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Bimodality of intratumor Ki67 expression is an independent prognostic factor of overall survival in patients with invasive breast carcinoma

Laurinavicius, Arvydas; Plancoulaine, Benoit; Rasmusson, Allan; Besusparis, Justinas; Augulis, Renaldas; Meskauskas, Raimundas; Herlin, Paulette; Laurinaviciene, Aida; Abdelhadi Muftah, Abir A.; Miligy, Islam; Aleskandarany, Mohammed; Rakha, Emad A.; Green, Andrew R.; Ellis, Ian O.


Arvydas Laurinavicius

Benoit Plancoulaine

Allan Rasmusson

Justinas Besusparis

Renaldas Augulis

Raimundas Meskauskas

Paulette Herlin

Aida Laurinaviciene

Abir A. Abdelhadi Muftah

Islam Miligy

Mohammed Aleskandarany

Professor of Breast Cancer Pathology


Proliferative activity, assessed by Ki67 immunohistochemistry (IHC), is an established prognostic and predictive biomarker of breast cancer (BC). However, it remains under-utilized due to lack of standardized robust measurement methodologies and significant intratumor heterogeneity of expression. A recently proposed methodology for IHC biomarker assessment in whole slide images (WSI), based on systematic subsampling of tissue information extracted by digital image analysis (DIA) into hexagonal tiling arrays, enables computation of a comprehensive set of Ki67 indicators, including intratumor variability. In this study, the tiling methodology was applied to assess Ki67 expression in WSI of 152 surgically removed Ki67-stained (on full-face sections) BC specimens and to test which, if any, Ki67 indicators can predict overall survival (OS). Visual Ki67 IHC estimates and conventional clinico-pathologic parameters were also included in the study. Analysis revealed linearly independent intrinsic factors of the Ki67 IHC variance: proliferation (level of expression), disordered texture (entropy), tumor size and Nottingham Prognostic Index, bimodality, and correlation. All visual and DIA-generated indicators of the level of Ki67 expression provided significant cutoff values as single predictors of OS. However, only bimodality indicators (Ashman’s D, in particular) were independent predictors of OS in the context of hormone receptor and HER2 status. From this, we conclude that spatial heterogeneity of proliferative tumor activity, measured by DIA of Ki67 IHC expression and analyzed by the hexagonal tiling approach, can serve as an independent prognostic indicator of OS in BC patients that outperforms the prognostic power of the level of proliferative activity.


Laurinavicius, A., Plancoulaine, B., Rasmusson, A., Besusparis, J., Augulis, R., Meskauskas, R., …Ellis, I. O. (2016). Bimodality of intratumor Ki67 expression is an independent prognostic factor of overall survival in patients with invasive breast carcinoma. Virchows Archiv, 468(4), 493-502. doi:10.1007/s00428-016-1907-z

Journal Article Type Article
Acceptance Date Jan 14, 2016
Online Publication Date Jan 27, 2016
Publication Date 2016-04
Deposit Date Oct 15, 2018
Publicly Available Date Oct 18, 2018
Journal Virchows Archiv
Print ISSN 0945-6317
Electronic ISSN 1432-2307
Publisher BMC
Peer Reviewed Peer Reviewed
Volume 468
Issue 4
Pages 493-502
Public URL
Publisher URL


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