An Intra- and Interobserver Reproducibility Analysis of the Ki-67 Proliferation Marker Assessment on Core Biopsies of Breast Cancer Patients and Its Potential Clinical Implications

Abstract

Objective: The Ki-67 proliferation index has received an important role in treatment tailoring and molecular classification of estrogen receptor-positive breast carcinomas. The aim was to analyze the reproducibility of assessing proliferation on the basis of Ki-67 immunohistochemistry. Methods: Thirty core biopsy samples of breast cancer patients were analyzed after immunostaining with B56, SP6 and MIB-1 monoclonal Ki-67 antibodies. All samples were evaluated twice and independently by 3 pathologists, with each observer performing his daily routine practice. The ratio of Ki-67-positive cells was estimated with 5% accuracy. Correlation was calculated for the results of each investigator for all pairs of antibodies and for the results of each antibody for all pairs of investigators. Ki-67 scores were divided into categories of either 4 quarters or into 3 groups reflecting the St. Gallen consensus recommendations with 15 and 30% as cutoff values. The reproducibility of classifying the tumors into these categories was assessed with ĸ statistics. Results: Altogether, 540 evaluations were made. Good to excellent correlation (Spearman’s and Pearson’s coefficient range 0.74–0.92 and 0.73–0.93, respectively) was noted for the pairwise comparison of antibodies by observer and of observers by antibody. The inter- and intraobserver reproducibility of the Ki-67 score classification into equal quarters (1–25, 26–50, 51–75 and 76–100%) or into 3 categories with cutoffs at 15 and 30% was fair to poor in the middle categories, but moderate to substantial in the low and high ranges. Interobserver differences in practice potentially impacted on less consistent classification. Conclusion: Our results indicate that the three different Ki-67 antibodies tested do not substantially influence the reproducibility of the estimated proliferation rates. Although reproducibility is better in the clinically more relevant distinction of high versus low proliferation, without standardization, the current practice of Ki-67 assessment in many laboratories does not allow proper and consistent therapeutic decision-making.

Tissue heterogeneity contributes to suboptimal precision of WHO 2010 scoring criteria for Ki67 labeling index in a subset of neuroendocrine neoplasms of the pancreascriteria for Ki67 labeling index in a subset of neuroendocrine neoplasms of the pancreas

“…Despite these efforts, it is probably still too early to recommend usage of Ki67 LI for management of patients with breast cancer [53,61,62]. Reproducibility of Ki67 scoring in breast cancer seems to be not enough to ensure consistent reporting [51,53,62,63]. Making therapeutic decisions for patients with breast cancer based on Ki67 scores should be made in caution [51,53,62,63].…”

“…Reproducibility of Ki67 scoring in breast cancer seems to be not enough to ensure consistent reporting [51,53,62,63]. Making therapeutic decisions for patients with breast cancer based on Ki67 scores should be made in caution [51,53,62,63]. Interpretation the KI67 LI obtained in particular breast cancer sample should always be done in the context of local laboratory values [64].…”

Various Aspects of Ki-67 Immunohistochemistry Determined Proliferation in Breast Cancer

“…This is in keeping with the results of the carefully designed study by Varga et al, cited earlier: estimation does not seem to be worse than counting, it may even be better [40]. This suggests that the simple approach of estimating by eyeballing has also diagnostic value, and may be better received by the pathological society as a simple and fast method, taking 4 to 12 times less time than counting [39,46]. The daily use of estimating rather than counting the Ki-67 LI by at least some pathologists was also highlighted in the series evaluating the distribution of Ki-67 LI values in different pathology departments [47].…”

“…The methods compared in this study had different reproducibility [39,46]. Although a good to excellent correlation was found between the results gained by different methods, antibodies and observers, the interobserver and intraobserver reproducibility of the everyday practice based counting on glass slides (Method 1) was only fair to moderate.…”

“…Although a good to excellent correlation was found between the results gained by different methods, antibodies and observers, the interobserver and intraobserver reproducibility of the everyday practice based counting on glass slides (Method 1) was only fair to moderate. Reproducibility of the Ki-67 LI has improved when the field to be assessed was limited to a digital image, chosen to represent the highest proliferation in the core biopsy sample (Method 2) [39,46].…”