The main objective of this prospective observational study was to investigate the diagnostic performance of the p16/Ki-67 dual stain technique (DST) for detecting CIN 2+ in a LLETZ referral setting. Test performances were compared with HR-HPV testing and Pap cytology.
All patients referred for a LLETZ procedure were candidates for participation in this trial. A total of 110 patients were enrolled between October 2016 and March 2017. From each participant, a cervical cytology sample was obtained before the onset of the LLETZ procedure. On each sample, the dual stain technique (Roche CINtec PLUS ® test), Pap cytology and an HPV DNA assay (identifying 17 different HPV types) were performed.
The overall disease prevalence of CIN 2+ was 56%. The mean age was 41 years, with 38% of patients being younger than 35 years.
The overall sensitivity and specificity of the dual stain technique for detecting CIN 2+ was 94% (95% CI: 84.30–98.21%) and 58% (95% CI: 43.21–72.93%) respectively with a PPV of 74% (95% CI: 67.34–80.31%) and a NPV of 88% (95% CI: 72.48–94.90%). HR-HPV testing results in a similar sensitivity of 92% (95% CI: 82.17–97.33%) but considerable lower specificity of 21% (95% CI: 11.17–33.35%) compared to the dual stain technique.
At an ASCUS or worse threshold, Pap cytology had the lowest sensitivity of 89% (95% CI 78.11–95.34%) compared to dual staining and HR-HPV testing. Specificity was better (48% with 95% CI of 33.29–62.81%) than that of HR-HPV testing but not as good as the DST.
p16/Ki-67 dual staining provides high sensitivity and improved specificity compared to HR-HPV testing and Pap cytology for detecting CIN 2+, making it an interesting tool for identifying relevant disease in patients referred for a LLETZ procedure.
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- Cervical cancer risk for women undergoing concurrent testing for human papillomavirus and cervical cytology: a population based study in routine clinical practice.Lancet Oncol. 2011; 12: 663-672
- Long term predictive values of cytology and human papillomavirus testing in cervical cander screening: joint European cohort study.BMJ. 2008; 337: a1754
- Pathology and epidemiology of HPV infections in females.Gynaecol Oncol. 2010; 117: S5-S10
- Colposcopy for the diagnosis of squamous intraepithelial lesions: a meta-analysis.Obstet Gynaecol. 1998; 91: 626-631
- Accuracy of the Papanicolaou test in screening for and follow up of cervical cytologic abnormalities: a systematic review.Ann Intern Med. 2000; 132: 810-819
- Inhibition of cyclin D-CDK4/CDK6 activity is associated with an E2F-mediated induction of cyclin kinase inhibitor activity.Proc Natl Acad Sci U S A. 1996; 1: 4350-4354
- Biomarkers in cervical cancer screening.Dis Markers. 2007; 23: 315-330
- Triage of HPV positive women in cervical cancer screening.Lancet Oncol. 2013; 14: 107-109
- et al. Screening for cervical cancer precursors with p16/Ki-67 dual-stained cytology: results of the PALMS study.J Natl Cancer Inst. 2013; 105: 1550-1557
- Performance of p16/Ki-67 immunostaining to detect cervical cancer precursors in a colposcopy referral population.Clin Cancer Res. 2012; 18: 4154-4162
- Prospective evaluation of p16/Ki-67 dual-stained cytology for managing women with abnormal Papanicolaou cytology: PALMS study results.Cancer Cytopathol. 2015; 123: 373-981
- Triaging borderline/mild dyskaryotic Pap cytology with p16/Ki-67 dual-stained cytology testing: cross-sectional and longitudinal outcome study.Br J Cancer. 2014; 110: 1579-1586
- p16/ki-67 dual-stain cytology in the triage of ASCUS and LSIL Papanicolaou cytology: results from the European equivocal or mildly abnormal Papanicolaou cytology study.Cancer Cytopathol. 2011; 119: 158-166
- Predictive value of p16/Ki-67 immunocytochemistry for triage of women with abnormal Papanicolaou test in cervical cancer screening: a systematic review and meta-analysis.Ann Saudi Med. 2016; 36: 245-251
- A systematic review of p16/Ki-67 immuno-testing for triage of low grade cervical cytology.BJOG. 2015; 122: 64-70
- Triaging Pap cytology negative, HPV positive cervical cancer screening results with p16/Ki-67 dual-stained cytology.Gynecol Oncol. 2011; 121: 505-509
- p16/Ki-67 dual stain cytology for detection of cervical precancer in HPV-positive women.J Natl Cancer Inst. 2015; 107: djv257
- Triaging HPV-positive women with normal cytology by p16/Ki-67 dual-stained cytology testing: baseline and longitudinal data.Int J Cancer. 2015; 136: 2361-2368
- Triaging HPV-positive women with p16/Ki-67 dual-stained cytology: results from a sub-study nested into the ATHENA trial.Gynecol Oncol. 2017; 144: 51-56
- Interpretation of p16INK4A/Ki-67 dual immunostaining for the triage of human papillomavirus-positive women by experts and nonexperts in cervical cytology.Cancer Cytopathol. 2015; 123: 212-218
- 2011 colposcopic terminology of the International Federation for cevrical pathology and colposcopy.Obstet Gynecol. 2012; 120: 166-172
- The 2001 Bethesda system: terminology for reporting results of cervical cytology.JAMA. 2002; 287: 2114-2119
- Interobserver reproducibility and accuracy of p16/KI-67 dual-stain cytology in cervical cancer screening.Cancer Cytopathol. 2014; 122: 914-920
- A long-term prospective study of type-specific human papillomavirus infection and risk of cervical neoplasia among 20,000 women in the Portland Kaiser Cohort Study.Cancer Epidemiol Biomarkers Prev. 2011; 20: 1398-1409
- Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional worldwide study.Lancet Oncol. 2010; 11: 1048-1056
- 2006 consensus guidelines for the management of women with abnormal cervical cancer screening tests.Am J Obstet Gynecol. 2007; 197: 346-355
- Prospective follow-up suggests similar risk of subsequent cervical intraepithelial neoplasia garde 2 or 3 among women with cervical intraepithelial neoplasia grade 1 or negative colposcopy and directed biopsy.Am J Obstet Gynecol. 2003; 188: 1406-11412
- Chapter 9: clinical applications of HPV testing: a summary of meta-analyses.Vaccine. 2006; 24: S78-89
Published online: June 21, 2018
Accepted: June 12, 2018
Received: April 27, 2018
© 2018 Elsevier B.V. All rights reserved.