Since the WHO classification system for human astrocytomas is not optimal, novel biomarkers are needed. Antibodies reactive against proliferation-associated antigens have therefore come into focus. This study was designed to evaluate the prognostic significance of the proliferation marker Mcm2 in a series of diffuse astrocytoma WHO grade II with thorough follow-up, and to compare its expression with histopathological features, mitoses, as well as Ki67/MIB-1 immunostaining. We found that Mcm2 expression correlated well with mitotic counts and Ki67/MIB-1 PIs but was not associated with any specific histopathology. Higher Mcm-2 PIs showed a trend to poorer survival, but statistical significance was not achieved.
The positive correlations between mitotic counts, Mcm2 PIs, and Ki67/MIB-1 PIs found in this study are in accordance with studies on other human tumours [16, 20–22]. It seems, however, that the range of Mcm2 PIs varies between types of neoplasms. In our study Mcm2 PIs were lower than Ki67/MIB-1 PIs and comparable with those in pilocytic astrocytomas, whereas in oligodendrogliomas the Mcm2 indices were higher [16, 20]. In colorectal cancer Mcm2 was shown to be a stronger indicator of proliferative cells than Ki67/MIB-1 . The reasons for these various findings are not obvious, but may be related to different tumour types, malignancy grades, counting procedures, type of antibody, and antigen preservation [8, 24]. Further, the immunoprofile of cycling tumour cells may vary. Mcm2 has been shown to stain cell-cycle initiation and continues to be expressed throughout the cycle including cells leaving G0 to enter early G1 . In comparison, Ki67/MIB-1 immunoreactivity occurs during all active phases of the cell cycle except G0 [26, 27]. Mcm2 may therefore be a biomarker of cells with replication potential (licensed to cycle), and suggestions on potential as a pre-cancer marker have been made .
Our survival analyses did not demonstrate any significant prognostic value of Mcm2. Nevertheless, a difference in survival of 14 months between the patients with high and low Mcm2 PIs indicates a promising trend. Actually, there is scarce knowledge about the value of Mcm2 in low-grade astrocytomas, so further studies are highly desired to fully establish its clinical significance in these tumours. Regarding other neoplasms, the findings are diverging. In a study on oligodendrogliomas with both low- and high-grade tumours positive association with survival was found . In meningiomas high Mcm2 PI was associated with early recurrence . On the contrary, no correlation to survival was established in a series of pilocytic astrocytomas .
Beyond the correlation with mitoses, Mcm2 was not associated with any other histological features related to malignancy in our series of astrocytomas, such as cell density, apoptoses, and atypia. In contrast, in a previous study Ki67/MIB-1 showed positive correlation with apoptoses, cellularity, and atypia . We have no obvious reasons for this difference, but it may be related to lower values of Mcm2 in grade II due to earlier stage in the gliomagenesis.
Due to a limited number of patients and the well-known heterogeneity of astrocytic tumours, our data must be interpreted with discretion. The wide range of Mcm2 PIs points to possible overlap of values between astrocytomas of various malignancy grades comparable with that of Ki67/MIB-1 immunostaining . It seems as if this phenomenon is a rather typical trait for proliferation markers reducing their utility in the routine diagnostics. Additionally, immunohistochemistry has its intrinsic adversity, such as the definition of immunoreactive cells (non-neoplastic and neoplastic cells, threshold values etc.), and several studies have poor definition of the quantitation procedures or reproducibility [7, 8, 29, 30]. On the other hand, reliable follow-up data, combination of two proliferation markers, and the attempt to compensate for intraobserver reliability through Kappa statistic, are some of the strengths of this study.
In conclusion, Mcm2 immunostaining correlates well with mitotic activity and Ki67/MIB-1 expression. However, none of these were shown not to have any significant influence on patient outcome, even if the markers were combined. Accordingly, Mcm2 does not seem to have any advantages over Ki67/MIB-1 in the evaluation of the prognosis of grade II astrocytomas. However, larger studies are necessary to clarify the definite role of Mcm2 in these tumours.