Risk-based triage strategy by extended HPV genotyping for women with ASC-US cytology

Abstract

Objective: We attempted to evaluate the immediate high-grade squamous intraepithelial lesion-cervical intraepithelial neoplasia grade 2/3 or worse (HSIL-CIN2+/3+, hereafter referred to as CIN2+/3+) risk of specific human papillomavirus (HPV) genotype and form the precise risk-based triage strategy for atypical squamous cells of undetermined significance (ASC-US) women.

Methods: The clinical data of ASC-US women who underwent HPV genotyping testing and colposcopy were retrospectively reviewed. The distribution and CIN2+/3+ risks of specific HPV genotype were assessed by three approaches. The risk-based triage strategy was further established, and its efficacy in detecting CIN2+/3+ was estimated.

Results: Totally, 5553 ASC-US women including 3648 HPV-positive and 1905 HPV-negative were analysed. CIN2+/3+ were 662/319 cases, including 639/306 HPV-positive and 23/13 HPV-negative women. HPV16, HPV52, HPV58 and HPV18 were always among the top 5 ranking genotypes, no matter in HPV-positive women or in HPV-positive CIN2+/3+ cases. HPV16 and HPV33 carried the highest risk, while HPV73 and 26 carried the least risk for CIN2+/3+. Based on the immediate CIN2+/3+ risk of specific HPV genotype, 18 HPVs were divided into three risk-stratified groups. Only women infected with HPVs included in group A were necessary for immediate colposcopy. Compared with conventional strategy, this new risk-based strategy not only had higher specificity (CIN2+: p = .00; CIN3+: p = .01) and positive predictive value (CIN2+: p = .00; CIN3+: p = .03) for detecting CIN2+/3+, but also needed fewer colposcopies to identify each CIN2+/3+.

Conclusions: A new triage strategy for ASC-US women was successfully constructed based on CIN2+/3+ risks of 14 high-risk and 4 intermediate-risk HPVs, which could significantly reduce unnecessary colposcopies.

Keywords: Atypical squamous cells of undetermined significance; cervical intraepithelial neoplasia; colposcopy; extended genotyping; human papillomavirus; risk-based triage strategy.

Figure 1.

Distribution and the immediate risk of specific HPV genotype. (A) The distribution of specific HPV genotype in HPV-positive ASC-US women estimated by Min. (B) The distribution of specific HPV genotype in HPV-positive ASC-US women estimated by Any. (C) The distribution of specific HPV genotype in HPV-positive ASC-US women estimated by Hier. (D) The distribution of specific HPV genotype in HPV-positive CIN2+/3+ cases estimated by Min. (E) The distribution of specific HPV genotype in HPV-positive CIN2+/3+ cases estimated by Any. (F) The distribution of specific HPV genotype in HPV-positive CIN2+/3+ cases estimated by Hier. (G) The immediate CIN2+/3+ risk of specific HPV genotype in HPV-positive ASC-US women estimated by Min. (H) The immediate CIN2+/3+ risk of specific HPV genotype in HPV-positive ASC-US women estimated by Any. (I) The immediate CIN2+/3+ risk of specific HPV genotype in HPV-positive ASC-US women estimated by Hier. ASC-US: atypical squamous cells of undetermined significance; HPV: human papillomavirus; Min.: minimum estimate; Any.: any type estimate; Hier.: hierarchical attribution estimate; CIN: cervical intraepithelial neoplasia.

Figure 2.

Algorithms of risk stratification for specific HPV genotype grouping in ASC-US women. (A) HPV genotype grouping for CIN2+. HPVs that carried the immediate CIN2+ risk above the threshold of colposcopy referral (≥4.0%) were classified into group A, including HPV16, HPV33, HPV31, HPV58, HPV52, HPV35, HPV82, HPV18, HPV39, HPV45 and HPV68. HPVs that carried the immediate CIN2+ risk no more than that of HPV-negative women were group C, including HPV73 and HPV26. And the others were group B, including HPV56, HPV51, HPV66, HPV53 and HPV59. (B) HPV genotype grouping for CIN3+. According to prior studies, HPV18 was still grouped into A by default due to its critical role in cervical cancer and necessity for colposcopy referral. For remaining HPV genotypes, HPVs that carried the immediate CIN3+ risk above the threshold of colposcopy referral were classified into group A, including HPV16, HPV33, HPV35, HPV31, HPV82, HPV52, HPV39 and HPV58. HPVs that carried the immediate CIN3+ risk no more than that of HPV-negative women were group C, including HPV45, HPV53, HPV59, HPV73 and HPV26. And the others were group B, including HPV51, HPV68, HPV66 and HPV56. ASC-US: atypical squamous cells of undetermined significance; HPV: human papillomavirus; Min.: minimum estimate; CIN: cervical intraepithelial neoplasia.

Figure 3.

The immediate CIN2+/3+ risk of HPV-positive women, three risk-stratified groups, HPV-negative women and total population stratified by age. (A) The age-specific CIN2+ risk of HPV-positive women, three HPV risk groups, HPV-negative women and total population. (B) The age-specific CIN3+ risk of HPV-positive women, three HPV risk groups, HPV-negative women and total population. CIN: cervical intraepithelial neoplasia; HPV: human papillomavirus.