title: Mitosin and pHH3 predict poorer survival in astrocytomas WHO grades II and III.
abstract: OBJECTIVE
  The limitations of the current WHO classification of astrocytomas call for a sustained effort to improve diagnostic and prognostic accuracy. The relationship between tumour growth and clinical outcome suggests that proliferative activity should be examined. The objective of this study was to evaluate the diagnostic and prognostic value of the proliferation markers mitosin and phosphohistone H3 (pHH3) in infiltrative astrocytomas WHO grades II and III and compare the findings with mitotic count and Ki-67/MiB-1 immunostaining.
  
  
  METHODS
  Fifty-nine and thirty-three infiltrative astrocytomas WHO grades II and III, respectively, were immunostained with the proliferation markers mitosin and pHH3 using standard immunohistochemical procedures. The expression was quantified as a proliferative index (PI) and statistically evaluated with Spearman's rank correlation test, Wilcoxon-Mann-Whitney U test, and univariable and multivariable COX regression survival analyses.
  
  
  RESULTS
  Significant positive correlations were found between these proliferation markers. The number of mitoses, pHH3 mitotic figures (MFs), the Ki-67/MiB-1 PI and the mitosin PI were greater in WHOgrade III anaplastic astrocytomas compared to WHO grade II diffuse astrocytomas, while pHH3 PI only showed a trend. All proliferation markers were associated with poorer prognosis, but mitotic count was not. Ki-67/MiB-1, mitosin and pHH3 MF achieved statistical significance in the univariable analyses of both time to relapse (TTR) and overall survival (OS). Only mitosin remained significant in both multivariable analyses. pHH3 was significant in the multivariable analysis of OS but not of TTR. Clinical factors including age, extent of surgical resection and WHO performance status were also significantly correlated with survival.
  
  
  CONCLUSIONS
  In conclusion, mitosin and pHH3 immunostaining have prognostic and diagnostic value in the clinical assessment of patients with infiltrative astrocytomas. The inclusion of proliferation markers in a layered diagnosis should be considered in the upcoming revision of the WHO classification system.
authors.affiliation: Faculty of Medicine, Department of Laboratory Medicine, Children's and Women's Health, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
authors.forename: R K
authors.initials: RK
authors.lastname: Varughese
authors.affiliation: Faculty of Medicine, Department of Laboratory Medicine, Children's and Women's Health, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
authors.forename: T
authors.initials: T
authors.lastname: Lind-Landström
authors.affiliation: Faculty of Medicine, Department of Laboratory Medicine, Children's and Women's Health, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
authors.forename: A H
authors.initials: AH
authors.lastname: Habberstad
authors.affiliation: Faculty of Medicine, Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
authors.forename: Ø
authors.initials: Ø
authors.lastname: Salvesen
authors.affiliation: Faculty of Medicine, Department of Laboratory Medicine, Children's and Women's Health, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
authors.forename: C S
authors.initials: CS
authors.lastname: Haug
authors.affiliation: Department of Oncology, St. Olav's Hospital, Trondheim, Norway.
authors.forename: S
authors.initials: S
authors.lastname: Sundstrøm
authors.affiliation: Faculty of Medicine, Department of Laboratory Medicine, Children's and Women's Health, Norwegian University of Science and Technology (NTNU), Trondheim, Norway Department of Pathology and Medical Genetics, St Olav's Hospital, Trondheim, Norway.
authors.forename: S H
authors.initials: SH
authors.lastname: Torp
mesh_terms: D000328:Adult; D000368:Aged; D001254:Astrocytoma / Q000737:chemistry* / Q000145:classification / Q000401:mortality / Q000473:pathology / Q000628:therapy; D014408:Biomarkers, Tumor / Q000032:analysis*; D001932:Brain Neoplasms / Q000737:chemistry* / Q000145:classification / Q000401:mortality / Q000473:pathology / Q000628:therapy; D049109:Cell Proliferation; D002868:Chromosomal Proteins, Non-Histone / Q000032:analysis*; D018450:Disease Progression; D005260:Female; D006657:Histones / Q000032:analysis*; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D019394:Ki-67 Antigen / Q000032:analysis; D008297:Male; D008840:Microfilament Proteins / Q000032:analysis*; D008875:Middle Aged; D008938:Mitosis; D008940:Mitotic Index; D015999:Multivariate Analysis; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local; D010766:Phosphorylation; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D002868:Chromosomal Proteins, Non-Histone; D006657:Histones; D019394:Ki-67 Antigen; D008840:Microfilament Proteins; C094772:centromere protein F
keywords: BRAIN TUMOURS; HISTOPATHOLOGY; IMMUNOHISTOCHEMISTRY; KI 67; TUMOUR MARKERS