Abstract
Mitotic count, PhH3, and MIB-1 are used as measures of the proportion of proliferating malignant cells in surgical pathology. They highlight different stages of the cell cycle, but little is known about how this affects their counts. This study assesses the strength of their correlations and attempts to determine the relationship between them. Proliferation counts for forty-nine consecutive cases of invasive breast carcinomas were analyzed, with the same tumor area on each stain counted using digital image analysis. The integrated optical density (IOD) of nuclei was measured as an approximation of nuclear DNA content. PhH3 strongly correlated with mitotic count (r = 0.94). Weaker correlations were found between MIB-1 versus PhH3 (r = 0.79) and mitotic count (r = 0.83). Nuclear IOD showed stronger correlation with MIB-1 (r = 0.37) than to mitotic count (r = 0.23) and PhH3 (r = 0.34). With evidence from a literature review, it is suggested that the weaker correlations with MIB-1 are not explained by count imprecision or error, but relies on temporal decorrelation between cell cycle phases. Consequences on correlation between these proliferative markers are illustrated by mathematical models.
Highlights
Mitotic count, phosphorylated histone H3 (PhH3), and MIB-1 are used as measures of the proportion of proliferating malignant cells in surgical pathology
In addition to the mitotic count, immunohistochemical markers of proliferation have been more recently developed and include MIB-1 which is directed at the Ki-67 antigen and targets the whole cell cycle[2,12], proliferating cell nuclear antigen (PCNA) which targets the S phase[13], and phosphorylated histone H3 (PhH3) which targets the mitotic phase[14]
This study evaluated the correlations between MIB-1, PhH3, and mitotic count in a defined area, focusing on invasive breast carcinoma
Summary
PhH3, and MIB-1 are used as measures of the proportion of proliferating malignant cells in surgical pathology. They highlight different stages of the cell cycle, but little is known about how this affects their counts. MIB-1 would make the visualization of proliferating cells easier[16] It stains all nuclei involved in the cell cycle (G1, S, G2, and mitoses)[2] and has emerged as an important independent prognostic and predictive marker in several tumors, including breast cancer[1], sarcomas[16,18], cutaneous melanomas[11,19,20], meningiomas[21], and prostate cancer[22] among others. For breast cancer, the level of MIB-1 expression prior to neoadjuvant chemotherapy is a strong predictive factor for the potential effectiveness of the therapy, and post-therapy www.nature.com/scientificreports
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