Abstract
Histological grade is an independent prognostic variable in breast cancer (BC). Previous concordance studies of BC grade have reported moderate levels of agreement; a typical finding in morphological assessment of biological variables. This study aimed to investigate the impact of discordance on the prognostic value of grade and to identify the best reporting approach in borderline cases. A large (n = 1675) well-characterised annotated cohort of BC, originally graded in routine practice using glass slides, was re-graded twice by an expert breast pathologist using virtual microscopy with a 3-month washout period. Outcome was assessed using breast cancer-specific and distant metastasis-free survival (median follow-up = 135 months). Fifty-eight per cent of the cases showed absolute agreement in the three separate grading sessions, whereas grades 1/2 and 2/3 discordance were observed in 21% and 21%, respectively. Absolute intra-observer agreement using virtual microscopy was observed in 77% of the cases, whereas 13% and 10% showed grades 1/2 and 2/3 discordance, respectively. Despite the concordance, outcome analysis revealed significant associations between tumour grade and patients' outcome in the three grading sessions. Grades 1/2 and 2/3 discordant cases showed intermediate survival between grades 1 and 2 tumours and grades 2 and 3 tumours, respectively. Grades 1/2 discordant cases showed a worse outcome when compared with grade 1 tumours (P = 0.008) but no statistical difference was identified when compared with grade 2 tumours. Similarly, grades 2/3 discordant cases showed a significant difference from grade 2 tumours (P < 0.001), but no statistical difference was identified when compared with grade 3 tumours. Breast cancer grade discordance is probably a reflection of biologically, and hence morphologically, borderline tumours. Cases with borderline features for grade are more likely to behave similarly to the higher-grade category. Repeating histological grade of borderline cases or double reporting may improve correlation with outcome.
Highlights
Histological grade of breast cancer (BC) is one of the strongest prognostic factors in early stage disease [1,2,3]
In this study, two virtual microscopy (VM) grading sessions were performed by an expert breast pathologist for a large (n=1675) clinically annotated early-stage primary invasive BC with a three-months washout period. 58% of the cases showed absolute agreement in all three grading sessions (13%, 21% and 24% for grades [1, 2] and 3, respectively) whereas grade 1/2 and grade 2/3 discordance were observed in 21% and 21%, respectively (Table 2c)
The 276 discordant grade 2/3 tumours showed relatively better outcome compared to concordant grade 3 BC during the early follow-up times ; this meagre improvement disappeared after longer-term follow-up and the final outcome of these grade 2/3 discordant cases was similar to grade 3 concordant tumours
Summary
Histological grade of breast cancer (BC) is one of the strongest prognostic factors in early stage disease [1,2,3]. A supposed advantage of modern era techniques, such as molecular biomarkers, is the high objectivity with a corresponding increase in reproducibility In reality this perceived potential has yet to be realised as concordance of modern era molecular assays has not shown any improved agreement compared to human eye histological grading [11, 12]. Increasing emphasis is being placed upon obtaining second or multiple opinions and with increasing use of digital pathology [13,14,15,16,17], the number of second opinions is likely to further increase It is not well understood how discordant grade assignments might impact risk assignment. Absolute intra-observer agreement using virtual microscopy was observed in 77% of the cases whereas 13% and 10% showed grade 1/2 and grade 2/3 discordance respectively. Repeating histological grade of borderline cases or double reporting may improve correlation with outcome
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