Positive Predictive Value For CIN2 Research Articles

Predictable changes in the accuracy of human papillomavirus tests after vaccination: review with implications for performance monitoring in cervical screening.

Vaccination against human papillomavirus (HPV) is changing the performance of cytology as a cervical screening test, but its effect on HPV testing is unclear. We review the effect of HPV16/18 vaccination on the epidemiology and the detection of HPV infections and high-grade cervical lesions (CIN2+) to evaluate the likely direction of changes in HPV test accuracy. The reduction in HPV16/18 infections and cross-protection against certain non-16/18 high-risk genotypes, most notably 31, 33, and/or 45, will likely increase the test's specificity but decrease its positive predictive value (PPV) for CIN2+. Post-vaccination viral unmasking of non-16/18 genotypes due to fewer HPV16 co-infections might reduce the specificity and the PPV for CIN2+. Post-vaccination clinical unmasking exposing a higher frequency of CIN2+ related to non-16/18 high-risk genotypes is likely to increase the specificity and the PPV of HPV tests. The effect of HPV16/18 vaccination on HPV test sensitivity is difficult to predict based on these changes alone. Programmes relying on HPV detection for primary screening should monitor the frequency of false-positive and false-negative tests in vaccinated (younger) vs. unvaccinated (older) cohorts, to assess the outcomes and performance of their service.

Performance of Human Gene EPB41L3 and HPV 16/18 Viral DNA Methylation to Triage hrHPV-Positive Women.

More evidence from population-based cohort studies is required to confirm the application of methylation-based biomarkers in real-world settings. The cross-sectional and 24-month cumulative triage performance of a novel methylation assay targeting the host gene EPB41LE and HPV16/18 DNA L1/L2 regions among hrHPV-positive women was evaluated based on a population-based cohort study from China. Overall methylation positivity was 12.4% among hrHPV-positive women. Methylation-positive women had significantly higher risks of hrHPV persistence at 12M and 24M follow-up (RR12M = 1.9, 95%CI: 1.5-2.6 and RR24M = 1.7, 95%CI: 1.2-2.5). For CIN2+, cross-sectional triage sensitivity of methylation was similar to HPV16/18 (70.6% vs. 64.7%, pexact = 1.000), but was lower than cytology (94.1%), although not significantly (pexact = 0.213). The specificity (91.2%) of methylation was significantly higher than other triage methods (p < 0.001 for all). The longitudinal sensitivity of methylation over 24M follow-up was 56.0%, lower (but not significantly so) than HPV16/18 (64.0%, pexact = 0.688) and cytology (76.0%, pexact = 0.125). Methylation testing showed high positive predictive values for CIN2+ (41.4% at baseline, 50.0% at 24-month), while the CIN2+ risk of methylation negative women (cNPV) remained considerable (2.5% at baseline, 6.9% at 24-month). Study findings indicate that methylation has better specificity and predictive values for the presence or development of cervical precancer and might therefore be considered for the strategy of HPV screening and methylation triage followed by immediate treatment of triage-positive women and delayed follow-up of hrHPV-positive/methylation-negative women.

Utilization of PAX1 methylation test for cervical cancer screening of non-HPV16/18 high-risk HPV infection in women.

Aim: To evaluate the clinical performance of PAX1 methylation (PAX1m) and cytology for patients with non-HPV16/18 high-risk HPV (hrHPV) infection. Methods: Cervical exfoliated cells from 387 outpatients with non-HPV16/18 hrHPV - positive were collected for cytology and PAX1m assays. Results: The PAX1m level increased with the severity of cytology and histopathology. For cervical intraepithelial neoplasia (CIN)CIN2+/CIN3+, the areas under the curve were both 0.87. The specificity and positive predictive value (PPV) of PAX1m were greater than abnormal cytology (CIN2+specificity: 75.5vs 24.8%; PPV: 38.8vs 18.7%; CIN3+specificity: 69.3vs 22.7%; PPV: 14.0vs 6.7%). Conclusion: PAX1m increased specificity and PPV for CIN2+/CIN3+ compared with cytology for women with non-HPV16/18hrHPV (+).

Cervical Cancer Screening with DNA-HPV Testing and Precancerous Lesions Detection: A Brazilian Population-based Demonstration Study.

To evaluate the rates of precancerous lesions, colposcopy referral, and positive predictive value (PPV) by age groups of a population-based screening with DNA-HPV testing. The present demonstration study compared 16,384 HPV tests performed in the first 30 months of the program with 19,992 women tested in the cytology screening. The colposcopy referral rate and PPV for CIN2+ and CIN3+ by age group and screening program were compared. The statistical analysis used the chi-squared test and odds ratio (OR) with 95% confidence interval (95%CI). The HPV tests were 3.26% positive for HPV16-HPV18 and 9.92% positive for 12 other HPVs with a 3.7 times higher colposcopy referral rate than the cytology program, which had 1.68% abnormalities. Human Papillomavirus testing detected 103 CIN2, 89 CIN3, and one AIS, compared with 24 CIN2 and 54 CIN3 detected by cytology (p < 0.0001). The age group between 25 and 29 years old screened by HPV testing had 2.4 to 3.0 times more positivity, 13.0% colposcopy referral, twice more than women aged 30 to 39 years old (7.7%; p < 0.0001), and detected 20 CIN3 and 3 early-stage cancer versus 9 CIN3 and no cancer by cytology screening (CIN3 OR= 2.10; 95%CI: 0.91-5.25; p = 0.043). The PPV of colposcopy for CIN2+ ranged from 29.5 to 41.0% in the HPV testing program. There was a significant increase in detections of cervix precancerous lesions in a short period of screening with HPV testing. In women < 30 years old, the HPV testing exhibited more positivity, high colposcopy referral rate, similar colposcopy PPV to older women, and more detection of HSIL and early-stage cervical cancer.

Age-specific outcomes from the first round of HPV screening in unvaccinated women: Observational study from the English cervical screening pilot.

To report detailed age-specific outcomes from the first round of an English pilot studying the implementation of high-risk human papillomavirus (HR-HPV) testing in primary cervical screening. Observational study with screening in 2013-2016, followed by two early recalls and/or colposcopy until the end of 2019. Six NHS laboratory sites. A total of 1341584 women undergoing screening with HR-HPV testing or liquid-based cytology (LBC). Early recall tests and colposcopies were recommended, depending on the nature of the screening-detected abnormality. We reported standard screening process indicators, e.g. proportions with an abnormality, including high-grade cervical intraepithelial neoplasia (CIN2+) or cancer, and the positive predictive value (PPV) of colposcopy for CIN2+, by screening test and age group. Among unvaccinated women screened with HR-HPV testing at age 24-29years, 26.9% had a positive test and 10.4% were directly referred to colposcopy following cytology triage, with a PPV for CIN2+ of 47%. At 50-64years of age, these proportions were much lower: 5.3%, 1.2% and 27%, respectively. The proportions of women testing positive for HR-HPV without cytological abnormalities, whose early recall HR-HPV tests returned negative results, were similar across the age spans: 54% at 24-29years and 55% at 50-64years. Two-thirds of infections at any age were linked to non-16/18 genotypes. Among women with CIN2, CIN3 or cervical cancer, however, the proportion of non-16/18 infections increased with age. As expected, the detection of abnormalities was lower following screening with LBC. These data provide a reliable reference for future epidemiological studies, including those concerning the effectiveness of HPV vaccination. Data from the English pilot study provide a comprehensive overview of abnormalities detected through HPV screening.

Lower accuracy of cytological screening for high-grade squamous intraepithelial neoplasia in women over 50\xa0years of age in Japan

BackgroundAs the population ages in developed countries, the number of Pap smears for cervical cancer screening of older women is increasing. There is concern that cervical atrophy may cause misinterpretation of results for this segment of the population. The present study evaluated the accuracy of screening for high-grade intraepithelial lesions (HSILs) in women younger or older than 50 years, to determine whether aging affects cytological interpretation.MethodsPatients with HSIL cytology (N = 1565) were dichotomized into those aged 20–49 years or aged ≥ 50 years. Association between histology results and age was examined. Pearson’s chi-squared test and Cochran-Armitage trend test were used for statistical analysis.ResultsThe positive predictive value (PPV) for cervical intraepithelial neoplasia (CIN)2 and worse was 65.2% (62/95) in older women but 87.3% (482/552) in younger women (p < 0.001). Older patients had a significantly lower PPV (p = 1.69 × 10–8). Separately analyzing chronic cervicitis, CIN1 and overt cancer grouped together, compared with another group composed of CIN2 and CIN3, we found that the PPV for CIN2 and CIN3 was lower in older than in younger women [44.2% (42/95)-vs-82.4% (455/552), p < 0.001], respectively.ConclusionsHSILs are associated with a wide range of disease categories as age increases, and the accuracy of HSIL interpretation is lower in older women.

Abstract 69: To Triage or Not? Positive Predictive Value of Visual Inspection with Acetic Acid for Diagnosis of Cervical Intraepithelial Neoplasia Grade 2 or Worse (CIN2+) among HIV-Positive Women in a Low-Resource Setting

Abstract Purpose: The World Health Organization (WHO) recommends human papillomavirus (HPV) as a primary screening test within "screen-and-treat" cervical cancer programs in low- and middle-income countries (LMICs). Following a positive test, two alternative strategies are endorsed within the single-visit approach. All HPV positive women can be offered immediate treatment, or visual inspection with acetic acid (VIA) is used to triage. Thus, we calculated the positive predictive value (PPV) of VIA for histologically confirmed CIN2+ among HPV-positive women living with HIV (WLWH). Methods: Between August 2019 and March 2020, as part of a clinical trial (NCT04191967) in western Kenya, high-risk HPV-positive WLWH age 25-65 years underwent VIA and colposcopy-directed biopsies regardless of VIA result. All women received treatment. The PPV of VIA for CIN2+ was determined. Results: Three hundred and sixty-six HPV-positive WLWH were evaluated during the study period. Mean age was 40.2 years (SD 8.5), median CD4 count was 420 (IQR 359), and 94.5% were virally suppressed. Seventy-four (20.2%) women had CIN2+ on histology (14 CIN2, 54 CIN3, six microinvasive carcinoma), of whom only 33 were also VIA-positive. The PPV of VIA for diagnosis of CIN2+ was 44.6% (95% CI 33.0 – 56.6) and was similar when limited to CIN3+. The PPV decreased with age, ranging from 72.7% (95% CI 54.5–86.7), to 24.2% (95% CI 11.1 – 42.3) to 3.0% (95% CI 0.1 – 15.8) among ages 30-39 years, 40-49 years, and 50 years and greater, respectively. Conclusions: While HPV testing has low specificity among WLWH, triage with VIA has a low positive predictive value for CIN2+ and would result in missed opportunities for treatment in this high-risk population. This highlights the need for more objective, affordable, and accessible triage tests, e.g. artificial intelligence-assisted cervicography or biomarkers of dysplasia to improve the PPV of the HPV-based screen-and-treat single-visit approach in LMICs. Citation Format: Chemtai Mungo, Cyrillus Ogollah, Jennifer Ambaka, Magdalene Randa, Jackton Omoto, Craig Cohen. To Triage or Not? Positive Predictive Value of Visual Inspection with Acetic Acid for Diagnosis of Cervical Intraepithelial Neoplasia Grade 2 or Worse (CIN2+) among HIV-Positive Women in a Low-Resource Setting [abstract]. In: Proceedings of the 9th Annual Symposium on Global Cancer Research; Global Cancer Research and Control: Looking Back and Charting a Path Forward; 2021 Mar 10-11. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2021;30(7 Suppl):Abstract nr 69.

4223 Changes in positive predictive value of cervical cytology following HPV vaccination

OBJECTIVES/GOALS: To determine if current U.S. HPV vaccination rates have decreased dysplasia prevalence enough to decrease the positive predictive value (PPV) of abnormal cervical cytology. METHODS/STUDY POPULATION: This retrospective cohort study comprised a chart review of all patients 21-35 years of age who had at least 1 Pap test result within MHealth/Fairview 2016-2018. HPV vaccination data, cervical cancer screening data and dysplasia results were abstracted. Vaccinated was defined as receiving at least 1 dose of HPV vaccine, with subgroup analyses performed for those completing vaccination per ACIP guidelines and by age of initiation dichotomized as 21+ years versus &lt;21 years. RESULTS/ANTICIPATED RESULTS: 49,764 patients meeting study criteria were identified. Among the entire study population, 10% had abnormal cytology results during the study period. Among the 4,928 patients with abnormal cytology, PPV for CIN2+ was lower among vaccinated individuals (13% vs. 18%; p &lt; 0.0001). Among vaccinated individuals, PPV was lower among those completing vaccination (12% vs. 16% for incomplete vaccination; p = 0.04) and among those initiating vaccination at &lt;21 years of age (9% vs 26% for 21+y; p &lt; 0.0001). DISCUSSION/SIGNIFICANCE OF IMPACT: Among a population with low HPV vaccine coverage, the decrease in dysplasia prevalence among vaccinated individuals is resulting in a subsequent decrease in PPV of cervical cytology, particularly in those initiating vaccination prior to 21 years of age and among those completing the series. Confirmation of these results will call for changes in screening strategies for vaccinated individuals. CONFLICT OF INTEREST DESCRIPTION: Acelity: Industry grant for an investigator-initiated industry-sponsored clinical trial. Tesaro: Site PI for industry-sponsored clinical trial. NOTE: Funding from the industries above are unrelated to the research presented in the abstract.

Comparative performance evaluation of different HPV tests and triaging strategies using self-samples and feasibility assessment of thermal ablation in 'colposcopy and treat' approach: A population-based study in rural China.

Human papillomavirus (HPV) test, self-sampling and thermal ablation for cervical intraepithelial neoplasia (CIN) have been developed separately to increase screening coverage and treatment compliance of cervical cancer screening programmes. A large-scale study in rural China screened 9,526 women with their combinations to explore the optimal cervical cancer-screening cascade in the real-world. Participants received careHPV and polymerase chain reaction (PCR) HPV tests on self-collected samples. Women positive on either HPV test underwent colposcopy, biopsy and thermal ablation in a single visit. Samples positive on either HPV test were retested for genotyping. Absolute and relative performance of HPV tests, triage strategies, 'colposcopy and thermal ablation' approach were statistically evaluated. PCR HPV test detected 33.3% more CIN grade two or worse (CIN2+) at a cost of 28.1% more colposcopies compared to careHPV. Sensitivities of PCR HPV and careHPV tests to detect CIN2+ were 96.7 and 72.5%. Specificities for the same disease outcome were 82.1 and 86.0%. Triaging HPV-positive women with HPV16/18 genotyping considerably improved the positive predictive value for CIN2+ (4.8-5.0 to 18.2-19.2%). Ninety-six women positive on HPV and having abnormal colposcopy were eligible for thermal ablation and all accepted same-day treatment, contributing to 64.6% being treated appropriately (CIN1+ on histopathology), which reached up to 84.8% among women positive on HPV 16/18 triage. No serious side-effects/complications were reported. The combination of PCR HPV test followed by HPV 16/18 triaging on self-collected samples and colposcopy of triage positive women followed by immediate thermal ablation might be the appropriate screening cascade for rural China.

Predictive Value of HPV Testing in Self-collected and Clinician-Collected Samples Compared with Cytology in Detecting High-grade Cervical Lesions.

Self-sampling has become an attractive proposition now that human papillomavirus (HPV) primary testing is being incorporated into cervical cancer screening programs worldwide. We compared predictive values of HPV testing based on self- and physician-collected samples, and cytology, in detecting high-grade cervical intraepithelial neoplasia (CIN). The Cervical And Self-Sample In Screening (CASSIS) study enrolled 1,217 women ages 16-70 years prior to scheduled colposcopies. Vaginal specimens were self-collected using the validated HerSwab device. Cervical specimens were collected by gynecologists. Specimens were tested for presence of high-risk HPV (hrHPV) by the Cobas 4800 HPV test. We estimated positive predictive values (PPV) and negative predictive values (NPV) and 95% confidence intervals (CI) for a subset of women (n = 700) who underwent cervical biopsy and cytology at the actual CASSIS visit. hrHPV was detected in 329 women (47%) with HerSwab and in 327 (46.7%) with physician sampling. Respective values for HPV16/18 were 119 (17%) and 121 (17.3%). On histology, 134 women had CIN1, 49 had CIN2, 48 had CIN3, 5 had CIN2/CIN3, and 3 had cancers. PPVs for CIN2+ of any hrHPV were 28% (95% CI, 23.2-33.1) and 29.7% (95% CI, 24.8-34.9) for HerSwab and physician samples, respectively. Corresponding values for HPV16/18 were 43.7% (95% CI, 34.6-53.1) and 43.8% (95% CI, 34.8-53.1). PPV of cytology (ASC-US+) was 26.6% (95% CI, 21.6-32.0). Corresponding NPVs (same order as PPVs) were 96.4% (95% CI, 93.9-98.1), 97.8% (95% CI, 95.6-99), 90.9% (95% CI, 88.2-93.1), 91% (95% CI, 88.4-93.2), and 94.7% (95% CI, 91.8-96.8). Our results confirm that HPV self-sampling has comparable performance with a physician-collected sample in detecting cervical lesions. HPV self-sampling has the potential to increase coverage in cervical cancer screening.

Cervical cancer screening using the Cervista high-risk human papillomavirus test: opportunistic screening of a hospital-based population in Fujian province, China.

ObjectivesThe Cervista® high-risk human papillomavirus (HR-HPV) test was evaluated as a primary screening method for cervical cancer in women aged ≥21 years and was compared with different screening and triage combinations.Materials and methodsA nested case–control study within the Fujian provincial Cervical Lesion Screening Cohorts was used to evaluate the Cervista test as the primary cervical screening method in a hospital-based population. Strategy 1 primarily screened using a cytology screen with HR-HPV testing used for triage. Strategy 2 primarily screened using cytology and HR-HPV co-testing. Strategy 3 primarily screened using HR-HPV testing and triaged HPV-positive women based on cytology. Strategy 4 primarily screened using HR-HPV testing and referred A9 pool HPV-positive women to colposcopy directly, whereas non-A9 HPV-positive women were triaged using cytology.ResultsThere were 10,183 women included in this study; 16.49% (1677/10,183) were HR-HPV-positive, 9.52% had abnormal cytology, and 9907 women were normal during followup. A total of 276 women were diagnosed with cervical intraepithelial neoplasia 2 or worse (CIN2+), 197 with CIN3 or worse (CIN3+), and 70 with cervical cancer. Moreover, 10.15% (20/197) women who were CIN3+ were identified as cytology-negative, while 8.63% (17/197) were HR-HPV negative (P>0.05). The cumulative risk rate for HPV–/cytology– was 0.836 (95% CI, 0.424–1.648) in CIN3+ cases. Strategy 4 yielded the highest sensitivity for CIN2+ or CIN3+ and the lowest positive predictive value for CIN2+ or CIN3+ among the four screening strategies.ConclusionThe Cervista HR-HPV test can provide a reliable and sensitive clinical reference for the cervical cancer primary screen.

Randomised healthcare policy evaluation of organised primary human papillomavirus screening of women aged 56–60

ObjectiveThe aim of this research is to implement and reliably evaluate primary human papillomavirus (HPV) screening in an established and routinely running organised, large-scale population-based screening programme.ParticipantsResident women in the...

Prospective evaluation of p16/Ki-67 dual-stained cytology for managing women with abnormal Papanicolaou cytology: PALMS study results.

Testing for the presence of the human papillomavirus (HPV) is widely accepted for triaging Papanicolaou cytology results categorized as atypical squamous cells of undetermined significance (ASC-US). In contrast, HPV testing has limited use in triaging cytological low-grade squamous intraepithelial lesions (LSILs) due to prevalence rates of typically >80%. In the current study, the authors assessed the diagnostic performance of p16/Ki-67 dual-stained cytology in triaging ASC-US and LSIL cases within the prospective, multicentric Primary ASC-US LSIL Marker Study (PALMS). A total of 575 ASC-US cases and 529 LSIL cases from a cohort of 27,349 women who were prospectively enrolled into the PALMS study in 5 European countries were tested with p16/Ki-67 dual-stained cytology and Hybrid Capture 2 (HC2) HPV testing. Colposcopy-guided biopsy results of cervical intraepithelial neoplasia of grade 2 or worse (CIN2+) were used as clinical endpoints. p16/Ki-67 dual-stained cytology demonstrated comparable (ASC-US: 94.4% for dual-stained cytology vs 100% for HC2 testing; P = .317) or lower (LSIL: 85.7% for dual-stained cytology vs 98.4% for HC2 testing; P = .005) sensitivity for CIN2+, but higher levels of specificity compared with HC2 HPV testing in both ASC-US (78.7% vs 60.4%; P<.001) and LSIL (53.3% vs 15.6%; P<.001) cases. Positive predictive values for CIN2+ were substantially higher for dual-stained cytology versus HC2 HPV testing, especially in LSIL, and in ASC-US cases for women aged <30 years. The clinical usefulness and efficiency of triaging women with ASC-US or LSIL Papanicolaou cytology results by p16/Ki-67 dual-stained cytology testing has been confirmed in this prospective, pan-European study. The high positive predictive value of dual-stained cytology for the presence of high-grade CIN may help to reduce the number of unnecessary colposcopy referrals.

Performance of Siriraj Liquid-Based Cytology: a Single Center Report Concerning over 100,000 Samples

To evaluate the performance of Siriraj liquid-based cytology (LBC) for cervical neoplasia screening after increasing use of this technology. Cytological reports of 103,057 Siriraj-LBC specimens obtained in 2007-2009 were compared with those of 23,676 specimens obtained in 2006. Comparing with the year 2006, the 2007-2009 patients were slightly older (43.4 ± 12.yr vs 42.7 ± 12.2 yr, p <0.001), and their specimens had much lower proportion of unsatisfactory slides (OR=0.06, 95%CI 0.04-0.09) with comparable detection rates (3.96% vs 3.70%, p=0.052) but different proportions of various cytological abnormalities (p<0.001). The 2007-2009 Siriraj-LBC had a negative predictive value (NPV) for cervical intraepithelial neoplasia 2+ (CIN2+) of 97.6% and an overall positive predictive value (PPV) of 43.9%. The PPV for CIN2+ varied with types of abnormal cytology, from 13.7% to 93.8% in atypical squamous cells of undetermined significance (ASCUS), low-grade squamous intraepithelial lesion (LSIL), atypical squamous cells cannot exclude HSIL (ASC-H), high-grade squamous intraepithelial lesion (HSIL), atypical glandular cells (AGC), to squamous cell carcinoma (SCC), respectively. The PPVs for CIN2+ in ASCUS and LSIL were comparable, but the PPV for CIN1 was higher for LSIL than for ASCUS (41.63% vs 16.32%). Siriraj-LBC has demonstrated a stable detection rate and NPV for CIN2+ of >95% since the first year of use. The comparable PPVs for CIN2+ of ASCUS and LSIL suggests that these two conditions may undergo similar management; other cytological abnormalities need immediate evaluation.

HPV DNAtesting improvesCIN2+ risk stratification and detection ofCIN2+ in delayed triage ofASCUSandLSIL. A population‐based follow‐up study fromWesternNorway

In Norway, Pap smears with atypical squamous cells of uncertain significance (ASCUS) and low-grade squamous intraepithelial lesions (LSIL) are triaged after 6 months. The aim of the study was to evaluate effects of implementing human papillomavirus (HPV) test (2005) in delayed triage of ASCUS and LSIL in a cohort of women from Western Norway. After a survey of 119,469 cervical Pap smears during 2005–2007, a total of 1055 women with an index ASCUS or LSIL were included in the study and followed up for 3–6 years with respect to progression into cervical intraepithelial neoplasia grade 2 or worse (CIN2+). Overall sensitivity for detection of CIN2+ with HPV testing and cytology was 96% and 72%, respectively. The sensitivity for detection of CIN2+ was not affected by age, but the specificity of the HPV test increased with age. Thus, for the age groups <34 years, 34–50 years, and >50 years, the specificity of a positive HPV test to detect CIN2+ was 47%, 71%, and 82%, respectively. Positive predictive values for CIN2+ in women with positive cytology, positive HPV test, negative cytology, negative HPV test, or negative HPV and cytology tests were 52%, 41%, 8%, 1.5%, and 0.4%, respectively. HPV testing resulted in a net 22% increased detection of CIN2+. Fifty-six percent of CIN2+ was detected at an earlier time point with HPV testing in triage. Implementation of HPV testing in delayed triage of ASCUS and LSIL improved the stratification of CIN2+ risk and increased CIN2+ detection and at an earlier time point than with triage by cytology alone.

Is a liquid‐based cytology more sensitive than a conventional Pap smear?

The comparative sensitivity of liquid-based cytology (LBC) test and conventional Papanicolaou (Pap) smears is controversial. This study analyses the distribution of cytology, histology, colposcopy and large loop excision of the transformation zone among women screened in Iceland with LBC at the Cancer Detection Clinic in Reykjavik and with a conventional Pap smear outside the Detection Clinic in 2007-2011. The study material included 42 654 LBC tests from 20 439 women and 103 909 Pap smears from 61 574 women. The period 2000-2004 is used to correct for potential bias as a result of unequal distribution of the studied parameters between the study sites before the introduction of LBC. The observed results indicated that women screened with an LBC sample had significantly decreased detection rates of inadequate smears, increased detection of low-grade squamous intraepithelial lesion (LSIL)/atypical cytology and referrals to colposcopy, and an increased detection rate of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) irrespective of age. LBC increased significantly the detection rates of high-grade squamous intraepithelial lesion or worse (HSIL+) cytology and CIN3+ histology only in women under 40 years of age. Taking into consideration the unequal prevalence of the studied parameters between the study sites in 2000-2004 indicated, however, that LBC only affected the rate of inadequate and low-grade cytology tests under the age of 40 years. Positive predictive values for CIN2+ were not significantly different between the tests. The study results support the view that LBC is no more sensitive than Pap smears for the detection of HSIL+ and CIN2+ irrespective of age. LBC decreased the rate of inadequate smears, but increased the rate of low-grade cytology under the age of 40 years and decreased the total rate of abnormal smears over the age of 40 years.

Use of the ThinPrep Imaging System for internal quality control of cervical cytology

To audit the use of the ThinPrep Imaging System (TIS) for internal quality control (IQC) in the place of rapid review (RR), and to compare its performance with routine primary screening. During 9 months, 16 462 ThinPrep slides were processed by TIS. Slides were initially reviewed using the TIS review scope, as recommended by the manufacturer: 22 fields of view were observed and, if considered abnormal, a full microscopic review was conducted using the review scope. Different biomedical scientists (BMSs), working on each procedure in rotation, performed batches of TIS-assisted quality control and routine primary screening independently on unmarked slides. Any slides with abnormalities detected by either method were referred to a consultant pathologist or advanced BMS practitioner for a final report. TIS results were compared with both previous records of RR and routine primary screening carried out on the same slides. We used the UK terminology in which 'dyskaryosis' is equivalent to squamous intraepithelial lesion (SIL) and borderline to atypical (including squamous and glandular cells). TIS preview detected significantly more high-grade dyskaryosis compared with RR during the previous 4 years: 2.0-4.2 compared with 0.1-1.8 detected per 1000 slides (P = 0.0001). TIS and routine screening were equivalent in sensitivity and specificity for the final cytology result, but BMSs were significantly more likely to classify slides as dyskaryotic rather than borderline when using TIS compared with routine screening. Referrals for potentially high-grade abnormalities detected by TIS-assisted IQC alone found 28 biopsies of at least cervical intraepithelial neoplasia grade 2 (CIN2+), whereas 15 CIN2+ biopsies were found on routine screening but missed using TIS. There was no significant change in the rates of inadequate tests, high- or low-grade cytological abnormalities, or positive predictive value for CIN2+ when TIS was in use. Screening with TIS was more sensitive than RR for IQC, providing a rescreening method equivalent to routine primary screening in overall accuracy.

Human papillomavirus testing for triage of women with low‐grade squamous intraepithelial lesions

Low-grade squamous intraepithelial lesion (LSIL) is a common cytologic finding in cervical screening, yet only about 10-20% have significant histologic abnormalities and these are almost always positive for high-risk human papillomavirus (hrHPV). This analysis aims to clarify the role of hrHPV DNA testing in the triage of women with LSIL cytology. In the ATHENA screening trial, we examined 1,084 cases of LSIL, of which 925 had an evaluable biopsy, to determine the extent to which hrHPV testing can identify those patients who have precursor lesions in need of immediate clinical referral and those who have changes more likely to regress spontaneously. Overall, 71.2% of LSIL cases were hrHPV positive, but the prevalence was age dependent, with only 56.1% in women ≥ 40 years. Among women with LSIL, 11.6% (107/925) had a cervical intraepithelial neoplasia grade 2 or worse (CIN2+) histologic diagnosis and, of these, only nine were hrHPV negative. For CIN3+, 91.7% (44/48) of women with LSIL were hrHPV positive. The negative predictive value of hrHPV testing for CIN3+ in LSIL was 100% for women aged ≥ 40 years. Women who were HPV16 positive had a higher positive predictive value for CIN2+ (25.4%) than those who were positive for 12 other pooled hrHPV types (11.5%). Testing for hrHPV in women with LSIL is effective in identifying high-grade cervical lesions, thereby avoiding unnecessary referrals to colposcopy and potential over-treatment of non-progressive lesions, especially for women aged ≥ 40 years.

Human papilloma virus testing in patient follow-up post cone biopsy due to high-grade cervical intraepithelial neoplasia

Objectives We evaluated the contribution of the human papilloma virus (HPV) load in planning follow-up and management of women post cone biopsy for high-grade cervical intraepithelial neoplasia (CIN2–3). Methods Ninety-six suitable women were followed-up by Pap smears: two consecutive abnormal smears dictated referral for colposcopy-directed biopsy. Before colposcopy, HPV tests determined high-risk HPV DNA type and load (Hybrid Capture System type I). Patients histologically diagnosed with CIN1 or CIN2–3 underwent repeat conization or hysterectomy for residual disease. HPV load was compared to cytology for the detection of residual disease. Results At follow-up, 20/89 (22.4%) studied women had positive cytology reports of either low- ( n = 11) or high-grade ( n = 9) squamous intraepithelial lesion (SIL). Colposcopic biopsies diagnosed 9 CIN1 and 8 CIN2–3 cases. Residual disease was corroborated in 16/17 (94.1%) women and the status was readjusted based on cone biopsy/hysterectomy: CIN2–3 in 9 and CIN1 in 7. The positive prediction values for CIN2–3 residual disease with high-grade SIL, CIN2–3 on colposcopic punch biopsy, and high HPV load were 89, 100, and 100%, respectively. For CIN1 residual disease with low-grade SIL, CIN1 on colposcopic punch biopsy, and low and borderline HPV load, they were 54.5, 77.7, and 100%. The HPV load was a more accurate predictor for CIN1 or CIN2–3 on the cervical specimen in cases with low-grade SIL or CIN1 on colposcopic biopsy. Conclusions Evaluating HPV loads after a positive cytology report may assist in triaging women post conization biopsy for CIN2–3 to appropriate treatment. Its high positive predictive value, specificity, and sensitivity for CIN1 and CIN2–3 and supplementary information could be especially pertinent for clinical management of low-grade SIL cases.