An international Ki67 reproducibility study in adrenal cortical Carcinoma

Thomas G. Papathomas, Eugenio Pucci, Thomas J. Giordano, Hao Lu, Eleonora Duregon, Marco Volante, Mauro Papotti, Ricardo V. Lloyd, Arthur S. Tischler, Francien H. Van Nederveen, Vania Nose, Lori Erickson, Ozgur Mete, Sylvia L. Asa, John Turchini, Anthony J. Gill, Xavier Matias-Guiu, Kassiani Skordilis, Timothy J. Stephenson, Frederique TissierRichard A. Feelders, Marcel Smid, Alex Nigg, Esther Korpershoek, Peter J. Van Der Spek, Winand N.M. Dinjens, Andrew P. Stubbs, Ronald R. De Krijger

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

Despite the established role of Ki67 labeling index in prognostic stratification of adrenocortical carcinomas and its recent integration into treatment flow charts, the reproducibility of the assessment method has not been determined. The aim of this study was to investigate interobserver variability among endocrine pathologists using a web-based virtual microscopy approach. Ki67-stained slides of 76 adrenocortical carcinomas were analyzed independently by 14 observers, each according to their method of preference including eyeballing, formal manual counting, and digital image analysis. The interobserver variation was statistically significant (P<0.001) in the absence of any correlation between the various methods. Subsequently, 61 static images were distributed among 15 observers who were instructed to follow a category-based scoring approach. Low levels of interobserver (F=6.99; Fcrit=1.70; P<0.001) as well as intraobserver concordance (n=11; Cohen k ranging from 0.057 to 0.361) were detected. To improve harmonization of Ki67 analysis, we tested the utility of an open-source Galaxy virtual machine application, namely Automated Selection of Hotspots, in 61 virtual slides. The software-provided Ki67 values were validated by digital image analysis in identical images, displaying a strong correlation of 0.96 (P<0.0001) and dividing the cases into 3 classes (cutoffs of 0%-15%-30% and/or 0%-10%-20%) with significantly different overall survivals (P<0.05). We conclude that current practices in Ki67 scoring assessment vary greatly, and interobserver variation sets particular limitations to its clinical utility, especially around clinically relevant cutoff values. Novel digital microscopy-enabled methods could provide critical aid in reducing variation, increasing reproducibility, and improving reliability in the clinical setting.

Original languageEnglish (US)
Pages (from-to)569-576
Number of pages8
JournalAmerican Journal of Surgical Pathology
Volume40
Issue number4
DOIs
StatePublished - Jan 1 2016

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Keywords

  • Adrenal cortical carcinoma
  • Digital pathology
  • Interobserver variation
  • Ki67 labeling index
  • Proliferation

ASJC Scopus subject areas

  • Anatomy
  • Surgery
  • Pathology and Forensic Medicine

Cite this

Papathomas, T. G., Pucci, E., Giordano, T. J., Lu, H., Duregon, E., Volante, M., Papotti, M., Lloyd, R. V., Tischler, A. S., Van Nederveen, F. H., Nose, V., Erickson, L., Mete, O., Asa, S. L., Turchini, J., Gill, A. J., Matias-Guiu, X., Skordilis, K., Stephenson, T. J., ... De Krijger, R. R. (2016). An international Ki67 reproducibility study in adrenal cortical Carcinoma. American Journal of Surgical Pathology, 40(4), 569-576. https://doi.org/10.1097/PAS.0000000000000574