title: Inter-laboratory and inter-observer reproducibility of immunohistochemical assessment of the Ki-67 labelling index in a large multi-centre trial.
abstract: Proliferative activity of tumour cells, as assessed by the Ki-67 labelling index, has been suggested as a potential prognostic indicator in many neoplastic diseases. Meaningful application of the immunohistochemically determined tumour cell growth fraction in clinical decision-making requires information about its inter-laboratory reproducibility. To assess the reproducibility of Ki-67 determined growth fraction, a multi-centre immunohistochemical trial was performed with 172 participating laboratories, each testing 30 different tissue samples. Evaluating 5160 Ki-67 labelling indices with a newly developed tissue microarray, good inter-observer reproducibility but high inter-laboratory variability was found. Reassessment of all stainings revealed considerable inter-laboratory differences in the intensity and frequency of labelled nuclei, suggesting that antigen retrieval or staining techniques are predominantly responsible for the inter-laboratory variability found in this trial. Consequently, cut-off levels for Ki-67, suggested to distinguish prognostic subgroups in tumours, appear to have limited reproducibility in a multi-centre approach. It is concluded that there is a need to standardize the immunohistochemical determination of the Ki-67 labelling index when it is used as a prognostic indicator in surgical pathology.
authors.affiliation: Institut für Pathologie, Medizinische Hochschule Hannover, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Mengel
authors.forename: Reinhard
authors.initials: R
authors.lastname: von Wasielewski
authors.forename: Birgitt
authors.initials: B
authors.lastname: Wiese
authors.forename: Thomas
authors.initials: T
authors.lastname: Rüdiger
authors.forename: Hans Konrad
authors.initials: HK
authors.lastname: Müller-Hermelink
authors.forename: Hans
authors.initials: H
authors.lastname: Kreipe
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000473:pathology*; D002455:Cell Division; D005260:Female; D016591:Histocytological Preparation Techniques / Q000592:standards*; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000032:analysis*; D015588:Observer Variation; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D011379:Prognosis; D011785:Quality Assurance, Health Care; D015203:Reproducibility of Results; D013194:Staining and Labeling / Q000379:methods; D016707:Tissue Fixation / Q000379:methods
chemical_list: D014408:Biomarkers, Tumor; D019394:Ki-67 Antigen