Ki-67 expression is superior to mitotic count and novel proliferation markers PHH3, MCM4 and mitosin as a prognostic factor in thick cutaneous melanoma

BMC Cancer. 2010 Apr 14;10:140. doi: 10.1186/1471-2407-10-140.


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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Biomarkers, Tumor / analysis*
  • Cell Cycle Proteins / analysis*
  • Cell Proliferation*
  • Chi-Square Distribution
  • Chromosomal Proteins, Non-Histone / analysis*
  • DNA-Binding Proteins / analysis*
  • Histones / analysis*
  • Humans
  • Immunohistochemistry
  • Kaplan-Meier Estimate
  • Ki-67 Antigen / analysis*
  • Melanoma / chemistry*
  • Melanoma / mortality
  • Melanoma / pathology
  • Microfilament Proteins / analysis*
  • Middle Aged
  • Minichromosome Maintenance Complex Component 4
  • Mitotic Index*
  • Necrosis
  • Neoplasm Invasiveness
  • Neoplasm Staging
  • Nuclear Proteins / analysis*
  • Phosphorylation
  • Predictive Value of Tests
  • Prognosis
  • Proportional Hazards Models
  • Skin Neoplasms / chemistry*
  • Skin Neoplasms / mortality
  • Skin Neoplasms / pathology
  • Tissue Array Analysis
  • Up-Regulation


  • Biomarkers, Tumor
  • Cell Cycle Proteins
  • Chromosomal Proteins, Non-Histone
  • DNA-Binding Proteins
  • Histones
  • Ki-67 Antigen
  • Microfilament Proteins
  • Nuclear Proteins
  • centromere protein F
  • MCM4 protein, human
  • Minichromosome Maintenance Complex Component 4