Breast cancer histologic grading using digital microscopy: concordance and outcome association

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 whole slide imaging (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 three months washout period. Outcome was assessed using breast cancer specific and distant metastasis free survival. Results: The concordance between LM grading and WSI was strong (LM/SWI 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 intra-observer 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-value <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