Eleonora Duregon et al., Ki-67 proliferation index but not mitotic thresholds integrates the molecular prognostic stratification of lower grade gliomas. Oncotarget

Eleonora Duregon2, Luca Bertero1, Alessandra Pittaro1, Riccardo Soffietti4, Roberta Rudà4, Morena Trevisan5,6, Mauro Papotti2, Laura Ventura3, Rebecca Senetta1 and Paola Cassoni1

1 Department of Medical Sciences, University of Turin, Turin, Italy
2 Department of Oncology, University of Turin, Turin, Italy
3 Department of Statistical Sciences, University of Padua, Padova, Italy
4 Department of Neuro-Oncology, University and City of Health and Science Hospital of Turin, Turin, Italy
5 Cancer Epidemiology Unit-CERMS, Department of Medical Sciences, University of Turin, Turin, Italy
6 CPO-Piemonte, Turin, Italy


Despite several molecular signatures for “lower grade diffuse gliomas” (LGG) have been identified, WHO grade still remains a cornerstone of treatment guidelines. Mitotic count bears a crucial role in its definition, although limited by the poor reproducibility of standard Hematoxylin & Eosin (H&E) evaluation. Phospho-histone-H3 (PHH3) and Ki-67 have been proposed as alternative assays of cellular proliferation. Therefore in the present series of 141 LGG, the molecular characterization (namely IDH status, 1p/19q co-deletion and MGMT promoter methylation) was integrated with the tumor “proliferative trait” (conventional H&E or PHH3-guided mitotic count and Ki-67 index) in term of prognosis definition. Exclusively high PHH3 and Ki-67 values were predictor of poor prognosis (log rank test, P = 0.0281 for PHH3 and P = 0.032 for Ki-67), unlike standard mitotic count. Based on Cox proportional hazard regression analyses, among all clinical (age), pathological (PHH3 and Ki-67) and molecular variables (IDH, 1p/19q codeletion and MGMT methylation) with a prognostic relevance at univariate survival analysis, only IDH expression (P = 0.001) and Ki-67 proliferation index (P = 0.027) proved to be independent prognostic factors. In addition, stratifying by IDH expression status, high Ki-67 retained its prognostic relevance uniquely in the IDH negative patient (P = 0.029) doubling their risk of death (hazard ratio = 2.27). Overall, PHH3 immunostaining is the sole reliable method with a prognostic value to highlight mitotic figures in LGG. Ki-67 proliferation index exceeds PHH3 mitotic count as a predictor of patient’s prognosis, and should be integrated with molecular markers in a comprehensive grading system for LGG.

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