Cytology-based Cervical Screening Research Articles

Primary screening of cervical cancer by Pap smear in women of reproductive age group.

Cancer cervix is a major health problem responsible for causing a higher mortality rate in women worldwide; the exponential increase in such cases can be reduced by early screening of women. The cytology-based cervical screening had a higher success rate in reducing the incidence of cervical cancer. The present study aimed to evaluate the use of Pap smear screening to find cytological abnormalities and precancerous lesions. Sexually active women over 21 years of age were enrolled for the study. A detailed history was taken on the preformed proforma, and all were subjected to vaginal examination. Samples for Pap smear were taken with the help of Ayre spatula and immediately spread over a marked grease-free glass slide and dipped into 95% ethyl alcohol fixative for cytological examination. Most of the abnormality of the epithelial cells found was in the age range of 31-50 years, and most of them were multiparous. 47.92% of the women had a chief complaint of vaginal discharge, an irregular menstrual cycle in 11.07%, and abdominal pain in 7.83%, while 30.41% were asymptomatic. Women found negative for intraepithelial neoplasia were 82.94%, while 13.36% had an inflammatory smear. 0.92% atypical squamous cells of undetermined significance (ASCUS), 2.78% Low-grade squamous intraepithelial lesion (LSIL) were found, no woman had High-grade squamous intraepithelial lesion (HSIL). Pap smear is a simple, cost-effective, non-invasive, and easy to perform tool for early detection of precancerous lesions, and it is evident that every woman above the age of 25-30 years must be recommended for cervical screening.

Triage human papillomavirus testing for cytology-based cervical screening in women of different ages in primary hospitals: A retrospective clinical study.

Cervical cancer is a serious global health problem. The objective of this study was to provide a suitable cytology-based cervical screening method in women of different ages in primary hospitals.This study was a retrospective cohort study that included 9765 women who underwent primary cytology-based cervical screening and were grouped by age (35–44, 45–54, and 55–64 years old). Patients with abnormal cytology on the primary cervical thin-prep cytologic test (TCT) were advised to undergo triage human papillomavirus (HPV) test. Furthermore, patients with positive outcomes of the 2 indices underwent cervical tissue biopsy. The positive rate of TCT and HPV was compared among the 3 defined age groups. The sensitivity, specificity, and positive predictive value of TCT and HPV were assessed.In total, 2.5% (241/9765) of women had atypical squamous cells of undetermined significance or worse by TCT. High-risk (HR)-HPV infection was found in 70 triage participants. Neoplastic changes were confirmed in 95 patients (95/437, 21.7%) by biopsies. Among the different age groups, the positive rate of abnormal cytology was significantly different (P = .003), and the positive rate of HR-HPV was similar (P = .299). The sensitivity of initial TCT testing to detect intraepithelial neoplasia was higher than that of triage HPV testing, whereas the specificity, the positive predictive value of triage HPV testing was higher than that of TCT. The Youden index of HPV testing was higher than that of TCT detection in the 3 age groups, namely 0.582 versus 0.432, 0.553 versus 0.228, and 0.416 versus 0.332, respectively.The results of this study indicate that TCT testing is suitable as a cervical cancer screening method for women ≥35 years old in primary hospitals. Triage testing for women with HR-HPV has a high negative predictive value, reduces the rate of misdiagnosis, seems to be an excellent triage method for repeat atypical squamous cells of undetermined significance, and reduces the number of referral colposcopies preventing unnecessary overtreatment. The results of this study provide a crucial foundation for a unified guideline cervical cancer screening for primary health care institutions.

An economical Nanopore sequencing assay for human papillomavirus (HPV) genotyping

BackgroundHuman papillomavirus (HPV) testing has been employed by several European countries to augment cytology-based cervical screening programs. A number of research groups have demonstrated potential utility of next-generation sequencing (NGS) for HPV genotyping, with comparable performance and broader detection spectrum than current gold standards. Nevertheless, most of these NGS platforms may not be the best choice for medium sample throughput and laboratories with less resources and space. In light of this, we developed a Nanopore sequencing assay for HPV genotyping and compared its performance with cobas HPV Test and Roche Linear Array HPV Genotyping Test (LA).MethodsTwo hundred and one cervicovaginal swabs were routinely tested for Papanicolaou smear, cobas HPV Test and LA. Residual DNA was used for Nanopore protocol after routine testing. Briefly, HPV L1 region was amplified using PGMY and MGP primers, and PCR-positive specimens were sequenced on MinION flow cells (R9.4.1). Data generated in first 2 h were aligned with reference sequences from Papillomavirus Episteme database for genotyping.ResultsNanopore detected 96 HPV-positive (47.76%) and 95 HPV-negative (47.26%) specimens, with 10 lacking β-globin band and not further analyzed (4.98%). Substantial agreement was achieved with cobas HPV Test and LA (κ: 0.83–0.93). In particular, Nanopore appeared to be more sensitive than cobas HPV Test for HPV 52 (n = 7). For LA, Nanopore revealed higher concordance for high-risk (κ: 0.93) than non-high risk types (κ: 0.83), and with similar high-risk positivity in each cytology grading. Nanopore also provided better resolution for HPV 52 in 3 specimens co-infected with HPV 33 or 58, and for HPV 87 which was identified as HPV 84 by LA. Interestingly, Nanopore identified 5 additional HPV types, with an unexpected high incidence of HPV 90 (n = 12) which was reported in North America and Belgium but not in Hong Kong.ConclusionsWe developed a Nanopore workflow for HPV genotyping which was economical (about USD 50.77 per patient specimen for 24-plex runs), and with comparable or better performance than 2 reference methods in the market. Future prospective study with larger sample size is warranted to further evaluate test performance and streamline the protocol.

Primary HPV screening for cervical cancer.

Cytology-based cervical screening had unequivocal success in reducing the incidence and mortality of cervical cancer in the last century. The recognition of the role of human papillomavirus (HPV) as a necessary cause of cervical cancer led to the development of HPV testing. Gradually, there has been a shift from reflex HPV testing for mild cytological abnormalities, to co-testing with cytology and HPV, and lately to primary HPV screening, based on evidence from well-designed large randomized controlled trials and meta-analyses. Advantages of primary HPV screening include higher sensitivity to detect pre-neoplastic lesions, better re-assurance with a negative test, and safe prolongation of screening intervals. However, clinicians and policy makers must ensure the availability of clinically validated HPV assays and triage protocols of screen positive cases prior to implementation of primary HPV screening. This is likely to reduce potential harm from over-treatment as well as extra burden on the health care system.

Trichomonas Vaginalis (TV) Infection and Its Association With Risk of Cervical Cancer and HPV Status

Abstract Background The prevalence of trichomonas vaginalis (TV) infection is low in developed countries and may be due to its incidental diagnosis and treatment during routine screening. Many countries are adopting a new model based on testing for high-risk (HR) human papillomavirus (HPV) instead of cytology. HPV is known to be associated with squamous intraepithelial lesions (SIL). There is limited and conflicting literature on the relationship between TV and SIL. The aim of this study is to determine the prevalence of TV in different age groups and evaluate the association between TV with SIL, BV (bacterial vaginosis), and HPV infection. Design Retrospective study for cytological histologic correlation was performed on 10,546 cases dated between January 2012 and December 2017. HPV results were available in 7,081 cases. Results The age range was 15 to 84 with a mean of 49 years; 249 patients were TV positive (2.3%). The prevalence was highest in 30 to 65 age group (71.5%). HPV was present in 4,386/7,081 cases (61.9%). The associated between TV and HPV infection was not significant (P < .07). There was a significant association between TV and BV infection (P < .001). In total, 4,649/10,546 patients showed squamous abnormalities (44%), of which 52.6% were TV positive and 43.9% were TV negative. CIN2-3/SCC was significantly greater in TV-positive versus TV-negative patients (P < .007). HPV-positive patients that were TV positive showed more squamous abnormalities than those that were TV negative (P < .043). TV-positive patients with ASCH showed higher grade lesions (CIN2-3/SCC) on follow-up than TV-negative patients (P < .003). Conclusion TV is more common among patients with BV and HPV infection and significantly associated with squamous abnormalities. HPV and ASCH patients with TV showed significant squamous abnormalities. Although TV can be detected incidentally through cytology-based cervical screening, a transition to HPV testing is likely to result in increasing TV prevalence over time.

Impact of replacing cytology with human papillomavirus testing for cervical cancer screening on the prevalence of Trichomonas vaginalis: a modelling study

ObjectivesTrichomonas vaginalis (TV) is the most common curable STI worldwide and is associated with increased risk of HIV acquisition and serious reproductive morbidities. The prevalence of TV infection is very...

Projected impact of HPV vaccination and primary HPV screening on cervical adenocarcinoma: Example from Australia

Cytology-based cervical screening appears to have had a limited effect on the incidence of adenocarcinoma, however HPV vaccination and HPV-based screening will likely play a role in reducing future burden. Using Australia as an example, we estimated the future burden (2015–2040) of adenocarcinoma in the absence of other interventions; and the impact of HPV vaccination (introduced 2007) and HPV-based screening (commencing 2017).Future burden was estimated considering underlying trends in adenocarcinoma, using national data (1982–2010). The relative reduction in adenocarcinoma due to HPV vaccination and HPV-based screening was derived from observed clinical data.Adenocarcinoma incidence rates have been increasing since the early-mid 2000s (average annual increases from 3.0%(25–49 years) −8.1%(20–24 years)). If these trends continue, rates would increase from 1.4 to 2.4/100,000 in <50 years and from 2.2 to 4.4/100,000 in 50+ years by 2040. Taking into account coverage, HPV vaccination will reduce 2040 incidence by 36–39%, mainly in women <50 years (61% reduction). Taking into account uncertainties in trends and screening effectiveness, HPV-based screening will reduce incidence by an additional 19–43%, mainly in women 50+ years (additional 30–68% reduction). Together, these interventions will reduce incidence by 55–81%.

Primary HPV testing versus cytology-based cervical screening in women in Australia vaccinated for HPV and unvaccinated: effectiveness and economic assessment for the National Cervical Screening Program

Australia's National Cervical Screening Program currently recommends cytological screening every 2 years for women aged 18-69 years. Human papillomavirus (HPV) vaccination was implemented in 2007 with high population coverage, and falls in high-grade lesions in young women have been reported extensively. This decline prompted a major review of the National Cervical Screening Program and new clinical management guidelines, for which we undertook this analysis. We did effectiveness modelling and an economic assessment of potential new screening strategies, using a model of HPV transmission, vaccination, natural history, and cervical screening. First, we evaluated 132 screening strategies, including those based on cytology and primary HPV testing. Second, after a recommendation was made to adopt primary HPV screening with partial genotyping and direct referral to colposcopy of women positive for HPV16/18, we evaluated the final effect of HPV screening after incorporating new clinical guidelines for women positive for HPV. Both evaluations considered both unvaccinated and vaccinated cohorts. Strategies entailing HPV testing every 5 years and either partial genotyping for HPV16/18 or cytological co-testing were the most effective. One of the most effective and cost-effective strategies comprised primary HPV screening with referral of women positive for oncogenic HPV16/18 direct to colposcopy, with reflex cytological triage for women with other oncogenic types and direct referral for those in this group with high-grade cytological findings. After incorporating detailed clinical guidelines recommendations, this strategy is predicted to reduce cervical cancer incidence and mortality by 31% and 36%, respectively, in unvaccinated cohorts, and by 24% and 29%, respectively, in cohorts offered vaccination. Furthermore, this strategy is predicted to reduce costs by up to 19% for unvaccinated cohorts and 26% for cohorts offered vaccination, compared with the current programme. Primary HPV screening every 5 years with partial genotyping is predicted to be substantially more effective and potentially cost-saving compared with the current cytology-based screening programme undertaken every 2 years. These findings underpin the decision to transition to primary HPV screening with partial genotyping in the Australian National Cervical Screening Program, which will occur in May, 2017. Department of Health, Australia.

Carcinogenic human papillomavirus infection.

Infections with human papillomavirus (HPV) are common and transmitted by direct contact. Although the great majority of infections resolve within 2 years, 13 phylogenetically related, sexually transmitted HPV genotypes, notably HPV16, cause - if not controlled immunologically or by screening - virtually all cervical cancers worldwide, a large fraction of other anogenital cancers and an increasing proportion of oropharyngeal cancers. The carcinogenicity of these HPV types results primarily from the activity of the oncoproteins E6 and E7, which impair growth regulatory pathways. Persistent high-risk HPVs can transition from a productive (virion-producing) to an abortive or transforming infection, after which cancer can result after typically slow accumulation of host genetic mutations. However, which precancerous lesions progress and which do not is unclear; the majority of screening-detected precancers are treated, leading to overtreatment. The discovery of HPV as a carcinogen led to the development of effective preventive vaccines and sensitive HPV DNA and RNA tests. Together, vaccination programmes (the ultimate long-term preventive strategy) and screening using HPV tests could dramatically alter the landscape of HPV-related cancers. HPV testing will probably replace cytology-based cervical screening owing to greater reassurance when the test is negative. However, the effective implementation of HPV vaccination and screening globally remains a challenge.

Inequalities in cervical screening practices

Theoretically, the cytology-based cervical screening is capable of early detection of precancerous epithelial lesions of cervix uteri and its cancer, and of early referral to treatment. In this way, screening can inmprove the quality of life of the patients and reduce mortality from the target disease. Unfortunately, this often remains unexploited, because there might be inequalities on both "supply" and "demand" side of screening. In addition to the geopolitical situation of a country, inequalities might result from differences in the health care systems, and heavy access to the screening services. On the other hand, the socioeconomic status, the health-conciousness of the target population, and their knowledge and information of the benefits and potential harms of screening examination might have a bearing on the acceptance or refusal of the offered screening. Efforts need to be made to increase the uptake of cervical screening programmes.

Implementation status of cervical screening in Europe

Following the recommendation of the Council of the European Union, almost all governments made a policy statement on the introduction of cytology-based cervical screening for the health care system. However, the status of implementation is uneven. In the majority of the developed countries an organised model of screening recommended by the relevant international professional organisations are in use, while occasional screening is applied in some other countries. Screening strategies (i.e. age range, screening intervals), coverage of the target population, and compliance rates vary significantly. The screening activities are in a planning phase is some less developed Central-Eastern and South European countries. In Hungary, the transition from the traditional "gynaecological cancer screening" into the recommended organised cervical screening is in progress; the active involvement of the district health visitors in the cervical screening would provide further improvement.

Cervical cancer screening program in Thimphu, Bhutan: population coverage and characteristics associated with screening attendance.

BackgroundBhutan has been engaged in good-quality cytology-based cervical screening since 2000 and has vaccinated >90% girls against human papillomavirus (HPV) since 2010. We explored the characteristics associated with lack of previous screening and screening coverage in women age ≥25 years.MethodsWomen were invited at home or during their attendance at 2 outpatient clinics, in the capital, Thimphu, and nearby Lungthenphu. Age-adjusted odds ratios for lack of previous screening by selected characteristics were computed among 1,620 participating women. In Thimphu an invitation registry allowed to estimate screening history not only among participating women but also among additional 500 women who did not accept to join our study.ResultsAmong women who had a Pap smear, lack of previous screening was associated with age <35 or ≥45 years. It was also associated with some occupations; being single, or widowed/separated; and presence of HPV infection. Multiparity and use of contraceptive methods were associated with having been screened. In women invited at home in Thimphu screening history substantially differed by participation. Past screening attendance was 59% among women recruited in the 2 clinics, 53% in women who were invited from home and accepted the invitation, but only 25% in those who refused it. Based on all women recruited from home the estimate of population-based coverage in Thimphu is 34% (95% CI: 31-37).ConclusionsTransition from an opportunistic screening to an all-reaching population-based screening is yet to be achieved in Bhutan, even in the capital. Better ways to target never-screened women are needed.

Efficacy of HPV-based screening for prevention of invasive cervical cancer: follow-up of four European randomised controlled trials

In four randomised trials, human papillomavirus (HPV)-based screening for cervical cancer was compared with cytology-based cervical screening, and precursors of cancer were the endpoint in every trial. However, direct estimates are missing of the relative efficacy of HPV-based versus cytology-based screening for prevention of invasive cancer in women who undergo regular screening, of modifiers (eg, age) of this relative efficacy, and of the duration of protection. We did a follow-up study of the four randomised trials to investigate these outcomes. 176,464 women aged 20-64 years were randomly assigned to HPV-based (experimental arm) or cytology-based (control arm) screening in Sweden (Swedescreen), the Netherlands (POBASCAM), England (ARTISTIC), and Italy (NTCC). We followed up these women for a median of 6·5 years (1,214,415 person-years) and identified 107 invasive cervical carcinomas by linkage with screening, pathology, and cancer registries, by masked review of histological specimens, or from reports. Cumulative and study-adjusted rate ratios (experimental vs control) were calculated for incidence of invasive cervical carcinoma. The rate ratio for invasive cervical carcinoma among all women from recruitment to end of follow-up was 0·60 (95% CI 0·40-0·89), with no heterogeneity between studies (p=0·52). Detection of invasive cervical carcinoma was similar between screening methods during the first 2·5 years of follow-up (0·79, 0·46-1·36) but was significantly lower in the experimental arm thereafter (0·45, 0·25-0·81). In women with a negative screening test at entry, the rate ratio was 0·30 (0·15-0·60). The cumulative incidence of invasive cervical carcinoma in women with negative entry tests was 4·6 per 10(5) (1·1-12·1) and 8·7 per 10(5) (3·3-18·6) at 3·5 and 5·5 years, respectively, in the experimental arm, and 15·4 per 10(5) (7·9-27·0) and 36·0 per 10(5) (23·2-53·5), respectively, in the control arm. Rate ratios did not differ by cancer stage, but were lower for adenocarcinoma (0·31, 0·14-0·69) than for squamous-cell carcinoma (0·78, 0·49-1·25). The rate ratio was lowest in women aged 30-34 years (0·36, 0·14-0·94). HPV-based screening provides 60-70% greater protection against invasive cervical carcinomas compared with cytology. Data of large-scale randomised trials support initiation of HPV-based screening from age 30 years and extension of screening intervals to at least 5 years. European Union, Belgian Foundation Against Cancer, KCE-Centre d'Expertise, IARC, The Netherlands Organisation for Health Research and Development, the Italian Ministry of Health.

HPV Testing in Primary Cervical Screening: A Systematic Review and Meta-Analysis

ObjectivePrevious findings from cross-sectional studies have shown human papillomavirus (HPV) testing to be more sensitive than cytology testing for primary cervical screening. This systematic review aims to assess whether the increase in baseline detection with HPV testing corresponds to lower rates in subsequent screening rounds. MethodsWe searched Medline, EMBASE, and the Cochrane Library for randomized controlled trials (published from 2005 to 2010) comparing HPV-based and cytology-based cervical screening. Primary outcomes of interest were relative rates of higher grade cervical intraepithelial neoplasia and invasive cervical cancer. Secondary outcomes included test performance characteristics and colposcopy referral rates. Results were pooled where possible using a random effects model. ResultsSeven randomized trials were identified. Across studies, HPV testing was more accurate than conventional cytology and detected significantly more CIN3+ in the first screening round (Mantel-Haenszel [M-H] risk ratio 1.67; 95% CI 1.27 to 2.19) and significantly less in the second screening round (M-H RR 0.49; 95% CI 0.37 to 0.66). There were no differences in pooled rates of CIN2+ (M-H RR 1.19; 95% CI 0.94 to 1.50) and CIN3+ (M-H RR 1.09; 95% CI 0.84 to 1.42), but there was a higher pooled rate of CIN2 (M-H RR 1.37; 95% CI 1.12 to 1.68) over two screening rounds. A trend towards lower rates of invasive cervical cancer was observed. ConclusionOrganized screening programs in higher resource settings should consider adopting HPV testing as the primary screening test for women 30 or 35 years of age and older. Further research is needed to determine optimal screening strategies for younger women.

A 7.5-year prospective study of longer than 18 months type-specific human papillomavirus persistence in a routine cytology-based cervical screening population of about 31 000 women in West Germany

The objective of this study was to analyse the prevalence, infection pattern, duration and outcome of long-term, type-specific, persistent human papillomavirus (HPV) infections in a routine cytology-based cervical screening population of West German women followed up for 7.5 years. From a screening population of 31,000 women, a strictly selected cohort of 100 patients with > or =18-month persistent, type-specific HPV infection were prospectively followed up for a mean of 35.52 months (+/-13.0). HPV type prevalence and odds ratios for regression, progression and steady state were analysed, as well as the influence of age and HPV coinfection on outcome. Altogether, 21 different genotypes were detected. Seventy-two percent of women were infected with high-risk HPVs, 24% with low-risk and 4% with unknown risk HPV types; 44% of cases had coinfections with multiple HPV types. The risk of progression in low-grade squamous intraepithelial lesions and high-grade squamous intraepithelial lesions was the highest for infections with high-risk HPVs [odds ratio: 2.2 (0.79-6.11, 95% confidence interval)], whereas cases with low-risk and unknown risk HPVs tended to regress or remained unchanged during follow-up. The mean duration of infections showed considerable variation among the different HPV types and risk groups detected and ranged between 19.7 and 54.3 months. Age was not significantly associated with disease progression and infection duration, and histology had a poor sensitivity for detecting high-grade dysplasia. In conclusion, detecting long-term persistent HPV infections by genotyping may help to identify women with cervical intraepithelial lesions who are at lower and higher risk of developing high-grade precancer and cancer. This may influence future screening strategies and therapy decisions.

The role of human papillomavirus testing in cervical screening

Organised, cytology-based cervical screening has led to a reduction in deaths associated with cervical cancer. Human papillomavirus (HPV) is necessary for the development of cervical cancer and associated pre-cursor cervical intraepithelial neoplasia and accumulated evidence suggests that incorporation of HPV testing could further refine screening programmes. HPV testing is discussed in the context of primary screening, for triage, and as a test of cure of treatment and possible value in developing countries. The high negative predictive value of a "double negative" cytology and HPV result could allow considerable changes in policy such as increased intervals between screening rounds, adjustment of age ranges for testing and schedule for return to routine screening post treatment. HPV testing for the triage of women to colposcopy with borderline or atypical squamous cells of undetermined significance (ASCUS) cytology could be clinically effective, but may be limited in women with low-grade squamous intraepithelial lesions (LSIL) or mild dyskaryosis by high HPV prevalence. Markers of HPV persistence harbour enormous potential to identify women at greatest risk of disease progression. Due to the diversity of existing cytology-based screening programmes, full cost-effectiveness analyses of HPV testing should be performed and assessed within local contexts.

Editor's note

Cytology-based cervical screening had unequivocal success in reducing the incidence and mortality of cervical cancer in the last century. The recognition of the role of human papillomavirus (HPV) as a necessary cause of cervical cancer led to the development of HPV testing. Gradually, there has been a shift from reflex HPV testing for mild cytological abnormalities, to co-testing with cytology and HPV, and lately to primary HPV screening, based on evidence from well-designed large randomized controlled trials and meta-analyses. Advantages of primary HPV screening include higher sensitivity to detect pre-neoplastic lesions, better re-assurance with a negative test, and safe prolongation of screening intervals. However, clinicians and policy makers must ensure the availability of clinically validated HPV assays and triage protocols of screen positive cases prior to implementation of primary HPV screening. This is likely to reduce potential harm from over-treatment as well as extra burden on the health care system.