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.
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.
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.
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.
Summary Background Australia introduced a human papillomavirus (HPV) vaccination programme with the quadrivalent HPV vaccine for all women aged 12–26 years between 2007 and 2009. We analysed trends ...in cervical abnormalities in women in Victoria, Australia, before and after introduction of the vaccination programme. Methods With data from the Victorian Cervical Cytology Registry between 2003 and 2009, we compared the incidence of histopathologically defined high-grade cervical abnormalities (HGAs, lesions coded as cervical intraepithelial neoplasia of grade 2 or worse or adenocarcinoma in situ; primary outcome) and low-grade cytological abnormalities (LGAs) in five age groups before (Jan 1, 2003, to March 31, 2007) and after (April 1, 2007, to Dec 31, 2009) the vaccination programme began. Binary comparisons between the two periods were done with Fisher's exact test. Poisson piecewise regression analysis was used to compare incident rate trends. Findings After the introduction of the vaccination programme, we recorded a decrease in the incidence of HGAs by 0·38% (95% CI 0·61–0·16) in girls younger than 18 years. This decrease was progressive and significantly different to the linear trend in incidence before introduction of the vaccination (incident rate ratio 1·14, 1·00–1·30, p=0·05). No similar temporal decline was recorded for LGAs or in older age groups. Interpretation This is the first report of a decrease in incidence of HGAs within 3 years after the implementation of a population-wide HPV vaccination programme. Linkage between vaccination and screening registers is needed to confirm that this ecological observation is attributable to vaccination and to monitor participation in screening among vaccinated women. Funding None.
Abstract Objectives ATHENA evaluated the cobas HPV Test as the primary screen for cervical cancer in women ≥ 25 years. This reports the 3-year end-of-study results comparing the performance of HPV ...primary screening to different screening and triage combinations. Methods 42,209 women ≥ 25 years were enrolled and had cytology and hrHPV testing. Women with abnormal cytology (≥ atypical squamous cells of undetermined significance) and those HPV positive were referred to colposcopy. Women not reaching the study endpoint of CIN2 + entered the 3-year follow-up phase. Results 3-year CIR of CIN3 + in cytology-negative women was 0.8% (95% CI; 0.5–1.1%), 0.3% (95% CI 0.1–0.7%) in HPV-negative women, and 0.3% (95% CI; 0.1–0.6%) in cytology and HPV negative women. The sensitivity for CIN3 + of cytology was 47.8% (95% CI; 41.6–54.1%) compared to 61.7% (95% CI; 56.0–67.5%) for the hybrid strategy (cytology if 25–29 years and cotesting with cytology and HPV if ≥ 30 years) and 76.1% (95% CI; 70.3–81.8%) for HPV primary . The specificity for CIN3 + was 97.1% (95% CI; 96.9–97.2%), 94.6% (95% CI; 94.4–94.8%), and 93.5% (95% CI; 93.3–93.8%) for cytology , hybrid strategy , and HPV primary , respectively. Although HPV primary detects significantly more cases of CIN3 + in women ≥ 25 years than either cytology or hybrid strategy , it requires significantly more colposcopies. However, the number of colposcopies required to detect a single CIN3 + is the same as for the hybrid strategy. Conclusions HPV primary screening in women ≥ 25 years is as effective as a hybrid screening strategy that uses cytology if 25–29 years and cotesting if ≥ 30 years. However, HPV primary screening requires less screening tests.
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