Send to

Choose Destination
Mod Pathol. 2015 Jun;28(6):778-86. doi: 10.1038/modpathol.2015.38. Epub 2015 Feb 20.

An international study to increase concordance in Ki67 scoring.

Author information

Biometric Research Branch, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland, USA.
Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
Division of Pathology and Laboratory Medicine, European Institute of Oncology, Milan, Italy.
Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK.
Transformative Pathology, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
The Emmes Corporation, Rockville, Maryland, USA.
Indiana University Simon Cancer Center, Indianapolis, Indiana, USA.
Department of Pathology and Molecular Medicine, Juravinski Hospital and Cancer Centre, McMaster University, Hamilton, Ontario, Canada.
Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Lund, Sweden.
Montefiore Medical Center and the Albert Einstein College of Medicine, Bronx, New York, USA.
Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
PhenoPath Laboratories, Seattle, Washington, USA.
Lester and Sue Smith Breast Center and Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, USA.
Department of Laboratory Medicine and Pathology, University of Alberta, Alberta, Canada.
Department of Pathology, Kawasaki Medical School, Kurashiki City, Japan.
Department of Pathology, Hakuaikai Sagara Hospital, Matsubaracho, Kagoshima, Japan.
Department of Pathology, Centre Jean Perrin and Université d'Auvergne, Clermont-Ferrand, France.
Edinburgh Cancer Research Centre, Western General Hospital, Edinburgh, UK.
Department of Pathology, Jichi Medical University, Shimotsuke, Tochigi, Japan.
Institut Jules Bordet, Brussels, Belgium.
Birmingham Heart of England, National Health Service, Birmingham, UK.
Slagelse Hospital, Slagelse, Region Sjælland, Denmark.
Division of Pathology and Laboratory Medicine, European Institute of Oncology, and University of Milan, Milan, Italy.
Academic Department of Biochemistry, Royal Marsden Hospital, London, UK.
Breast Oncology Program, University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan, USA.


Although an important biomarker in breast cancer, Ki67 lacks scoring standardization, which has limited its clinical use. Our previous study found variability when laboratories used their own scoring methods on centrally stained tissue microarray slides. In this current study, 16 laboratories from eight countries calibrated to a specific Ki67 scoring method and then scored 50 centrally MIB-1 stained tissue microarray cases. Simple instructions prescribed scoring pattern and staining thresholds for determination of the percentage of stained tumor cells. To calibrate, laboratories scored 18 'training' and 'test' web-based images. Software tracked object selection and scoring. Success for the calibration was prespecified as Root Mean Square Error of scores compared with reference <0.6 and Maximum Absolute Deviation from reference <1.0 (log2-transformed data). Prespecified success criteria for tissue microarray scoring required intraclass correlation significantly >0.70 but aiming for observed intraclass correlation ≥0.90. Laboratory performance showed non-significant but promising trends of improvement through the calibration exercise (mean Root Mean Square Error decreased from 0.6 to 0.4, Maximum Absolute Deviation from 1.6 to 0.9; paired t-test: P=0.07 for Root Mean Square Error, 0.06 for Maximum Absolute Deviation). For tissue microarray scoring, the intraclass correlation estimate was 0.94 (95% credible interval: 0.90-0.97), markedly and significantly >0.70, the prespecified minimum target for success. Some discrepancies persisted, including around clinically relevant cutoffs. After calibrating to a common scoring method via a web-based tool, laboratories can achieve high inter-laboratory reproducibility in Ki67 scoring on centrally stained tissue microarray slides. Although these data are potentially encouraging, suggesting that it may be possible to standardize scoring of Ki67 among pathology laboratories, clinically important discrepancies persist. Before this biomarker could be recommended for clinical use, future research will need to extend this approach to biopsies and whole sections, account for staining variability, and link to outcomes.

[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center