufen, um Ki67 sinnvoll anzuwenden.

Abstract

Since its first description at the Institute of Pathology in Kiel more than 34 years ago, the immunohistochemical proliferation marker Ki67 has been shown to be of prognostic significance in a huge number of retrospective and even some prospective trials on malignant tumours of various tissue derivation. Lack of standardization in the evaluation provides potential sources of variance in assessment. Tumour area to be assessed, minimum number of cells to be analyzed, tedious counting cell by cell or semiquantitative eyeballing, choice of immunohistochemical techniques represent nonstandardized issues that potentially lead to considerable assay heterogeneity. In addition, interpretation is not homogeneous, in particular with regard to thresholds between high and low proliferative activity. Due to these numerous potential methodological limitations, for a long time Ki67 was not generally accepted as a prognostic marker, in particular outside Germany and by nonpathologists. However, in recent years a shift has taken place. Despite the challenge that biological heterogeneity may be hidden by differences in assay performance, Ki67 now plays an important auxiliary role in grading of malignant neoplasms such as breast cancer, neuroendocrine tumours and malignant lymphomas. In this context it is applied in clinical diagnostics as well as in clinical trials for the purpose of stratification. Because of its widespread use, it is of utmost importance to raise awareness of the potential methodological limitations in order to use Ki67 in a meaningful way.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Abb. 1
Abb. 2
Abb. 3

Literatur

  1. Boege F, Andersen A, Jensen S, Zeidler R, Kreipe H (1995) Proliferation-associated nuclear antigen Ki-S1 is identical with topoisomerase II alpha (1995). Delineation of a carboxy-terminal epitope with peptide antibodies. Am J Pathol 146:1302–1308

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Cheang MC, Chia SK, Voduc D, Gao D, Leung S, Snider J, Watson M, Davies S, Bernard PS, Parker JS, Perou CM, Ellis MJ, Nielsen TO (2009) Ki67 index, HER2 status, and prognosis of patients with luminal B breast cancer. J Natl Cancer Inst 101:736–750

    Article  CAS  Google Scholar 

  3. Christgen M, Winkens W, Kreipe HH (2014) Determination of proliferation in breast cancer by immunohistochemical detection of Ki67. Pathologe 35:54–60

    Article  CAS  Google Scholar 

  4. Christgen M, von Ahsen S, Christgen H, Länger F, Kreipe H (2015) The region-of-interest size impacts on Ki67 quantification by computer-assisted image analysis in breast cancer. Hum Pathol 46:1341–1349

    Article  Google Scholar 

  5. Denkert C, Loibl S, Müller BM, Eidtmann H, Schmitt WD, Eiermann W et al (2013) Ki67 levels as predictive and prognostic parameters in pretherapeutic breast cancer core biopsies: a translational investigation in the neoadjuvant GeparTrio trial. Ann Oncol 24(11):2786–2793. https://doi.org/10.1093/annonc/mdt350

    Article  CAS  PubMed  Google Scholar 

  6. De Azambuja E, Cardoso F, de Castro G Jr, Colozza M, Mano MS, Durbecq V et al (2007) Ki67 as prognostic marker in early breast cancer: a meta-analysis of published studies involving 12,155 patients. Br J Cancer 96:1504–1513

    Article  Google Scholar 

  7. Dowsett M, Nielsen TO, A’Hern R, Bartlett J, Coombes RC, Cuzick J et al (2011) International Ki67 in Breast Cancer Working Group. Assessment of Ki67 in breast cancer: recommendations from the International Ki67 in breast cancer working group. J Natl Cancer Inst 103:1656–1664

    Article  CAS  Google Scholar 

  8. Frierson HF Jr, Wolber RA, Berean KW, Franquemont DW, Gaffey MJ, Boyd JC et al (1995) Interobserver reproducibility of the Nottingham modification of the Bloom and Richardson histologic grading scheme for infiltrating ductal carcinoma. Am J Clin Pathol 103:195–198

    Article  Google Scholar 

  9. Gerdes J, Lemke H, Baisch H, Wacker HH, Schwab U, Stein H (1984) Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki67. J Immunol 133:1710–1715

    CAS  PubMed  Google Scholar 

  10. Lellé RJ, Heidenreich W, Stauch G, Gerdes J (1987) The correlation of growth fractions with histologic grading and lymph node status in human mammary carcinoma. Cancer 59:83–88

    Article  Google Scholar 

  11. Gluz O, Nitz UA, Christgen M, Kates RE, Shak S, Clemens M et al (2016) West German study group phase III planB trial: first prospective outcome data for the 21-gene recurrence score assay and concordance of prognostic markers by central and local pathology assessment. J Clin Oncol 34:2341–2349

    Article  Google Scholar 

  12. Goldhirsch A, Ingle JN, Gelber RD, Coates AS, Thürlimann B, Senn HJ, Panel members (2009) Thresholds for therapies: highlights of the St Gallen International Expert Consensus on the primary therapy of early breast cancer 2009. Ann Oncol 20:1319–1329

    Article  CAS  Google Scholar 

  13. Goldhirsch A, Wood WC, Coates AS, Gelber RD, Thürlimann B, Senn HJ, Panel members (2001) Strategies for subtypes – dealing with the diversity of breast cancer: highlights of the St.Gallen international expert consensus on the primary therapy of early breast cancer 2011. Ann Oncol 22:1736–1747

    Article  Google Scholar 

  14. Goldhirsch A, Winer EP, Coates AS, Gelber RD, Piccart-Gebhart M, Thürlimann B et al (2013) Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013. Ann Oncol 24:2206–2223

    Article  CAS  Google Scholar 

  15. Hall PA, McKee PH, Menage HD, Dover R, Lane DP (1993) High levels of p53 protein in UV-irradiated normal human skin. Oncogene 8:203–207

    CAS  PubMed  Google Scholar 

  16. Inwald EC, Klinkhammer-Schalke M, Hofstädter F, Zeman F, Koller M, Gerstenhauer M, Ortmann O (2013) Ki67 is a prognostic parameter in breast cancer patients: results of a large population-based cohort of a cancer registry. Breast Cancer Res Treat 139:539–552

    Article  CAS  Google Scholar 

  17. Jones RL, Salter J, A’Hern R, Nerurkar A, Parton M, Reis-Filho JS et al (2009) The prognostic significance of Ki67 before and after neoadjuvant chemotherapy in breast cancer. Breast Cancer Res Treat 116:53–68

    Article  CAS  Google Scholar 

  18. Kreipe H, Alm P, Olsson H, Hauberg M, Fischer L, Parwaresch R (1993) Prognostic significance of a formalin-resistant nuclear proliferation antigen in mammary carcinomas as determined by the monoclonal antibody Ki-S1. Am J Pathol 142:651–657

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Kwok TC, Rakha EA, Lee AH, Grainge M, Green AR, Ellis IO et al (2010) Histological grading of breast cancer on needle core biopsy: the role of immunohistochemical assessment of proliferation. Histopathology 57:212–219

    Article  Google Scholar 

  20. Lehr HA, Hansen DA, Kussick S, Li M, Hwang H, Krummenauer F et al (1999) Assessment of proliferative activity in breast cancer: MIB-1 immunohistochemistry versus mitotic figure count. Hum Pathol 30:1314–1320

    Article  CAS  Google Scholar 

  21. Raap M, Ließem S, Rüschoff J, Fisseler-Eckhoff A, Reiner A, Dirnhofer S, von Wasielewski R, Kreipe H (2017) Quality assurance trials for Ki67 assessment in pathology. Virchows Arch 471:501–508

    Article  CAS  Google Scholar 

  22. Mengel M, von Wasielewski R, Wiese B, Rüdiger T, Müller-Hermelink HK, Kreipe H (2002) Inter-laboratory and inter-observer reproducibility of immunohistochemical assessment of the Ki67 labelling index in a large multi-centre trial. J Pathol 198:292–299

    Article  Google Scholar 

  23. O’Shea AM, Rakha EA, Hodi Z, Ellis IO, Lee AH (2011) Histological grade of invasive carcinoma of the breast assessed on needle core biopsy – modifications to mitotic count assessment to improve agreement with surgical specimens. Histopathology 59:543–548

    Article  Google Scholar 

  24. Penault-Llorca F, André F, Sagan C, Lacroix-Triki M, Denoux Y, Verriele V et al (2009) Ki67 expression and docetaxel efficacy in patients with estrogen receptor-positive breast cancer. J Clin Oncol 27:2809–2815

    Article  CAS  Google Scholar 

  25. Scholzen T, Gerdes J (2000) The Ki67 protein: from the known and the unknown. J Cell Physiol 182:311–322

    Article  CAS  Google Scholar 

  26. Schwab U, Stein H, Gerdes J, Lemke H, Kirchner H, Schaadt M et al (1982) Production of a monoclonal antibody specific for Hodgkin and Sternberg-Reed cells of Hodgkin’s disease and a subset of normal lymphoid cells. Nature 1982(299):65–67

    Article  Google Scholar 

  27. Sheri A, Dowsett M (2012) Developments in Ki67 and other biomarkers for treatment decision making in breast cancer. Ann Oncol 23(Suppl 10):x219–x227

    Article  Google Scholar 

  28. Stuart-Harris R, Caldas C, Pinder SE, Pharoah P (2008) Proliferation markers and survival in early breast cancer: a systematic review and meta-analysis of 85 studies in 32,825 patients. Breast 17:323–334

    Article  CAS  Google Scholar 

  29. Varga Z, Diebold J, Dommann-Scherrer C, Frick H, Kaup D, Noske et al (2012) How reliable is Ki67 immunohistochemistry in grade 2 breast carcinomas? A QA study of the Swiss working group of breast and gynekopathologists. PLoS ONE 7:e37379

    Article  CAS  Google Scholar 

  30. Viale G, Giobbie-Hurder A, Regan MM, Coates AS, Mastropasqua MG, Dell’Orto P (2008) Prognostic and predictive value of centrally reviewed Ki67 labeling index in postmenopausal women with endocrine-responsive breast cancer: results from Breast International Group Trial 1‑98 comparing adjuvant tamoxifen with letrozole. J Clin Oncol 26:5569–5575

    Article  Google Scholar 

  31. Viale G, Regan MM, Mastropasqua MG, Maffini F, Maiorano E, Colleoni M (2008) Predictive value of tumor Ki67 expression in two randomized trials of adjuvant chemoendocrine therapy for node-negative breast cancer. J Natl Cancer Inst 100:207–212

    Article  CAS  Google Scholar 

  32. von Wasielewski R, Klöpper K, Lück HJ, Kreipe H (2006) Improvement of breast cancer grading in punch biopsies: grading with the Ki67 marker. Pathologe 27:337–345

    Article  Google Scholar 

  33. Yerushalmi R, Woods R, Ravdin PM, Hayes MM, Gelmon KA (2010) Ki67 in breast cancer: prognostic and predictive potential. Lancet Oncol 11:174–183

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institut für Pathologie, Medizinische Hochschule Hannover, Carl-Neuberg-Straße 1, 30625, Hannover, Deutschland

    H. Kreipe

Authors
  1. H. Kreipe
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to H. Kreipe.

Ethics declarations

Interessenkonflikt

H. Kreipe gibt an, dass kein Interessenkonflikt besteht.

Dieser Beitrag beinhaltet keine von den Autoren durchgeführten Studien an Menschen oder Tieren.

The supplement containing this article is not sponsored by industry.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kreipe, H. Ki67-Tumorheterogenität vs. Assayheterogenität. Pathologe 39 (Suppl 2), 272–277 (2018). https://doi.org/10.1007/s00292-018-0502-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00292-018-0502-2

Schlüsselwörter

Keywords

Search

Navigation