Evaluation of a nuclear score for p16INK4a-stained cervical squamous cells in liquid-based cytology samples

Cancer. 2005 Dec 25;105(6):461-7. doi: 10.1002/cncr.21378.


Background: The p16INK4a gene product is overexpressed strongly in abnormal cervical epithelia and may serve as a valuable biomarker to identify abnormal cells in cervical smears or liquid-based cytology samples.

Methods: The authors performed p16INK4a immunocytochemistry to locate cells that expressed p16INK4a in liquid-based cytology samples and used a nuclear scoring system based on several morphologic criteria to interpret the degree of abnormality of these cells.

Results: Among 108 samples that were scored as normal in Papanicolaou-stained, parallel slides, any p16INK4a-positive cells were observed in 13 samples (12%), but only 1 of 108 samples (1%) was scored abnormal after applying nuclear scoring criteria. In the group of 52 low-grade squamous intraepithelial lesion (LSIL) samples, 19 samples (37%) were positive for any p16INK4a reactivity, but only 5 of those samples (10%) were scored abnormal after applying the nuclear score. Among the 50 high-grade squamous intraepithelial lesion (HSIL) samples, 49 samples (98%) were positive for p16INK4a and were scored as abnormal. Comparison of the scoring results of independent observers revealed good reproducibility of the nuclear score.

Conclusions: The current results suggested that p16INK4a enables the location of potentially abnormal cells on liquid-based cytology samples. The nuclear score facilitated interpretation of the degree of abnormality of p16INK4a-stained cells. Thus, locating potentially abnormal cells by p16INK4a immunocytochemistry and their interpretation based on the nuclear score described here may help to identify patients with HSIL in cytologic screening programs and may represent a new approach for reducing the number of equivocal or misinterpreted cytologic specimens.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Biomarkers, Tumor / metabolism*
  • Cell Nucleus / pathology*
  • Cervical Intraepithelial Neoplasia / diagnosis*
  • Cervical Intraepithelial Neoplasia / pathology
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism*
  • Female
  • Humans
  • Middle Aged
  • Neoplasms, Squamous Cell / diagnosis*
  • Neoplasms, Squamous Cell / pathology
  • Papanicolaou Test
  • Staining and Labeling
  • Uterine Cervical Neoplasms / diagnosis*
  • Uterine Cervical Neoplasms / pathology
  • Vaginal Smears


  • Biomarkers, Tumor
  • Cyclin-Dependent Kinase Inhibitor p16