Prognostic role of Ki-67 in glioblastomas excluding contribution from non-neoplastic cells

Abstract

Survival of glioblastoma patients varies and prognostic markers are important in the clinical setting. With digital pathology and improved immunohistochemical multiplexing becoming a part of daily diagnostics, we investigated the prognostic value of the Ki-67 labelling index (LI) in glioblastomas more precisely than previously by excluding proliferation in non-tumor cells from the analysis. We investigated the Ki-67 LI in a well-annotated population-based glioblastoma patient cohort (178 IDH-wildtype, 3 IDH-mutated). Ki-67 was identified in full tumor sections with automated digital image analysis and the contribution from non-tumor cells was excluded using quantitative double-immunohistochemistry. For comparison of the Ki-67 LI between WHO grades (II-IV), 9 IDH-mutated diffuse astrocytomas and 9 IDH-mutated anaplastic astrocytomas were stained. Median Ki-67 LI increased with increasing WHO grade (median 2.7%, 6.4% and 27.5%). There was no difference in median Ki-67 LI between IDH-mutated and IDH-wildtype glioblastomas (p = 0.9) and Ki-67 LI was not associated with survival in glioblastomas in neither univariate (p = 0.9) nor multivariate analysis including MGMT promoter methylation status and excluding IDH-mutated glioblastomas (p = 0.2). Ki-67 may be of value in the differential diagnostic setting, but it must not be over-interpreted in the clinico-pathological context.

KAT5 regulates neurodevelopmental states associated with G0-like populations in glioblastoma

“…We can draw several additional conclusions from these analyses. First, GSC-0827 tumors are highly proliferative with ∼24% of tumor cells in S/G2 phase, which is in line with measurements of Ki67, a marker of proliferation, in GBM tumors (median = 27.5%)(Dahlrot et al, 2021). Second, GSC-0827 tumors have multiple G0/G1 populations that are not apparent in in vitro cultures.…”

“…It is estimated that ~30% of glioblastoma tumor cells at a given moment are actively dividing (e.g., stain positive for the proliferation marker Ki67) (Dahlrot et al, 2021). The nature of the remaining ~70% of cells is largely unknown; although it is presumed that some portion are in a state of transient or long-term quiescence (Lathia et al, 2015).…”

Monocentric evaluation of Ki-67 labeling index in combination with a modified RPA score as a prognostic factor for survival in IDH-wildtype glioblastoma patients treated with radiochemotherapy

“…As mentioned above, the role of Ki-67 LI as a prognostic factor is still disputed due to differing results concerning impact of Ki-67 LI on survival. A previous study has discussed suboptimal methodological approaches as a possible factor in this variance [ 75 ]. In our eyes, the strength of the present study lies firstly in the monocentric approach, seeing as Ki-67 LI detection took place at a single laboratory and with minimal examiner variance, and secondly in the inclusion of treatment criteria via analysis of the partial collective “favorable subgroup,” making the significant results regarding Ki-67 LI and PFS more reliable.…”

“…Ki-67 is expressed exclusively in proliferating cells [ 58 , 59 ], with the Ki-67 labeling index (Ki-67 LI; % of cells expressing Ki-67) correlating closely with histological tumor grade in gliomas [ 14 , 60 – 64 ] and a Ki-67 LI of 10% being regarded as a reliable criterium for malignancy [ 65 , 66 ]. Although some studies see Ki-67 LI as a reliable predictor of survival with higher Ki-67 LI indicating worse prognosis [ 14 , 58 , 66 – 70 ], more reliable even than histologic grade [ 44 , 71 ] or age [ 44 ], other studies could not find this association [ 56 , 72 – 74 ], possibly due to low reproducibility of Ki-67 LI detection between laboratories and examiners [ 75 ]. Therefore, the role of Ki-67 LI as a prognostic factor is still disputed.…”

Aggressiveness of Grade 4 Gliomas of Adults

“…A study by Dahlort R.H. demonstrated a slight difference between the mean value of Ki-67 and the IDH mutation, without statistical significance: non-mutant grade 4 gliomas averaged 24.4% and mutant grade 4 gliomas averaged 27.5% [ 31 ]. Such a difference was also observed in our study, which is the first to identify a statistically significant correlation between the proliferative index of grade 4 gliomas, depending on the status of the IDH1 gene.…”