Reflex Human Papillomavirus Testing Research Articles

High-risk HPV testing improves accuracy in detection of CIN2+ lesions in ASC-H postmenopausal women? An academic hospital experiences.

Reflex human papilloma virus (HPV) testing with "atypical squamous cells, cannot exclude high-grade squamous lesion (ASC-H)" cytologic diagnosis is not recommended by American Society for Colposcopy and Cervical Pathology guidelines. Studies have shown human papillomavirus (HPV)-negative ASC-H patients of increased age are low risk for cervical intraepithelial neoplasia 2 or worse (CIN2+) lesions on colposcopic follow-up. We retrospectively assessed the efficacy of reflex HPV testing in postmenopausal women with ASC-H in the Los Angeles County hospitals and clinics in a 5-year period. Of a total 85 clinically postmenopausal women with ASC-H, 31 (36.5%) women were found to have CIN2+ lesions on follow-up biopsy and five of them were HPV-negative. Of the women with CIN2+ lesions and positive HPV, 13 (41.9%) were high-risk HPV (hrHPV) 16/18/45 positive and 13 (41.9%) were hrHPV-other subtype positive. Women with positive HPV had an over 3-fold increased risk of developing CIN2+ lesions (P= 0.008). Relative risk of hrHPV16/18/45 was 1.79-fold higher than that of hrHPV-other subtype. The positive predictive value and negative predictive value of hrHPV were 49.1% and 84.4%, respectively. CIN2+ detection rate in Hispanic women with positive hrHPV was higher than in non-Hispanic women (53.8% versus 35.7%). Overall, postmenopausal women with ASC-H cytology result and negative hrHPV were less likely to develop CIN2+ lesions, whereas about half of ASC-H postmenopausal women develop CIN2+ lesions if hrHPV positive, especially if hrHPV 16/18/45 positive. Therefore, triaging ASC-H postmenopausal women with cotesting or, ideally, hrHPV genotyping should be considered as optimal clinical practice to avoid overtreatment.

Human papillomavirus genotype distribution in low-grade squamous intraepithelial lesion cytology, and its immediate risk for high-grade cervical lesion or cancer: a single-center, cross-sectional study

ObjectiveTo investigate the distribution of human papillomavirus (HPV) genotypes in low-grade squamous intraepithelial lesion (LSIL) cytology and the immediate risk of cervical intraepithelial neoplasia grade 2 or higher (CIN2+) lesions.MethodsThis prospective cross-sectional study enrolled women aged ≥21 years that were diagnosed with LSIL cytology at Siriraj Hospital (Bangkok, Thailand) during 2017–2019. Anyplex II HPV testing was performed to detect 14 high-risk HPV cases prior to colposcopy-directed biopsy.ResultsIn total, 318 patients were included in the final analysis. Of those, 24 (7.5%), 241 (75.8%), 53 (16.7%) were aged 21–25 years, 25–50 years, and ≥50 years, respectively. Eighty-two patients (25.8%) had abnormal screening results within the previous 5 years. High-risk HPV infection was found in 188 patients (59.1%) with 127 (39.9%) having single and 61 (19.2%) having multiple infections. The five most common HPV genotypes were HPV 66 (18.6%), HPV51 (9.7%), HPV58 (9.4%), HPV16 (9.1%), and HPV56 (8.2%). The immediate risk of CIN2+ was 6% in LSIL, regardless of the HPV status, 8% in high-risk HPV-positive LSIL, and 3.1% in high-risk HPV-negative LSIL. When using 6% as the threshold risk for colposcopy, performing reflex HPV testing in LSIL cytology can decrease the number of colposcopies by 40.9%, with an area under the receiver operating characteristic curve of 0.6 (95% confidence interval, 0.5–0.7).ConclusionThe study findings support the idea that geographic variations affect the HPV genotype. Reflex HPV testing may decrease the number of colposcopies in cytology-based screening regions with a high prevalence of low-carcinogenic HPV.

Improving the performance of reflex Human Papilloma Virus (HPV) testing in triaging women with atypical squamous cells of undetermined significance (ASCUS): A restrospective study in a tertiary hospital in United Arab Emirates (UAE)

IntroductionCervical cancer is the second commonest cancer in women worldwide. Infection with oncogenic types of human Papillomavirus (HPV) is the most important risk factor for developing cervical cancer. Reflex High risk HPV (HR-HPV) testing is of significant value in the assessment of Papanicolaou (Pap) smear results where ASCUS are identified. ObjectiveTo improve the performance of reflex HR-HPV testing in triage of ASCUS and analyze the factors impacting it. MethodologyIn this study, we generated a database of 9641 women who had cervical smears collected during the study period from the cytopathology record in a large tertiary hospital in UAE. These included 297 smears with ASCUS diagnosis. All cases were retrospectively followed up with a mean duration of 2.44 years. We analyzed data according to the outcome based on several follow-up Pap smear analysis as the reference assessment. ResultsWe detected HR-HPV infection in 17.9% of cases. 9.1% <25, 28.8% 25–34 and 62.1% ≥35 years old. HR-HPV prevalence was higher among premenopausal women (20.7%) compared to postmenopausal women (9.5%) (P-value=0.044). The rate of progression to high grade lesions was also higher (28.7%) in the premenopausal group compared to (12.8%) in the postmenopausal group. Reflex HPV testing had an overall sensitivity of 41.1%, specificity of 88.2%, positive predictive value (PPV) of 62.1%, and negative predictive value (NPV) of 75.9% in detection of cervical lesions. These figures were higher on combining premenopausal status and complaint of abnormal bleeding or discharge/itching (66.7%, 93.3%, 66.8% and 93.3% respectively). ConclusionsThe sensitivity, specificity and NPV of reflex HPV testing in the triage of ASCUS cases can be more accurate in premenopausal women upon adding age group and presenting complaint as a triage item. This improves the performance of reflex HPV testing and the subsequent selection of high risk patients for colposcopy.

Reflex Human Papillomavirus Test Results as an Option for the Management of Korean Women With Atypical Squamous Cells Cannot Exclude High-Grade Squamous Intraepithelial Lesion.

Current guidelines recommend initial colposcopy with biopsy regardless of human papillomavirus (HPV) test results in women with atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion (ASC-H). The purpose of this study was to evaluate the value of HPV testing in women with ASC-H based on colposcopic pathology results. A multicenter cross-sectional study was carried out at three academic hospitals and involved 40,847 Korean women who underwent cervical cancer screening with cytology and HPV tests with or without subsequent colposcopic biopsies between January 2007 and December 2013. ASC-H was diagnosed in 276 women (0.7%). Only 6 of 68 (8.8%) women with ASC-H who were HPV negative had cervical intraepithelial neoplasia grade ≥2 (CIN ≥2) lesions, whereas 47.4% of the women with ASC-H who were HPV positive had CIN ≥2 lesions. No cases of invasive cervical cancer were diagnosed among women with ASC-H who were HPV negative. Logistic regression analysis was performed using the group with normal Papanicolaou test results and HPV-negative status as the reference group. Women with ASC-H who were HPV positive had a significantly increased risk of CIN ≥2 lesions, whereas no significant increase was observed in patients with ASC-H and HPV-negative status. If the result of the HPV test was negative, the risk of CIN ≥2 lesions in Korean women with ASC-H cytology was low. Reflex HPV testing should be an option for the management of women with cytology showing ASC-H to decrease unnecessary colposcopic biopsies, which are expensive and invasive. Current American Society for Colposcopy and Cervical Pathology guidelines recommend universal colposcopy for the management of women with atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion (ASC-H) on cytology, regardless of human papillomavirus (HPV) test results. The present study suggested that HPV cotesting in patients with ASC-H cytology can provide more detailed and useful information regarding the risk of high-grade cervical intraepithelial neoplasia (CIN) lesions and the need for further treatment. When the result of the HPV test was negative, the risk of CIN lesions of grade ≥2 in women with ASC-H cytology was low. Consequently, reflex HPV testing, rather than immediately performance of invasive and expensive colposcopy with biopsy, should be an option for the management of women with ASC-H.

Use of Electronic Medical Record–Based Tools to Improve Compliance With Cervical Cancer Screening Guidelines

This study aimed to determine whether electronic medical record (EMR)-based tools influence providers' compliance with guidelines for cervical cancer screening in adolescent (<21 y) patients. Three EMR-based tools to educate providers on cervical cancer screening guidelines were implemented midyear in 2010. Charts of adolescents with Pap and/or human papillomavirus results from January to December 2010 were reviewed. Physicians' demographic data were collected. Appropriateness of the index Pap and follow-up were determined using American Society for Colposcopy and Cervical Pathology guidelines. A total of 380 Pap tests were completed on 374 adolescents. Fewer Pap tests were done after the EMR interventions (229 vs 151, p < .0005). The proportion of Pap tests ordered by primary care providers was significantly higher than obstetrician-gynecologists (Ob/Gyns) (70% vs 30%, p < .0005). The number of Pap tests done by Ob/Gyns decreased 60% after EMR interventions (from 82 to 33, p < .0005) and that done by primary care physicians decreased 20% (from 147 to 118, p = .08). Indicated Pap tests were more often ordered by Ob/Gyn than by primary care, especially after EMR changes (31.4% vs 7.6%, p < .0005). Reflex human papillomavirus testing (if atypical squamous cells of undetermined significance) was high (74%) and did not improve after the EMR changes (72% vs 76%). The rate of co-testing in adolescents decreased in the primary care department after the EMR changes (13% vs 6%, p = .049). Electronic medical record prompts improved compliance with cervical cytology guidelines for adolescents, suggesting that EMR may be an important tool to enhance compliance with changing recommendations.

Updates of the current screening guidelines for the early detection of cervical cancer

Updates of the current screening guidelines for the early detection of cervical cancer

Assessment of reflex human papillomavirus DNA testing in patients with atypical endocervical cells on cervical cytology

Reflex human papillomavirus (HPV) testing for atypical squamous cells of undetermined significance (ASC-US) has improved the sensitivity and specificity in detecting high-grade squamous dysplasia (cervical intraepithelial neoplasia [CIN]2+). However, to the authors' knowledge there are no guidelines for performing reflex HPV testing in women with atypical endocervical cells (AEC) before colposcopy. This report is of a 5-year experience with reflex HPV testing in women with AEC and assessment of the potential role of reflex HPV testing in guiding subsequent colposcopy-directed cervical biopsy/curettage in a large tertiary care hospital setting. All AEC cases cytologically diagnosed from July 2001 to June 2006 were retrieved from the Cleveland Clinic database. The histopathologic diagnoses and the results of HPV testing using the Hybrid Capture 2 (HC-II) method were reviewed. The most severe histopathologic diagnosis was recorded. Of a total 332,470 Papanicolaou (Pap) tests performed, 317 cases of AEC had histopathologic follow-up and reflex testing for high-risk HPV. Histopathologic examination of the 64 HPV-positive AEC cases revealed 18 cases of endocervical adenocarcinoma in situ/adenocarcinoma (AIS+) and 22 cases of CIN2+. Among 253 of the HPV-negative AEC women, AIS+ was found in only 3 cases and CIN2+ in 1 case. Cervical AIS+ was found in 28% of the HPV-positive AEC patients and in only 0.9% of the HPV-negative patients (P<.0001). When the significant glandular (AIS+) and squamous (CIN2+) lesions were combined, 62.5% of the lesions were detected in HPV-positive AEC cases compared with 1.6% in the HPV-negative AEC cases (P<.0001). Because of a high sensitivity (91.0%) and high specificity (91.2%) in detecting significant cervical lesions, reflex HPV testing for cytologic diagnosis of AEC appears to be a useful ancillary tool in the selection of high-risk patients for colposcopy.

Evaluation of primary cervical cancer screening with an oncogenic human papillomavirus DNA test and cervical cytologic findings among women who attended family planning clinics in the United States

Our goal was to evaluate the performance of screening with (1) Papanicolaou and human papillomavirus (HPV) DNA testing and (2) Papanicolaou testing with reflex HPV testing of atypical squamous cells of undetermined significance for detecting cervical intraepithelial neoplasia grade 3 or more in clinics that serve low-income women in the United States. There were 4799 women who were recruited primarily from Planned Parenthood clinics and who were screened with liquid-based Papanicolaou testing and HPV DNA testing and referred for biopsy based on a positive test result for oncogenic HPV DNA or a Papanicolaou test that showed atypical squamous cells of undetermined significance or more. Among 931 women who were 30-50 years of age, the sensitivity of reflex HPV testing was 53.8% (range, 38.2%-72.3%). The sensitivity of HPV DNA and Papanicolaou testing was 91% (range, 74.6%-100%). The specificity of reflex HPV testing was 95.1% (range, 93.8%-96.3%). Generally, the specificity of HPV DNA and Papanicolaou testing was low. Among US women who are >or=30 years old, HPV DNA and Papanicolaou testing is a reasonable cervical cancer screening strategy.

Use of the ThinPrep® Imaging System does not alter the frequency of interpreting Papanicolaou tests as atypical squamous cells of undetermined significance

BackgroundAutomated screening of Papanicolaou tests (Pap tests) improves the productivity of cytopathology laboratories. The ThinPrep® Imaging System (TIS) has been widely adopted primarily for this reason for use on ThinPrep® Pap tests (TPPT). However, TIS may also influence the interpretation of Pap tests, leading to changes in the frequency of various interpretive categories. The effect of the TIS on rates of TPPT interpretation as atypical squamous cells of undetermined significance (ASC-US) is of concern because any shift in the frequency of ASC-US will alter the sensitivity and specificity of the Pap test. We have sought to determine whether automated screening of TPPT has altered ASC-US rates in our institution when compared with manual screening (MS) of TPPT.MethodsA computerized search for all ASC-US with reflex Human Papillomavirus (HPV) testing over a one-year-period (7/1/06 to 6/30/07) was conducted. Cases included both TPPT screened utilizing TIS and screened manually. HPV test results for both groups were recorded. Pertinent follow-up cervical cytology and histology results were retrieved for the period extending to 11/30/07. Automated screening was in clinical use for 10 months prior to the start of the study.ResultsAutomated screening was performed on 23,103 TPPT, of which 977 (4.23%) were interpreted as ASC-US. Over the same period, MS was performed on 45,789 TPPT, of which 1924 (4.20%) were interpreted as ASC-US. Reflex HPV testing was positive for high risk (HR) types in 47.4% of the TIS cases and 50.2% of MS cases. Follow-up cervical dysplasia found by colposcopy was also distributed proportionally between the two groups. Cervical intraepithelial neoplasia (CIN) was found on follow-up biopsy of 20.1% of the TIS cases (5.2% CIN 2/3) and 21.2% of MS cases (5.1% CIN 2/3). None of these differences were statistically significant.ConclusionUse of the ThinPrep® Imaging System did not appreciably change ASC-US rates or follow-up reflex HPV test results in our laboratory. This demonstrates that the benefits of automated screening may be obtained without increasing the rate of referral to colposcopy for ASC-US follow-up.

Longitudinal Cytological Follow-up of Patients With a Papanicolaou Test Interpretation of "Atypical Squamous Cells of Undetermined Significance" That Was Followed by a Negative Reflex Test for High-Risk Human Papillomavirus Types

The 2001 consensus guidelines essentially equated the follow-up management of patients with a Papanicolaou (Pap) test interpretation of negative for intraepithelial lesion or malignancy and those with an interpretation of atypical squamous cells of undetermined significance (ASC-US) that was followed by a negative reflex test for high-risk human papillomavirus (HR HPV) types: follow-up cytology in 12 months. As several years have elapsed since these guidelines attained some measure of widespread implementation, we sought to determine whether, in routinely diagnosed cases, the full spectrum of follow-up cytological findings are indeed identical in these 2 groups. Clinical and pathological data of consecutive patients with a Pap test interpretation of ASC-US during a 6-week period (n = 587), in which reflex human papillomavirus testing was performed (n = 497) and in which HR HPV types were not detected (n = 300), were reviewed (study group). A randomly selected control group of 300 patients whose Pap tests were reported as negative (negative for intraepithelial lesion or malignancy) during the same period were similarly reviewed. The follow-up Pap tests were classified into the various Bethesda 2001 diagnostic categories, and both groups were compared. The average follow-up duration in the study and control groups was 26.03 and 25.9 months, respectively. When all of the follow-up Pap tests in each group (study, n = 555; control, n = 356) were used for the comparisons, patients in the study group were significantly more likely to have an abnormal follow-up Pap test result than the control group patients (24.9% vs 7.6%, P < 0.0001); this was primarily attributable to the more frequent repeat interpretations of ASC-US in the former group (20.5% vs 5.1%, P < 0.0001). The HR HPV detection rates in the follow-up ASC-US cases were not significantly different between the study and control groups. There were no significant differences between both groups regarding the diagnostic frequencies of low-grade squamous intraepithelial lesion and atypical squamous cells-cannot exclude high-grade squamous intraepithelial lesion (HGSIL). No examples of HGSIL or invasive cancer were identified in the follow-up of either group. All comparisons of statistical significance retained their significance when only 1 follow-up Pap test per patient, the most severe interpretation, was used. Our findings suggest that some significant differences exist between these 2 groups, most notably the comparatively increased frequency of repeat ASC-US interpretations in the study group. However, the extraordinary rarity of the most clinically significant interpretations of HGSIL and carcinoma in this setting can be confirmed because no such cases were identified during the follow-up of either group.

Attitudes Toward HPV Testing: Interview Findings From a Random Sample of Women in Ontario, Canada

As most women diagnosed with cervical carcinoma have been “inadequately screened,” improvements in screening are critical. After abnormal Pap test findings (through liquid-based cytology), residual specimens now can be tested simultaneously for oncogenic types of Human Papilloma virus (HPV). If these “reflex” HPV tests are negative, Pap tests need not be repeated for 12 months. Women with positive oncogenic HPV tests, however, can be referred immediately for colposcopy. There has been concern that “stigma” issues could be associated with positive HPV status (because of its sexual transmission) that might cause women to avoid this reflex HPV testing. We addressed this concern by assessing whether stigma issues surface in relation to HPV testing. We randomly selected 20 women and administered to them semistructured telephone interviews that included responses to a scenario of reflex HPV–DNA testing. Interview transcripts were analyzed qualitatively. Highly limited knowledge levels were found about HPV, but, following education about screening options, there was no rejection of HPV testing. In conclusion, it appears that women favor reflex HPV testing due to its “convenience” and perceptions that it is “the least intrusive option more definitive than Pap testing.”

Significance and possible causes of false-negative results of reflex human papillomavirus infection testing

The objective of this study was to assess the rate and possible reasons for false-negative (FN) reflex human papillomavirus (HPV)-DNA tests. The authors reviewed all ThinPrep cervical specimens that were submitted for reflex HPV-DNA testing using the Digene Hybrid Capture II (HC2) method from January 2002 to January 2004. Follow-up biopsies were reviewed. The results were considered HPV-FN if the HPV-DNA test was negative and the biopsy was positive for grade > or =2 cervical intraepithelial neoplasia (CIN2+), and the results were considered true positive (HPV-TP) if the HPV-DNA test was positive and the biopsy showed CIN2+. HPV-FN cases were compared with HPV-TP cases regarding the grade and extent of CIN, the number of abnormal cells on the original ThinPrep slide, and the presence of amplifiable, viral DNA on biopsy. In total, 1520 (66%) of 2309 patients who had diagnoses of atypical squamous cells of undetermined significance (ASCUS) were negative for HPV DNA and 789 patients of 2309 patients (34%) were positive for HPV DNA. Three hundred sixteen women (40%) who had a positive HPV-DNA test underwent a biopsy. Of those, 36 biopsies (11%) showed CIN2+ (HPV-TP), and 154 biopsies (66%) showed CIN1. Cervical tissue was available for review from 82 women who had negative HPV-DNA tests; of these, 6 tissue samples (7%) showed CIN2+ (HPV-FN), and 13 tissue samples (16%) showed CIN1. Therefore, in the total ASCUS population that was triaged with reflex HPV testing, there were at least 42 women who were diagnosed with CIN2+, for an estimated CIN2+ FN fraction of 14% (6 of 42 women). HPV-FN lesions were smaller (but the difference was not statistically significant) and shed significantly fewer abnormal cells than HPV-TP cases. Polymerase chain reaction testing for viral DNA in the biopsy was detected in 3 of 6 women who had HPV-FN results; none of those positive results demonstrated a viral type that was not included in the Digene probes. Although the rate of FN high-grade lesions was significantly higher than that reported in the ASCUS/Low-grade Squamous Intraepithelial Lesion Triage trial, most missed lesions were small and shed few abnormal cells. It was assumed that those lesions were either in early stages or in regressing stages, which made their clinical significance uncertain.

Atypical Squamous Cells of Undetermined Significance, Human Papillomavirus, and Cervical Intraepithelial Neoplasia 2 or 3 in Adolescents

To determine rates of and factors associated with cervical intraepithelial neoplasia (CIN) 2 or 3 among women with atypical squamous cells of undetermined significance (ASC-US) and oncogenic human papillomavirus (HPV) infection. This is a retrospective review of 357 women with ASC-US and known high-risk HPV infection. To be eligible for inclusion, patients had to have subsequently undergone colposcopic-directed cervical biopsy and/or endocervical sampling. Univariate and multivariable regression analyses were used to estimate crude and adjusted odds ratios of CIN 2 or 3 by risk factors associated with HPV and CIN. Thirty-three of 215 (15%) women with ASC-US and oncogenic HPV who underwent histological sampling demonstrated CIN 2 or 3. In the adjusted model, only nulliparity (adjusted odds ratio = 2.2, 95% CI = 1.0-4.8) retained a marginal association with the outcome. No significant age-related differences in the prevalence of high-grade disease emerged. The high-grade lesions seen in adolescents consisted of single, small lesions. In the light of these findings, and in conjunction with the high rate of oncogenic HPV infection among adolescents with ASC-US, both reflex HPV testing and immediate colposcopy do not appear to be of benefit in the initial management of teenagers with this cytological diagnosis.

Cost-Effectiveness Analysis of Liquid-Based Cytology and Human Papillomavirus Testing in Cervical Cancer Screening

To compare the outcomes of several cervix cancer screening strategies in a military population using a model that considers both direct and indirect costs of health care. A Markov model of the natural history of cervical cancer was used to simulate an age-stratified cohort of 100,000 active duty women in the U.S. Army. Total costs and incremental cost-effectiveness ratios were estimated for different modalities of screening: liquid-based cytology with testing for human papillomavirus (HPV) irrespective of cytologic results compared with liquid-based cytology with HPV detection for cytologic results of atypical cells of undetermined significance (reflex HPV). The costs and outcomes of these screening methods were evaluated separately as well as in combination (liquid-based cytology and reflex HPV before age 30 years and DNA and Pap test every 3 years thereafter). Each of these screening methods was evaluated at 1-, 2-, and 3-year intervals. A screening strategy of liquid-based cytology and reflex HPV every 2 or 3 years is the least costly strategy among active duty women irrespective of age, especially when accounting for time costs associated with screening, diagnosis, and treatment of cervix cancer. A strategy of liquid-based cytology and HPV testing irrespective of cytology results is the most effective strategy; however, it is also the most costly of the strategies tested, even when performed in patients older than 30 years of age. In the U.S. Army, cervix cancer screening performed with liquid-based cytology and reflex HPV testing of atypical squamous cells of undetermined significance performed every 2 years is cost-effective, especially when indirect costs are considered.

A cost‐effectiveness analysis of four management strategies in the determination and follow‐up of atypical squamous cells of undetermined significance

Atypical squamous cells of undetermined significance (ASC-US) are the most common abnormal cytological result on Papanicolaou (Pap) smear. We analyzed four management strategies in a hypothetical cohort of women divided by age group: (1) immediate colposcopy, (2) repeat cytology after an ASC-US Pap smear result, (3) conventional Pap with reflex human papillomavirus (HPV) testing, and (4) liquid-based cytology with reflex HPV testing. Parameter variables were collected from previously published data. Strategies that included reflex HPV testing had the lowest overall costs for all age groups combined. Repeat Pap smears had the highest number of true positive results throughout all stages but also had the uppermost number of missed cancers and highest costs. Immediate colposcopy had the second highest overall costs and detected fewer true positive results than liquid-based cytology. Younger women (aged 18-24 yr) consistently had higher total costs for all strategies investigated. Using the incremental cost-effectiveness (CE) ratio, the immediate colposcopy strategy was more costly and less effective than liquid-based cytology and, therefore, was dominated. The incremental CE ratio was lowest for liquid-based cytology compared with conventional cytology and liquid-based cytology with reflex HPV testing was the most cost-effective strategy.

A Cost-Effectiveness Analysis of Screening Strategies for Cervical Intraepithelial Neoplasia

To assess the costs and usefulness of colposcopy using three screening strategies for cervical intraepithelial neoplasia (CIN). A decision model compared three screening strategies for CIN: (1) patients were screened annually with a conventional Pap smear, (2) patients were screened annually with a liquid-based cytologic method and reflex human papillomavirus testing for atypical squamous cells of undetermined significance results, and (3) patients were screened biennially with a liquid-based cytologic method and reflex human papillomavirus testing for atypical squamous cells of undetermined significance results. Biennial liquid-based screening was the least expensive strategy with a cost of $9.5 million per 100,000 patients. Annual liquid-based screening was the most expensive strategy at $13.7 million. Annual conventional screening had an intermediate cost of $11.6 million. Biennial liquid-based screening referred the fewest patients to colposcopy (11.8%), followed by annual conventional screening and annual liquid-based screening (15.2% and 15.6%, respectively). Each of these treatment strategies is reasonable; however, biennial liquid-based screening would reduce medical costs significantly.

Human Papillomavirus Triage of Patients with Atypical Squamous Cells of Undetermined Significance on Cervical Papanicolaou Smear

Introduction: The recent development of affordable human papillomavirus (HPV) testing has prompted consideration of its use as adjuvant and primary screening for cervical dysplasia. This review focuses on the use of HPV testing in triage management of atypical squamous cells of undetermined significance (ASC-US) Pap smears. Materials and Methods: A Medline search was performed for articles relevant to HPV testing as a triage strategy for ASC-US Paps. Key references from other papers that were not included in the search were also reviewed. Findings from the major randomised trials were then summarised. Results: Reflex HPV testing with hybrid capture is at least as effective and potentially cheaper than repeat cytology for evaluation of an ASC-US Pap. It also avoids 50% of colposcopies that would normally be performed if immediate colposcopy were done for all ASC-US Paps, while retaining excellent negative predictive value. Conclusion: Reflex HPV testing using liquid-based cytology is the preferred management strategy for triage of ASC-US Paps.

Reflex human papillomavirus DNA testing on residual liquid-based (TPPT) cervical samples: focus on age-stratified clinical performance.

Liquid-based ThinPrep technology has made reflex human papillomavirus (HPV) DNA testing possible. In the current study, the clinical performance of reflex HPV testing as an adjunct to routine ThinPrep testing (TPPT) and the impact of age on various test parameters in a predominantly high-risk, minority population were evaluated retrospectively. Reflex HPV testing was performed in 2114 women with atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intraepithelial lesion (LSIL) cytology, using probes for low-risk (LR) and high-risk (HR) HPV types. Six hundred thirty women underwent subsequent biopsies with which HPV testing results were correlated. Approximately 86% of the patients were Hispanic and African-American and 12% were white. Of the younger women (ages 14-29 years), 81% were positive for HR types versus 50% in the older women (ages 30-77 years) (P < 0.0001). In women with ASCUS, 47% were found to be positive for HR types versus 78% of women with LSIL. The percentage of histologic high-grade lesions was 24% in younger patients versus 17% in older patients. Overall, 91% of high-grade lesions were positive for HPV DNA (HR-positive = 89% and LR-positive = 2%), and 9% were negative for both types. The sensitivities and specificities in "younger" versus "older" women were 92% (95% confidence interval [95% CI], 89-95%) and 22%% (95% CI, 17-26%), respectively, versus 84% (95% CI, 77-90%) and 59% (95% CI, 53-65%), respectively. The results of the current study demonstrate that reflex HPV testing performed in a routine clinical practice helps to identify the majority of women with high-grade disease. However, testing may be more beneficial in older women (age > or = 30 years) with ASCUS. Strategy using out-of-vial reflex testing is more cost-effective and sensitive than referring all women for colposcopies.

Thin-layer liquid-based cervical cytology and PCR for detecting and typing human papillomavirus DNA in Flemish women.

The objective of this study was to document the occurrence and to correlate the prevalence of different human papillomavirus (HPV) types with the cytological results on simultaneously performed thin-layer preparations in a large population of Flemish women. During 1 year, 69 290 thin-layer preparations were interpreted using the Bethesda classification system. Using an algorithm for HPV testing based on consensus primers and type-specific PCRs in combination with liquid-based cytology, we determined the occurrence and distribution of 14 different oncogenic HPV types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68). Reflex HPV testing was performed on cytologically abnormal samples and on an age matched randomly selected control group with normal cervical cytology (n=1351). Correlation between cytology, age and prevalence for the 14 different high-risk HPV types is given. There is a significant increase in predominance of high-risk HPV types, with increasing abnormal cytology. Coinfection with multiple HPV types also increased with cytological abnormalities, and was highest in HSIL (16.7%). In Flanders, HSIL was most often associated with HPV types 16, 33, 35, 31, 18 and 51. Using thin-layer liquid-based cytology and PCR to detect HPV, it is feasible to screen large numbers of women.

Cost-effectiveness of alternative triage strategies for atypical squamous cells of undetermined significance.

Every year approximately 2 million US women are diagnosed as having a cervical cytological result of atypical squamous cells of undetermined significance (ASC-US). To determine the most efficient and cost-effective management strategy for women in the United States diagnosed as having ASC-US. Cost-effectiveness analysis of data from clinical trials, prospective studies, and other published literature. A computer-based model was used to compare 4 management strategies for a cytological result of ASC-US: immediate colposcopy; human papillomavirus (HPV) triage, which includes colposcopy if high-risk HPV types are detected; repeat cytology, which includes follow-up cytology at 6 and 12 months and referral for colposcopy if a repeat abnormal result occurs; and reclassifying ASC-US as normal in which a cytological result of ASC-US is ignored. Reflex HPV DNA testing uses either residual liquid-based cytological specimens or samples co-collected at the time of the initial screening for conventional cytology. Another method, referred to as the 2-visit HPV DNA triage, requires a woman with an ASC-US result to return within 1 month to provide another speciman sample. Years of life saved (YLS), quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios. The least costly strategy for biennial screening was to reclassify ASC-US as normal, resulting in a reduction in total cancer incidence of 75% for conventional cytology and 84% for liquid-based cytology compared with no screening. The next least costly strategy was HPV DNA testing resulting in a reduction in total cancer incidence of 86% for conventional cytology and 90% for liquid-based cytology, followed by immediate colposcopy with a reduction of 87% and 91%, respectively. Compared with reflex HPV DNA testing, a strategy of repeat cervical cytology or delayed HPV testing costs more but is less effective. When all strategies were compared simultaneously, varying frequency and type of cytological test, biennial (vs every 3 years) liquid-based cytology with reflex HPV testing had a cost of $174 200 per YLS. In a similar comparison, liquid-based cytology with reflex HPV testing conducted every 3 years (vs every 5 years) had a cost of $59 600 per YLS and was more effective and less costly than a strategy of conventional cytology incorporating repeat cytology or immediate colposcopy conducted biennially. Reflex HPV DNA testing provides the same or greater life expectancy benefits and is more cost-effective than other management strategies for women diagnosed as having ASC-US.