title: High phosphohistone H3 expression correlates with adverse clinical, biological, and pathological factors in neuroblastomas.
abstract: Phosphohistone H3 (pHH3), a biomarker of the late G2- and M-phase of the cell cycle, provides a powerful indication of the proliferative state of many cancers. We investigated the prognostic significance of pHH3 by immunostaining 80 neuroblastomas and counting the average number of strongly stained nuclei and mitotic figures. The median and 75th percentile pHH3 proliferation indices (PIs) were 0.54% and 1.06% (range, 0.01% to 2.23%) respectively. pHH3 expression was significantly higher in neuroblastomas from patients with adverse clinical characteristics, all unfavorable pathological factors including high mitosis karyorrhexis index (MKI), and adverse biological factors including MYCN oncogene amplification. High pHH3-PIs, at 1% threshold, were significantly associated with a shorter overall survival (OS) and event-free survival (EFS) in the univariable Cox regression analyses. In the multivariable models, high pHH3 counts were significantly associated with worse OS after adjustment for age but were not independent of either high MKI or MYCN amplification. In children less than 18 months of age, high MKIs and high PHH3-PIs were associated with significantly worse OS and EFS. In conclusion, high pHH3 expression correlates strongly with high MKI and MYCN amplification and indicates poor prognosis in neuroblastomas.
authors.affiliation: Department of Histopathology, Bristol Royal Infirmary, Bristol, United Kingdom (PR, ST, EM, ESA)|Department of Cellular and Molecular Medicine, School of Medical Sciences, University of Bristol, Bristol, United Kingdom(PR)
authors.forename: Pramila
authors.initials: P
authors.lastname: Ramani
authors.affiliation: Department of Histopathology, Bristol Royal Infirmary, Bristol, United Kingdom (PR, ST, EM, ESA)
authors.forename: Scott
authors.initials: S
authors.lastname: Taylor
authors.affiliation: Department of Histopathology, Bristol Royal Infirmary, Bristol, United Kingdom (PR, ST, EM, ESA)
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Miller
authors.affiliation: Department of Histopathology, Bristol Royal Infirmary, Bristol, United Kingdom (PR, ST, EM, ESA)
authors.forename: Emile
authors.initials: E
authors.lastname: Sowa-Avugrah
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom (MTM)
authors.forename: Margaret T
authors.initials: MT
authors.lastname: May
mesh_terms: D000293:Adolescent; D014408:Biomarkers, Tumor / Q000032:analysis; D049109:Cell Proliferation; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D006657:Histones / Q000032:analysis*; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D007231:Infant, Newborn; D053208:Kaplan-Meier Estimate; D008938:Mitosis; D008940:Mitotic Index; D009447:Neuroblastoma / Q000175:diagnosis* / Q000473:pathology; D010766:Phosphorylation; D011379:Prognosis; D016016:Proportional Hazards Models
chemical_list: D014408:Biomarkers, Tumor; D006657:Histones
keywords: Ki67; mitosis karyorrhexis index; neuroblastoma; pHH3; phosphohistone H3; proliferation indices