Evaluation of cytology versus human papillomavirus-based cervical cancer screening algorithms in Bhutan

To evaluate the performance of existing versus alternative cervical cancer screening protocols in Bhutan, cervical exfoliated cells were collected for cytology and high-risk human papillomavirus (HR-HPV) testing among 1,048 women aged 30-69 years. Conventional smears were prepared and read locally. HR-HPV was tested by GP5+/6+ polymerase chain reaction, followed by genotyping and human DNA methylation analysis among HR-HPV-positives, in Europe. Test positivity was 7.5% for ASCUS or worse (ASCUS+) cytology and 14.0% for HR-HPV. All women with ASCUS+ and/or HR-HPV positivity (n=192) were recalled for colposcopy, among whom a total of 29 cases of histologically confirmed cervical intraepithelial neoplasia grade 2 or worse (CIN2+) were identified. An additional 7 CIN2+ cases were imputed among women without colposcopy. Corrected sensitivities for CIN2+ and CIN3+ were 61% and 74% for ASCUS+, 86% and 96% for HR-HPV, and 47% and 70% for ASCUS+ triage of HR-HPV. Specificity varied from 88% for HR-HPV up to 98% for ASCUS+ triage of HR-HPV, similarly for CIN2+ and CIN3+. Among HR-HPV-positive women with biopsies, methylation analysis offered similar discrimination of CIN2/3 and cervical cancer as ASCUS+, and better than HPV16/18 genotyping alone, but sample sizes were limited. In conclusion, the performance of cytology in Bhutan is in the mid-range of that reported in other screening settings. HR-HPV testing has the potential to improve detection of CIN2+, albeit with a higher referral rate for colposcopy. Cytological triage of HR-HPV-positives (performed in the absence of knowledge of HR-HPV status) reduced referral but missed more than one third of CIN2+.