title: Comparison of the prognostic value of four methods to assess mitotic activity in 186 invasive breast cancer patients: classical and random mitotic activity assessments with correction for volume percentage of epithelium.
abstract: Proliferation markers and especially the Mitotic Activity Index (MAI) are strong and reproducible prognosticators in invasive breast cancer. Traditionally, the MAI has been defined as the total number of mitoses counted in 10 consecutive high-power fields (objective, x40; numeric aperture, .75; field diameter, 450 microns), in the most cellular area at the periphery of the tumor, with the subjectively highest mitotic activity. No correction for epithelial percentage or cellularity was applied. This study investigates whether the prognostic value of mitotic activity could be improved by a random sampling procedure or correction for percentage of epithelium present. For this purpose the prognostic value of four methods used to assess mitotic activity in invasive breast cancer was compared in 4-microns-thick hematoxylin-eosin (H&E)-stained sections of 186 primary invasive breast cancer patients. These were the MAI, the random MAI (rMAI), the Mitosis per Volume (M/V) Index, and the random M/V Index (rM/V Index). The rMAI was defined as the total number of mitotic figures counted in 10 random fields through the whole outlined tumor at x400 magnification. A correction for the volume percentage of epithelium assessed with stereology yielded the M/V Index and the rM/V Index, respectively. The results of all four methods showed moderate to high correlations. Univariate survival analysis (Kaplan-Meier curves; Mantel-Cox test) confirmed that all four methods had a strong prognostic value (P < .001). The MAI, however, produced the best results (Mantel-Cox value, 17.1). Multivariate analysis showed that all four methods had additional prognostic value to tumor size and lymph node status. The M/V Index provided most additional prognostic information, followed by the MAI. Assessment of rMAI took 20 to 30 minutes on average, about two times longer than MAI. The correction for volume percentage of epithelium took about 10 minutes longer for both methods than the uncorrected methods. In conclusion, the rMAI gives an impression of the mitotic activity through the whole tumor, with almost similar prognostic value as the traditional MAI, especially when correcting for percentage of epithelium. Nevertheless, the MAI is still to be preferred, because the assessment is easy to apply and less time consuming.
authors.affiliation: Department of Pathology, Free University Hospital, Amsterdam, The Netherlands.
authors.forename: I
authors.initials: I
authors.lastname: Jannink
authors.forename: P J
authors.initials: PJ
authors.lastname: van Diest
authors.forename: J P
authors.initials: JP
authors.lastname: Baak
mesh_terms: D000230:Adenocarcinoma / Q000401:mortality / Q000473:pathology*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis; D001943:Breast Neoplasms / Q000401:mortality / Q000473:pathology*; D004848:Epithelium / Q000473:pathology; D006801:Humans; D008875:Middle Aged; D008940:Mitotic Index; D011379:Prognosis; D012680:Sensitivity and Specificity
chemical_list: D014408:Biomarkers, Tumor