Research Papers: Pathology:
Ki-67 proliferation index but not mitotic thresholds integrates the molecular prognostic stratification of lower grade gliomas
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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
Paola Cassoni, email:
Keywords: lower grade gliomas, Ki-67 index, phospho-histone H3, prognosis, Pathology Section
Received: February 28, 2016 Accepted: March 26, 2016 Published: March 30, 2016
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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