Colposcopic and histopathologic evaluation of women participating in population-based screening for human papillomavirus deoxyribonucleic acid persistence

doi:10.1016/j.ajog.2005.01.056

American Journal of Obstetrics and Gynecology

Volume 193, Issue 3, September 2005, Pages 650-657

https://doi.org/10.1016/j.ajog.2005.01.056 Get rights and content

Objective

Evaluation of colposcopic and histopathological findings in women screened for cervical human papillomavirus deoxyribonucleic acid persistence.

Study design

A total of 12 527 women, aged 32 to 38 years old, attending the population-based cervical cancer screening program in Sweden were randomized 1:1 to mock testing or human papillomavirus deoxyribonucleic acid testing by general primer 5+/6+ polymerase chain reaction and subsequent typing. Human papillomavirus deoxyribonucleic acid–positive women with a normal Papanicolaou smear (n = 341) and an equal number from the control group were human papillomavirus tested on average 19 months later. One hundred nineteen women with type-specific human papillomavirus persistence and 111 controls were referred to colposcopy, and 84.8% attended.

Results

Histopathology from colposcopically directed biopsies confirmed cervical intraepithelial neoplasia grade 2 or 3 in 28 of 100 of the women with human papillomavirus deoxyribonucleic acid persistence and in 2 of 95 among controls.

Conclusion

Among women with normal Papanicolaou smear attending population-based screening, the positive predictive value of human papillomavirus deoxyribonucleic acid persistence for detection of biopsy-confirmed cervical intraepithelial neoplasia 2 or 3 was 29%.

Section snippets

Study group

In the organized screening program, women aged 23 to 50 years are invited by letter for screening at 3-year intervals. The files of the population registry are first checked against cytology registries and women who have had a Papanicolaou smear taken within the previous 18 months are not invited. In the present study, the study base was defined as the entire population aged 32 to 38 years resident in 5 different regions in Sweden (Stockholm, Gothenburg, Malmö, Umeå, and Uppsala), with the

Results

Altogether 95 of 195 (48.7%) of the women who underwent colposcopy had an abnormal colposcopy (including all acetowhite lesions), 59 of 100 (59%) in the intervention group with persistent HPV infection and 36 of 95 (37.9%) in the population-based control group (Table I). These lesions predicted CIN 2 or 3 in colposcopy-directed biopsy verified by expert histopathological re-review in 23 of 58 (39.7%) of the women in the intervention group but in only 2 of 36 women in the control group (Table I

Comment

We found that population-based screening for HPV persistence and subsequent referral to colposcopy has a high predictive value (29%) for the presence of CIN 2 or 3. Even among women with 2 consecutive normal cytologies, the positive predictive value was 10%, supporting the concept that additional or alternative screening tools may be required. By design, all women with atypical Papanicolaou smears at enrollment into the study (whether HPV positive or negative) were taken care of according to

Acknowledgments

The participants of the Swedescreen study group were: Ann Kristin Andersson, Ola Forslund, Bengt-Göran Hansson, Anna Palmstierna-Bengtsson, Björn Hagmar, Anders Hjerpe, Bo Johansson, Hilde Larsson, Sven Törnberg, Charlotte Wistrand, Karin Edlund, Göran Wadell, and Margareta Larsson.

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Persistence of type-specific human papillomavirus infection among cytologically normal women
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Cited by (63)

Options for triage and implications for colposcopists within European HPV-based cervical screening programmes
2021, European Journal of Obstetrics and Gynecology and Reproductive Biology
The development of human papillomavirus (HPV)-based screening should detect more pre-cancerous changes and so reduce the incidence and mortality from cervical squamous carcinoma and cervical adenocarcinoma. However, many more women are high risk HPV (hrHPV) screen positive compared to cytology-based screening, especially in younger age-women. A variety of tests have become available which may triage into those hrHPV test-positive women who need immediate referral to colposcopy from those who need early repeat HPV tests or recall on the basis of their disease status.
We performed a literature review of publications and a manual search from 2010, reporting cytology, HPV partial genotyping, dual-staining and DNA methylation for triage of hrHPV positive tests, including their comparative performance between these methods as well as the effectiveness of some triage combinations with reference to HPV-based screening services in Europe. Cost effectiveness and the structure of triage algorithms for colposcopists also have been considered. From one report evaluating four options for triage as single options or as combined algorithms, partial genotyping for HPV 16 and 18 with dual-staining yielded the highest risk of cervical intraepithelial neoplasia grade three or worse within an HPV positive population and with an acceptable colposcopy rate. From a separate paper, this option appeared cost effective. However, publications were difficult to compare objectively.
All options have their merits but a combination triage involving any two of cytology, HPV partial genotyping or dual-staining seems most efficient at present. HPV vaccination may impact upon the performance of future partial genotyping. DNA Methylation may become an acceptable future option.
Colposcopic and histopathologic evaluation of women with HPV persistence exiting an organized screening program
2020, American Journal of Obstetrics and Gynecology
Human papillomavirus–based screening has a higher sensitivity for precursors of cervical cancer compared with cytology-based screening. However, more evidence is needed on optimal management of human papillomavirus–positive women.
The objective of the study was to compare the risk of histopathologically confirmed cervical intraepithelial lesions grade 2 or worse after 1 and 3 years of human papillomavirus persistence, respectively, and evaluate the clinical management of human papillomavirus–positive women in the 56–60 year age group.
This was a randomized health care policy offering human papillomavirus screening to 50% of resident women aged 56–60 years in the Stockholm/Gotland region of Sweden during January 2012 through May 2014. Women who were human papillomavirus positive/cytology negative at baseline were referred for a repeat test after 1 or 3 years. In case of human papillomavirus persistence, women were referred for colposcopy, including biopsies and endocervical sampling.
The human papillomavirus prevalence was 5.5% (405 women of 7325 attending). Among the 405 human papillomavirus–positive women, 313 were reflex test cytology negative at baseline and were referred for a repeat human papillomavirus test, 176 women after 1 year and 137 women after 3 years. After 1 year, 91 of 176 (52%) were persistently human papillomavirus positive and after 3 years 55 of 137 (40%) (P = .042). In repeat cytology, 10 of the 91 (12%) were positive after 1 year and 15 of 55 (33%) after 3 years (P = .005). The attendance rates for colposcopy were similar: 82 of 91 (90%) in the 1 year group and 45 of 55 (82%) in the 3 year group. All women attending colposcopy were postmenopausal, and endocervical sampling and punch biopsies were performed to facilitate colposcopic management, with a positive predictive value of 43–50% and 28–31%, respectively. Histopathologically confirmed cervical intraepithelial lesions grade 2 or worse was found in 19 of 82 women (23%) and 9 of 45 women (20%) in the 1 year and 3 year groups, respectively, and registry linkage follow-up found no cancers in either group. Human papillomavirus genotyping was predictive of cervical intraepithelial lesions grade 2 or worse, and human papillomavirus 16 was the most common genotype at human papillomavirus persistence, occurring in 18% of the cases in the 1 year group and 20% in the 3 year group.
It was safe to postpone repeat human papillomavirus tests for 3 years in postmenopausal women attending the organized cervical screening program. There was a high risk for cervical intraepithelial lesions grade 2 or worse at follow-up and noteworthy yields from human papillomavirus genotyping as well as endocervical sampling and random biopsies in the absence of visible colposcopic lesions.
Diagnostic excision of the cervix in women over 40 years with human papilloma virus persistency and normal cytology
2019, European Journal of Obstetrics and Gynecology and Reproductive Biology: X
Citation Excerpt :
Kjaer et al did a population based prospective cohort study on HPV positive women <30 years with normal Pap smear at baseline showing risks of developing CIN3 in 12 years in different HPV genotypes as following: HPV16 26,7%, HPV18 19,1% and HPV31/33 over 14% [9]. The Swedescreen study, involving women aged 32–38 years, described that among women with a normal Pap smear attending organized screening, the positive predictive value of HPV persistence as regards detection of biopsy-confirmed CIN2+ was 29% [10]. Long-term follow-up of this study pointed out that all the HPV-positive women with initially normal cytology either become HPV-negative or developed CIN2+ within seven years [11].
Persistent infection with human papillomavirus (HPV) is recognized as the main risk factor of cervical cancer. Investigation via cytology and colposcopy have lower sensitivity than HPV testing in the diagnosis of high-grade cervical intraepithelial neoplasia (CIN2+). Despite normal cytology and colposcopy findings women with persistent HPV infection have an increased risk of CIN2+. The aim of the study was to evaluate the proportion of histologically confirmed CIN2+ in women with persistent HPV infection and normal Pap smears.
From April 2013 until March 2016 we prospectively recruited 91 women over 40 years with persistent HPV infection without any abnormalities in cytology. Of these, 40 women attended a gynecological examination including an HPV test, Pap smear, endocervical cytology, colposcopy with biopsies and diagnostic loop electrosurgical excision procedure (LEEP). Biopsy and LEEP samples were subjected to histological examination
CIN2+ was verified by histological examination of the LEEP sample in 6/40 (15%) of the women. All the cytological samples were normal and none of the biopsies confirmed CIN2+. Only 19/40 women still had a persistent HPV infection at the study visit. None of the 21/40 women who had cleared their HPV infection at the study visit had CIN2+ in histology of the LEEP sample.
A persistent HPV infection needs to be monitored despite normal Pap smears, since 6/40 (15%) women older than 40 years, was revealed to have an undiagnosed CIN2+ when LEEP was performed. Counseling women regarding the risk of cervical cancer and the expected effect of an eventual LEEP can help them to make an optimal informed choice.
Management of women with human papillomavirus persistence: long-term follow-up of a randomized clinical trial
2017, American Journal of Obstetrics and Gynecology
Citation Excerpt :
In the control arm, 111 women were selected at random for mock HPV testing and subsequent colposcopies to control for ascertainment bias (95 women attended). The results of the first study colposcopies have been published.13 Following the first study colposcopy, women who had not been treated for CIN2+ were invited for yearly repeat HPV tests.
Introduction of human papillomavirus–based screening is ongoing in many countries, given its higher sensitivity and longer-lasting protection compared with cytology-based screening. However, optimal clinical management of human papillomavirus–positive but cytology-negative women is unclear, and additional studies with clinical follow-up are warranted.
The aim of the current study was to investigate the long-term outcomes of the clinical management used in a double-blind, randomized clinical trial of human papillomavirus screening conducted in the context of the routine, organized screening program in Sweden.
Among 12,527 women aged 32–38 years enrolled in the trial, we followed up the 195 women who attended the colposcopy screening who were cytologically normal but persistently human papillomavirus positive (at least 12 months later; median, 19 months) in the human papillomavirus testing arm (n = 100) or were randomly selected from the control arm (n = 95). Women in the human papillomavirus testing arm were followed up with repeated human papillomavirus testing, cytologies, and colposcopies if persistently human papillomavirus–positive without cervical intraepithelial neoplasia grade 2 or worse. A similar number of random colposcopies and tests were carried out in the control arm. Women were followed up over 13 years for the main outcome measures: cumulative incidence of cervical intraepithelial neoplasia grade 2 or worse and cervical intraepithelial neoplasia grade 3 or worse.
Among women who continued to attend and had continuous human papillomavirus persistence, all (40 of 40, 100% [95% confidence interval, 91–100%]) developed cervical intraepithelial neoplasia grade 2 or worse. There were no cases among women who cleared their human papillomavirus persistence (0 of 35, 0% (95% confidence interval, 0–10%) (P < .001). Among women who had had human papillomavirus persistence but did not continue with repeated human papillomavirus tests (unknown persistence status), 56% (15 of 27 women) developed cervical intraepithelial neoplasia grade 2 or worse. Almost all cases occurred within 6 years. The intensive clinical management in the trial appeared to result in diagnoses of earlier cervical intraepithelial neoplasia grade 2 or worse but apparently did not prevent cervical intraepithelial neoplasia grade 2 or worse.
Women with human papillomavirus persistence will, in general, either become human papillomavirus negative or develop cervical intraepithelial neoplasia grade 2 or worse within 6 years, even with intensive clinical follow-up.
Three-year longitudinal data on the clinical performance of the Abbott RealTime High Risk HPV test in a cervical cancer screening setting
2016, Journal of Clinical Virology
Citation Excerpt :
Primary hrHPV-based cervical cancer screening is an important scientific and clinical advance because it offers better reassurance of low cancer risk compared to cytology-only cervical cancer screening conducted at the same interval [11]. The effectiveness and safety of HPV-based primary cervical cancer screening has been assessed in large-scale randomized clinical trials performed in several European countries, Canada, and India [12–25] and in screening cohorts with longitudinal follow-up data from Europe and the United States [26–39]. According to their results, hrHPV testing as a stand-alone test or in combination with cytology (co-testing) increases the sensitivity for detecting women with underlying cervical intraepithelial neoplasia (CIN) grade 2 or worse (CIN2+) and grade 3 or worse (CIN3+), provides better and longer protection against invasive cervical cancer, and reduces cervical cancer mortality compared to cytology testing alone [12,13,15,18,19,26,32,33,40,41].
Testing cervical smears for the presence of high-risk human papillomaviruses (hrHPV) increases the sensitivity for detecting women with underlying high-grade cervical intraepithelial neoplasia (CIN) and provides better and longer protection against invasive cervical cancer compared to cytology testing alone. The Abbott RealTime High Risk HPV test (RealTime) is a hrHPV DNA test with concurrent partial genotyping for HPV16 and HPV18 and aggregate detection of 12 other hrHPV types that have been extensively analytically and clinically evaluated over the last 6 years.
To provide the first 3-year longitudinal data regarding the clinical performance of RealTime, the risk of CIN2+ according to various negative baseline characteristics, and baseline and future risk for CIN2+ at 3 years for women with baseline infection with various hrHPV types were assessed in a cohort of 3,920 Slovenian women that had hrHPV DNA and/or cytology in 36- to 48-month follow-up results after a baseline screening round in 2009/2010.
A total of 36 CIN2+ cases were identified in the second screening round. Of these, 17 CIN2+ cases were identified passively through questionnaires/data registries and 19 cases actively as the result of actions triggered by second-round cytology and/or HPV test results. Accumulation of CIN2+ cases during follow-up occurred predominantly in woman with normal cytology at baseline. Among women >30 years old, significantly better protection against CIN2+ at 3 years was associated with a negative hrHPV DNA result at baseline (risk for CIN2+ 0.04% [95 CI, 0.00–0.22%]) than by normal cytology at baseline (risk for CIN2+ 0.68% [95 CI, 0.40–1.08%]). Women with baseline HPV16 infection had a significantly higher risk of CIN2+ at baseline (21.9% [95 CI, 15.2–30.4%]) and baseline plus future risk at 3 years for CIN2+ (33.3% [95 CI, 24.7–44.0%]) in comparison to women with baseline non-HPV16/18 hrHPV infection (7.0% [95 CI, 4.6–10.2%]) or those that were hrHPV-positive (11.7% [95 CI, 9.1–14.9%]).
3-year longitudinal data reinforce evidence from previous studies that RealTime can be safely used in primary HPV-based cervical cancer screening. Concurrent partial genotyping for HPV16/18 should be strongly considered as a triage method for HPV screen-positive women.
Projected Impact of HPV and LBC Primary Testing on Rates of Referral for Colposcopy in a Canadian Cervical Cancer Screening Program
2015, Journal of Obstetrics and Gynaecology Canada
To estimate the impact of implementing primary human papilloma virus liquid-based cytology (LBC) screening on four-year rates of referral for colposcopy in the British Columbia screening program.
We used data on referral for colposcopy from an RCT (HPV FOCAL) comparing HPV testing every four years with LBC testing every two years. We also used data from population screening with conventional cytology among women aged 25 to 69. The predicted effect of adoption of either trial protocol on rates of referral for colposcopy was estimated using trial age-specific result and screening result-specific rates weighted by their screening program distribution. The cumulative age-specific rates of referral for colposcopy over four years were calculated.
Use of HPV testing initially increased rates of referral for colposcopy in the trial, but over four years the cumulative rates of referral were similar to those for LBC except in women aged 25 to 29, in whom a substantial excess persisted. Four-year rates of referral for colposcopy declined with age in women screened with HPV testing, LBC, and conventional cytology. Extrapolating the trial results to the distribution in the provincial screening program, implementation of either HPV or LBC throughout the provincial population would approximately double the current rates of referral for colposcopy.
Compared with LBC screening, primary screening for HPV increased rates of referral for colposcopy only among women aged 25 to 29. In contrast to current practice, referral for colposcopy was largely driven by the trial protocol recommendations for the management of abnormal results and not by which screening test was used.
Estimer les effets de la mise en œuvre d’un dépistage primaire du virus du papillome humain par cytologie en milieu liquide (CML) sur les taux d’orientation en colposcopie sur quatre ans, dans le cadre du programme de dépistage de la Colombie-Britannique.
Nous avons utilisé les données sur l’orientation en colposcopie issues d’un ECR (HPV FOCAL) comparant le dépistage du VPH tous les quatre ans au dépistage par CML tous les deux ans. Nous avons également utilisé des données issues du dépistage populationnel par cytologie conventionnelle mené auprès des femmes de 25 à 69 ans. Le taux d’orientation en colposcopie en fonction de l’âge et le taux d’orientation en colposcopie en fonction des résultats de dépistage ont été pondérés en fonction de la distribution de leurs programmes de dépistage respectifs, ce qui a permis d’estimer l’effet populationnel prévu de l’adoption de l’un ou l’autre des protocoles d’essai en question sur les taux d’orientation en colposcopie. Les taux cumulatifs (en fonction de l’âge) de l’orientation en colposcopie sur quatre ans ont été calculés.
Le recours au dépistage du VPH a initialement mené à la hausse des taux d’orientation en colposcopie dans le cadre de l’essai; toutefois, sur quatre ans, les taux cumulatifs d’orientation ont été semblables à ceux de la CML, sauf chez les femmes de 25 à 29 ans (chez lesquelles un excès substantiel a persisté). Les taux d’orientation en colposcopie sur quatre ans ont connu une baisse en fonction de l’âge chez les femmes ayant fait l’objet d’un dépistage du VPH, d’une CML et d’une cytologie conventionnelle. En extrapolant les résultats de l’essai à la distribution qui existe au sein du programme provincial de dépistage, nous avons constaté que la mise en œuvre du dépistage du VPH ou de la CML au sein de la population provinciale mènerait au doublement approximatif des taux actuels d’orientation en colposcopie.
Par comparaison avec le dépistage par CML, le dépistage primaire du VPH n’a entraîné la hausse des taux d’orientation en colposcopie que chez les femmes de 25 à 29 ans. Contrairement à la pratique actuelle, l’orientation en colposcopie était largement motivée par les recommandations du protocole d’essai en ce qui concerne la prise en charge des résultats anormaux, et non par le test de dépistage utilisé.

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: Supported by grants from the Swedish Cancer Society, Europe Against Cancer, and the EU Biomed 5 project HPV-Based Cervical Cancer Screening.

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General Obstetrics and Gynecology: GynecologyColposcopic and histopathologic evaluation of women participating in population-based screening for human papillomavirus deoxyribonucleic acid persistence

Objective

Study design

Results

Conclusion

Section snippets

Study group

Results

Comment

Acknowledgments

Lancet

Am J Obstet Gynecol

Lancet

Estimates of the world incidence of 25 major cancers in 1990

Int J Cancer

Estimates of the worldwide mortality from 25 cancers in 1990

Int J Cancer

Papillomaviruses and cancer: from basic studies to clinical application

Natl Rev Cancer

Epidemiological evidence that human papillomavirus causes most cervical intraepithelial neoplasia

J Natl Cancer Inst

Epidemiologic classification of human papillomavirus types associated with cervical cancer

N Engl J Med

Lifetime number of partners as the only independent risk factor for human papillomavirus infection: a population-based study

Sex Transm Dis

Persistence of type-specific human papillomavirus infection among cytologically normal women

J Infect Dis

Human papillomavirus infection is transient in young women: a population-based cohort study

J Infect Dis

Natural history of cervicovaginal papillomavirus infection in young women

N Engl J Med

General Obstetrics and Gynecology: Gynecology
Colposcopic and histopathologic evaluation of women participating in population-based screening for human papillomavirus deoxyribonucleic acid persistence