title: Ki-67 expression is superior to mitotic count and novel proliferation markers PHH3, MCM4 and mitosin as a prognostic factor in thick cutaneous melanoma.
abstract: BACKGROUND
  Tumor cell proliferation is a predictor of survival in cutaneous melanoma. The aim of the present study was to evaluate the prognostic impact of mitotic count, Ki-67 expression and novel proliferation markers phosphohistone H3 (PHH3), minichromosome maintenance protein 4 (MCM4) and mitosin, and to compare the results with histopathological variables.
  
  
  METHODS
  202 consecutive cases of nodular cutaneous melanoma were initially included. Mitotic count (mitosis per mm2) was assessed on H&E sections, and Ki-67 expression was estimated by immunohistochemistry on standard sections. PHH3, MCM4 and mitosin were examined by staining of tissue microarrays (TMA) sections.
  
  
  RESULTS
  Increased mitotic count and elevated Ki-67 expression were strongly associated with increased tumor thickness, presence of ulceration and tumor necrosis. Furthermore, high mitotic count and elevated Ki-67 expression were also associated with Clark's level of invasion and presence of vascular invasion. High expression of PHH3 and MCM4 was correlated with high mitotic count, elevated Ki-67 expression and tumor ulceration, and increased PHH3 frequencies were associated with tumor thickness and presence of tumor necrosis. Univariate analyses showed a worse outcome in cases with elevated Ki-67 expression and high mitotic count, whereas PHH3, MCM4 and mitosin were not significant. Tumor cell proliferation by Ki-67 had significant prognostic impact by multivariate analysis.
  
  
  CONCLUSIONS
  Ki-67 was a stronger and more robust prognostic indicator than mitotic count in this series of nodular melanoma. PHH3, MCM4 and mitosin did not predict patient survival.
authors.affiliation: The Gade Institute, Section for Pathology, University of Bergen, Bergen, Norway.
authors.forename: Rita G
authors.initials: RG
authors.lastname: Ladstein
authors.forename: Ingeborg M
authors.initials: IM
authors.lastname: Bachmann
authors.forename: Oddbjørn
authors.initials: O
authors.lastname: Straume
authors.forename: Lars A
authors.initials: LA
authors.lastname: Akslen
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis*; D018797:Cell Cycle Proteins / Q000032:analysis*; D049109:Cell Proliferation; D016009:Chi-Square Distribution; D002868:Chromosomal Proteins, Non-Histone / Q000032:analysis*; D004268:DNA-Binding Proteins / Q000032:analysis*; D006657:Histones / Q000032:analysis*; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D019394:Ki-67 Antigen / Q000032:analysis*; D008545:Melanoma / Q000737:chemistry* / Q000401:mortality / Q000473:pathology; D008840:Microfilament Proteins / Q000032:analysis*; D008875:Middle Aged; D064148:Minichromosome Maintenance Complex Component 4; D008940:Mitotic Index; D009336:Necrosis; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000032:analysis*; D010766:Phosphorylation; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D012878:Skin Neoplasms / Q000737:chemistry* / Q000401:mortality / Q000473:pathology; D046888:Tissue Array Analysis; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D006657:Histones; D019394:Ki-67 Antigen; D008840:Microfilament Proteins; D009687:Nuclear Proteins; C094772:centromere protein F; C099243:MCM4 protein, human; D064148:Minichromosome Maintenance Complex Component 4
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