F. J. van Kemenade

Human papillomavirus DNA testing for the detection of cervical intraepithelial neoplasia grade 3 and cancer: 5-year follow-up of a randomised controlled implementation trial.

BACKGROUND Tests for the DNA of high-risk types of human papillomavirus (HPV) have a higher sensitivity for cervical intraepithelial neoplasia grade 3 or worse (CIN3+) than does cytological testing, but the necessity of such testing in cervical screening has been debated. Our aim was to determine whether the effectiveness of cervical screening improves when HPV DNA testing is implemented. METHODS Women aged 29-56 years who were participating in the regular cervical screening programme in the Netherlands were randomly assigned to combined cytological and HPV DNA testing or to conventional cytological testing only. After 5 years, combined cytological and HPV DNA testing were done in both groups. The primary outcome measure was the number of CIN3+ lesions detected. Analyses were done by intention to treat. This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN20781131. FINDINGS 8575 women in the intervention group and 8580 in the control group were recruited, followed up for sufficient time (> or =6.5 years), and met eligibility criteria for our analyses. More CIN3+ lesions were detected at baseline in the intervention group than in the control group (68/8575 vs 40/8580, 70% increase, 95% CI 15-151; p=0.007). The number of CIN3+ lesions detected in the subsequent round was lower in the intervention group than in the control group (24/8413 vs 54/8456, 55% decrease, 95% CI 28-72; p=0.001). The number of CIN3+ lesions over the two rounds did not differ between groups. INTERPRETATION The implementation of HPV DNA testing in cervical screening leads to earlier detection of CIN3+ lesions. Earlier detection of such lesions could permit an extension of the screening interval.

HPV testing and monitoring of women after treatment of CIN 3: review of the literature and meta-analysis.

According to the current guidelines in most western countries, women treated for cervical intraepithelial neoplasia grade 3 (CIN 3) are followed for at least 2 years after treatment by cytology. High-risk human papillomavirus (hrHPV) infections are necessary for the development and maintenance of CIN 3. HrHPV testing could be used to improve monitoring of women treated for CIN 3. This has prompted numerous studies for the implementation of hrHPV testing in monitoring of women treated for CIN 3. Included in this review are 20 studies, published between 1996 and 2003, comparing hrHPV testing with either resection margins or cervical cytology to predict recurrent/residual disease, and 11 of them could be used in a meta-analysis. In the meta-analysis of the 11 studies, the negative predictive value (NPV) for recurrent/residual disease of hrHPV testing was 98% (95% CI 97–99%), that of resection margins 91% (95% CI 87–94%), and that of cervical cytology 93% (95% CI 90–95%). When hrHPV testing was performed in conjunction with cytology, the sensitivity was 96% (95% CI 89–99%), specificity was 81% (95% CI 77–84%), the associated positive predictive value (PPV) was 46% (95% CI 38–54%), and the NPV was 99% (95% CI 98–100%). Combined hrHPV and cytology testing yielded the best test characteristics. We propose to include hrHPV testing in conjunction with cytology for monitoring women treated for CIN 3. Some follow-up visits for women testing negative for both hrHPV and cytology can be skipped. In western countries, this could mean that for women double negative at 6 months, retesting at 12 months should be skipped while keeping the 24-month follow-up visit. Target Audience: Obstetricians & Gynecologists, Family Physicians Learning Objectives: After completion of this article, the reader should be able to describe the various types of HPV detection systems, to compare the various HPV detection methods against the currently available methods of monitoring, and to outline a potential post-treatment management plan for patients treated for HPV-associated cervical neoplasia.

The Dutch CISOE-A framework for cytology reporting increases efficacy of screening upon standardisation since 1996

Aim: To describe the effect of introducing the CISOE-A framework for reporting cervical cytology results, including changes in repeat and referral advice in the Netherlands, on the efficacy of the screening programme. Changes in the distribution of cytological results, the detection rate of cervical intraepithelial neoplasia (CIN) lesions, and the detection rate of squamous cervical carcinoma are reported. Methods: The results of all gynaecology cytological and histological examinations, as registered in the nationwide database for histopathology and cytopathology (PALGA) from 1990 to 2000, were retrieved from seven laboratories in the greater Amsterdam area. Results: After the introduction of the CISOE-A classification, cytological results with equivocal diagnoses decreased significantly from 11.3% to 2.6%, without an increase in the percentages of moderate dyskaryosis or worse. During the study period, the detection rate of histologically diagnosed high grade CIN lesions increased significantly from 4.1 to 6.4/1000 smears, whereas there was no change in the detection rates of low grade lesions or invasive cervical cancer. Conclusions: The introduction of the new CISOE-A classification system resulted in a substantial decrease of equivocal results and repeat recommendations, without a decrease in the detection rate of high grade lesions, making the screening programme more efficacious.

Preferential risk of HPV16 for squamous cell carcinoma and of HPV18 for adenocarcinoma of the cervix compared to women with normal cytology in The Netherlands

We present the type-distribution of high-risk human papillomavirus (HPV) types in women with normal cytology (n=1467), adenocarcinoma in situ (ACIS) (n=61), adenocarcinoma (n=70), and squamous cell carcinoma (SCC) (n=83). Cervical adenocarcinoma and ACIS were significantly more frequently associated with HPV18 (ORMH 15.0; 95% CI 8.6–26.1 and 21.8; 95% CI 11.9–39.8, respectively) than normal cytology. Human papillomavirus16 was only associated with adenocarcinoma and ACIS after exclusion of HPV18-positive cases (ORMH 6.6; 95% CI 2.8–16.0 and 9.4; 95% CI 2.8–31.2, respectively). For SCC, HPV16 prevalence was elevated (ORMH 7.0; 95% CI 3.9–12.4) compared to cases with normal cytology, and HPV18 prevalence was only increased after exclusion of HPV16-positive cases (ORMH 4.3; 95% CI 1.6–11.6). These results suggest that HPV18 is mainly a risk factor for the development of adenocarcinoma whereas HPV16 is associated with both SCC and adenocarcinoma.

High-risk HPV type-specific clearance rates in cervical screening

We assessed clearance rates of 14 high-risk human papillomavirus (hrHPV) types in hrHPV-positive women with normal cytology and borderline/mild dyskaryosis (BMD) in a population-based cervical screening cohort of 44 102 women. The 6-month hrHPV type-specific clearance rates, that is, clearance of the same type as detected at baseline, in women with normal and BMD smears were 43% (95% confidence interval (CI) 39–47) and 29% (95% CI 24–34), respectively. Corresponding 18-month clearance rates were markedly higher, namely 65% (95% CI 60–69) and 41% (95% CI 36–47), respectively. The lowest clearance rates in women with normal cytology were observed for HPV16, HPV18, HPV31, and HPV33. Significantly reduced 18-month clearance rates at a significance level of 1% were observed for HPV16 (49%, 95% CI 41–59) and HPV31 (50%, 95% CI 39–63) in women with normal cytology, and for HPV16 (19%, 95% CI 12–29) in women with BMD. Among women who did not clear hrHPV, women with HPV16 persistence displayed an increased detection rate of ⩾CIN3 (normal P<0.0001; BMD, P=0.005). The type-specific differences in clearance rates indicate the potential value of hrHPV genotyping in screening programs. Our data support close surveillance (i.e. referral directly, or within 6 months) of women with HPV16 and are inconclusive for surveillance of women with HPV18, HPV31, and HPV33. For the other hrHPV-positive women, it seems advisable to adopt a conservative management with a long waiting period, as hrHPV clearance is markedly higher after 18 months than after 6 months and the risk for ⩾CIN3 is low.

Clinical Validation of the cobas 4800 HPV Test for Cervical Screening Purposes

ABSTRACT This study shows that the clinical performance and reproducibility of the cobas 4800 HPV test for high-risk human papillomavirus (HPV) detection fulfill the criteria as formulated in international guidelines of HPV test requirements for cervical screening purposes. Accordingly, the cobas 4800 HPV test can be considered clinically validated for cervical screening.

HPV infection in women with and without cervical cancer in Conakry, Guinea

Background:Cervical cancer incidence in western Africa is among the highest in the world.Methods:To investigate human papillomavirus (HPV) infection in Guinea, we obtained cervical specimens from 831 women aged 18–64 years from the general population of the capital Conakry and from 77 locally diagnosed invasive cervical cancers (ICC). Human papillomavirus was detected using a GP5+/6+ PCR-based assay.Results:Among the general population, the prevalence of cervical abnormalities was 2.6% by visual inspection and 9.5% by liquid-based cytology. Fourteen of 15 high-grade squamous intraepithelial lesions were visual inspection-negative. Human papillomavirus prevalence was 50.8% (32.1% for high-risk types) and relatively constant across all age groups. Being single or reporting ⩾3 sexual partners was significantly associated with HPV positivity. HPV16 was the most common type, both among the general population (7.3%) and, notably in ICC (48.6%). HPV45 (18.6%) and HPV18 (14.3%), the next most common types in ICC, were also more common in ICC than in HPV-positive women with normal cytology from the general population.Conclusion:The heavy burden of HPV infection and severe cervical lesions in Guinean women calls for new effective interventions. Sixty-three per cent of cervical cancers are theoretically preventable by HPV16/18 vaccines in Guinea; perhaps more if some cross-protection exists with HPV45.

HPV DNA testing in population-based cervical screening (VUSA-Screen study): results and implications.

Background:Human papillomavirus (HPV) testing is more sensitive than cytology for detecting high-grade cervical intraepithelial neoplasia (CIN). We evaluated the performance of high-risk HPV (hrHPV) testing in routine screening.Methods:In all, 25 871 women (29–61) enrolled in our population-based cohort study were offered both cytology and hrHPV testing. High-risk HPV-positive women with normal cytology and an age-matched subcohort of hrHPV-negative women with normal cytology were invited for repeat testing after 1 and/or 2 years and were referred for colposcopy if they presented with abnormal cytology and/or a positive hrHPV test. The hrHPV-positive women with borderline or mild dyskaryosis (BMD) and all women with moderate dyskaryosis or worse (>BMD) were directly referred for colposcopy. Women with BMD and an hrHPV-negative test were advised to repeat cytology at 6 and 18 months and were referred for colposcopy if the repeat cytology test was abnormal. The main outcome measure was CIN grade 3 or worse (CIN3+). Results were adjusted for non-attendance at repeat testing.Results:The hrHPV-positive women with abnormal cytology had a CIN3+ risk of 42.2% (95% confidence interval (CI): 36.4–48.2), whereas the hrHPV-positive women with normal cytology had a much lower risk of 5.22% (95% CI: 3.72–7.91). In hrHPV-positive women with normal cytology, an additional cytology step after 1 year reduced the CIN3+ risk to only 1.6% (95% CI: 0.6–4.9) if the repeat test was normal. The CIN3+ risk in women with hrHPV-positive normal cytology was higher among women invited for the first time (29–33 years of age) (9.1%; 95% CI: 5.6–14.3) than among older women (3.0%; 95% CI: 1.5–5.5).Conclusion:Primary hrHPV screening with cytology triage in women aged ⩾30 years is an effective way to stratify women on CIN3+ risk and seems a feasible alternative to cytological screening. Repeat cytology after 1 year for hrHPV-positive women with normal cytology is however necessary before returning women to routine screening.

p16(INK4a) immunostaining as an alternative to histology review for reliable grading of cervical intraepithelial lesions

Background Histomorphological grading of cervical intraepithelial neoplasia (CIN) is crucial for clinical management. CIN grading is however subjective and affected by substantial rates of discordance among pathologists, which may lead to overtreatment. To minimise this problem, a histology review of CIN lesions by a consensus panel of pathologists is often used. Diffuse strong p16INK4a immunostaining has been proposed to aid the identification of true high-grade cervical lesions (ie, CIN2/3). Aim To assess the value of additional interpretation of p16INK4a immunostains for making a more reproducible diagnosis of CIN2/3 lesions. Methods The authors used a series of 406 biopsies of cervical lesions, with known HPV status, stained for both H&E- and p16INK4a. First, in a randomly selected set of 49 biopsies, we examined the effect of additional interpretation of p16INK4a immunostained slides, on the agreement of CIN diagnosis among three pathologists. Second, the full series of samples was used to assess the accuracy of p16INK4a-supported lesion grading by a single pathologist, by evaluating the degree of diagnostic agreement with the consensus diagnosis of expert pathologists based on H&E-stained sections only. Results The study shows that the interobserver agreement between three pathologists for the routine H&E-based diagnosis ranged from fair (weighted kappa 0.44 (95% CI 0.19 to 0.64)) to moderate (weighted kappa 0.66 (95% CI 0.47 to 0.79)). The concordance increased substantially for p16INK4a-supported grading (mean weighted kappa 0.80 (95% CI 0.66 to 0.89)). Furthermore, an almost perfect agreement was found between the p16INK4a-supported diagnosis of a single pathologist and the consensus diagnosis of an expert pathology panel (kappa 0.88 (95% CI 0.85 to 0.89)). Conclusions These data demonstrate that additive use of p16INK4a immunohistochemistry significantly improves the accuracy of grading CIN lesions by a single pathologist, equalling an expert consensus diagnosis. Hence, the authors advocate the combined use of p16INK4a-stained slides and conventional H&E sections in routine histopathology to improve accuracy of diagnosis.

Human papillomavirus infection in women with and without cervical cancer in Karachi, Pakistan.

Background:No data exist on the population prevalence of, or risk factors for, human papillomavirus (HPV) infection in predominantly Muslim countries in Asia.Methods:Cervical specimens were obtained from 899 married women aged 15–59 years from the general population of Karachi, Pakistan and from 91 locally diagnosed invasive cervical cancers (ICCs). HPV was detected using a GP5+/6+ PCR-based assay.Results:The prevalence of HPV in the general population was 2.8%, with no evidence of higher HPV prevalence in young women. The positivity of HPV was associated with womens lifetime number of sexual partners, but particularly with the age difference between spouses and other husbands’ characteristics, such as extramarital sexual relationships and regular absence from home. The HPV16/18 accounted for 24 and 88% of HPV-positive women in the general population and ICC, respectively.Conclusion:Cervical cancer prevention policies should take into account the low HPV prevalence and low acceptability of gynaecological examination in this population.