Triaging HPV-positive women with p16/Ki-67 dual-stained cytology: Results from a sub-study nested into the ATHENA trial

• Published in: Gynecologic oncology 2017-01, Vol.144 (1), p.51-56
• Main Authors: Wright, Thomas C, Behrens, Catherine M, Ranger-Moore, James, Rehm, Susanne, Sharma, Abha, Stoler, Mark H, Ridder, Ruediger
• Format: Article
• Language: English
• Subjects: Adult; ATHENA; Biopsy; Cervical cancer screening; Cervical Intraepithelial Neoplasia - chemistry; Cervical Intraepithelial Neoplasia - diagnosis; Cervical Intraepithelial Neoplasia - pathology; Cervical Intraepithelial Neoplasia - virology; Cervix Uteri - pathology; CINtec PLUS; Clinical Trials as Topic; Colposcopy; Cyclin-Dependent Kinase Inhibitor p16 - analysis; Female; Genotype; Genotyping; Hematology, Oncology and Palliative Medicine; HPV; Humans; Ki-67 Antigen - analysis; Obstetrics and Gynecology; p16/Ki-67 dual-stained cytology; Papanicolaou Test; Papillomaviridae - genetics; Papillomavirus Infections - diagnosis; Papillomavirus Infections - virology; Predictive Value of Tests; Referral and Consultation; Retrospective Studies; Triage; Triage - methods; Uterine Cervical Neoplasms - chemistry; Uterine Cervical Neoplasms - diagnosis; Uterine Cervical Neoplasms - pathology; Uterine Cervical Neoplasms - virology; Vaginal Smears
• ISSN: 0090-8258; 1095-6859
• DOI: 10.1016/j.ygyno.2016.10.031

Abstract Objectives In addition to genotyping for HPV16/18, dual-immunostaining for p16/Ki-67 has shown promise as a triage of HPV-positive women. We assessed the performance of p16/Ki-67 dual-stained cytology for triaging HPV-positive women undergoing primary HPV screening. Methods All women ≥ 25 years with valid cervical biopsy and cobas® HPV Test results from the cross-sectional phase of ATHENA who were referred to colposcopy (n = 7727) were eligible for enrolment. p16/Ki-67 dual-stained cytology was retrospectively performed on residual cytologic material collected into a second liquid-based cytology vial during the ATHENA enrolment visit. The diagnostic performance of dual-stained cytology, with or without HPV16/18 genotyping, for the detection of biopsy-confirmed cervical intraepithelial neoplasia grade 3 or worse (CIN3+) was determined and compared to Pap cytology. Furthermore, the number of colposcopies required per CIN3+ detected was determined. Results Dual-stained cytology was significantly more sensitive than Pap cytology (74.9% vs. 51.9%; p < 0.0001) for triaging HPV-positive women, whereas specificity was comparable (74.1% vs. 75.0%; p = 0.3198). Referral of all HPV16/18 positive women combined with dual-stained cytology triage of women positive for 12 “other” HPV genotypes provided the highest sensitivity for CIN3+ (86.8%; 95% CI: 81.9–90.8). A similar strategy but using Pap cytology for the triage of women positive for 12 “other” HPV genotypes was less sensitive (78.2%; 95% CI: 72.5–83.2; p = 0.0003), but required a similar number of colposcopies per CIN3+ detected. Conclusions p16/Ki-67 dual-stained cytology, either alone or combined with HPV16/18 genotyping, represents a promising approach as a sensitive and efficient triage for colposcopy of HPV-positive women when primary HPV screening is utilized.