Inter-laboratory comparison of Ki-67 proliferating index detected by visual assessment and automated digital image analysis

Abstract

BACKGROUND: Proliferation rate is a major determinant of the biologic behavior of the tumor and provides information that can be used to guide treatment decisions. METHODS: This ring study included 27 pathologists from 14 Institutions, in order to assess inter-observer concordance between pathologists in Croatia. We analyzed Ki-67 proliferative index on ten randomly selected breast cancer samples comparing consistency between visual assessment using light microscopy compared to digital image analyses results from one central laboratory as a referral value. RESULTS: When we analyzed Ki-67 as numeric value high concordance rate was found between Ki-67 score visually assessed in all participating Institutions compared to referral value assessed by digital image analysis (ICC 0.76, 95% CI 0.58-0.91), and Krippendorff's alpha was 0.79 (95% CI 0.58-1.00). Concordance was better in slides with higher Ki-67 values. When we categorized Ki-67 values according to generally accepted 20% cut-off value we noticed the lower concordance rate among participants in our study. CONCLUSION: Proliferation remains one of the most important parameters for tumor characterization helpful in making clinical decisions, but it should be used with great caution. Standardization of the Ki-67 assessment is essential and proliferating index should be expressed as exact numeric value. For patients with proliferative index near the cut-off value, other factors must be considered in making clinical decisions.

A semi-automated microscopic image analysis method for scoring Ki-67 nuclear immunostaining

“…The nuclear protein MIB-1 (Ki-67) is upregulated in the active phases of the cell cycle (28) and is usually assessed by IHC. Previous studies that evaluated Ki-67 as a biomarker focused on identifying the percentage of cells in each cell cycle phase (29,30). Modeling of cell cycle dynamics is being investigated as an important prognostic and predictive biomarker (12,13,28,30).…”

“…Previous studies that evaluated Ki-67 as a biomarker focused on identifying the percentage of cells in each cell cycle phase (29,30). Modeling of cell cycle dynamics is being investigated as an important prognostic and predictive biomarker (12,13,28,30). Studies using cultured cells, transmission electron microscopy, and flow cytometry can provide information on the location (27,31), nucleolus location (32), and Ki-67 in the different cell cycle phases (15,27).…”

“…For more than three decades, investigators have used antibodies to visualize protein abundance, distribution, and localization; variations in the distribution and concentration of Ki-67 are detected as intensely stained nucleoli and full staining of nuclei (16)(17)(18)(19)(20)(21)(22)(23)(24)(25). Recent studies have provided information on the role of Ki-67 during the cell cycle; these studies assessed the morphological, functional, and biochemical aspects of Ki-67, as well as its distribution and density during the cell cycle including interphase, chromatin arrangements, and nucleolar shape in relation to Ki-67 (26)(27)(28)(29)(30)(31)(32)(33)(34).…”

Proposal for a New Diagnostic Histopathological Approach in the Evaluation of Ki-67 in GEP-NETs

“…Ki-67 has always been considered a necessary biomarker for the identification of the percentage of cellular fraction in the cell cycle [ 31 , 32 ], a necessary tool for prognosis, indication and monitoring of therapy, and the identification of new pharmacological targets [ 33 , 34 , 35 , 36 ].…”