p16/ki67 and E6/E7 mRNA accuracy and prognostic value in triaging HPV DNA-positive women

Paolo Giorgi Rossi, Francesca Carozzi, Guglielmo Ronco, Elena Allia, Simonetta Bisanzi, Anna Gillio-Tos, Laura De Marco, Raffaella Rizzolo, Daniela Gustinucci, Annarosa Del Mistro, Helena Frayle, Massimo Confortini, Anna Iossa, Elena Cesarini, Simonetta Bulletti, Basilio Passamonti, Silvia Gori, Laura Toniolo, Alessandra Barca, Laura BonviciniPamela Mancuso, Francesco Venturelli, Maria Benevolo

Research output: Contribution to journalArticlepeer-review


BACKGROUND: The study presents cross-sectional accuracy of E6/E7 mRNA detection and p16/ki67 dual staining, alone or in combination with cytology and HPV16/18 genotyping, as triage test in HPV DNA-positive women and their impact on CIN2+ overdiagnosis. METHODS: Women aged 25-64 were recruited. HPV DNA-positives were triaged with cytology and tested for E6/E7 mRNA and p16/ki67. Cytology positives were referred to colposcopy, while negatives were randomised to immediate colposcopy or to one-year HPV retesting. Lesions found within 24 months since recruitment were included. All p-values were two-sided. RESULTS: 40,509 women were recruited and 3147 (7.8%) tested HPV DNA-positive; 174 CIN2+ were found: sensitivity was 61.0% (95% CI = 53.6 to 68.0), 94.4% (95% CI = 89.1 to 97.3), and 75.2% (95% CI = 68.1 to 81.6) for cytology, E6/E7 mRNA, and p16/ki67, respectively. Immediate referral was 25.6%, 66.8%, and 28.3%, respectively. Overall referral was 65.3%, 78.3%, and 63.3%. Cytology or p16/ki67 when combined with HPV16/18 typing reached higher sensitivity with a small impact on referral. Among the 2306 HPV DNA-positive/cytology-negative women, relative CIN2+ detection in those randomized at 1-year retesting vs. immediate colposcopy suggests a -28% CIN2+ regression (95% CI = -57% to + 20%); regression was higher in E6/E7 mRNA-negatives (pinteraction =.29). HPV clearance at 1 year in E6/E7 mRNA and in p16/ki67 negatives was about 2 times higher than in positive women (Pinteraction < .001 for both). CONCLUSIONS: p16/ki67 showed good performance as triage test. E6/E7 mRNA showed the highest sensitivity, at the price of too high a positivity rate to be efficient for triage. However, when negative, it showed a good prognostic value for clearance and CIN2+ regression.
Original languageEnglish
JournalJournal of the National Cancer Institute
Publication statusE-pub ahead of print - Aug 3 2020


  • accuracy
  • cervical cancer
  • cervical intraepithelial neoplasia
  • E6/E7 mRNA
  • mass screening
  • p16/ki67
  • prognostic biomarkers


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