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Breast cancer histologic grading using digital microscopy: concordance and outcome association
  1. Emad A Rakha1,
  2. Mohamed Aleskandarani1,
  3. Michael S Toss1,
  4. Andrew R Green1,
  5. Graham Ball2,
  6. Ian O Ellis1,
  7. Leslie W Dalton3
  1. 1 Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham City Hospital, Nottingham, UK
  2. 2 School of Science and Technology, John van Geest Cancer Research Centre, Nottingham Trent University, Nottingham, UK
  3. 3 Department of Histopathology, South Austin Hospital, Austin, Texas, USA
  1. Correspondence to Dr Emad A Rakha, Department of Histopathology, Nottingham University Hospital NHS Trust, Nottingham NG5 1PB, UK; emad.rakha{at}


Aims Virtual microscopy utilising digital whole slide imaging (WSI) is increasingly used in breast pathology. Histologic grade is one of the strongest prognostic factors in breast cancer (BC). This study aims at investigating the agreement between BC grading using traditional light microscopy (LM) and digital WSI with consideration of reproducibility and impact on outcome prediction.

Methods A large (n=1675) well-characterised cohort of BC originally graded by LM was re-graded using WSI. Two separate virtual-based grading sessions (V1 and V2) were performed with a 3-month washout period. Outcome was assessed using BC-specific and distant metastasis-free survival.

Results The concordance between LM grading and WSI was strong (LM/WSI Cramer’s V: V1=0.576, and V2=0.579). The agreement regarding grade components was as follows: tubule formation=0.538, pleomorphism=0.422 and mitosis=0.514. Greatest discordance was observed between adjacent grades, whereas high/low grade discordance was uncommon (1.5%). The intraobserver agreement for the two WSI sessions was substantial for grade (V1/V2 Cramer’s V=0.676; kappa=0.648) and grade components (Cramer’s V T=0.628, p=0.573 and M=0.580). Grading using both platforms showed strong association with outcome (all p values <0.001). Although mitotic scores assessed using both platforms were strongly associated with outcome, WSI tends to underestimate mitotic counts.

Conclusions Virtual microscopy is a reliable and reproducible method for assessing BC histologic grade. Regardless of the observer or assessment platform, histologic grade is a significant predictor of outcome. Continuing advances in imaging technology could potentially provide improved performance of WSI BC grading and in particular mitotic count assessment.

  • breast pathology
  • grade
  • agreement
  • virtual microscopy

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  • EAR and MA contributed equally.

  • Handling editor Dhirendra Govender.

  • Funding This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Ethics approval This study was approved by Nottingham Research Ethics Committee 2 under the title ‘Development of a molecular genetic classification of breast cancer’, and in compliance with current ethical and legal guidelines of the UK.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement Data are available upon request and at the discretion of the authors.