Screening for cervical cancer precursors with p16/Ki-67 dual-stained cytology: results of the PALMS study

J Natl Cancer Inst. 2013 Oct 16;105(20):1550-7. doi: 10.1093/jnci/djt235. Epub 2013 Oct 4.

Abstract

Background: Pap cytology is known to be more specific but less sensitive than testing for human papillomavirus (HPV) for the detection of high-grade cervical intraepithelial neoplasia (CIN2+). We assessed whether p16/Ki-67 dual-stained cytology, a biomarker combination indicative of transforming HPV infections, can provide high sensitivity for CIN2+ in screening while maintaining high specificity. Results were compared with Pap cytology and HPV testing.

Methods: A total of 27,349 women 18 years or older attending routine cervical cancer screening were prospectively enrolled in five European countries. Pap cytology, p16/Ki-67 immunostaining, and HPV testing were performed on all women. Positive test results triggered colposcopy referral, except for women younger than 30 years with only positive HPV test results. Presence of CIN2+ on adjudicated histology was used as the reference standard. Two-sided bias-corrected McNemar P values were determined.

Results: The p16/Ki-67 dual-stained cytology positivity rates were comparable with the prevalence of abnormal Pap cytology results and less than 50% of the positivity rates observed for HPV testing. In women of all ages, dual-stained cytology was more sensitive than Pap cytology (86.7% vs 68.5%; P < .001) for detecting CIN2+, with comparable specificity (95.2% vs 95.4%; P = .15). The relative performance of the tests was similar in both groups of women: younger than age 30 and 30 years or older. HPV testing in women 30 years or older was more sensitive than dual-stained cytology (93.3% vs 84.7%; P = .03) but less specific (93.0% vs 96.2%; P < .001).

Conclusions: The p16/Ki-67 dual-stained cytology combines superior sensitivity and noninferior specificity over Pap cytology for detecting CIN2+. It suggests a potential role of dual-stained cytology in screening, especially in younger women where HPV testing has its limitations.

Publication types

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

MeSH terms

  • Adult
  • Aged
  • Biomarkers, Tumor / analysis*
  • Cell Transformation, Neoplastic / chemistry
  • Cervical Intraepithelial Neoplasia / chemistry*
  • Cervical Intraepithelial Neoplasia / diagnosis*
  • Cervical Intraepithelial Neoplasia / pathology
  • Colposcopy
  • Cyclin-Dependent Kinase Inhibitor p16
  • Cytopathogenic Effect, Viral
  • Early Detection of Cancer / methods*
  • Europe
  • Female
  • Humans
  • Ki-67 Antigen / analysis*
  • Mass Screening / methods
  • Middle Aged
  • Neoplasm Grading
  • Neoplasm Proteins / analysis*
  • Papillomaviridae / isolation & purification
  • Papillomavirus Infections / diagnosis
  • Papillomavirus Infections / virology
  • Prospective Studies
  • Referral and Consultation
  • Sensitivity and Specificity
  • Uterine Cervical Neoplasms / chemistry*
  • Uterine Cervical Neoplasms / diagnosis*
  • Uterine Cervical Neoplasms / pathology
  • Vaginal Smears

Substances

  • Biomarkers, Tumor
  • Cyclin-Dependent Kinase Inhibitor p16
  • Ki-67 Antigen
  • Neoplasm Proteins
  • P16 protein, human