Evaluation of p16INK4a, minichromosome maintenance protein 2, DNA topoisomerase IIalpha, ProEX C, and p16INK4a/ProEX C in cervical squamous intraepithelial lesions

Hum Pathol. 2007 Sep;38(9):1335-44. doi: 10.1016/j.humpath.2007.01.025. Epub 2007 May 18.


p16INK4a has been shown to be overexpressed in nearly all high-grade squamous intraepithelial lesions (HSILs). Other cell-cycle regulators, such as minichromosome maintenance protein 2 (MCM2), DNA topoisomerase IIalpha (TOP IIA), and ProE(X) C (a cocktail of MCM2 and TOP IIA), have also demonstrated some value in identifying squamous intraepithelial lesions. Data on direct comparison of those cell regulatory proteins in the detection of squamous intraepithelial lesions, with a focus on low-grade squamous intraepithelial lesions (LSILs), are limited. We immunohistochemically evaluated the diagnostic value of p16, MCM2, TOP IIA, ProE(X) C, and a cocktail of p16 and ProE(X) C in 62 cervical biopsy specimens, including 14 cases of benign squamous mucosa (group 1), 34 cases of LSILs (group 2), and 14 cases of HSILs (group 3). The staining intensity and distribution were recorded. The results demonstrated that positive staining for p16 and the p16/ProE(X) C was observed in 100% of cases in group 3, whereas 79%, 86%, and 79% of cases were positive for CM2, TOP IIA, and ProE(X) C, respectively. ProE(X) C and the p16/ProE(X) C showed positive staining in 94% and 100% of cases in group 2, respectively. In contrast, immunoreactivity for p16, MCM2, and TOP IIA was detected in only 76% of cases in group 2. Importantly, all 8 p16-negative cases in group 2 were positive for p16/ProE(X) C (P = .003). Our data indicate that (1) p16 is a more sensitive and specific marker for identifying HSILs; (2) ProE(X) C is a better marker for the detection of LSILs; and (3) p16/ProE(X) C provides the highest diagnostic value for the detection of both HSILs and LSILs.

MeSH terms

  • Antigens, Neoplasm / analysis*
  • Biomarkers, Tumor / analysis*
  • Carcinoma, Squamous Cell / chemistry
  • Carcinoma, Squamous Cell / pathology*
  • Cell Cycle Proteins / analysis*
  • Cyclin-Dependent Kinase Inhibitor p16 / analysis*
  • DNA Topoisomerases, Type II / analysis*
  • DNA-Binding Proteins / analysis*
  • Female
  • Humans
  • Immunohistochemistry
  • Minichromosome Maintenance Complex Component 2
  • Nuclear Proteins / analysis*
  • Predictive Value of Tests
  • Retrospective Studies
  • Uterine Cervical Neoplasms / chemistry
  • Uterine Cervical Neoplasms / pathology*


  • Antigens, Neoplasm
  • Biomarkers, Tumor
  • Cell Cycle Proteins
  • Cyclin-Dependent Kinase Inhibitor p16
  • DNA-Binding Proteins
  • Nuclear Proteins
  • MCM2 protein, human
  • Minichromosome Maintenance Complex Component 2
  • DNA Topoisomerases, Type II