Assessment of mitotic activity in breast cancer: revisited in the digital pathology era

Abstract

The assessment of cell proliferation is a key morphological feature for diagnosing various pathological lesions and predicting their clinical behaviour. Visual assessment of mitotic figures in routine histological sections remains the gold-standard method to evaluate the proliferative activity and grading of cancer. Despite the apparent simplicity of such a well-established method, visual assessment of mitotic figures in breast cancer (BC) remains a challenging task with low concordance among pathologists which can lead to under or overestimation of tumour grade and hence affects management. Guideline recommendations for counting mitoses in BC have been published to standardise methodology and improve concordance; however, the results remain less satisfactory. Alternative approaches such as the use of the proliferation marker Ki67 have been recommended but these did not show better performance in terms of concordance or prognostic stratification. The advent of whole slide image technology has brought the issue of mitotic counting in BC into the light again with more challenges to develop objective criteria for identifying and scoring mitotic figures in digitalised images. Using reliable and reproducible morphological criteria can provide the highest degree of concordance among pathologists and could even benefit the further application of artificial intelligence (AI) in breast pathology, and this relies mainly on the explicit description of these figures. In this review, we highlight the morphology of mitotic figures and their mimickers, address the current caveats in counting mitoses in breast pathology and describe how to strictly apply the morphological criteria for accurate and reliable histological grade and AI models.

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“…The analytical validity of Ki67 is also questionable due to the lack of consensus on scoring methods and cut-off values, the reliability of various antibodies, and the actual clinical utility [102][103][104]. Until now, the traditional visual morphological detection of mitotic figures using well-established methods in H&E sections remains the most widely used and accepted method in routine practice in most laboratories as it is an easy, rapid, and simple technique for assessment of growth rate and tumour behaviour [101,105,106].…”

Multiparametric Classification of Non-Muscle Invasive Papillary Urothelial Neoplasms: Combining Morphological, Phenotypical, and Molecular Features for Improved Risk Stratification

“…Studies using mitotic activity evaluated by semi-quantitative methods showed low reproducibility for grading and poor correlation with prognosis [ 18 ]. However, studies in breast cancer suggest that mitotic counting can be improved by quantitative methods [ 22 ]. In our study, mitotic counting was performed using p-HH3 immunostaining to reduce subjectivity, although it has to be mentioned that p-HH3 staining cannot be compared directly to mitosis counting on H&E sections.…”

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“…with the highest mitotic count) should be assessed. If the mitotic frequency score falls very close to a score cut point, one or more further groups of 10 HPFs should be assessed to establish the correct (highest) score. Fields chosen for scoring are selected during a random meander along the peripheral margin of the selected tumour area. Only fields with a representative tumour burden should be used. The low‐power scan of the tumour can be used to provide an assessment of the typical tumour‐to‐stromal ratio. Only definite mitotic figures (in any phase of the growth cycle) should be counted 16 . Hyperchromatic nuclei and/or apoptotic nuclei should not be scored. The mitosis score depends on the number of mitoses per 10 HPFs.…”