Combined use of cytology, p16 immunostaining and genotyping for triage of women positive for high‐risk human papillomavirus at primary screening. Issue 7 (27th March 2020)

• Record Type: Journal Article
• Authors: Cuzick, Jack; Adcock, Rachael; Carozzi, Francesca; Gillio‐Tos, Anna; De Marco, Laura; Del Mistro, Annarosa; Frayle, Helena; Girlando, Salvatore; Sani, Cristina; Confortini, Massimo; Zorzi, Manuel; Giorgi‐Rossi, Paolo; Rizzolo, Raffaella; Ronco, Guglielmo
• Is Part Of: International journal of cancer. Volume 147:Issue 7(2020)
• Page Start: 1864
• Page End: 1873
• Publication Date: 2020-03-27
• Subjects: cervical screening -- HPV testing -- triage of HPV‐positive women -- cytology -- p16 immunocytochemistry -- HPV genotyping; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.32973
• Languages: English
• ISSNs: 0020-7136

Abstract

Abstract : Human papillomavirus (HPV) testing is very sensitive for primary cervical screening but has low specificity. Triage tests that improve specificity but maintain high sensitivity are needed. Women enrolled in the experimental arm of Phase 2 of the New Technologies for Cervical Cancer randomized controlled cervical screening trial were tested for high‐risk HPV (hrHPV) and referred to colposcopy if positive. hrHPV‐positive women also had HPV genotyping (by polymerase chain reaction with GP5+/GP6+ primers and reverse line blotting), immunostaining for p16 overexpression and cytology. We computed sensitivity, specificity and positive predictive value (PPV) for different combinations of tests and determined potential hierarchical ordering of triage tests. A number of 1, 091 HPV‐positive women had valid tests for cytology, p16 and genotyping. Ninety‐two of them had cervical intraepithelial neoplasia grade 2+ (CIN2+) histology and 40 of them had CIN grade 3+ (CIN3+) histology. The PPV for CIN2+ was >10% in hrHPV‐positive women with positive high‐grade squamous intraepithelial lesion (61.3%), positive low‐grade squamous intraepithelial lesion (LSIL+) (18.3%) and positive atypical squamous cells of undetermined significance (14.8%) cytology, p16 positive (16.7%) and, hierarchically, for infections by HPV33, 16, 35, 59, 31 and 52 (in decreasing order). Referral of women positive for either p16 or LSIL+ cytology had 97.8% sensitivity for CIN2+ and women negative for both of these had a 3‐year CIN3+ risk of 0.2%. Similar results were seen for women being either p16 or HPV16/33 positive. hrHPV‐positive women who were negative for p16 and cytology (LSIL threshold) had a very low CIN3+ rate in the following 3 years. Recalling them after that interval and referring those positive for either test to immediate colposcopy seem to be an efficient triage strategy. The same applies to p16 and HPV16. Abstract : What's new? Human papillomavirus (HPV) testing has revolutionized cervical cancer screening but alone cannot accurately predict the risk of cancerous lesions. Here the authors assessed its combined use with other predictive exams, cytology and p16 staining. They show that women testing positive for high‐risk HPV but negative for p16 and either cytology or HPV16 have a very low rate of cervical intraepithelial neoplasia or worse (CIN3+) in the three years after the exam and can be safely recalled after that time period, reducing overall colposcopy referrals.