Extended HPV Genotyping for Risk Assessment of Cervical Intraepithelial Neoplasia Grade 2/3 or Worse in a Cohort Study

Authors: Xiao Li MD1,2,3, Xuan Rao MMed1, Ming-Jing Wei MMed1, Wei-Guo Lu MD1,3,4, Xing Xie MD1, and Xin-Yu Wang MD1,3
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  • 1 Department of Gynecologic Oncology, Women’s Hospital, Zhejiang University School of Medicine;
  • | 2 Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases of Zhejiang Province;
  • | 3 Cancer Research Institute of Zhejiang University; and
  • | 4 Center for Uterine Cancer Diagnosis & Therapy Research of Zhejiang Province, Hangzhou, Zhejiang, China.

Background: We sought to identify the absolute risk of specific HPV genotype for cervical intraepithelial neoplasia grade 2/3 or worse (CIN2+/3+) and to develop a risk-based management strategy in an HPV-positive population. Methods: HPV genotyping was performed based on a 3-year cervical cancer screening cohort. The study endpoints were histologic CIN2+/3+. The prevalence of specific HPV genotype was calculated by minimum, any type, and hierarchical attribution estimate. The absolute CIN2+/3+ risks of specific HPV genotype were estimated and risk-based management strategy was established according to the American Society for Colposcopy and Cervical Pathology guideline. The efficacy of conventional and risk-based management strategies for non-16/18 HPVs were further evaluated. Results: Eligible data were available for 8,370 women with a median age of 48 years (interquartile range, 42–53 years). At baseline, there were 1,062 women with HPV-positive disease, including 424 with multiple and 639 with single infections. CIN2+/3+ cases represented 113/74, 23/8, 20/7, and 52/31 patients at baseline and first-, second-, and third-year visits, respectively. Women with multiple HPV infections at baseline were more prone to persistent infection than those with single infection (P<.0001). HPV16 and HPV52 were the top 2 ranking among baseline and 3-year cumulative CIN2+/3+ cases. Based on the absolute risk of specific HPV genotype combined with cytology for CIN2+/3+, all non-16/18 HPVs were divided into 4 risk-stratified groups. Compared with conventional strategy, the risk-based strategy had higher specificity (P=.0000) and positive predictive value (P=.0322) to detect CIN3+ and needed fewer colposcopies for each CIN3+ case. Conclusions: Based on our study findings, we propose a new extended HPV genotyping protocol, which would provide a better strategy for achieving precise risk-based management of HPV-positive populations.

Background

Cervical cancer (CC) was the fourth most commonly diagnosed cancer and the fourth leading cause of cancer death in women worldwide in 2020, with 604,000 new cases and 342,000 deaths according to estimates from the International Agency for Research on Cancer.1 Persistent infection with high-risk HPV is the key factor for development of cervical precancerous lesions and cancer.25 The CC screening strategy has changed from cytology-based testing to HPV-based testing, with accumulating evidence from high-quality clinical trials. The American Society for Colposcopy and Cervical Pathology (ASCCP) also recommends primary HPV testing or cotesting (HPV testing combined with cytology) for CC screening rather than cytology alone.6

Despite high sensitivity of HPV testing, the subsequent concern is that the proportion of histologic cervical intraepithelial neoplasia 2/3 or worse (CIN2+/3+) detected by positive HPV results might be significantly lower than that detected by cytologic abnormalities.7,8 Therefore, a triage strategy based on the principle of “equal management for equal risks” was recommended for HPV-positive women to avoid excessive colposcopy referrals.6 HPV16/18 genotyping and reflex cytology for HPV-others (non-16/18 HPV) are current conventional triage strategies for HPV-positive women in China, which are the same as those in the United States. Recent studies have shown that pooled HPV31/33/52/58 or HPV31, HPV33, or HPV58 individually carried higher CIN2+/3+ risk than HPV18,912 whereas pooled HPV56/59/68 carried extremely low risk.10,12 In addition, Wright et al13 reported that women with positive pooled HPV56/59/66 and atypical squamous cells of undetermined significance (ASCUS) or low-grade squamous intraepithelial lesion (LSIL) cytology carried lower immediate CIN2+/3+ risks than the risk threshold for colposcopy referral. These findings suggested that extended genotyping was urgently warranted for risk stratification of non-16/18 HPV-positive women, which would provide precise evaluation for their risk of CC and precancer.

To date, the BD Onclarity HPV Assay remains the only FDA-approved extended genotyping assay by detecting HPV31, HPV51, and HPV52 (beyond HPV16, HPV18, and HPV45) individually and detecting 3 separate groups of HPVs (HPV33/58, HPV35/39/68, and HPV56/59/66).14 Although there are numerous National Medical Products Administration (NMPA)–approved HPV full-genotyping kits in China, the significance of specific genotype still has not been verified thoroughly. Based on the CC screening cohorts of 2 premarketing clinical trials, the present study tried to clarify the risk of CIN2+/3+ of specific HPV genotypes and developed extended HPV genotyping protocols according to the ASCCP guideline, hoping to provide precise risk-based management strategies for the HPV-positive population.

Methods

Study Population

Between November 2016 and August 2020, a total of 10,314 women were enrolled in 1 of 2 NMPA clinical trials (approvals 20160380 [Zhejiang], 20160205 [Jiangsu]) and underwent a 3-year prospective population-based CC screening program in Zhejiang and Henan. Among them, subjects who met the following eligibility criteria were further selected for the present study: age ≥21 years, no surgical history of cervix uteri, and informed consent obtained for the clinical trial. Exclusion criteria included any one of the following: pregnancy or within 2 months of the postpartum period; previous total hysterectomy; a history of CIN or worse, vulvar intraepithelial neoplasia or worse, or vaginal intraepithelial neoplasia or worse; invalid HPV results at the baseline visit; insufficient residual samples for further HPV genotyping; and loss to follow-up.

Study Design

The study flowchart is shown in Figure 1. At the baseline visit (V0), samples of cervical exfoliated cells were collected for ThinPrep cytology testing (Hologic) and HPV testing. Cytologic results were reported according to the 2014 Bethesda System, including negative for intraepithelial lesion or malignancy (NILM), ASCUS, LSIL, atypical squamous cells–cannot exclude high-grade squamous intraepithelial lesion (ASC-H), high-grade squamous intraepithelial lesion (HSIL), atypical glandular cells (AGC), adenocarcinoma in situ (AIS), and cancer cells.15 Women with positive HPV16/18 or abnormal cytology (ASCUS or worse, ASCUS+) would be referred for colposcopy, according to the Guideline for Comprehensive Prevention and Control of Cervical Cancer in China.16 Due to clinical experience and ethical considerations, women with both negative HPV and cytologic results were regarded as histologic CIN1 or less by default and were not referred for colposcopy. Partly, women with positive HPV-others and normal cytology sought colposcopy because of fear of CC, which was defined as a protocol deviation. At the first-year and second-year visits (V1 and V2), only women with positive HPV or abnormal cytology at the baseline visit would be recalled for cytology testing, and those with abnormal cytologic results would be referred for colposcopy. At the third-year visit (V3), all enrolled women would be recalled for cytology and HPV testing.

Figure 1.
Figure 1.

Detailed flowchart of the cervical cancer screening procedure.

Abbreviations: ASCUS, atypical squamous cells of undetermined significance; CIN, cervical intraepithelial neoplasia; NILM, negative for intraepithelial lesion or malignancy; V0, baseline visit; V1, first-year visit; V2, second-year visit; V3, third-year visit.

Citation: Journal of the National Comprehensive Cancer Network 20, 8; 10.6004/jnccn.2022.7032

The primary endpoints were histologic CIN2+/3+. Vaginal intraepithelial neoplasia 2/3 would be regarded as CIN2/3. All women who reached primary endpoints would be managed according to the ASCCP guidelines.

This study was conducted strictly in accordance with the principles of good clinical practice and was approved by the ethics committee of Women’s Hospital, Zhejiang University School of Medicine (IRB-20200240-R).

HPV Genotyping

A DH3 HPV detection kit (Hangzhou Dalton Biosciences, Ltd.)17 and an HPV DNA genotyping kit (Jiangsu Bioperfectus Technologies, Ltd.)18 were applied in 2 clinical trials separately. The DH3 kit detects 14 high-risk HPV types (HPV16, HPV18, HPV31, HPV33, HPV35, HPV39, HPV45, HPV51, HPV52, HPV56, HPV58, HPV59, HPV66, and HPV68) with HPV16/18 genotyping, whereas the HPV DNA genotyping kit detects the aforementioned 14 high-risk, 4 intermediate-risk (HPV26, HPV53, HPV73, and HPV82), and 3 low-risk (HPV6, HPV11, and HPV81) HPV types. To obtain the genotyping information, the residual cytology samples with positive DH3 HPV at V0 and V3 were further genotyped by using the HPV DNA genotyping kit according to the manufacturer’s instructions.

Statistical Analysis

All statistical analyses were analyzed by using SPSS Statistics, version 25.0 (IBM Corp.). Pearson’s χ2 test was used for qualitative variables. All P values were 2-sided, and P<.05 was considered statistically significant. The prevalence of HPV genotype was calculated by 3 approaches, including minimum estimate (Min.), any type estimate (Any.), and hierarchical attribution estimate (Hier.) according to previous reports.19,20 Min. was calculated only in the single HPV infection population. Any. was calculated in all HPV infection populations, and multiple HPV infections were calculated more than once. Hier. was included to attribute multiple HPV infections to one specific HPV genotype with the highest ranking from Any. Furthermore, the absolute immediate and 3-year cumulative risks for each HPV genotype were calculated, which equaled the number of CIN2+/3+ related to specific HPV/the number of specific HPV × 100% (same as positive predictive value [PPV]). The efficacy of conventional and risk-based management strategies to detect CIN2+/3+ was evaluated, including sensitivity, specificity, PPV, and negative predictive value.

Results

Basic Characteristics of Study Population

Eligible baseline and 3-year follow-up data were available for 8,370 women, as shown in Figure 1. The median age at V0 was 48 years (interquartile range, 42–53 years). At V0, the overall HPV prevalence was 12.69% (1,062 cases), including 639 (60.17%) with a single infection and 423 (39.83%) with multiple infections. The cytologic results included 7,822 (93.45%) NILM, 366 (4.37%) ASCUS, 120 (1.43%) LSIL, and 62 (0.74%) high-grade cytology. ASC-H, HSIL, AGC, AIS, and cancer cells were defined as high-grade cytology because of the small sample size. CIN2+/3+ at V0 were 109/71 (10.26%/6.69%) and 4/3 (0.05%/0.04%) among HPV-positive and HPV-negative women, respectively. Three-year cumulative CIN2+/3+ were 185/109 (17.42/10.26%) and 23/11 (0.31/0.15%) among baseline HPV-positive and HPV-negative women, respectively. The baseline and 3-year cumulative CIN2+/3+ were 113/74 (2 cancers) and 208/120 (5 cancers) individually. Partly, women deviated from protocol to seek colposcopy and yielded 16 primary endpoint cases at V0 (6 CIN2, 6 CIN3) and V2 (2 CIN2, 2 CIN3).

Baseline CIN2+/3+ and 3-year cumulative CIN3+ incidences had no significant difference between single and multiple infections (all P>.05). However, 3-year cumulative CIN2+ incidences in multiple infections were significantly higher than in single infection (χ2=6.40; P=.0114) (supplemental eTable 1). Because of the lack of HPV genotype information at V1 and V2, persistent HPV infection was defined as the presence of the same HPV genotype at V0 and V3. In total, 911 HPV-positive women at V0 received HPV genotyping at V3 and persistent infections numbered 199. We found that women with multiple HPV infections at V0 were more prone to persistent infection (105/344) than those with a single infection (94/567) (χ2=24.39; P<.0001).

Prevalence of Specific HPV Genotype Infection

The prevalence of specific HPV genotype at baseline is listed in supplemental eFigure 1 and supplemental eTable 2. HPV52, HPV56, HPV16, and HPV58 were the top 4 ranking genotypes in almost all 3 approaches, with the exception of HPV56 which was replaced by HPV39 in Min. The prevalence of specific HPV genotype in CIN2+/3+ at baseline was further calculated (supplemental eFigure 2, supplemental eTables 3 and supplemental eTables 4). HPV prevalence ranking by Any. based on 3-year cumulative CIN2+ and CIN3+ was respectively adopted for Hier.1 and Hier.2. HPV16 and HPV52 were always the top 2 ranking disease-related genotypes using all approaches.

Immediate and 3-Year Cumulative CIN2+/3+ Risks of Specific HPV Genotype, Cytology, and Combined Test

As we know, the prevalence of HPV genotype in CIN2+/3+ might be affected by the prevalence of specific HPV in the population. Thus, we further analyzed CIN2+/3+ risks of specific HPV genotype (Figure 2, supplemental eTables 5 and 6). HPV risk ranking by Any. based on 3-year cumulative CIN2+ and CIN3+ was respectively adopted for Hier.1 and Hier.2. The CIN risks estimated by Hier.1 and Hier.2 were similar, except that HPV56 and HPV73 were only included in immediate CIN2+ risk ≥4% and HPV73 was only included in immediate CIN3+ risk ≥4% when using Hier.2 instead of Hier.1.

Figure 2.
Figure 2.

Immediate and 3-year cumulative risk of specific HPV genotype for CIN2+ and CIN3+. (A) Immediate CIN2+/3+ risk of specific HPV genotype estimated by Min. (B) 3-year cumulative CIN2+/3+ risk of specific HPV genotype estimated by Min. (C) Immediate CIN2+/3+ risk of specific HPV genotype estimated by Any. (D) 3-year cumulative CIN2+/3+ risk of specific HPV genotype estimated by Any. (E) Immediate CIN2+/3+ risk of specific HPV genotype estimated by Hier.1. (F) 3-year cumulative CIN2+/3+ risk of specific HPV genotype estimated by Hier.1. (G) Immediate CIN2+/3+ risk of specific HPV genotype estimated by Hier.2. (H) 3-year cumulative CIN2+/3+ risk of specific HPV genotype estimated by Hier.2.

Abbreviations: Any., any type estimate; CIN, cervical intraepithelial neoplasia; Hier., hierarchical attribution estimate; Min., minimum estimate; V0, baseline visit.

Citation: Journal of the National Comprehensive Cancer Network 20, 8; 10.6004/jnccn.2022.7032

Risk estimated by cytology suggested that abnormal cytology carried overall immediate CIN2+/3+ risks ≥4.17% (supplemental eTable 7). When using conventional HPV screening strategies (triage by HPV16/18 and cytology for HPV-others), low-risk HPV (HPV6, HPV11, HPV81), and HPV-negative cases would be excluded from the high-risk population (maximum immediate CIN2+/3+ risks: 1.49% and 1.12%). HPV16 and HPV18 always carried high immediate CIN2+/3+ risks (≥8.46%), regardless of cytology results, except for CIN3+ risk of HPV18 combined with NILM/LSIL cytology, although HPV-others with abnormal cytology also carried immediate CIN2+/3+ risks ≥7.14%, except for CIN3+ risk of HPV-others combined with LSIL cytology (supplemental eTable 8). Our results were almost exactly concordance with the 2019 ASCCP Risk-Based Management Consensus Guidelines,6 except that the risk of HPV18 was underestimated due to the small sample size.

Risk Stratification of HPV Types Combined With Cytology

Referring to the principle of “equal management for equal risks” in the ASCCP guideline, we used the immediate and 3-year cumulative CIN2+/3+ risks to further stratify the non-16/18 HPVs. To simplify the procedure, CIN2+ risks were calculated by Hier.1 and CIN3+ risks by Hier.2 separately. Four risk-based extended HPV groups were divided according to the following algorithms. Group A (ultrahigh risk) carried immediate CIN2+/3+ risk ≥4%, regardless of cytology results. Group D (low risk) carried 3-year cumulative CIN2+/3+ risks <0.55%. The remaining HPVs were further divided. Group B (high risk) included HPVs with immediate CIN2+/3+ risk ≥4% even combined with ASCUS/LSIL, whereas group C (intermediate risk) included the other HPVs (Figure 3, supplemental eTable 9).

Figure 3.
Figure 3.

Algorithms of risk stratification for specific HPV genotype grouping. (A) Extended HPV genotype grouping for CIN2+. Step 1: HPVs that carried immediate CIN2+ risk ≥4%, regardless of cytology results, were assigned to group A (ultra-high-risk), including HPV31/45. Step 2: HPVs that carried 3-year cumulative CIN2+ risk <0.55% were assigned to group D (low-risk), including HPV6/11/35/73/81. HPVs that carried immediate CIN2+ risk combined with ASCUS/LSIL cytology ≥4% were assigned to group B (high-risk), including HPV33/39/52/53/56/59/68. HPVs that carried immediate CIN2+ risk combined with ASCUS/LSIL cytology <4% and 3-year cumulative CIN2+ risk ≥0.55% were assigned to group C (intermediate-risk), including HPV26/51/58/66/82. (B) Extended HPV genotype grouping for CIN3+. Step 1: HPVs that carried immediate CIN3+ risk ≥4%, regardless of cytology results, were assigned to group A (ultra-high-risk), including HPV45. Step 2: HPVs that carried 3-year cumulative CIN3+ risk <0.55% were assigned to group D (low-risk), including HPV6/11/26/35/59/81/82. HPVs that carried immediate CIN3+ risk combined with ASCUS/LSIL cytology ≥4% were assigned to group B (high-risk), including HPV31/33/56/68/73. HPVs that carried immediate CIN3+ risk combined with ASCUS/LSIL cytology <4% and 3-year cumulative CIN3+ risk ≥0.55% were assigned to group C (intermediate-risk), including HPV39/51/52/53/58/66.

Abbreviations: ASCUS, atypical squamous cells of undetermined significance; CIN, cervical intraepithelial neoplasia; LSIL, low-grade squamous intraepithelial lesion; NILM, negative for intraepithelial lesion or malignancy.

Citation: Journal of the National Comprehensive Cancer Network 20, 8; 10.6004/jnccn.2022.7032

Risk-based management strategies were further established using extended HPV genotyping groups (Table 1). Compared with the conventional strategy, the sensitivity of risk-based management strategies showed a tendency to increase, although there were no significant differences. It was particularly encouraging that risk-based strategies had higher specificity (99.13% vs 98.41%; χ2=17.15; P=.0000) and PPV (26.80% vs 15.69%; χ2=4.59; P=.0322) for detecting CIN3+ than the conventional strategy. The number of colposcopies needed to detect each CIN3+ case using risk-based strategies was also less than with the conventional strategy (Table 2).

Table 1.

Risk-Based Management Strategies Based on Extended HPV Genotype (Non-16/18) Grouping Combined With Cytologya

Table 1.
Table 2.

Efficacy of Conventional and Risk-Based Strategiesa

Table 2.

Discussion

The distributions of specific HPV genotypes among the general population and patients with cervical lesions are critical for developing precise CC prevention strategies, such as HPV vaccines and screening programs.2125 The overall prevalence of HPV infection in the present study (12.69%) was in concordance with previous reports, which ranged from 4.6% to 34.5% worldwide and from 12.6% to 23.84% in China.21,2529 The different infection rate might be attributed to different countries or regions, population variation, sample size, different survey periods, and different HPV detection methods. Similar to most previous studies,21,22,28,30 in the present study, single HPV infection was more common than multiple infections. Although multiple infections did not increase the risk of CIN3+, they promoted persistent infection and the increased incidence of 3-year cumulative CIN2+ in the present study. These results supported the idea that multiple infections might increase the risk of progression through persistent infection.31,32

Recently, the largest nationwide study in China reported that the most frequent high-risk HPV genotypes were HPV52 (4.7%), HPV16 (3.4%), HPV53 (2.5%), and HPV58 (2.4%) in order among 2,458,227 samples,33 which exhibited trends similar to those in numerous studies in Asia.21,25,28,31,32,34 Our results also supported HPV52, HPV58, and HPV16 as the major genotypes in Asia. The good concordance in distribution of HPV genotype with previous reports suggested no notable deviance in population representation of the present study.

In the present study, CIN2+/3+ were used as the primary endpoints instead of CC as ASCCP suggested. As we know, the distribution of HPV in CC does not exactly match that in histologic HSIL, which would lead to the discrepancies among different reports, especially for HPV18 and HPV45.35,36 Nevertheless, solid evidence suggested that HPV16 was always the most common type in CC and HSIL histology worldwide, ranging from 52% in Asia to 58% in Europe.22,35 Moreover, the prevalence of HPV58 and HPV52 were notably higher in Asia than in other continents, especially for HSIL histology.35 In accordance with a previous study, HPV16 always ranks first, followed by HPV52 in CIN2+/3+ cases in the present study. HPV18 and HPV45 showed noticeable absence in the top 5 ranking among CIN2+/3+ cases by Hier. in the present study, due to CIN2+/3+ being chosen as a surrogate for cancer risk.22,37 The prevalence of specific HPV among HSIL was different from that in the overall population, which might be attributed to the different carcinogenicity of specific HPV genotypes.

With the improvement of HPV-based cancer screening strategy, the identification of specific HPV risks has become critical for precise management based on ASCCP guidelines. To exclude the influence of the varied prevalence of specific HPV genotype, we introduced the absolute risk to estimate HPV risks for CIN2+/3+. Our findings revealed that HPV16, HPV18, HPV31, HPV33, HPV45, HPV52, HPV53, HPV58, and HPV66 often carried high immediate risk for CIN2+/3+ (≥4%), whereas HPV59 and HPV68 carried high immediate risk only for CIN2+ and HPV73 carried high immediate risk for CIN3+. Although previous study supported pooled non-16/18 HPVs for cervical screening,9 the individual or pooled HPV genotypes that carried higher risk than HPV18 did deserve to be further stratified.

Based on the risks of specific HPV genotype combined with cytology, we further stratified non-16/18 HPVs into 4 groups (Table 1). HPV16 and HPV18 were not included for the extended HPV grouping because numerous studies had confirmed their role in CC screening.3840 Due to high immediate CIN2+/3+ risk carried by the abnormal cytology, we first used NILM cytology to stratify ultra-high-risk HPV. Unlike a previous report,41 HPV45 was classified into an ultra-high-risk group for CIN2+/3+ in the present study. Different regions and ethnicities might contribute to this discordance. HPV31 belonged to the ultra-high-risk group for CIN2+, which was consistent with a previous study.9 The CIN2+ risk estimated by Hier.1 and CIN3+ risk estimated by Hier.2 were significantly different, especially for groups B and C. The disparity may be related to the broader range of CIN2+, because a subset of CIN2 cases may not progress to CIN3+ but spontaneously regress.37,42 HPV35 was considered as low risk as HPV6/11/81, whereas HPV53 was regarded as high risk for CIN2+ and intermediate risk for CIN3+. Partial previously reported carcinogenic and possibly carcinogenic HPV genotypes (eg, HPV26, HPV59, and HPV82) were categorized into group D by CIN3+ risk besides HPV6/11/81, potentially cutting the cost of HPV detection kits.

To further identify the efficacy of the present extended genotyping protocol in application of CC screening, the stratified management strategy was formulated according to the principle of equal management for equal risks. According to the 2019 ASCCP guideline, any type in groups A, B, and C with HSIL cytology could alternatively be referred for expedited treatment (immediate CIN2+/3+ risk ≥25%). Hence, the present risk-based strategy could reduce the cost of frequent screening procedures and relieve anxiety for women actively seeking expedited treatment. When compared with the conventional strategy triaged by HPV16/18 and cytology, our risk-based stratified management strategy not only maintained high sensitivity for CIN2+/3+ but also possessed higher specificity and PPV for detecting CIN3+. Thus, the extended genotyping proposed in the present study would effectively reduce the need for colposcopy referral and precisely triage high-risk women. Our risk-based strategy could become a good complement to the conventional strategy.

The present study has some limitations. First, the enrolled population was from 2 independent clinical trials using different HPV detection kits, which would lead to inadequate evaluation of HPV26, HPV53, HPV73, and HPV82. Second, the sample size was not large enough, so the significance of certain HPV that contradicted previous reports requires further confirmation. For instance, although HPV73 was conferred as high-risk HPV for CIN3+, its role should be further evaluated because of the small number of infective cases in our study. Further investigation is also needed to confirm whether HPV35 could be excluded from high-risk HPV. Third, the number of AGC/AIS/CC cells cytology separately was not enough for precise assessment of the risk of CIN2+/3+, and we had to combine them into high-grade cytology.

Conclusions

To the best of our knowledge, the present study is the first in a prospective population-based cohort to assess cross-sectional and longitudinal risks of specific HPV genotype combined with cytology for CIN2+/3+. The comprehensive, risk-based, stratified management strategy using extended HPV genotyping not only precisely triaged HPV-positive women but also reduced the number of colposcopies needed for identifying CIN3+. However, more prospective studies with large sample sizes are warranted to verify our findings.

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    Stoler MH, Wright TC Jr, Parvu V, et al. Stratified risk of high-grade cervical disease using Onclarity HPV extended genotyping in women, ≥25years of age, with NILM cytology. Gynecol Oncol 2019;153:2633.

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Submitted December 14, 2021; final revision received April 25, 2022; accepted for publication May 10, 2022.

Disclosures: The authors have disclosed that they have not received any financial consideration from any person or organization to support the preparation, analysis, results, or discussion of this article.

Author contributions: Conceptualization: Li, Wang. Data curation: Li, Rao, Wei. Formal analysis: Li, Rao. Software: Rao, Wei. Methodology: Rao. Supervision: Lu, Xie, Wang. Validation: All authors. Writing—original draft: Li, Rao, Wei. Writing—review and editing: Li, Lu, Xie, Wang.

Funding: This study was supported by National Key R&D Program of China (grant number, 2021YFC2701204) and the Key Research and Development Program of Zhejiang province, China (grant number, 2020C03025).

Correspondence: Xiao Li, MD, Department of Gynecologic Oncology, Women’s Hospital, Zhejiang University School of Medicine, No. 1 Xueshi Road, Hangzhou, Zhejiang, 310006, China. Email: 5198008@zju.edu.cnl; and Xin-Yu Wang, MD, Department of Gynecologic Oncology, Women’s Hospital, Zhejiang University School of Medicine, No. 1 Xueshi Road, Hangzhou, Zhejiang, 310006, China. Email: wangxy@zju.edu.cn

Supplementary Materials

  • View in gallery

    Detailed flowchart of the cervical cancer screening procedure.

    Abbreviations: ASCUS, atypical squamous cells of undetermined significance; CIN, cervical intraepithelial neoplasia; NILM, negative for intraepithelial lesion or malignancy; V0, baseline visit; V1, first-year visit; V2, second-year visit; V3, third-year visit.

  • View in gallery

    Immediate and 3-year cumulative risk of specific HPV genotype for CIN2+ and CIN3+. (A) Immediate CIN2+/3+ risk of specific HPV genotype estimated by Min. (B) 3-year cumulative CIN2+/3+ risk of specific HPV genotype estimated by Min. (C) Immediate CIN2+/3+ risk of specific HPV genotype estimated by Any. (D) 3-year cumulative CIN2+/3+ risk of specific HPV genotype estimated by Any. (E) Immediate CIN2+/3+ risk of specific HPV genotype estimated by Hier.1. (F) 3-year cumulative CIN2+/3+ risk of specific HPV genotype estimated by Hier.1. (G) Immediate CIN2+/3+ risk of specific HPV genotype estimated by Hier.2. (H) 3-year cumulative CIN2+/3+ risk of specific HPV genotype estimated by Hier.2.

    Abbreviations: Any., any type estimate; CIN, cervical intraepithelial neoplasia; Hier., hierarchical attribution estimate; Min., minimum estimate; V0, baseline visit.

  • View in gallery

    Algorithms of risk stratification for specific HPV genotype grouping. (A) Extended HPV genotype grouping for CIN2+. Step 1: HPVs that carried immediate CIN2+ risk ≥4%, regardless of cytology results, were assigned to group A (ultra-high-risk), including HPV31/45. Step 2: HPVs that carried 3-year cumulative CIN2+ risk <0.55% were assigned to group D (low-risk), including HPV6/11/35/73/81. HPVs that carried immediate CIN2+ risk combined with ASCUS/LSIL cytology ≥4% were assigned to group B (high-risk), including HPV33/39/52/53/56/59/68. HPVs that carried immediate CIN2+ risk combined with ASCUS/LSIL cytology <4% and 3-year cumulative CIN2+ risk ≥0.55% were assigned to group C (intermediate-risk), including HPV26/51/58/66/82. (B) Extended HPV genotype grouping for CIN3+. Step 1: HPVs that carried immediate CIN3+ risk ≥4%, regardless of cytology results, were assigned to group A (ultra-high-risk), including HPV45. Step 2: HPVs that carried 3-year cumulative CIN3+ risk <0.55% were assigned to group D (low-risk), including HPV6/11/26/35/59/81/82. HPVs that carried immediate CIN3+ risk combined with ASCUS/LSIL cytology ≥4% were assigned to group B (high-risk), including HPV31/33/56/68/73. HPVs that carried immediate CIN3+ risk combined with ASCUS/LSIL cytology <4% and 3-year cumulative CIN3+ risk ≥0.55% were assigned to group C (intermediate-risk), including HPV39/51/52/53/58/66.

    Abbreviations: ASCUS, atypical squamous cells of undetermined significance; CIN, cervical intraepithelial neoplasia; LSIL, low-grade squamous intraepithelial lesion; NILM, negative for intraepithelial lesion or malignancy.

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    Cox JT, Castle PE, Behrens CM, et al. Comparison of cervical cancer screening strategies incorporating different combinations of cytology, HPV testing, and genotyping for HPV 16/18: results from the ATHENA HPV study. Am J Obstet Gynecol 2013;208:184.e1184.e11.

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    Stoler MH, Wright TC Jr, Parvu V, et al. Stratified risk of high-grade cervical disease using Onclarity HPV extended genotyping in women, ≥25years of age, with NILM cytology. Gynecol Oncol 2019;153:2633.

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    Tainio K, Athanasiou A, Tikkinen KAO, et al. Clinical course of untreated cervical intraepithelial neoplasia grade 2 under active surveillance: systematic review and meta-analysis. BMJ 2018;360:k499.

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    • Export Citation
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