Abstract
BackgroundSelf-sampling for human papillomavirus (HPV) testing is a feasible option to improve the cervical screening coverage. However, an ideal triage method for HPV-positive self-samples does not yet exist. The aim of this study was to explore the utility of HPV genotyping and p16INK4a immunostaining (p16) in triaging HPV-positive self-samples, focusing on HPV-positive, cytology-negative (HPCN) women.MethodsA total of 73,699 women were screened in a cervical screening project in China via SeqHPV assay on self-samples. HPV-positive women were called-back and collected cervical sample for p16 immunostaining and liquid-based cytology, those who met any result of HPV16/18+ or visual inspection with acetic acid (VIA) + or p16+ were referred for colposcopy, and HPCN women with adequate data on p16 and pathology were analyzed. A triage strategy was considered acceptable if the negative predictive value (NPV) for cervical intraepithelial neoplasia 3 or worse (CIN3+) was 98% or more, combined with an improvement of sensitivity and specificity for CIN2+/CIN3+ in reference to the comparator, being HPV16/18 + .ResultsA total of 2731 HPCN women aged 30–64 years were enrolled, 136 (5.0%) CIN2+ and 53 (1.9%) CIN3+ were detected. Five triage strategies met the criteria: p16+; HPV16/33+; ‘HPV16+ or HPV33/58/31/35+&p16+’; ‘HPV16/33+ or HPV58/31/35+&p16+’; HPV16/18/31/33/45/52/58 + & p16+. These strategies required less or similar colposcopy referrals, and less colposcopies to detected one case of CIN2+/CIN3+, achieving favorable false positive (negative) rates to the comparator. Among them, p16 staining detected 83.1% (79.2%) of underlying CIN2 + (CIN3+) in HPCN women. Moreover, three triage strategies were favorable in sensitivity and/or specificity to the ‘HPV16/33+’ strategy: p16+; ‘HPV16+ or HPV33/58/31/35 + &p16+’; HPV16/18/31/33/45/52/58 + &p16 + .ConclusionsGenotyping for HPV16/33 could be utilized to optimize the management of HPCN women. Moreover, p16 immunostaining, either alone or combined with extended genotypes, is more effective than HPV genotypes alone in the triage of HPCN women.
Highlights
Self-sampling for human papillomavirus (HPV) testing is a feasible option to improve the cervical screening coverage
The average risks of cervical intraepithelial neoplasia 3 or worse (CIN3+) among HPCN women were relatively low (2.1%/4.3%/6.4% at 1/3/ 5 years, respectively) [9], given that the cytology is affected by many factors such as slides production and the highly subjective nature of slides interpretation, cervical highgrade lesions missed by cytology often occur in HPVpositive women [10], in countries with limited well-trained cytologists like China
The 2012 ASCCP guidelines recommend that HPCN women infected with the most oncogenic genotype-16/18 should be referred for immediate colposcopy, whereas those positive for other High-risk human papillomavirus (hrHPV) be followed-up in one-year [5]
Summary
Self-sampling for human papillomavirus (HPV) testing is a feasible option to improve the cervical screening coverage. HPVpositive women with abnormal cytology require a referral to colposcopy, but the management of HPV-positive, cytology-negative (HPCN) women remains controversial [5]. Triage options for HPCN women including immediate referral to colposcopy, repeat cytology/HPV within 12 months, or triaging with genotypes, viral loads, HPV E6/E7 protein, or other biomarkers [11]. Immediate referral of HPCN women causes substantial colposcopy burden and overtreatment, while short-term repeat tests can produce anxiety for women involved and entail appreciable loss to follow-up [11]. The 2012 ASCCP guidelines recommend that HPCN women infected with the most oncogenic genotype-16/18 should be referred for immediate colposcopy, whereas those positive for other hrHPV be followed-up in one-year [5]. The 2019 ASCCP guidelines recommend that any set of results predicting an underlying immediate risk of ≥4.0% for CIN3+ are referred to colposcopy [12]
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