Detection of cervical high-grade squamous intraepithelial lesions from cytologic samples using a novel immunocytochemical assay (ProEx C)

Cancer. 2006 Dec 25;108(6):494-500. doi: 10.1002/cncr.22288.


Background: Routine liquid-based cytology (LBC) provides excellent sensitivity for the detection of cervical high-grade squamous intraepithelial lesion (HSIL); however, its specificity is low. Consequently, many women who have atypical squamous cells of undetermined significance (ASC-US) or low-grade squamous intraepithelial lesion (LSIL) cytology undergo unnecessary colposcopy. The authors hypothesized that a novel immunocytochemical assay (ProEx C) that can be performed on LBC slides had a significantly higher positive predictive value (PPV) for biopsy-proven HSIL compared with routine LBC.

Methods: The ProEx C immunocytochemical assay utilizes a cocktail of monoclonal antibodies directed against proteins associated with aberrant S-phase cell cycle induction (topoisomerase IIA, minichromosome maintenance protein 2). The ProEx C reagents were validated in the authors' laboratory for staining and scoring reproducibility, open-vial stability, and accuracy before a retrospective analysis using these reagents was performed on 317 residual cytology samples. Sensitivity, specificity, PPV, and negative predictive value (NPV) for the detection of biopsy-proven HSIL were determined.

Results: The ProEx C assay was validated successfully in the authors' cytology laboratory. Using biopsy-proven HSIL as an endpoint, the ProEx C assay yielded a sensitivity of 85.3%, specificity of 71.7%, PPV of 44.6%, and NPV of 94.8%. Compared with the routine LBC results in the same cohort, the ProEx C sensitivity for biopsy-proven HSIL was 70.6% greater than HSIL+ cytology (50% vs. 85.3%). ProEx C also showed a 114% increase in PPV relative to ASC-US cytology (21.1% vs. 44.6%).

Conclusions: The ProEx C immunocytochemical assay can be integrated into a clinical cytology laboratory and may increase the PPV of LBC for biopsy-proven HSIL.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Antigens, Neoplasm / metabolism*
  • Biological Assay
  • Cell Cycle Proteins / metabolism*
  • Cervical Intraepithelial Neoplasia / diagnosis*
  • Cervical Intraepithelial Neoplasia / metabolism
  • DNA Topoisomerases, Type II / metabolism*
  • DNA-Binding Proteins / metabolism*
  • Female
  • Humans
  • Minichromosome Maintenance Complex Component 2
  • Neoplasms, Squamous Cell / diagnosis*
  • Neoplasms, Squamous Cell / metabolism
  • Nuclear Proteins / metabolism*
  • Predictive Value of Tests
  • Retrospective Studies
  • Sensitivity and Specificity
  • Uterine Cervical Neoplasms / diagnosis*
  • Uterine Cervical Neoplasms / metabolism
  • Vaginal Smears


  • Antigens, Neoplasm
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Nuclear Proteins
  • MCM2 protein, human
  • Minichromosome Maintenance Complex Component 2
  • DNA Topoisomerases, Type II