title: Ki-67 proliferation index but not mitotic thresholds integrates the molecular prognostic stratification of lower grade gliomas.
abstract: 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.
authors.affiliation: Department of Oncology, University of Turin, Turin, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Duregon
authors.affiliation: Department of Medical Sciences, University of Turin, Turin, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Bertero
authors.affiliation: Department of Medical Sciences, University of Turin, Turin, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Pittaro
authors.affiliation: Department of Neuro-Oncology, University and City of Health and Science Hospital of Turin, Turin, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Soffietti
authors.affiliation: Department of Neuro-Oncology, University and City of Health and Science Hospital of Turin, Turin, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Rudà
authors.affiliation: Cancer Epidemiology Unit-CERMS, Department of Medical Sciences, University of Turin, Turin, Italy.|CPO-Piemonte, Turin, Italy.
authors.forename: Morena
authors.initials: M
authors.lastname: Trevisan
authors.affiliation: Department of Oncology, University of Turin, Turin, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Papotti
authors.affiliation: Department of Statistical Sciences, University of Padua, Padova, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Ventura
authors.affiliation: Department of Medical Sciences, University of Turin, Turin, Italy.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Senetta
authors.affiliation: Department of Medical Sciences, University of Turin, Turin, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Cassoni
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D049109:Cell Proliferation; D003131:Combined Modality Therapy; D005260:Female; D005500:Follow-Up Studies; D005910:Glioma / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D006657:Histones / Q000378:metabolism; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D008938:Mitosis / Q000502:physiology*; D008940:Mitotic Index; D010766:Phosphorylation; D011379:Prognosis; D015996:Survival Rate; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D006657:Histones; D019394:Ki-67 Antigen
keywords: Ki-67 index; Pathology Section; lower grade gliomas; phospho-histone H3; prognosis