[Ki67: biological intertumor variance versus variance of assay]

Since its first description at the Institute of Pathology in Kiel more than 34 years ago, the immunohistochemical proliferation marker Ki67 has been shown to be of prognostic significance in a huge number of retrospective and even some prospective trials on malignant tumours of various tissue derivation. Lack of standardization in the evaluation provides potential sources of variance in assessment. Tumour area to be assessed, minimum number of cells to be analyzed, tedious counting cell by cell or semiquantitative eyeballing, choice of immunohistochemical techniques represent nonstandardized issues that potentially lead to considerable assay heterogeneity. In addition, interpretation is not homogeneous, in particular with regard to thresholds between high and low proliferative activity. Due to these numerous potential methodological limitations, for a long time Ki67 was not generally accepted as a prognostic marker, in particular outside Germany and by nonpathologists. However, in recent years a shift has taken place. Despite the challenge that biological heterogeneity may be hidden by differences in assay performance, Ki67 now plays an important auxiliary role in grading of malignant neoplasms such as breast cancer, neuroendocrine tumours and malignant lymphomas. In this context it is applied in clinical diagnostics as well as in clinical trials for the purpose of stratification. Because of its widespread use, it is of utmost importance to raise awareness of the potential methodological limitations in order to use Ki67 in a meaningful way.