The Utility of Phosphohistone H3 (PHH3) in Breast Cancer Grading
Xiaoyan Cui, Gene P Siegal, Shi Wei. University of Alabama at Birmingham, Birmingham, AL
Background: Histologic grading has been recognized as a powerful prognostic indicator in breast cancer (BC). The widely accepted Bloom-Richardson grading system employs the combination of tubule formation, nuclear pleomorphism and mitotic indices (MI). In practice, accurate assessment of MI on H&E stained sections is an issue that requires experience and is subject to interobserver variability. Commonly used Ki-67 staining is a proliferation marker but is not specific for mitoses. Histone H3 Phosphorylation occurs only when chromosomes are fully condensed which is a strict mitotic event and thus may provide a more promising marker for MI. In this study, we sought to evaluate the utility of PHH3 labeling in grading BC and its prognostic significance.
Design: The Surgical Pathology database at the authors' institution was searched to identify breast biopsy cases with a diagnosis of BC between 2004 and 2006. A total of 61 consecutive cases with sufficient tissue were selected and subjected to immunohistochemical evaluation. Ki-67 was scored as the average fraction and PHH3 was scored as the total number of labeled tumor cells, in 10 high power fields where the immunolabeling was prevalent (hot spots). Chi-Square or student t-test was utilized for statistical analysis, when appropriate.
Results: Cells with mitotic activity could be easily identified by unequivocal nuclear PHH3 labeling. While there was a strong linear correlation and regression for MI between H&E and PHH3 stains (r=0.71; p<0.0001), 28 cases (46%) were upgraded by PHH3 (Chi-Square=25.5; p<0.00001), exclusively in those labeled grade II BCs by H&E staining. In addition, a strong correlation between PHH3 MI and the Ki-67 proliferation index was also seen (r=0.63; p<0.0001). There was no significant association between PHH3 MI and ER, PR or HER2 status. Further, no significant differences in PHH3 MI were found in BCs with and without lymph node involvement, or those with and without associated distant organ metastasis either at the time of diagnosis or subsequently.
Conclusions: While H&E assessment remains the most important tool in assessing MI in BC grading, PHH3 mitotic labeling can serve as a useful adjunct in the proper grading of equivocal cases, especially in small biopsies. Given that PHH3 may potentially label more mitotically active cells than by H&E staining (and thus substantially upgrade a significant proportion of BCs), integration of this marker into BC grading needs large-scaled, multicenter studies.
Tuesday, March 5, 2013 1:00 PM
Poster Session IV # 52, Tuesday Afternoon