Mitotic index of invasive breast carcinoma: achieving clinically meaningful precision and evaluating tertial cutoffs

* Context.--Mitotic figure counts are related to breast cancer behavior but have not been sufficiently reproducible to be accepted for clinical decision-making. Objective.--To improve reproducibility and accuracy of the mitotic count. Design.--Mitotic index (MI) was defined as the mitotic cell count per 10 high-power fields (HPFs), an area 0.183 [mm.sup.2]. Two to 6 replicate sets of 10 HPFs were counted from 328 invasive breast carcinomas. Standard errors and coefficients of variation for mean MI were compared with expected results predicted by the binomial distribution. Results.--The boundaries for MI that separated the data into equal thirds (tertials) were 1.14 and 5.33. Standard errors and coefficients of variation for MI followed distributions predicted by binomial probability. Mean coefficient of variation was 147% for the low tertial, 72% for the midtertial, and 34.6% for the upper tertial. Conclusions.--Standard errors for MI based on a single count of 10 HPFs are too broad and coefficients of variation too large to be acceptable for clinical use. This is explained as a binomial probability effect, possibly with a contribution from tumor heterogeneity. Errors can be reduced in proportion to the square root of the number of sets of 10 HPFs counted. Tertial cutoffs of MI of the Nottingham system currently used in breast carcinoma grading are too high to be applicable to the population we studied. We recommend validation of cutoffs before they are applied to a particular population of breast carcinomas. Counting 5 sets of 10 HPFs is necessary to accurately rank carcinomas with low MIs.
Breast carcinoma grading by histologic features has been performed for more than 50 years. (1) Despite some technical improvements, (2) grading, as commonly practiced, has not achieved sufficient reproducibility and [...]