Calendar-period trends in cervical precancer and cancer diagnoses since the introduction of human papillomavirus and cytology co-testing into routine cervical cancer screening at Kaiser Permanente Northern California.

OBJECTIVES: The longer-term impact of introducing human papillomavirus (HPV) testing into routine cervical cancer screening on precancer and cancer rates by histologic type has not been well described. Calendar trends in diagnoses were examined using data from Kaiser Permanente Northern California, which introduced triennial HPV and cytology co-testing in 2003 for women aged ≥30 years. METHODS: We examined trends in cervical precancer (cervical intraepithelial neoplasia grade 3 [CIN3] and adenocarcinoma in situ [AIS]) and cancer (squamous cell carcinoma [SCC] and adenocarcinoma [ADC]) diagnoses per 1000 screened during 2003-2018. We examined ratios of squamous vs. glandular diagnoses (SCC:ADC and CIN3:AIS). RESULTS: CIN3 and AIS diagnoses increased approximately 2% and 3% annually, respectively (ptrend < 0.001 for both). While SCC diagnoses decreased by 5% per annually (ptrend < 0.001), ADC diagnoses did not change. These patterns were generally observed within each age group (30-39, 40-49, and 50-64 years). ADC diagnoses per 1000 screened did not change even among those who underwent co-testing starting in 2003-2006. SCC:ADC decreased from approximately 2.5:1 in 2003-2006 to 1.3:1 in 2015-2018 while the CIN3:AIS remained relatively constant, ∼10:1. CONCLUSIONS: Since its introduction at KPNC, co-testing increased the detection of CIN3 over time, which likely caused a subsequent reduction of SCC. However, there has been no observed decrease in ADC. One possible explanation for lack of effectiveness against ADC is the underdiagnosis of AIS. Novel strategies to identify and treat women at high risk of ADC need to be developed and clinically validated.

Impact of HPV testing in opportunistic cervical screening: Support for primary HPV screening in the United States.

Human papillomavirus (HPV) testing for cervical screening increases diagnosis of precancer and reduces the incidence of cervical cancer more than cytology alone. However, real-world evidence from diverse practice settings is lacking for the United States (U.S.) to support clinician adoption of primary HPV screening. Using a population-based registry, which captures all cervical cytology (with or without HPV testing) and all cervical biopsies, we conducted a real-world evidence study of screening in women aged 30 to 64 years across the entire state of New Mexico. Negative cytology was used to distinguish cotests from reflex HPV tests. A total of 264 198 cervical screening tests (with exclusions based on clinical history) were recorded as the first screening test between 2014 and 2017. Diagnoses of cervical intraepithelial neoplasia grades 2 or 3 or greater (CIN2+, CIN3+) from 2014 to 2019 were the main outcomes. Of cytology-negative screens, 165 595 (67.1%) were cotests and 4.8% of these led to biopsy within 2 years vs 3.2% in the cytology-only group. Among cytology-negative, HPV tested women, 347 of 398 (87.2%) CIN2+ cases were diagnosed in HPV-positive women, as were 147 of 164 (89.6%) CIN3+ cases. Only 29/921 (3.2%) CIN3+ and 67/1964 (3.4%) CIN2+ cases were diagnosed in HPV-negative, cytology-positive women with biopsies. Under U.S. opportunistic screening, across a diversity of health care delivery practices, and in a population suffering multiple disparities, we show adding HPV testing to cytology substantially increased the yield of CIN2+ and CIN3+. CIN3+ was rarely diagnosed in HPV-negative women with abnormal cytology, supporting U.S. primary HPV-only screening.

Uptake of co-testing with HPV and cytology for cervical screening: A population-based evaluation in the United States.

OBJECTIVES: Human papillomavirus (HPV) testing for cervical screening has been shown to increase the yield of precancerous disease and reduce the incidence of cervical cancer more than cytology alone. Here we document the state-wide uptake of co-testing with HPV and cytology in women aged 30-64 years as recommended by national and international bodies. METHODS: Registry-based study of all screening cytology and HPV tests in New Mexico from 2008 to 2019 among women aged 21-64 years, with a focus on cytology negative tests to distinguish co-testing from reflex HPV testing to triage equivocal or mildly abnormal cytology. RESULTS: A total of 1,704,055 cervical screening tests from 681,440 women aged 21-64 years in the state of New Mexico were identified. The proportion of screening tests which were co-tests rose from 5.6% in 2008 to 84.3% in 2019 among women aged 30-64 years with a marked change from the near exclusive use of the Hybrid Capture II HPV test, (a signal amplified test method) to the use of target amplified HPV tests. The largest increases were seen between 2013 and 2015, reflecting the introduction and adoption of new clinical guidelines. Increases in co-testing were also seen in younger women. CONCLUSIONS: Co-testing is now well established in women aged 30-64 years, but smaller increases have also been seen at younger ages, although this is not currently recommended. The impact of co-testing on cervical disease outcomes and number of colposcopies and biopsies in routine population settings remain important, especially in young women.

A study of the risks of CIN3+ detection after multiple rounds of HPV testing: Results of the 15-year cervical cancer screening experience at Kaiser Permanente Northern California.

Many countries are transitioning to HPV testing for cervical cancer screening, despite a lack of long-term experience. To anticipate multi-round screening performance, we analyzed 15-year HPV testing results at Kaiser Permanente Northern California (KPNC). We evaluated HPV test result patterns among women aged 30-64 undergoing triennial HPV/cytology cotesting at KPNC during 2003-2018. We calculated incidence rates and proportion of CIN3+ diagnoses associated with the most frequent HPV testing patterns overall and stratified by age. From 2003 to 2018, a total of 1,361,581 women had a valid HPV test result, and 7,087 were diagnosed with CIN3+. Incidence rates of CIN3+ after HPV positivity were lowest when HPV detection was new and highest in women with prevalent infections (770 vs. 13,910/100,000 person-years). Repeat test negativity reduced subsequent incidence rates of CIN3+ to extremely low levels (18/100,000 person-years following four consecutive negative results). For mixed patterns of positivity/negativity, the recency and frequency of positive tests were associated with increased rates of CIN3+ diagnosis. Most CIN3+ cases (76%) were diagnosed in women who were positive at baseline (the first known positive HPV result); 16% were attributed to apparent newly detected infections and 3% to possible reappearing infections. These results corroborate previous findings that current HPV positivity, particularly when prevalent rather than new, is associated with the highest rates of CIN3+. In a screening program implementing HPV testing, most CIN3+ is detected at the first HPV positive test.

Absolute risks of cervical precancer among women who fulfill exiting guidelines based on HPV and cytology cotesting.

US guidelines recommend that most women older than 65 years cease cervical screening after two consecutive negative cotests (concurrent HPV and cytology tests) in the previous 10 years, with one in the last 5 years. However, this recommendation was based on expert opinion and modeling rather than empirical data on cancer risk. We therefore estimated the 5-year risks of cervical precancer (cervical intraepithelial neoplasia grade 3 or adenocarcinoma in situ [CIN3]) after one, two and three negative cotests among 346,760 women aged 55-64 years undergoing routine cotesting at Kaiser Permanente Northern California (2003-2015). Women with a history of excisional treatment or CIN2+ were excluded. No woman with one or more negative cotests was diagnosed with cancer during follow-up. Five-year risks of CIN3 after one, two, and three consecutive negative cotests were 0.034% (95% CI: 0.023%-0.046%), 0.041% (95% CI: 0.007%-0.076%) and 0.016% (95% CI: 0.000%-0.052%), respectively (ptrend < 0.001). These risks did not appreciably differ by a positive cotest result prior to the one, two or three negative cotest(s). Since CIN3 risks after one or more negative cotests were significantly below a proposed 0.12% CIN3+ risk threshold for a 5-year screening interval, a longer screening interval in these women is justified. However, the choice of how many negative cotests provide sufficient safety against invasive cancer over a woman's remaining life represents a value judgment based on the harms versus benefits of continued screening. Ideally, this guideline should be informed by longer-term follow-up given that exiting is a long-term decision.

Risk Estimates Supporting the 2019 ASCCP Risk-Based Management Consensus Guidelines.

The 2019 American Society for Colposcopy and Cervical Pathology Risk-Based Management Consensus Guidelines for the management of cervical cancer screening abnormalities recommend 1 of 6 clinical actions (treatment, optional treatment or colposcopy/biopsy, colposcopy/biopsy, 1-year surveillance, 3-year surveillance, 5-year return to regular screening) based on the risk of cervical intraepithelial neoplasia grade 3, adenocarcinoma in situ, or cancer (CIN 3+) for the many different combinations of current and recent past screening results. This article supports the main guidelines presentation by presenting and explaining the risk estimates that supported the guidelines. METHODS: From 2003 to 2017 at Kaiser Permanente Northern California (KPNC), 1.5 million individuals aged 25 to 65 years were screened with human papillomavirus (HPV) and cytology cotesting scheduled every 3 years. We estimated immediate and 5-year risks of CIN 3+ for combinations of current test results paired with history of screening test and colposcopy/biopsy results. RESULTS: Risk tables are presented for different clinical scenarios. Examples of important results are highlighted; for example, the risk posed by most current abnormalities is greatly reduced if the prior screening round was HPV-negative. The immediate and 5-year risks of CIN 3+ used to decide clinical management are shown. CONCLUSIONS: The new risk-based guidelines present recommendations for the management of abnormal screening test and histology results; the key risk estimates supporting guidelines are presented in this article. Comprehensive risk estimates are freely available online at https://CervixCa.nlm.nih.gov/RiskTables.

Impact of human papillomavirus vaccination on the clinical meaning of cervical screening results.

Women previously vaccinated against human papillomavirus (HPV) type 16 and 18 are now reaching the age (21 years) at which cervical-cancer screening is recommended in the U.S. The impact of HPV vaccination on risks of cervical precancer following a positive and negative screen among women aged 21-24 years who just started routine cervical screening are not well described. Therefore, three-year absolute and relative (RR) cumulative risks of cervical intraepithelial neoplasia grade 2 or more severe diagnoses (≥CIN2) and grade 3 or more severe diagnoses (≥CIN3) were estimated for women undergoing cervical screening at Kaiser Permanente Northern California. Risks were estimated in women aged 21-24 years (n = 75,008) undergoing cervical screening since late 2006, 6 months after HPV vaccination became available; women were categorized vaccinated at ages <18, 18-20, and 21-24 years and compared to those who were unvaccinated. Three-year risks were estimated for normal, low-grade, and high-grade cytology results. Three-year risks of ≥CIN2 and ≥CIN3 for unvaccinated women following low-grade cytology were 10.89% for and 3.70%, respectively. By comparison, Three-year risks of ≥CIN2 and ≥CIN3 were 5.26% (RR = 0.48, 95%CI = 0.24-0.99) and 0.99% (RR = 0.27, 95%CI = 0.06-1.13), respectively, for women vaccinated under the age of 18 years. Three-year ≥CIN2 and ≥CIN3 risks were lower for those HPV vaccinated at younger age for any screening result (ptrend ≤ 0.01 for all comparisons). These data support initiating cervical screening at an older age or changing the management of a low-grade cytology result in women aged 21-24 years who were vaccinated against HPV younger than age of 18 years.

Effect of Several Negative Rounds of Human Papillomavirus and Cytology Co-testing on Safety Against Cervical Cancer: An Observational Cohort Study.

Background: Current U.S. cervical cancer screening and management guidelines do not consider previous screening history, because data on multiple-round human papillomavirus (HPV) and cytology "co-testing" have been unavailable. Objective: To measure cervical cancer risk in routine practice after successive negative screening co-tests at 3-year intervals. Design: Observational cohort study. Setting: Integrated health care system (Kaiser Permanente Northern California, Oakland, California). Patients: 990 013 women who had 1 or more co-tests from 2003 to 2014. Measurements: 3- and 5-year cumulative detection of (risk for) cervical intraepithelial neoplasia grade 3, adenocarcinoma in situ, and cervical cancer (≥CIN3) in women with different numbers of negative co-tests, overall and within subgroups defined by previous co-test results or baseline age. Results: Five-year ≥CIN3 risks decreased after each successive negative co-test screening round (0.098%, 0.052%, and 0.035%). Five-year ≥CIN3 risks for an HPV-negative co-test, regardless of the cytology result, nearly matched the performance (reassurance) of a negative co-test for each successive round of screening (0.114%, 0.061%, and 0.041%). By comparison, ≥CIN3 risks for the cytology-negative co-test, regardless of the HPV result, also decreased with each successive round, but 3-year risks were as high as 5-year risks after an HPV-negative co-test (0.199%, 0.065%, and 0.043%). No interval cervical cancer cases were diagnosed after the second negative co-test. Independently, ≥CIN3 risks decreased with age. Length of previous screening interval did not influence future ≥CIN3 risks. Limitation: Interval-censored observational data. Conclusion: After 1 or more negative cervical co-tests (or HPV tests), longer screening intervals (every 5 years or more) might be feasible and safe. Primary Funding Source: National Cancer Institute Intramural Research Program.

Adherence patterns to extended cervical screening intervals in women undergoing human papillomavirus (HPV) and cytology cotesting.

Although guidelines have recommended extended interval cervical screening using concurrent human papillomavirus (HPV) and cytology ("cotesting") for over a decade, little is known about its adoption into routine care. Using longitudinal medical record data (2003-2015) from Kaiser Permanente Northern California (KPNC), which adopted triennial cotesting in 2003, we examined adherence to extended interval screening. We analyzed predictors of screening intervals among 491,588 women undergoing routine screening, categorizing interval length into early (<2.5years), adherent (2.5<3.5years), or late (3.5<6.0years). We also examined repeated early screening in a subgroup of 50,691 women. Predictors examined included: cohort year (defined by baseline cotest, 2003-2009), race/ethnicity, and baseline age. Compared to the 2003 cohort, women in the 2009 cohort were significantly less likely to screen early (aOR=0.22, 95% CI=0.21, 0.23) or late (aOR=0.47, 95% CI=0.45, 0.49). African American (AA) and Hispanic women were less adherent overall than Non-Hispanic White women, with increased early [(AA: aOR=1.21, 95%CI=1.17, 1.25) (Hispanic: aOR=1.08, 95%CI=1.06, 1.11)] and late screening [(AA: aOR=1.23, 95%CI=1.19, 1.27) (Hispanic: aOR=1.06, 95%CI=1.03, 1.08)]. Asian women were slightly more likely to screen early (aOR=1.03, 95%CI=1.01, 1.05), and less likely to screen late (aOR=0.92, 95% CI=0.90, 0.94). Women aged 60-64years were most likely to screen early for two consecutive intervals (aOR=2.09, 95%CI=1.91, 2.29). Our study found that widespread and rapid adoption of extended interval cervical cancer screening is possible, at least in this managed care setting. Further research examining multilevel drivers promoting or restricting extended interval screening across diverse healthcare settings is needed.

Challenges in risk estimation using routinely collected clinical data: The example of estimating cervical cancer risks from electronic health-records.

Electronic health-records (EHR) are increasingly used by epidemiologists studying disease following surveillance testing to provide evidence for screening intervals and referral guidelines. Although cost-effective, undiagnosed prevalent disease and interval censoring (in which asymptomatic disease is only observed at the time of testing) raise substantial analytic issues when estimating risk that cannot be addressed using Kaplan-Meier methods. Based on our experience analysing EHR from cervical cancer screening, we previously proposed the logistic-Weibull model to address these issues. Here we demonstrate how the choice of statistical method can impact risk estimates. We use observed data on 41,067 women in the cervical cancer screening program at Kaiser Permanente Northern California, 2003-2013, as well as simulations to evaluate the ability of different methods (Kaplan-Meier, Turnbull, Weibull and logistic-Weibull) to accurately estimate risk within a screening program. Cumulative risk estimates from the statistical methods varied considerably, with the largest differences occurring for prevalent disease risk when baseline disease ascertainment was random but incomplete. Kaplan-Meier underestimated risk at earlier times and overestimated risk at later times in the presence of interval censoring or undiagnosed prevalent disease. Turnbull performed well, though was inefficient and not smooth. The logistic-Weibull model performed well, except when event times didn't follow a Weibull distribution. We have demonstrated that methods for right-censored data, such as Kaplan-Meier, result in biased estimates of disease risks when applied to interval-censored data, such as screening programs using EHR data. The logistic-Weibull model is attractive, but the model fit must be checked against Turnbull non-parametric risk estimates.

Low Risk of Cervical Cancer/Precancer Among Most Women Under Surveillance Postcolposcopy.

OBJECTIVE: To inform impending postcolposcopy guidelines, this analysis examined the subsequent risk of CIN 3+ among women with a grade lower than CIN 2 (< CIN 2) colposcopy results, taking into account the referring results that brought them to colposcopy and cotest results postcolposcopy. METHODS: We analyzed 107,005 women from 25 to 65 years old, recommended for colposcopy at Kaiser Permanente Northern California. We estimated absolute risks of CIN 3+ among women: (1) recommended for colposcopy (precolposcopy), (2) following colposcopy and with histology results < CIN 2 (postcolposcopy), and (3) with cotest results 12 months after a < CIN 2 colposcopy (return cotest). RESULTS: After colposcopy showing < CIN 2 (n = 69,790; 87% of the women at colposcopy), the 1-year risk of CIN 3+ was 1.2%, compared with 6.3% at the time of colposcopy recommendation. Negative cotest results 1 year after colposcopy identified a large group (37.1%) of women whose risk of CIN 3+ (i.e., <0.2% at 3 years after postcolposcopy cotest) was comparable with women with normal cytology in the screening population. These risks are consistent with current guidelines recommending repeat cotesting 12 months after colposcopy < CIN 2 and a 3-year return for women with a negative postcolposcopy cotest. CONCLUSIONS: Most women are at low risk of subsequent CIN 3+ after a colposcopy showing < CIN 2, especially those who are human papillomavirus-negative postcolposcopy, consistent with current management guidelines for repeat testing intervals. Before the finalizing the upcoming guidelines, we will consider additional rounds of postcolposcopy cotesting.

Why does cervical cancer occur in a state-of-the-art screening program?

BACKGROUND: The goal of cervical screening is to detect and treat precancers before some become cancer. We wanted to understand why, despite state-of-the-art methods, cervical cancers occured in relationship to programmatic performance at Kaiser Permanente Northern California (KPNC), where >1,000,000 women aged ≥30years have undergone cervical cancer screening by triennial HPV and cytology cotesting since 2003. METHODS: We reviewed clinical histories preceding cervical cancer diagnoses to assign "causes" of cancer. We calculated surrogate measures of programmatic effectiveness (precancers/(precancers and cancers)) and diagnostic yield (precancers and cancers per 1000 cotests), overall and by age at cotest (30-39, 40-49, and ≥50years). RESULTS: Cancer was rare and found mainly in a localized (treatable) stage. Of 623 cervical cancers with at least one preceding or concurrent cotest, 360 (57.8%) were judged to be prevalent (diagnosed at a localized stage within one year or regional/distant stage within two years of the first cotest). Non-compliance with recommended screening and management preceded 9.0% of all cancers. False-negative cotests/sampling errors (HPV and cytology negative), false-negative histologic diagnoses, and treatment failures preceded 11.2%, 9.0%, and 4.3%, respectively, of all cancers. There was significant heterogeneity in the causes of cancer by histologic category (p<0.001 for all; p=0.002 excluding prevalent cases). Programmatic effectiveness (95.3%) and diagnostic yield were greater for squamous cell versus adenocarcinoma histology (p<0.0001) and both decreased with older ages (ptrend<0.0001). CONCLUSIONS: A state-of-the-art intensive screening program results in very few cervical cancers, most of which are detected early by screening. Screening may become less efficient at older ages.

Protection against cervical cancer versus decreasing harms from screening - What would U.S. patients and clinicians prefer, and do their preferences matter?

The primary goal for many providers in the United States has been to deliver the level of protection against cervical cancer afforded by annual cervical cytology while improving screening test performance. Adoption of recent screening recommendations has been inconsistent and has created considerable consternation and confusion. This editorial addresses the perspective of U.S. patients and providers and how their preferences may run counter to current screening recommendations.

Risks of CIN 2+, CIN 3+, and Cancer by Cytology and Human Papillomavirus Status: The Foundation of Risk-Based Cervical Screening Guidelines.

OBJECTIVES: The next round of the American Society for Colposcopy and Cervical Pathology (ASCCP)-sponsored cervical cancer screening and management guidelines will recommend clinical actions based on risk, rather than test-based algorithms. This article gives preliminary risk estimates for the screening setting, showing combinations of the 2 most important predictors, human papillomavirus (HPV) status and cytology result. MATERIALS AND METHODS: Among 1,262,713 women aged 25 to 77 years co-tested with HC2 (Qiagen) and cytology at Kaiser Permanente Northern California, we estimated 0-5-year cumulative risk of cervical intraepithelial neoplasia (CIN) 2+, CIN 3+, and cancer for combinations of cytology (negative for intraepithelial lesion or malignancy [NILM], atypical squamous cells of undetermined significance [ASC-US], low-grade squamous intraepithelial lesion [LSIL], atypical squamous cells cannot exclude HSIL [ASC-H], high-grade squamous intraepithelial lesion [HSIL], atypical glandular cells [AGC]) and HPV status. RESULTS: Ninety percent of screened women had HPV-negative NILM and an extremely low risk of subsequent cancer. Five-year risks of CIN 3+ were lower after HPV negativity (0.12%) than after NILM (0.25%). Among HPV-negative women, 5-year risks for CIN 3+ were 0.10% for NILM, 0.44% for ASC-US, 1.8% for LSIL, 3.0% for ASC-H, 1.2% for AGC, and 29% for HSIL+ cytology (which was very rare). Among HPV-positive women, 5-year risks were 4.0% for NILM, 6.8% for ASC-US, 6.1% for LSIL, 28% for ASC-H, 30% for AGC, and 50% for HSIL+ cytology. CONCLUSIONS: As a foundation for the next guidelines revision, we confirmed with additional precision the risk estimates previously reported for combinations of HPV and cytology. Future analyses will estimate risks for women being followed in colposcopy clinic and posttreatment and will consider the role of risk modifiers such as age, HPV vaccine status, HPV type, and screening and treatment history.

The population impact of human papillomavirus/cytology cervical cotesting at 3-year intervals: Reduced cervical cancer risk and decreased yield of precancer per screen.

BACKGROUND: The objective of cervical screening is to detect and treat precancer to prevent cervical cancer mortality and morbidity while minimizing overtreatment of benign human papillomavirus (HPV) infections and related minor abnormalities. HPV/cytology cotesting at extended 5-year intervals currently is a recommended screening strategy in the United States, but the interval extension is controversial. In the current study, the authors examined the impact of a decade of an alternative, 3-year cotesting, on rates of precancer and cancer at Kaiser Permanente Northern California. The effect on screening efficiency, defined as numbers of cotests/colposcopy visits needed to detect a precancer, also was considered. METHODS: Two cohorts were defined. The "open cohort" included all women screened at least once during the study period; > 1 million cotests were performed. In a fixed "long-term screening cohort," the authors considered the cumulative impact of repeated screening at 3-year intervals by restricting the cohort to women first cotested in 2003 through 2004 (ie, no women entering screening later were added to this group). RESULTS: Detection of cervical intraepithelial neoplasia 3/adenocarcinoma in situ (CIN3/AIS) increased in the open cohort (2004-2006: 82.0/100,000 women screened; 2007-2009: 140.6/100,000 women screened; and 2010-2012: 126.0/100,000 women screened); cancer diagnoses were unchanged. In the long-term screening cohort, the detection of CIN3/AIS increased and then decreased to the original level (2004-2006: 80.5/100,000 women screened; 2007-2009: 118.6/100,000 women screened; and 2010-2012: 84.9./100,000 women screened). The number of cancer diagnoses was found to decrease. When viewed in terms of screening efficiency, the number of colposcopies performed to detect a single case of CIN3/AIS increased in the cohort with repeat screening. CONCLUSIONS: Repeated cotesting at a 3-year interval eventually lowers population rates of precancer and cancer. However, a greater number of colposcopies are required to detect a single precancer. Cancer 2016;122:3682-6. © 2016 American Cancer Society.

A common clinical dilemma: Management of abnormal vaginal cytology and human papillomavirus test results.

OBJECTIVE: Vaginal cancer is an uncommon cancer of the lower genital tract, and standardized screening is not recommended. Risk factors for vaginal cancer include a history of other lower genital tract neoplasia or cancer, smoking, immunosuppression, and exposure to diethylstilbestrol in utero. Although cervical cancer screening after total hysterectomy for benign disease is not recommended, many women inappropriately undergo vaginal cytology and/or human papillomavirus (hrHPV) tests, and clinicians are faced with managing their abnormal results. Our objective is to review the literature on vaginal cytology and hrHPV testing and to develop guidance for the management of abnormal vaginal screening tests. METHODS: An electronic search of the PubMed database through 2015 was performed. Articles describing vaginal cytology or vaginal hrHPV testing were reviewed, and diagnostic accuracy of these tests when available was noted. RESULTS: The available literature was too limited to develop evidence-based recommendations for managing abnormal vaginal cytology and hrHPV screening tests. However, the data did show that 1) the risk of vaginal cancer in women after hysterectomy is extremely low, justifying the recommendation against routine screening, and 2) in women for whom surveillance is recommended, e.g. women post-treatment for cervical precancer or cancer, hrHPV testing may be useful in identification of vaginal cancer precursors. CONCLUSION: Vaginal cancer is rare, and asymptomatic low-risk women should not be screened. An algorithm based on expert opinion is proposed for managing women with abnormal vaginal test results.

A Common Clinical Dilemma: Management of Abnormal Vaginal Cytology and Human Papillomavirus Test Results.

OBJECTIVE: Vaginal cancer is an uncommon cancer of the lower genital tract, and standardized screening is not recommended. Risk factors for vaginal cancer include a history of other lower genital tract neoplasia or cancer, smoking, immunosuppression, and exposure to diethylstilbestrol in utero. Although cervical cancer screening after total hysterectomy for benign disease is not recommended, many women inappropriately undergo vaginal cytology and/or human papillomavirus (HPV) tests, and clinicians are faced with managing their abnormal results. Our objectives were to review the literature on vaginal cytology and high-risk HPV (hrHPV) testing and to develop guidance for the management of abnormal vaginal screening tests. MATERIALS AND METHODS: An electronic search of the PubMed database through 2015 was performed. Articles describing vaginal cytology or vaginal hrHPV testing were reviewed, and diagnostic accuracy of these tests when available was noted. RESULTS: The available literature was too limited to develop evidence-based recommendations for managing abnormal vaginal cytology and hrHPV screening tests. However, the data did show that (1) the risk of vaginal cancer in women after hysterectomy is extremely low, justifying the recommendation against routine screening, and (2) in women for whom surveillance is recommended, e.g., women posttreatment for cervical precancer or cancer, hrHPV testing may be useful in identification of vaginal cancer precursors. CONCLUSIONS: Vaginal cancer is rare, and asymptomatic low-risk women should not be screened. An algorithm based on expert opinion is proposed for managing women with abnormal vaginal test results.

Human papillomavirus testing 2007-2012: co-testing and triage utilization and impact on subsequent clinical management.

In the United States, high-risk human papillomavirus (HPV) testing is recommended for women with atypical squamous cells of unknown significance (ASC-US) cytology, and co-testing with cytology and HPV is a recommended option for screening women aged ≥ 30 years. No population-based data are available to examine utilization of HPV testing in the United States. Using the New Mexico HPV Pap Registry data resource, we describe population trends (2007-2012) in utilization and positivity rates for HPV testing as a routine co-testing screening procedure and for triage of ASC-US and other cytologic outcomes. For women aged 30-65 years co-testing increased from 5.2% in 2007 to 19.1% in 2012 (p < 0.001). Overall 82% of women with ASC-US cytology who did not receive co-testing also had an HPV test. HPV positivity was age and cytology result dependent but did not show time trends. For women with negative cytology, 64% received an additional screening test within 3 years if no co-test was done or if it was positive, but this was reduced to 47% with a negative co-test. Reflex HPV testing for ASC-US cytology is well established and occurs in most women. Evidence for reflex testing is also observed following other abnormal cytology outcomes. Co-testing in women aged 30-65 years has more than tripled from 2007 to 2012, but was still only used in 19.1% of women aged 30-65 years attending for screening in 2012. Women receiving co-testing had longer repeat screening intervals, but rescreening within 3 years is still very common even with co-testing.

Age-stratified 5-year risks of cervical precancer among women with enrollment and newly detected HPV infection.

It is unclear whether a woman's age influences her risk of cervical intraepithelial neoplasia grade 3 or worse (CIN3+) upon detection of HPV. A large change in risk as women age would influence vaccination and screening policies. Among 972,029 women age 30-64 undergoing screening with Pap and HPV testing (Hybrid Capture 2, Qiagen, Germantown, MD) at Kaiser Permanente Northern California (KPNC), we calculated age-specific 5-year CIN3+ risks among women with HPV infections detected at enrollment, and among women with "newly detected" HPV infections at their second screening visit. Women (57,899, 6.0%) had an enrollment HPV infection. Among the women testing HPV negative at enrollment with a second screening visit, 16,724 (3.3%) had a newly detected HPV infection at their second visit. Both enrollment and newly detected HPV rates declined with age (p < 0.001). Women with enrollment versus newly detected HPV infection had higher 5-year CIN3+ risks: 8.5% versus 3.9%, (p < 0.0001). Risks did not increase with age but declined slightly from 30-34 years to 60-64 years: 9.4% versus 7.4% (p = 0.017) for enrollment HPV and 5.1% versus 3.5% (p = 0.014) for newly detected HPV. Among women age 30-64 in an established screening program, women with newly detected HPV infections were at lower risk than women with enrollment infections, suggesting reduced benefit vaccinating women at older ages. Although the rates of HPV infection declined dramatically with age, the subsequent CIN3+ risks associated with HPV infection declined only slightly. The CIN3+ risks among older women are sufficiently elevated to warrant continued screening through age 65.

Use of primary high-risk human papillomavirus testing for cervical cancer screening: interim clinical guidance.

In 2011, the American Cancer Society, the American Society for Colposcopy and Cervical Pathology, and the American Society for Clinical Pathology updated screening guidelines for the early detection of cervical cancer and its precursors. Recommended screening strategies were cytology and cotesting (cytology in combination with hrHPV testing). These guidelines also addressed the use of hrHPV testing alone as a primary screening approach, which was not recommended for use at that time. There is now a growing body of evidence for screening with primary hrHPV testing, including a prospective US-based registration study. Thirteen experts including representatives from the Society of Gynecologic Oncology, American Society for Colposcopy and Cervical Pathology, American College of Obstetricians and Gynecologists, American Cancer Society, American Society of Cytopathology, College of American Pathologists, and the American Society for Clinical Pathology, convened to provide interim guidance for primary hrHPV screening. This guidance panel was specifically triggered by an application to the FDA for a currently marketed HPV test to be labeled for the additional indication of primary cervical cancer screening. Guidance was based on literature review and review of data from the FDA registration study, supplemented by expert opinion. This document aims to provide information for healthcare providers who are interested in primary hrHPV testing and an overview of the potential advantages and disadvantages of this strategy for screening as well as to highlight areas in need of further investigation.