Digital image analysis of Ki67 in hot spots is superior to both manual Ki67 and mitotic counts in breast cancer

Abstract

Aims

During pathological examination of breast tumours, proliferative activity is routinely evaluated by a count of mitoses. Adding immunohistochemical stains of Ki67 provides extra prognostic and predictive information. However, currently used methods for these evaluations suffer from imperfect reproducibility. It is still unclear whether analysis of Ki67 should be performed in hot spots, in the tumour periphery or as an average of the whole tumour section. In this paper, we compare the clinical relevance of mitoses, Ki67 and Phosphohistone H3 in two cohorts of primary breast cancer specimens (total n=294).

Methods and results

Both manual and digital image analysis scores were evaluated for sensitivity and specificity for Luminal B versus A subtype as defined by PAM50 gene expression assays, for high versus low transcriptomic grade, for axillary lymph node status as well as for prognostic value in terms of prediction of overall and relapse-free survival. Digital image analysis of Ki67 outperformed the other markers, especially evident in hot spots. Tumours with high expression of Ki67 and high numbers of Phosphohistone H3-positive cells had significantly increased hazard ratios for all-cause mortality within 10 years from diagnosis. Replacing manual mitotic counts with digital image analysis of Ki67 in hot spots increased differences in overall survival between the highest and lowest histological grades and added significant prognostic information.

Conclusions

Digital image analysis of Ki67 in hot spots is the marker of choice for routine analysis of proliferation in breast cancer.

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