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.
This paper briefly reviews the role of hypermethylation of host cell genes in cervical carcinogenesis and discusses potential clinical applications of methylation analysis in the management of ...high‐risk HPV (hrHPV) ‐positive women. We argue that methylation assays can be used: 1. for primary triage of hrHPV‐positive women to detect cervical cancer and advanced cervical intraepithelial neoplasia (CIN); 2. as secondary triage for women with minor cytological abnormalities to identify those with the highest risk of CIN3 or worse; 3. as exit test for women leaving the screening programme to identify cervical cancer and advanced CIN; and 4. to support management of CIN.
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This paper discusses potential clinical applications of DNA methylation analysis in the management of women with a high‐risk HPV infection.
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This paper discusses potential clinical applications of DNA methylation analysis in the management of women with a high‐risk HPV infection.
Dysregulated expression of oncogenic types of E6 and E7 is necessary for human papillomavirus (HPV)-driven carcinogenesis. An HPV E6/E7 mRNA in situ hybridization (ISH) assay covering 18 common ...high-risk types ("HR-RISH," aka HR-HPV RNA18 ISH) has not been extensively studied in the anogenital tract or validated on automated technology. We herein compare HR-RISH to DNA polymerase chain reaction (PCR), p16 immunohistochemistry, and a previously available HPV DNA ISH assay in HPV-related anogenital and head and neck (H&N) neoplasia. A total of 102 squamous intraepithelial lesions (16 CIN1, 25 CIN3, 3 AIN1, 12 AIN3, 9 VIN3)/invasive squamous cell carcinomas (17 cervical, 2 anal, 18 H&N) as well as 10 normal and 15 reactive cervix samples were collected. HR-RISH, DNA ISH, and p16 immunohistochemistry were performed on whole formalin-fixed, paraffin-embedded sections. RNA ISH for 6 low-risk HPV types (LR-RISH) was also performed. RNA and DNA ISH assays used automated systems. HR-HPV PCR was performed on morphology-directed formalin-fixed, paraffin-embedded punches. HR-RISH was ≥97% sensitive for PCR+ and p16+ neoplasia, as well as morphologically defined anogenital high grade squamous intraepithelial lesion/invasive squamous cell carcinoma. HR-RISH was also positive in 78% of anogenital low grade squamous intraepithelial lesion, including 81% of CIN1. Furthermore, a subset of PCR-negative/invalid and p16-negative lesions was positive for HR-RISH. Only 1 problematic reactive cervix sample and no normal cervix samples stained. These results demonstrate that HR-RISH is a robust method for the detection of HR-HPV-related neoplasia and provides insight into HPV pathobiology. Performance meets or exceeds that of existing assays in anogenital and H&N lesions and may play a role in resolving diagnostically challenging CIN1 versus reactive cases.
A systematic review of the literature was conducted to determine the estimates of and definitions for human papillomavirus (HPV) persistence in women following treatment of cervical intra‐epithelial ...neoplasia (CIN). A total of 45 studies presented data on post‐treatment HPV persistence among 6,106 women. Most studies assessed HPV persistence after loop excision (42%), followed by conization (7%), cryotherapy (11%), laser treatment (4%), interferon‐alpha, therapeutic vaccination, and photodynamic therapy (2% each) and mixed treatment (38%). Baseline HPV testing was conducted before or at treatment for most studies (96%). Follow‐up HPV testing ranged from 1.5 to 80 months after baseline. Median HPV persistence tended to decrease with increasing follow‐up time, declining from 27% at 3 months after treatment to 21% at 6 months, 15% at 12 months, and 10% at 24 months. Post‐treatment HPV persistence estimates varied widely and were influenced by patient age, HPV‐type, detection method, treatment method, and minimum HPV post‐treatment testing interval. Loop excision and conization appeared to outperform cryotherapy procedures in terms of their ability to clear HPV infection. This systematic review provides evidence for the substantial heterogeneity in post‐treatment HPV DNA testing practices and persistence estimates.
The incidence of cervical cancer in the United States has decreased more than 50% in the past 30 years because of widespread screening. In 1975, the rate was 14.8 per 100,000 women. By 2011, it ...decreased to 6.7 per 100,000 women. Mortality from the disease has undergone a similar decrease from 5.55 per 100,000 women in 1975 to 2.3 per 100,000 women in 2011 (1). The American Cancer Society (ACS) estimated that there would be 12,900 new cases of cervical cancer in the United States in 2015, with 4,100 deaths from the disease (2). Cervical cancer is much more common worldwide, particularly in countries without screening programs, with an estimated 527,624 new cases of the disease and 265,672 resultant deaths each year (3). When cervical cancer screening programs have been introduced into communities, marked reductions in cervical cancer incidence have followed (4, 5).New technologies for cervical cancer screening continue to evolve, as do recommendations for managing the results. In addition, there are different risk-benefit considerations for women at different ages, as reflected in age-specific screening recommendations. In 2011, the ACS, the American Society for Colposcopy and Cervical Pathology (ASCCP), and the American Society for Clinical Pathology (ASCP) updated their joint guidelines for cervical cancer screening (6), as did the U.S. Preventive Services Task Force (USPSTF) (7). Subsequently, in 2015, ASCCP and the Society of Gynecologic Oncology (SGO) issued interim guidance for the use of a human papillomavirus (HPV) test for primary screening for cervical cancer that was approved in 2014 by the U.S. Food and Drug Administration (FDA) (8). The purpose of this document is to provide a review of the best available evidence regarding the prevention and early detection of cervical cancer.
Artificial intelligence (AI) could automatedly detect abnormalities in digital cytological images, however, the effect in cervical cancer screening is inconclusive. We aim to evaluate the performance ...of AI-assisted cytology for the detection of histologically cervical intraepithelial lesions (CIN) or cancer.
We trained a supervised deep learning algorithm based on 188,542 digital cytological images. Between Mar 13, 2017, and Oct 20, 2018, 2145 referral women from organized screening were enrolled in a multicenter, clinical-based, observational study. Cervical specimen was sampled to generate two liquid-based slides: one random slide was allocated to AI-assisted reading, and the other to manual reading conducted by skilled cytologists from senior hospital and cytology doctors from primary hospitals. HPV testing and colposcopy-directed biopsy was performed, and histological result was regarded as reference. We calculated the relative sensitivity and relative specificity of AI-assisted reading compared to manual reading for CIN2+. This trial was registered, number ChiCTR2000034131.
In the referral population, AI-assisted reading detected 92.6% of CIN 2 and 96.1% of CIN 3+, significantly higher than or similar to manual reading. AI-assisted reading had equivalent sensitivity (relative sensitivity 1.01, 95%CI, 0.97–1.05) and higher specificity (relative specificity 1.26, 1.20–1.32) compared to skilled cytologists; whereas higher sensitivity (1.12, 1.05–1.20) and specificity (1.36, 1.25–1.48) compared to cytology doctors. In HPV-positive women, AI-assisted reading improved specificity for CIN1 or less at no expense of reduction of sensitivity compared to manual reading.
AI-assisted cytology may contribute to the primary cytology screening or triage. Further studies are needed in general population.
•AI based on deep learning could generated severity scores of abnomal cytology associating with histological lesions.•AI-assisted cytology show comparable performance for the detection of CIN2+ relative to skilled cytologist in referral women.•AI-assisted cytology would improve specificity at no expense of sensitivity in HPV-positive triage.•AI-assisted cytology may contribute to the primary cytology screening or HPV-positive triage.
Background Human papillomavirus vaccines prevent human papillomavirus infection and cervical precancers. The impact of vaccinating women with a current infection or after treatment for an human ...papillomavirus-associated lesion is not fully understood. Objectives To determine whether human papillomavirus-16/18 vaccination influences the outcome of infections present at vaccination and the rate of infection and disease after treatment of lesions. Study Design We included 1711 women (18−25 years) with carcinogenic human papillomavirus infection and 311 women of similar age who underwent treatment for cervical precancer and who participated in a community-based trial of the AS04-adjuvanted human papillomavirus-16/18 virus-like particle vaccine. Participants were randomized (human papillomavirus or hepatitis A vaccine) and offered 3 vaccinations over 6 months. Follow-up included annual visits (more frequently if clinically indicated), referral to colposcopy of high-grade and persistent low-grade lesions, treatment by loop electrosurgical excisional procedure when clinically indicated, and cytologic and virologic follow-up after treatment. Among women with human papillomavirus infection at the time of vaccination, we considered type-specific viral clearance, and development of cytologic (squamous intraepithelial lesions) and histologic (cervical intraepithelial neoplasia) lesions. Among treated women, we considered single-time and persistent human papillomavirus infection, squamous intraepithelial lesions, and cervical intraepithelial neoplasia 2 or greater. Outcomes associated with infections absent before treatment also were evaluated. Infection-level analyses were performed and vaccine efficacy estimated. Results Median follow-up was 56.7 months (women with human papillomavirus infection) and 27.3 months (treated women). There was no evidence of vaccine efficacy to increase clearance of human papillomavirus infections or decrease incidence of cytologic/histologic abnormalities associated with human papillomavirus types present at enrollment. Vaccine efficacy for human papillomavirus 16/18 clearance and against human papillomavirus 16/18 progression from infection to cervical intraepithelial neoplasia 2 or greater were −5.4% (95% confidence interval −19,10) and 0.3% (95% confidence interval −69,41), respectively. Among treated women, 34.1% had oncogenic infection and 1.6% had cervical intraepithelial neoplasia 2 or greater detected after treatment, respectively, and of these 69.8% and 20.0% were the result of new infections. We observed no significant effect of vaccination on rates of infection/lesions after treatment. Vaccine efficacy estimates for human papillomavirus 16/18 associated persistent infection and cervical intraepithelial neoplasia 2 or greater after treatment were 34.7% (95% confidence interval −131, 82) and −211% (95% confidence interval −2901, 68), respectively. We observed evidence for a partial and nonsignificant protective effect of vaccination against new infections absent before treatment. For incident human papillomavirus 16/18, human papillomavirus 31/33/45, and oncogenic human papillomavirus infections post-treatment, vaccine efficacy estimates were 57.9% (95% confidence interval −43, 88), 72.9% (95% confidence interval 29, 90), and 36.7% (95% confidence interval 1.5, 59), respectively. Conclusion We find no evidence for a vaccine effect on the fate of detectable human papillomavirus infections. We show that vaccination does not protect against infections/lesions after treatment. Evaluation of vaccine protection against new infections after treatment and resultant lesions warrants further consideration in future studies.
In 2017, the Dutch cervical cancer screening program had replaced the primary cytology-based screening with primary high-risk human papillomavirus-based screening, including the opportunity to ...participate through self-sampling. Evaluation and balancing benefit (detection of high-grade cervical intraepithelial neoplasia) and burden of screening (unnecessary referrals, invasive diagnostics, and overtreatment) is needed.
This study aimed to compare the referral rates, detection of high-grade cervical intraepithelial neoplasia, overdiagnosis, and overtreatment in the new high-risk human papillomavirus-based screening program, including physician-sampled and self-sampled material, with the previous cytology-based screening program in the Netherlands.
A retrospective cohort study was conducted within the Dutch population-based cervical cancer screening program. Screenees with referrals for colposcopy between 2014 and 2015 (cytology-based screening) and 2017 and 2018 (high-risk human papillomavirus-based screening) were included. Data were retrieved from the Dutch Pathology Registry (PALGA) and compared between the 2 screening programs. The main outcome measures were referral rate, detection of high-grade cervical intraepithelial neoplasia or worse, overdiagnosis (cervical intraepithelial neoplasia grade 1 or less in the histologic specimen), and overtreatment (cervical intraepithelial neoplasia grade 1 or less in the treatment specimen).
Of the women included in the study, 19,109 received cytology-based screening, and 26,171 received high-risk human papillomavirus-based screening. Referral rates increased from 2.5% in cytology-based screening to 4.2% in high-risk human papillomavirus-based screening (+70.2%). Detection rates increased to 46.2% for cervical intraepithelial neoplasia grade 2 or worse, 32.2% for cervical intraepithelial neoplasia grade 3 or worse, and 31.0% for cervical cancer, and overdiagnosis increased to 143.4% with high-risk human papillomavirus-based screening. Overtreatment rates were similar in both screening periods. The positive predictive value of referral for detection of cervical intraepithelial neoplasia grade 2 or worse in high-risk human papillomavirus-based screening was 34.6% compared with 40.2% in cytology-based screening. Women screened through self-sampling were at higher risk of cervical intraepithelial neoplasia grade 2 or worse detection (odds ratio, 1.38; 95% confidence interval, 1.20–1.59) and receiving treatment (odds ratio, 1.31; 95% confidence interval, 1.16–1.48) than those screened through physician-sampling.
Compared with cytology-based screening, high-risk human papillomavirus-based screening increases detection of high-grade cervical intraepithelial neoplasia, with 462 more cervical intraepithelial neoplasia grade 2 or worse cases per 100,000 women but at the expense of 850 more cases per 100,000 women with invasive diagnostics indicating cervical intraepithelial neoplasia grade 1 or less.
Objective
To compare the sensitivity of high‐risk human papillomavirus (hrHPV) and genotype detection in self‐collected urine samples in the morning (U1), and later on (U2), brush‐based self‐samples ...(SS), and clinician‐taken smears (CTS) for detecting cervical intraepithelial neoplasia grade 2+ (CIN2+) in a colposcopic referral population.
Design
Cross‐sectional single‐centre study.
Setting
A colposcopy clinic in Spain.
Population
A cohort of 113 women referred for colposcopy after an abnormal Pap smear.
Methods
Women undergoing colposcopy with biopsy for abnormal Pap smears were sent a device (Colli‐Pee™, Novosanis, Wijnegem, Belgium) to collect U1 on the morning of colposcopy. U2, CTS, and SS (Evalyn brush™, Rovers Medical Devices B.V., Oss, the Netherlands) were also analysed. All samples were tested for HPV DNA using the analytically sensitive SPF10‐DEIA‐LiPA25 assay and the clinically validated GP5+/6+‐EIA‐LMNX.
Main outcome measures
Histologically confirmed CIN2+ and hrHPV positivity for 14 high‐risk HPV types.
Results
Samples from 91 patients were analysed. All CIN3 cases (n = 6) tested positive for hrHPV in CTS, SS, U1, and U2 with both HPV assays. Sensitivity for CIN2+ with the SPF10 system was 100, 100, 95, and 100%, respectively. With the GP5+/6+ assay, sensitivity was 95% in all sample types. The sensitivities and specificities for both tests on each of the sample types did not significantly differ. There was 10–14% discordance on hrHPV genotype.
Conclusions
CIN2+ detection using HPV testing of U1 shows a sensitivity similar to that of CTS or brush‐based SS, and is convenient. There was substantial to almost excellent agreement between all samples on genotype with both hrHPV assays. There was no advantage in testing U1 compared with U2 samples.
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Similar CIN2+ sensitivity for HPV testing in first‐void urine, physician‐taken smear and brush‐based self‐sample.
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Similar CIN2+ sensitivity for HPV testing in first‐void urine, physician‐taken smear and brush‐based self‐sample.
This review elaborates on the accuracy and feasibility of human papillomavirus (HPV) self‐sampling, i.e., offering self‐sampling of (cervico‐)vaginal cell material by women themselves in nonclinical ...settings for high‐risk HPV (hrHPV) detection in the laboratory, for cervical screening. To that end a bibliographic database search (PubMed) was performed to identify studies (published between January 1992 and January 2012) that compared clinical accuracy of HPV testing on self‐sampled material with that of cytology or HPV testing on clinician‐taken samples, and studies comparing response to offering HPV self‐sampling with a recall invitation. Overall, hrHPV testing on self‐samples appeared to be at least as, if not more, sensitive for cervical intraepithelial neoplasia grade 2 or worse (CIN2+) as cytology on clinician‐obtained cervical samples, though often less specific. In most studies, hrHPV testing on self‐ and clinician‐sampled specimens is similarly accurate with respect to CIN2+ detection. Variations in clinical performance likely reflect the use of different combinations of collection devices and HPV tests. Because it is known that underscreened women are at increased risk of cervical cancer, targeting non‐attendees of the screening program could improve the effectiveness of cervical screening. In developed countries offering self‐sampling has shown to be superior to a recall invitation for cytology in re‐attracting original non‐attendees into the screening program. Additionally, self‐testing has shown to facilitate access to cervical screening for women in low resource areas. This updated review of the literature suggests that HPV self‐sampling could be an additional strategy that can improve screening performance compared to current cytology‐based call‐recall programs.
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