Evaluation of triage strategies for high-risk human papillomavirus-positive women in cervical cancer screening: A multicenter randomized controlled trial in different resource settings in China

ObjectiveWe aimed to evaluate the effectiveness of different triage strategies for high-risk human papillomavirus (hrHPV)-positive women in primary healthcare settings in China.MethodsThis study was undertaken in 11 rural and 9 urban sites. Women aged 35−64 years old were enrolled. HrHPV-positive women were randomly allocated to liquid-based cytology (LBC), visual inspection with acetic acid and Lugol’s iodine (VIA/VILI) (rural only) triage, or directly referred to colposcopy (direct COLP). At 24 months, hrHPV testing, LBC and VIA/VILI were conducted for combined screening.ResultsIn rural sites, 1,949 hrHPV-positive women were analyzed. A total of 852, 218 and 480 women were randomly assigned to direct COLP, LBC and VIA/VILI. At baseline, colposcopy referral rates of LBC or VIA/VILI triage could be reduced by 70%−80%. LBC (n=3 and n=7) or VIA/VILI (n=8 and n=26) could significantly decrease the number of colposcopies needed to detect one cervical intraepithelial neoplasia (CIN) 2 or worse and CIN3+ compared with direct COLP (n=14 and n=23). For the 24-month cumulative detection rate of CIN2+, VIA/VILI triage was 0.50-fold compared with LBC triage and 0.46-fold with the direct COLP. When stratified by age, baseline LBC triage+ performed best (P<0.001), peaking among women aged 35−44 years (P_trend=0.002). In urban sites, 1,728 women were hrHPV genotyping test positive. A total of 408, 571 and 568 women were randomly assigned to direct COLP for HPV16/18+, direct COLP for other hrHPV subtypes+, and LBC triage for other hrHPV subtypes+. LBC (n=12 and n=31) significantly decreased the number of colposcopies needed to detect one CIN2+ and CIN3+ compared with direct COLP (n=14 and n=44). HPV16/18+ increased the 24-month cumulative detection rate of CIN2+ (17.89%, P<0.001).ConclusionsLBC triage for hrHPV-positive women in rural settings and direct COLP for HPV16/18+ women and LBC triage for other hrHPV subtype+ women in urban settings might be feasible strategies.     

Risk stratification and long‐term risk prediction of E6 oncoprotein in a prospective screening cohort in China

E6 oncoprotein is a necessary agent of HPV driven oncogenic transformation. This study is aimed at evaluating the risk stratification potency of HPV 16/18 E6 oncoprotein (E6) as a triage method for HPV positivity. Moreover, it also acts as a predictor of cervical intraepithelial neoplasia grade 3 or worse (CIN3+). The screening cohort of 1,997 women was followed for a 15 year period in approximate five‐year intervals. Participants were concurrently screened by HPV DNA testing (HC2), liquid based cytology (LBC), visual inspection with acetic acid (VIA) and were referred to colposcopy and biopsy if any tests reflected positive. E6 was performed on cervical samples collected from this cohort in 2005 and 2014. The ability of E6 to predict CIN3+ risk after the five‐ and ten‐year interval was evaluated. Among HPV positive women in 2005, E6 indicated the lowest positive rate (9.9%) compared to LBC (48.4%) and VIA (28.0%), however, a higher prevalence rate (10.3%) and 10‐year cumulative incidence rate (53.0%) of CIN3+ were detected among women who were E6 positive. Meanwhile, only 4.2% and 2.9% of women with abnormal LBC and positive VIA were diagnosed as prevalent CIN3+ in 2005, 23.0% and 16.5% developed to CIN3+ after year 10, respectively. Strong associations were found between precedent and subsequent HPV persistence and E6 oncoprotein expression (OR_adjusted = 40.0 and 21.2, respectively). E6 oncoprotein could serve as a low‐cost, highly specific, strongly indicative point‐of‐care method in the triage and treatment of HPV positive women.     

Lower cost strategies for triage of human papillomavirus DNA‐positive women

Using human papillomavirus (HPV) testing for cervical cancer screening in lower‐resource settings (LRS) will result in a significant number of screen‐positive women. This analysis compares different triage strategies for detecting cervical precancer and cancer among HPV‐positive women in LRS. This was a population‐based study of women aged 25–65 years living in China (n = 7,541). Each woman provided a self‐collected and two clinician‐collected specimens. The self‐collected and one clinician‐collected specimen were tested by two HPV DNA tests—careHPV? and Hybrid Capture 2; the other clinician‐collected specimen was tested for HPV16/18/45 E6 protein. CareHPV?‐positive specimens were tested for HPV16/18/45 DNA. HPV DNA‐positive women underwent visual inspection with acetic acid (VIA) and then colposcopic evaluation with biopsies. The performance for detection of cervical intraepithelial neoplasia grade 3 or cancer (CIN3+) among HPV DNA‐positive women was assessed for different triage strategies: HPV16/18/45 E6 or DNA detection, VIA, colposcopic impression, or higher signal strength (≥10 relative light units/positive control [rlu/pc]). The percent triage positive ranges were 14.8–17.4% for VIA, 17.8–20.9% for an abnormal colposcopic impression; 7.9–10.5% for HPV16/18/45 E6; 23.4–28.4% for HPV16/18/45 DNA; and 48.0–62.6% for higher signal strength (≥10 rlu/pc), depending on the HPV test/specimen combination. The positivity for all triage tests increased with severity of diagnosis. HPV16/18/45 DNA detection was approximately 70% sensitive and had positive predictive values (PPV) of approximately 25% for CIN3+. HPV16/18/45 E6 detection was approximately 50% sensitive with a PPV of nearly 50% for CIN3+. Different triage strategies for HPV DNA‐positive women provide important tradeoffs in colposcopy or treatment referral percentages and sensitivity for prevalent CIN3+.     

Human papillomavirus E7 protein detection as a method of triage to colposcopy of HPV positive women,in comparison to genotyping and cytology. Final results of the PIPAVIR study

The objective of the presented cross‐sectional‐evaluation‐screening study is the clinical evaluation of high‐risk(hr)HPVE7‐protein detection as a triage method to colposcopy for hrHPV‐positive women, using a newly developed sandwich‐ELISA‐assay. Between 2013‐2015, 2424 women, 30‐60 years old, were recruited at the Hippokratio Hospital, Thessaloniki/Greece and the Im Mare Klinikum, Kiel/Germany, and provided a cervical sample used for Liquid Based Cytology, HPV DNA genotyping, and E7 detection using five different E7‐assays: “recomWell HPV16/18/45KJhigh”, “recomWell HPV16/18/45KJlow”, “recomWell HPV39/51/56/59”, “recomWell HPV16/31/33/35/52/58” and “recomWell HPVHRscreen” (for 16,18,31,33,35,39,45,51,52,56,58,59 E7), corresponding to different combinations of hrHPVE7‐proteins. Among 1473 women with eligible samples, those positive for cytology (ASCUS+ 7.2%), and/or hrHPV DNA (19.1%) were referred for colposcopy. Cervical Intraepithelial Neoplasia grade 2 or worse (CIN2+) was detected in 27 women (1.8%). For HPV16/18‐positive women with no triage, sensitivity, positive predictive value (PPV) and the number of colposcopies needed to detect one case of CIN2+ were 100.0%, 11.11% and 9.0 respectively. The respective values for E7‐testing as a triage method to colposcopy ranged from 75.0‐100.0%, 16.86‐26.08% and 3.83‐5.93. Sensitivity and PPV for cytology as triage for hrHPV(non16/18)‐positive women were 45.45% and 27.77%; for E7 test the respective values ranged from 72.72‐100.0% and 16.32‐25.0%. Triage of HPV 16/18‐positive women to colposcopy with the E7 test presents better performance than no triage, decreasing the number of colposcopies needed to detect one CIN2+. In addition, triage of hrHPV(non16/18)‐positive women with E7 test presents better sensitivity and slightly worse PPV than cytology, a fact that advocates for a full molecular screening approach.     

Cost and Effectiveness Comparison of Immediate Colposcopy Versus Human Papillomavirus DNA Testing in Management of Atypical Squamous Cells of Undetermined Significance in Turkish Women

Background: A small but significant proportion of cases with atypical squamous cells of undeterminedsignificance (ASCUS) may harbour CIN 2-3, or even invasive carcinoma. Although immediate colposcopy,HPV-DNA testing or expectant management are three recommended options in ASCUS triage, a consensus doesnot currently exist on which one of these approaches is the most efficient. In this study, we aimed to comparethe performance and cost of immediate colposcopy and colposcopy based on the human papillomavirus (HPV)testing for detecting histologically confirmed high-grade cervical intraepithelial neoplasia (CIN) in women withASCUS. Materials and Methods: Records of 594 women with an index Papanicolaou smear showing ASCUSwere retrospectively analyzed. Women in the immediate colposcopy arm were referred directly to colposcopy(immediate colposcopy group, n=255) and those in the HPV triage arm were proceeded to colposcopy if thehigh-risk HPV (hrHPV) test was positive (HPV triage group, n=339). High grade CIN (CIN2+) detection rateand treatment costs were compared between the groups. Results: The detected rate of CIN2+ was higher inthe HPV triage group compared to immediate colposcopy group (8% vs. 1.6%, p=0.011). In the HPV triagegroup, the total cost, cost per patient, and the cost for detecting one case of high grade CIN were higher thanthe immediate colposcopy group (p<0.001). Conclusions: In women with ASCUS cytology, HPV DNA testingfollowed by colposcopy is more costly than immediate colposcopy, but this approach is associated with a higherrate of CIN2+ detection. This findings suggest that HPV DNA testing combined with cervical cytology couldreduce the referral rate to colposcopy     

宫颈癌多种筛查方案的研究

目的 探索适宜我国不同地区的宫颈癌筛查方案,以提高我国妇女宫颈癌的防治水平.方法 利用1999年在山西省襄垣县开展的一项以人群为基础的宫颈癌筛查横断面研究的资料,所有筛查对象均进行了薄层液基细胞学(LBC)、荧光镜检、醋酸染色法(VIA)、阴道镜检查、自我取样人乳头瘤病毒(HPv)检测和医生取样HPV检测等6种宫颈癌筛查方法 ,而且每位筛查对象均有病理诊断结果 .采用筛查试验的串、并联法组合各种筛查技术,比较所得方案识别宫颈高度以上病变[≥宫颈上皮内瘤变(CIN)2]的灵敏度、特异度和阴道镜转诊率等指标,以受试者工作特征曲线(ROC)下面积综合分析各筛查方案.结果 LBC检测以未明确意义的不典型鳞状细胞(ASC-US)为阳性,HPV检测以HPV DNA≥1.0 ps/mi为阳性.在LBC和HPV检测组合方案中,并联初筛方法 (即两者任一项阳性即判断为筛查阳性)的灵敏度为100.O%,特异度为68.6%,阴道镜转诊率为34.4%;LBC初筛HPV分流方法 (即ASC-US者进行HPV检测)的灵敏度为93.0%,特异度为89.9%,阴道镜转诊率为13.7%;HPV初筛LBC分流方法 (即 HPV阳性者进行LBC检测)的灵敏度为91.7%,特异度为93.0%,阴道镜转诊率为10.6%.经ROC分析,LBC初筛HPV分流方法 和HPV初筛LBC分流方法 明显优于单纯并联初筛方法 (P=0.0003;P=0.0002).单独以LBC或HPV检测作为筛查方案时,以ASC-US或低度病变(LSIL)为筛查阳性的LBC方法 灵敏度、特异度和阴道镜转诊率分别为94.2%、77.3%、25.7%和87.2%、93.5%、10.O%;医生取样HPV检测方法 和自我取样HPV检测方法 的灵敏度、特异度和阴道镜转诊率分别为97.6%、84.8%、18.8%和83.5%、85.9%、17.1%.经ROC分析,医生取样HPV检测方法 优于以ASC-US为筛查阳性的LBC方法 或自我取样HPV检测方法 (P=0.005,P=0.002).在VIA及其与HPV检测的组合方案中,单独采用VIA筛查方法 的灵敏度为70.9%,特异度为74.3%,阴道镜转诊率为27.6%;HPV初筛VIA分流方法 (即自我取样HPV检测阳性者进行VIA检查)的灵敏度、特异度和阴道镜转诊率分别为65.9%、95.2%和7.4%.经ROC分析,HPV初筛VIA分流方法 明显优于单独使用VIA方法 (P=0.004).结论 根据地区资源条件和个人意愿,我国经济发达地区可选用HPV初筛LBC分流方法 或LBC初筛HPV分流方法 作筛查手段;中等经济发展水平的中小城市可选用单独以LBC或HPV检测方法 作为筛查手段;VLA是欠发达地区可行的筛查方法 ,在廉价HPV检测试剂盒上市后,可选择HPV初筛VIA分流方法 ,以进一步提高宫颈癌的筛查效力.     

Risk assessment to guide cervical screening strategies in a large Chinese population

Three different cervical screening methods [cytology, human papillomavirus(HPV) testing and visual inspection with acetic acid(VIA)] are being considered in China for the national cervical screening program. Comparing risks of CIN3 and cervical cancer (CIN3+) for different results can inform test choice and management guidelines. We evaluated the immediate risk of CIN3+ for different screening results generated from individual and combined tests. We compared tests using a novel statistic designed for this purpose called Mean Risk Stratification (MRS), in a pooled analysis of 17 cross sectional population‐based studies of 30,371Chinese women screened with all 3 methods and diagnosed by colposcopically‐directed biopsies. The 3 tests combined powerfully distinguished CIN3+ risk; triple‐negative screening conferred a risk of 0.01%, while HPV‐positive HSIL+ that was VIA‐positive yielded a risk of 57.8%. Among the three screening tests, HPV status most strongly stratified CIN3+ risk. Among HPV‐positive women, cytology was the more useful second test. In HPV‐negative women, the immediate risks of CIN3+ ranged from 0.01% (negative cytology), 0.00% (ASC‐US), 1.1% (LSIL), to 6.6 (HSIL+). In HPV‐positive women, the CIN3+ risks were 0.9% (negative cytology), 3.6% (ASC‐US), 6.3% (LSIL) and 38.5% (HSIL+). VIA results did not meaningful stratify CIN3+ risk among HPV‐negative women with negative or ASC‐US cytology; however, positive VIA substantially elevated CIN3+ risk for all other, more positive combinations of HPV and cytology compared with a negative VIA. Because all 3 screening tests had independent value in defining risk of CIN3+, different combinations can be optimized as pragmatic strategies in different resource settings.     

Validation of a DNA methylation HPV triage classifier in a screening sample

High‐risk human papillomavirus (hrHPV) DNA tests have excellent sensitivity for detection of cervical intraepithelial neoplasia 2 or higher (CIN2+). A drawback of hrHPV screening, however, is modest specificity. Therefore, hrHPV‐positive women might need triage to reduce adverse events and costs associated with unnecessary colposcopy. We compared the performance of HPV16/18 genotyping with a predefined DNA methylation triage test (S5) based on target regions of the human gene EPB41L3, and viral late gene regions of HPV16, HPV18, HPV31 and HPV33. Assays were run using exfoliated cervical specimens from 710 women attending routine screening, of whom 38 were diagnosed with CIN2+ within a year after triage to colposcopy based on cytology and 341 were hrHPV positive. Sensitivity and specificity of the investigated triage methods were compared by McNemar's test. At the predefined cutoff, S5 showed better sensitivity than HPV16/18 genotyping (74% vs 54%, P = 0.04) in identifying CIN2+ in hrHPV‐positive women, and similar specificity (65% vs 71%, P = 0.07). When the S5 cutoff was altered to allow equal sensitivity to that of genotyping, a significantly higher specificity of 91% was reached (P < 0.0001). Thus, a DNA methylation test for the triage of hrHPV‐positive women on original screening specimens might be a valid approach with better performance than genotyping.     

Performance of visual inspection of the cervix with acetic acid (VIA) for triage of HPV screen-positive women: results from the ESTAMPA study

VIA is recommended for triage of HPV-positive women attending cervical screening. In the multicentric ESTAMPA study, VIA performance for detection of cervical intraepithelial neoplasia grade 3 or worse (CIN3+) among HPV-positive women was evaluated. Women aged 30-64 years were screened with HPV testing and cytology and referred to colposcopy if either test was positive. At colposcopy visit, study-trained midwives/nurses/GPs performed VIA ahead of colposcopy. VIA was considered positive if acetowhite lesions were observed in or close to the transformation zone. Ablative treatment eligibility was assessed for VIA positives. Performance indicators were estimated. Three thousand one hundred and forty-two HPV-positive women were included. Sensitivity for CIN3+ was 85.9% (95% CI 81.2-89.5) among women <50 years and, although not significant, slightly lower in women 50+ (78.0%, 95% CI 65.9-86.6). Overall specificity was 58.6% (95% CI 56.7-60.5) and was significantly higher among women 50+ (70.3%, 95% CI 66.8-73.5) compared to women <50 (54.3%, 95% CI 52.1-56.5). VIA positivity was lower among women 50+ (35.2%, 95% CI 31.9-38.6) compared to women <50 (53.2, 95% CI 51.1-55.2). Overall eligibility for ablative treatment was 74.5% and did not differ by age. VIA sensitivity, specificity, and positivity, and ablative treatment eligibility varied highly by provider (ranges: 25%-95.4%, 44.9%-94.4%, 8.2%-65.3%, 0%-98.7%, respectively). VIA sensitivity for cervical precancer detection among HPV-positive women performed by trained providers was high with an important reduction in referral rates. However, scaling-up HPV screening triaged by VIA will be challenging due to the high variability of VIA performance and providers' need for training and supervision.     

Comparison of HPV and cytology triage algorithms for women with borderline or mild dyskaryosis in population‐based cervical screening (VUSA‐screen study)

We studied the effectiveness of high‐risk human papillomavirus (hrHPV) triage for immediate colposcopy in women with borderline or mild dyskaryosis (BMD). In the Utrecht province of the Netherlands, women aged 30–60 years who participated in the regular cervical screening programme were offered hrHPV testing and cytology (intervention group) or cytology only (control group). In the intervention group (n = 337), women with BMD were immediately referred for colposcopy only if the sample was hrHPV positive. Women with a hrHPV negative test were advised to repeat cytology at 6 and 18 months and were referred for colposcopy if and when the repeat test result was positive (BMD or worse). In the control group (n = 329), referral of women with BMD was delayed until cytology was repeatedly positive at 6 or 18 months. The CIN3 detection rates were 10.7% (36/337) in the intervention group and 6.4% (21/329) in the control group (p = 0.047). Moreover, hrHPV triaging resulted in shorter time to diagnosis (154 vs. 381 days). Although the number of colposcopy referrals was 51.5% higher in the intervention group than in the control group, the medical costs per detected CIN3 were slightly lower ([euro] 4781 vs. [euro] 6235). If, in addition, hrHPV negative women had been referred back to routine screening at baseline, the CIN3 rate would have been 10.1% (34/337) and colposcopy rate would only have been 30.4% higher than in the control group. This study shows that hrHPV triaging of women with BMD is at least as effective for detecting CIN3 as repeat cytology, also when hrHPV negative women are referred back to routine screening.     

Initial results of population based cervical cancer screening program using HPV testing in one million Turkish women

To evaluate the Turkey's nationwide HPV DNA screening program on the basis of first 1 million screened women. Women over age 30 were invited for population based screening via HPV DNA and conventional cytology. Samples were collected by family physicians and the evaluations and reports had been performed in the National Central HPV laboratories. The acceptance rate for HPV based cervical cancer screening after first invitation was nearly 36.5%. Since HPV DNA tests have been implemented, cervical cancer screening rates have shown 4–5‐fold increase in primary level. Through the evaluation of all, HPV positivity was seen in 3.5%. The commonest HPV genotypes were 16, followed by 51, 31, 52 and 18. Among the 37.515 HPV positive cases, cytological abnormality rate was 19.1%. Among HPV positive cases, 16.962 cases had HPV 16 or 18 or other oncogenic HPV types with abnormal cytology (>ASC‐US). These patients were referred to colposcopy. The colposcopy referral rate was 1.6%. Among these, final clinico‐pathological data of 3.499 patients were normal in 1.985 patients, CIN1 in 708, CIN2 in 285, CIN3 in 436 and cancer in 85 patients and only pap‐smear program could miss 45.9% of ≥CIN3 cases. The results of 1 million women including the evaluation of 13 HPV genotypes with respect to prevalence, geographic distribution and abnormal cytology results shows that HPV DNA can be used in primary level settings to have a high coverage rated screening program and is very effective compared to conventional pap‐smear.     

Grading the severity of cervical neoplasia based on combined histopathology,cytopathology, and HPV genotype distribution among 1,700 women referred to colposcopy in Oklahoma

Diagnosis and treatment of cervical cancer precursors rely on colposcopic biopsy, which is sometimes hampered by incorrect biopsy placement and the unclear prognostic value of poorly reproducible diagnoses such as cervical intraepithelial neoplasia (CIN) Grade 1 and 2. Searching for discrete disease categories that incorporate the value of cytology and that reflect the causal role of particular HPV types, we analyzed histology, cytology and HPV genotype distributions in the Study to Understand Cervical Cancer Endpoints and Early Determinants (SUCCEED). This cross‐sectional study comprises ～1,700 women referred to colposcopy or treatment for the spectrum of cervical disease, including 439 women with <CIN1, 429 CIN1, 322 CIN2, 297 CIN3 and 107 with cancer. Using hierarchical clustering of histology‐cytology groups based on HPV genotype distributions, we could plainly distinguish in this referral population 5 increasingly severe diagnostic groups of HPV‐positive women: (i) HPV‐positive women with <CIN2 histology and normal cytology, (ii) HPV positive women with <CIN2 histology and ASC or LSIL cytology; (iii) CIN2, including histologic CIN2 and HSIL cytology with any histology <CIN2; (iv) CIN3; and (v) invasive cervical cancer. The grouping of women with HSIL cytology, but without histological abnormalities to women with CIN2 suggests that in these cases the worst lesion was missed during colposcopy‐biopsy. We are now using these sharpened diagnostic categories to search for novel biomarkers predicting the risk of progression and invasion. © 2008 Wiley‐Liss, Inc.     

A cohort study of cervical screening using partial HPV typing and cytology triage

HPV testing is more sensitive than cytology for cervical screening. However, to incorporate HPV tests into screening, risk‐stratification (“triage”) of HPV‐positive women is needed to avoid excessive colposcopy and overtreatment. We prospectively evaluated combinations of partial HPV typing (Onclarity, BD) and cytology triage, and explored whether management could be simplified, based on grouping combinations yielding similar 3‐year or 18‐month CIN3+ risks. We typed ～9,000 archived specimens, taken at enrollment (2007–2011) into the NCI‐Kaiser Permanente Northern California (KPNC) HPV Persistence and Progression (PaP) cohort. Stratified sampling, with reweighting in the statistical analysis, permitted risk estimation of HPV/cytology combinations for the 700,000+‐woman KPNC screening population. Based on 3‐year CIN3+ risks, Onclarity results could be combined into five groups (HPV16, else HPV18/45, else HPV31/33/58/52, else HPV51/35/39/68/56/66/68, else HPV negative); cytology results fell into three risk groups (“high‐grade,” ASC‐US/LSIL, NILM). For the resultant 15 HPV group‐cytology combinations, 3‐year CIN3+ risks ranged 1,000‐fold from 60.6% to 0.06%. To guide management, we compared the risks to established “benchmark” risk/management thresholds in this same population (e.g., LSIL predicted 3‐year CIN3+ risk of 5.8% in the screening population, providing the benchmark for colposcopic referral). By benchmarking to 3‐year risk thresholds (supplemented by 18‐month estimates), the widely varying risk strata could be condensed into four action bands (very high risk of CIN3+ mandating consideration of cone biopsy if colposcopy did not find precancer; moderate risk justifying colposcopy; low risk managed by intensified follow‐up to permit HPV “clearance”; and very low risk permitting routine screening.) Overall, the results support primary HPV testing, with management of HPV‐positive women using partial HPV typing and cytology.     

HPV testing as a triage for borderline or mild dyskaryosis on cervical cytology: results from the Sentinel Sites study

Background:

Earlier pilot studies of human papillomavirus (HPV) triage concluded that HPV triage was feasible and cost-effective. The aim of the present study was to study the impact of wider rollout of HPV triage for women with low-grade cytology on colposcopy referral and outcomes.

Methods:

Human papillomavirus testing of liquid-based cytology (LBC) samples showing low-grade abnormalities was used to select women for colposcopy referral at six sites in England. Samples from 10 051 women aged 25–64 years with routine call or recall cytology reported as borderline or mild dyskaryosis were included.

Results:

Human papillomavirus-positive rates were 53.7% in women with borderline cytology and 83.9% in those with mild dyskaryosis. The range between sites was 34.8–73.3% for borderline cytology, and 73.4–91.6% for mild dyskaryosis. In the single site using both LBC technologies there was no difference in rates between the two technologies. The positive predictive value of an HPV test was 16.3% for CIN2 or worse and 6.1% for CIN3 or worse, although there was considerable variation between sites.

Conclusion:

Triaging women with borderline cytological abnormalities and mild dyskaryosis with HPV testing would allow approximately a third of these women to be returned immediately to routine recall, and for a substantial proportion to be referred for colposcopy without repeat cytology. Variation in HPV-positive rates results in differing colposcopy workload.     

Combined use of cytology,p16 immunostaining and genotyping for triage of women positive for high-risk human papillomavirus at primary screening

Human papillomavirus (HPV) testing is very sensitive for primary cervical screening but has low specificity. Triage tests that improve specificity but maintain high sensitivity are needed. Women enrolled in the experimental arm of Phase 2 of the New Technologies for Cervical Cancer randomized controlled cervical screening trial were tested for high-risk HPV (hrHPV) and referred to colposcopy if positive. hrHPV-positive women also had HPV genotyping (by polymerase chain reaction with GP5+/GP6+ primers and reverse line blotting), immunostaining for p16 overexpression and cytology. We computed sensitivity, specificity and positive predictive value (PPV) for different combinations of tests and determined potential hierarchical ordering of triage tests. A number of 1,091 HPV-positive women had valid tests for cytology, p16 and genotyping. Ninety-two of them had cervical intraepithelial neoplasia grade 2+ (CIN2+) histology and 40 of them had CIN grade 3+ (CIN3+) histology. The PPV for CIN2+ was >10% in hrHPV-positive women with positive high-grade squamous intraepithelial lesion (61.3%), positive low-grade squamous intraepithelial lesion (LSIL+) (18.3%) and positive atypical squamous cells of undetermined significance (14.8%) cytology, p16 positive (16.7%) and, hierarchically, for infections by HPV33, 16, 35, 59, 31 and 52 (in decreasing order). Referral of women positive for either p16 or LSIL+ cytology had 97.8% sensitivity for CIN2+ and women negative for both of these had a 3-year CIN3+ risk of 0.2%. Similar results were seen for women being either p16 or HPV16/33 positive. hrHPV-positive women who were negative for p16 and cytology (LSIL threshold) had a very low CIN3+ rate in the following 3 years. Recalling them after that interval and referring those positive for either test to immediate colposcopy seem to be an efficient triage strategy. The same applies to p16 and HPV16.     

Triaging HPV‐positive women with normal cytology by p16/Ki‐67 dual‐stained cytology testing: Baseline and longitudinal data

Primary human papillomavirus (HPV)‐based screening results in a 2–5% lower specificity for cervical intraepithelial neoplasia Grade 2 or worse (CIN2+) compared to Pap cytology. To identify HPV‐positive women with CIN2+, we retrospectively evaluated the cross‐sectional and longitudinal performance of p16/Ki‐67 dual‐stained cytology in HPV‐positive women with normal cytology participating in population‐based cervical screening. Conventional Pap cytology specimens of 847 of these women derived from the VUSA‐Screen study were dual‐stained for p16/Ki‐67. Cross‐sectional clinical performance in detecting CIN3 or worse (CIN3+), and CIN2+ was compared to that of baseline HPV genotyping. Moreover, 5‐year cumulative incidence risks (CIR) for CIN3+ (CIN2+) were determined. The sensitivity of p16/Ki‐67 dual‐stained cytology for CIN3+ (CIN2+) was 73.3% (68.8%) with a specificity of 70.0% (72.8%). HPV16/18 genotyping showed a sensitivity for CIN3+ (CIN2+) of 46.7% (43.8%), with a specificity of 78.3% (79.4%). The 5‐year CIR for CIN3+ in HPV‐positive women with normal cytology was 6.9%. Testing these women with p16/Ki‐67 dual‐stained cytology resulted in a significantly lower CIN3+ 5‐year CIR of 3.3% (p = 0.017) in case of a negative test result. A negative HPV16/18 genotyping test result also led to a lower 5‐year CIN3+ CIR of 3.6%. p16/Ki‐67 dual‐stained cytology detects more than 70% of underlying CIN3+ lesions in HPV‐positive women with normal cytology at baseline and is therefore suitable for triaging these women to colposcopy. Furthermore, the CIN3+ 5‐year CIR of 3.3% after a negative dual‐stain result is significantly lower compared to the 5‐year CIR of 6.9% in women without p16/Ki‐67 dual‐stained cytology triage.     

Comparison of three management strategies for patients with atypical squamous cells of undetermined significance: baseline results from a randomized trial

BACKGROUND: More than 2 million U.S. women receive an equivocal cervical cytologic diagnosis (atypical squamous cells of undetermined significance [ASCUS]) each year. Effective colposcopy triage strategies are needed to identify the minority of women who have clinically significant disease while avoiding excessive follow-up evaluation for others. METHODS: The ASCUS/LSIL (i.e., low-grade squamous intraepithelial lesion) Triage Study (ALTS) is a multicenter, randomized trial comparing the sensitivity and specificity of the following three management strategies to detect cervical intraepithelial neoplasia grade 3 (CIN3): 1) immediate colposcopy (considered to be the reference standard), 2) triage to colposcopy based on human papillomavirus (HPV) results from Hybrid Capture 2(TM) (HC 2) and thin-layer cytology results, or 3) triage based on cytology results alone. This article summarizes the cross-sectional enrollment results for 3488 women with a referral diagnosis of ASCUS. All statistical tests are two-sided. RESULTS: Among participants with ASCUS, the underlying prevalence of histologically confirmed CIN3 was 5.1%. Sensitivity to detect CIN3 or above by testing for cancer-associated HPV DNA was 96.3% (95% confidence interval [CI] = 91.6% to 98.8%), with 56.1% of women referred to colposcopy. Sensitivity of a single repeat cytology specimen with a triage threshold of HSIL or above was 44.1% (95% CI = 35.6% to 52.9%), with 6.9% referred. Sensitivity of a lower cytology triage threshold of ASCUS or above was 85.3% (95% CI = 78.2% to 90.8%), with 58.6% referred. CONCLUSIONS: HC 2 testing for cancer-associated HPV DNA is a viable option in the management of women with ASCUS. It has greater sensitivity to detect CIN3 or above and specificity comparable to a single additional cytologic test indicating ASCUS or above.     

醋酸染色肉眼观察在子宫颈癌筛查分流中的应用价值

目的:评价醋酸染色肉眼观察(VIA)在宫颈癌筛查中分流自我取样人乳头瘤病毒(HPV) DNA阳性人群的可行性及应用价值.方法:对2 500名河南省新密市25～65岁的妇女进行宫颈癌筛查.初次访视时每位妇女均接受了自我取样HPV DNA检测和VIA.任何筛查阳性及随机10％阴性的妇女进行第2次VIA和阴道镜检查.阴道镜下可见病变处直接活检;无可见病变但筛查阳性时行四象限随机活检+宫颈管搔刮术(ECC).以病理诊断为金标准.结果:最终有2 463名妇女纳入分析.目标人群自我取样HPV的阳性率为17.3％(427/2 463),检出CINⅡ+的灵敏度为89.2％(33/37),特异度为83.8％(2 032/2 426),阳性预测值(PPV)为7.7％(33/427).用VIA对自我取样HPV DNA阳性者进行分流,阴道镜转诊率由17.3％(427/2 463)降至2.5％(61/2 463),x2=304.7,P＜0.001;特异度和PPV可分别达到98.3％(2 384/2 426)(x2=350.0,P＜0.001)和31.2％(19/61),x2=30.7,P＜0.001,灵敏度为51.4％.结论:用VIA分流自我取样HPV DNA阳性妇女,可以显著提高宫颈癌筛查的特异度和PPV值,明显降低阴道镜转诊率,对于未绝经妇女,意义更为显著.这种分流方法可以有效节约卫生资源,有望成为宫颈癌筛查分流的一种新选择.     

Evaluation of 14 triage strategies for HPV DNA-positive women in population-based cervical screening

High-risk human papillomavirus (hrHPV) testing has a higher sensitivity but lower specificity than cytology for detection of high-grade intraepithelial neoplasia (CIN). To avoid over-referral to colposcopy and overtreatment, hrHPV-positive women require triage testing and/or followup. A total of 25,658 women (30-60 years) enrolled in a population-based cohort study had an adequate baseline Pap smear and hrHPV test. The end-point was cumulative two-year risk of CIN grade 3 or worse (CIN3+). In a post-hoc analysis, fourteen triage/followup strategies for hrHPV-positive women (n = 1,303) were evaluated for colposcopy referral rate, positive (PPV) and negative predictive value (NPV). Five strategies involved triage testing without a repeat test and nine strategies involved triage testing followed by one repeat testing. The tests were cytology, hrHPV, HPV16/18 genotyping and HPV16/18/31/33/45 genotyping. Results were adjusted for women in the cohort study who did not attend repeat testing. Of the strategies without repeat testing, combined cytology and HPV16/18/31/33/45 genotyping gave the highest NPV of 98.9% (95%CI 97.6-99.5%). The corresponding colposcopy referral rate was 58.1% (95%CI 55.4-60.8%). Eight of the nine strategies with retesting had an estimated NPV of at least 98%. Of those, cytology triage followed by cytology at 12 months had a markedly lower colposcopy referral rate of 33.4% (95%CI 30.2-36.7%) than the other strategies. The NPV of the latter strategy was 99.3% (95%CI 98.1-99.8%). Triage hrHPV-positive women with cytology, followed by repeat cytology testing yielded a high NPV and modest colposcopy referral rate and appear to be the most feasible management strategy.     

Comparative performance evaluation of different HPV tests and triaging strategies using self-samples and feasibility assessment of thermal ablation in ‘colposcopy and treat’ approach: A population-based study in rural China

Human papillomavirus (HPV) test, self-sampling and thermal ablation for cervical intraepithelial neoplasia (CIN) have been developed separately to increase screening coverage and treatment compliance of cervical cancer screening programmes. A large-scale study in rural China screened 9,526 women with their combinations to explore the optimal cervical cancer-screening cascade in the real-world. Participants received careHPV and polymerase chain reaction (PCR) HPV tests on self-collected samples. Women positive on either HPV test underwent colposcopy, biopsy and thermal ablation in a single visit. Samples positive on either HPV test were retested for genotyping. Absolute and relative performance of HPV tests, triage strategies, ‘colposcopy and thermal ablation’ approach were statistically evaluated. PCR HPV test detected 33.3% more CIN grade two or worse (CIN2+) at a cost of 28.1% more colposcopies compared to careHPV. Sensitivities of PCR HPV and careHPV tests to detect CIN2+ were 96.7 and 72.5%. Specificities for the same disease outcome were 82.1 and 86.0%. Triaging HPV-positive women with HPV16/18 genotyping considerably improved the positive predictive value for CIN2+ (4.8–5.0 to 18.2–19.2%). Ninety-six women positive on HPV and having abnormal colposcopy were eligible for thermal ablation and all accepted same-day treatment, contributing to 64.6% being treated appropriately (CIN1+ on histopathology), which reached up to 84.8% among women positive on HPV 16/18 triage. No serious side-effects/complications were reported. The combination of PCR HPV test followed by HPV 16/18 triaging on self-collected samples and colposcopy of triage positive women followed by immediate thermal ablation might be the appropriate screening cascade for rural China.