Comparison of the effect of different techniques for measurement of Ki67 proliferation on reproducibility and prognosis prediction accuracy in breast cancer

  1. Einar Gudlaugsson1,
  2. Ivar Skaland1,
  3. Emiel A M Janssen1,
  4. Rune Smaaland2,
  5. Zhiming Shao3,
  6. Anais Malpica4,
  7. Feja Voorhorst5,
  8. Jan P A Baak1,3

Article first published online: 11 SEP 2012

DOI: 10.1111/j.1365-2559.2012.04329.x

Issue

Histopathology

Histopathology

Volume 61, Issue 6, pages 1134–1144, December 2012

Additional Information

How to Cite

Gudlaugsson, E., Skaland, I., Janssen, E. A. M., Smaaland, R., Shao, Z., Malpica, A., Voorhorst, F. and Baak, J. P. A. (2012), Comparison of the effect of different techniques for measurement of Ki67 proliferation on reproducibility and prognosis prediction accuracy in breast cancer. Histopathology, 61: 1134–1144. doi: 10.1111/j.1365-2559.2012.04329.x

Author Information

  1. 1

    Department of Pathology, Stavanger University Hospital, Stavanger, Norway

  2. 2

    Oncology, Stavanger University Hospital, Stavanger, Norway

  3. 3

    Department of Breast Surgery, Fudan University Cancer Hospital, Shanghai, China

  4. 4

    Departments of Pathology and Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

  5. 5

    Department of Epidemiology and Biostatistics, Vrije Universiteit Medical Center, Amsterdam, the Netherlands

*Professor J P A Baak, MD, PhD, FRCPath, FICP(Hon), FIAC(Hon), Department of Pathology, Stavanger University Hospital, Armauer Hansen Road 20, N-4068 Stavanger, Norway. e-mail: jpabaak47@yahoo.com

Publication History

  1. Issue published online: 28 NOV 2012
  2. Article first published online: 11 SEP 2012
  3. Accepted manuscript online: 28 MAY 2012 10:05PM EST
  4. Date of submission 13 September 2011 Accepted for publication 24 May 2012

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Keywords:

  • breast cancer;
  • digital image analysis;
  • Ki67;
  • prognosis;
  • proliferation;
  • quantification;
  • reproducibility

Gudlaugsson E, Skaland I, Janssen E A M, Smaaland R, Shao Z, Malpica A, Voorhorst F & Baak J P A (2012) Histopathology Comparison of the effect of different techniques for measurement of Ki67 proliferation on reproducibility and prognosis prediction accuracy in breast cancer

Aims:  The proliferation factor Ki67 is prognostic in breast cancer and included in international therapy guidelines, but measurement procedures differ between laboratories. We compared the reproducibility and prognostic value of different Ki67 sampling and measurement methods.

Methods and results:  In 237 T1,2N0M0 breast cancers without adjuvant systemic treatment, strictly standardized section thickness, automated antigen retrieval and immunohistochemistry were used. The percentages of Ki67-positive nuclei were assessed using (i) a ‘quick-scan rapid estimate’, (ii) ocular-square-guided counts by independent pathologists, (iii) computerized point-grid-sampling interactive morphometry (CIM) and (iv) automated digital image analysis (DIA). Quick-scan rapid estimates were poorly reproducible. The optimal prognostic thresholds of Ki67 counts by two pathologists differed greatly (4%, 14%; kappa: 0.36), with many therapeutic differences. CIM-Ki67 and DIA-Ki67 were strongly prognostic (P < 0.0001) and reproducible. DIA-Ki67 (threshold: 6.5%) was the strongest and most robust prognosticator (the threshold could vary from 4 to 15% without significant prognostic loss). Ki67 was prognostically strongest in the periphery of the tumour.

Conclusion:   In node-negative breast cancer without adjuvant systemic treatment, Ki67% by DIA, but not subjective counts, is reproducible and prognostically strong. This casts serious doubt on therapeutic guidelines using subjective counts of Ki67.

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