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Objectives: Extended testing for high-risk human papillomavirus genotypes (hrHPVGTs) is increasingly investigated for risk stratification in cervical cancer screening., Methods: Age and hrHPVGT results from 16,993 women with atypical squamous cells of undetermined significance (ASC-US) cytology between November 2015 and August 2021 were studied and correlated with available histopathologic findings within 6 months., Results: High-risk human papillomavirus (hrHPV)-positive rate was 66.9% in women with ASC-US cytology, and the most prevalent genotypes were HPV 52 (20.9%), 16 (15.7%), and 58 (12.8%). Single hrHPV genotypes and multiple HPV genotypes were detected in 77.2% and 22.8% of women with hrHPV-positive results. Cervical intraepithelial neoplasia grade 2 or more (CIN2+) severe lesions were identified in 19.5% of women with hrHPV-positive ASC-US. The greatest risk for CIN2+ was found in single genotype infections with HPV 16 (33.1%), followed by women with multiple genotype infections, including HPV 16 (32.7%), 82 (30.8%), and 31 (30.0%). hrHPVGT testing for genotypes 16, 31, 35, 45, 82, 58, 33, 52, and 18 was identified in 91.9% (965/1,050) of CIN2+ cases, with 88.9% sensitivity, 43.2% specificity, positive predictive value of 23.9%, and negative predictive value of 95.1%., Conclusions: Extended hrHPV genotyping for women with ASC-US cytology could identify those hrHPV genotypes (HPV 16, 31, 35, 45, 82, 58, 33, 52, 18) associated with higher risk of CIN2+ and allows for refined risk stratification of women being screened., (© The Author(s) 2022. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Extended high-risk human papillomavirus (hrHPV) genotype testing has recently been introduced in routine cervical cancer screening. Changes in national and regional hrHPV genotype prevalence offer an objective baseline indicator of the future impact of mass HPV vaccination and HPV-based cervical screening., Methods: This retrospective study reports nationwide hrHPV genotyping results from July 2018 to June 2019 in 29 KingMed Diagnostics laboratories throughout China., Results: In total, 2,458,227 hrHPV genotyping results were documented from KingMed's nationwide laboratory database during the study period. The overall prevalence of hrHPV-positive results was 19.1%, with twin peaks for highest hrHPV infection rates in women younger than 30 years of age (22.0%) and 50 years of age and older (21.8%). The most frequently detected hrHPV genotypes were HPV-52 (4.7%), HPV-16 (3.4%), HPV-53 (2.5%), HPV-58 (2.4%), HPV-51 (2.0%), and HPV-68 (1.6%). Overall, hrHPV-positive results varied regionally from 15.3% to 24.4%., Conclusions: Nationwide hrHPV genotyping results from KingMed laboratories offer a baseline for measuring the future impact of large-scale HPV vaccination. High hrHPV infection rates in older (≥50 years) Chinese women likely reflect the limited extent of cervical screening in China. High rates of hrHPV infection and variable regional hrHPV genotype distribution may represent limiting factors for cost-effective implementation of hrHPV-based cervical screening in China., (© American Society for Clinical Pathology, 2021. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Extended high-risk human papillomavirus (hrHPV) genotype testing (hrHPVGT) has emerged as a new strategy to help optimize the efficiency of hrHPV triage., Methods: Women with an atypical squamous cells of undetermined significance (ASC-US) cervical Papanicolaou test result who underwent hrHPVGT between October 2017 and May 2021 at the Obstetrics and Gynecology Hospital of Fudan University in Shanghai, China, were studied. For hrHPVGT, a proprietary multiplex real-time polymerase chain reaction assay was used. hrHPVGT and viral load test results in selected patients were correlated with histopathologic follow-up findings available within 6 months., Results: In total, 17,235 women with ASC-US cytology who had hrHPVGT results were identified in the Obstetrics and Gynecology Hospital of Fudan University database. The hrHPV-positive rate was 61.8%, and the most prevalent hrHPV genotypes were type 52 (HPV52) (16%), HPV16 (11.3%), HPV58 (10.2%), and HPV53 (8.4%). Single hrHPV genotypes were detected in 65.9% of women with hrHPV-positive results, and multiple genotypes were detected in 34.1%. Histopathologic cervical findings within 6 months were available in 5627 hrHPV-positive women and 2223 hrHPV-negative women. High-grade cervical intraepithelial lesions or cervical cancer (cervical intraepithelial neoplasia 2 or greater [CIN2+]) were identified in 7.5% of hrHPV-positive women who had ASC-US cytology and in 0.9% of hrHPV-negative women who had ASC-US cytology. The greatest risk for CIN2+ was in single hrHPV genotype infections with HPV16 (21.1%), HPV33 (15.2%), HPV82 (10%), and HPV18 (9.9%). hrHPVGT for genotypes HPV16, HPV33, HPV82, HPV18, HPV31, HPV45, HPV58, and HPV52 identified 95% of CIN2+ cases with 90.8% sensitivity, 53.8% specificity, a positive predictive value of 10.2%, and a negative predictive value of 99%. A significantly increased viral load was associated only with women who had HPV16-related CIN2+., Conclusions: hrHPVGT for women who have ASC-US cytology allows for risk stratification capable of optimizing the efficiency of triage for hrHPV-positive women., (© 2021 American Cancer Society.)

Background: High-risk human papillomavirus (hrHPV) messenger RNA (mRNA) testing, the Food and Drug Administration-approved testing platform since 2013, has been increasing as a cervical screening alternative to hrHPV DNA testing methods. This study reports the largest routine clinical follow-up study reported to date of hrHPV mRNA cotesting and histopathologic follow-up results for women with high-grade squamous intraepithelial lesion (HSIL) cytology results., Methods: HSIL Papanicolaou test results for women cotested with Aptima hrHPV mRNA testing between June 2015 and November 2020 were analyzed along with recorded histopathologic follow-up results within 6 months of screening., Results: Aptima hrHPV mRNA-positive results were reported for 95.2% of the cotested HSIL cytology cases (905 of 951). Histopathologic cervical intraepithelial neoplasia grade 2 or worse (CIN2+) was diagnosed on follow-up in 538 of 701 hrHPV mRNA-positive cases (76.8%) and in 15 of 36 hrHPV mRNA-negative cases (41.7%). Additional reviews of the hrHPV mRNA-negative HSIL cases showed variable interpretations, and confirmatory blinded-review interpretations of HSIL or atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion were more likely in cases with histopathologic CIN2+ (77.5% [93 of 120]) than those with cervical intraepithelial neoplasia grade 1 or negative findings (63.1% [101 of 160]; P < .01)., Conclusions: This large routine-clinical-practice study confirms the previously reported high sensitivity of hrHPV mRNA testing for the detection of high-grade cervical dysplasia and cervical cancers. The blinded-review findings indicate that additional cytology review may be helpful for confirming an interpretation of HSIL in daily practice, especially for hrHPV-negative HSIL cases., (© 2021 American Cancer Society.)

Objectives: Cervical stenosis can jeopardize adequate posttreatment cytologic follow-up of patients treated for high-grade cervical intraepithelial lesions. An impact on human papillomavirus (HPV) testing has not been described., Materials and Methods: We describe 2 patients with cervical stenosis, followed by cytology and HPV co-testing after excisions of high-grade cervical intraepithelial lesions. Each had 1 or more co-test "double-negative" results. Hysterectomies revealed unexpected cervical carcinomas., Results: In case 1, an 80-year-old woman with complete cervical stenosis and earlier high-grade squamous dysplasia presented with abdominal pain, nausea, and an enlarged uterus. Attempted endometrial biopsy was unsuccessful. Cytology and HPV tests 9 months earlier were negative. Hysterectomy revealed a cervical squamous carcinoma. In case 2, a 40-year-old woman followed conservatively after excision of endocervical adenocarcinoma in situ had 5 follow-up cytology and HPV co-tests. All were HPV negative. Elective hysterectomy revealed cervical adenocarcinoma. Both carcinomas tested HPV positive., Conclusions: Cervical stenosis in women developing cervical cancer can cause misleading sampling and false-negative HPV test results.

Objectives: Given the recent debate challenging the contribution of cytology in cervical screening, we evaluated results of liquid-based cytology (LBC) and human papillomavirus (HPV) testing in cotesting preceding cervical cancer (CxCa) and precancer diagnoses in a national, heterogeneous population., Methods: We assessed the results of cotesting, performed by Quest Diagnostics, in 13,633,071 women 30 years and older, tested 2010 to 2018. Cotest results preceding CxCa or precancer diagnoses were analyzed and stratified by histopathology., Results: Among all screening results, 1,615 cotests preceded 1,259 CxCa diagnoses, and 11,164 cotests preceded 8,048 cervical precancer diagnoses. More women who were subsequently diagnosed with CxCa within 1 year were identified by the LBC result than by the HPV result (85.1%, 1,015/1,193 vs 77.5%, 925/1,193). Among all women with CxCa, the overall rate of nondetection was 13.1% (212/1,615) for cotesting results (LBC negative/HPV negative) and this rate increased substantially when testing exceeded 12 months compared to within 1 year prediagnosis of either CxCa or precancer., Conclusions: Analysis of 9-year cotest results from a national reference laboratory confirms the value of LBC element in cotesting. This supports that LBC/HPV cotesting enhances screening for the identification of CxCa in women 30 years and older, more so than LBC or HPV alone within cotesting., (© American Society for Clinical Pathology, 2020.)

Introduction: Our objective was to evaluate the impact on the incidence of cervical cancer in New Zealand of 5-yearly human papillomavirus (HPV) primary screening compared with 3-yearly cytology., Materials and Methods: Unbiased estimates of the screening test sensitivity of HPV and cytology screening, and screening coverage, were used to calculate the reduction in cervical cancer incidence obtained by current cytology screening and the new HPV screening policy., Results: HPV screening in New Zealand is predicted to increase the incidence of cervical cancer in women being screened by 81.7% (95% CI: 38.9%-124.7%). The overall increase in the population incidence of cervical cancer in New Zealand was estimated to be 46.7% (95% CI 42.6%-50.8%), leading to about 57 more women developing cervical cancer each year., Conclusions: The results indicate that lengthening the screening interval concurrently with changing to HPV testing may reduce the protection from invasive cervical cancer for women. Women in New Zealand should continue to be screened by cytology every 3 years. Changes to screening policy should be carefully designed so that changes in screening effectiveness can be accurately measured., (Copyright © 2019 American Society of Cytopathology. Published by Elsevier Inc. All rights reserved.)

Objectives: Cervical screening strives to prevent cervical cancer (CxCa), minimizing morbidity and mortality. Most large US reports on cytology and human papillomavirus (HPV) cotesting of women aged 30 years and older are from one laboratory, which used conventional Papanicolaou (Pap) smears from 2003 to 2009., Methods: We quantified detection of CxCa and precancer (cervical intraepithelial neoplasia 3/adenocarcinoma in situ [CIN3/AIS]) in 300,800 cotests at Magee Womens Hospital since 2005. Screening histories preceding CxCa and CIN3/AIS diagnoses were examined to assess the contribution of cytology and HPV testing. Cotesting utilized Food and Drug Administration-approved imaged liquid-based cytology (LBC) and from-the-vial HPV tests., Results: LBC identified more women subsequently diagnosed with CxCa and CIN3/AIS than HPV testing. HPV-negative/cytology-positive results preceded 13.1% of CxCa and 7.2% of CIN3/AIS diagnoses., Conclusions: LBC enhanced cotesting detection of CxCa and CIN3/AIS to a greater extent than previously reported with conventional Pap smear and HPV cotesting.

Background: Cervical cancer screening in China is largely limited to occasional opportunistic screening in urban centers. The current study reports histopathologic follow-up and human papillomavirus (HPV) results in women with high-grade squamous intraepithelial lesion (HSIL) Papanicolaou (Pap) tests reported at the largest academic women's hospital in China and compares these findings with those of published Western studies among frequently screened women., Methods: A retrospective cohort study documented HSIL Pap tests, patient age, HPV results, and histopathologic follow-up from 2011 through 2015 in the Obstetrics and Gynecology Hospital of Fudan University (OGHFU) in Shanghai, China. Of 886,122 Pap test results, 4269 (0.48%) reported HSIL. Histopathologic follow-up was available for 2351 cases and HPV results were available for 2092 cases., Results: HSIL reporting rates increased with patient age from 0.16% at age <30 years to 0.58% at ages 30 to 49 years and 0.75% at age ≥50 years. HSIL rates were found to be significantly higher for women tested using liquid-based cytology (0.52%-0.55%) compared with conventional Pap tests (0.19%). Among 2351 cases with histopathologic follow-up, cervical intraepithelial neoplasia of type 2/3 was diagnosed in 74.1% of cases and squamous cell carcinoma in 14.2% of cases. Squamous cell carcinoma was diagnosed in 22.8% of patients aged ≥50 years who underwent biopsy. HPV-positive HSIL rates using 3 different HPV tests ranged from 88.1% to 93.9%., Conclusions: At OGHFU, the finding of an increase in HSIL cytology rates with increasing patient age contrasted with a finding of decreasing HSIL rates with increasing age previously reported in regularly screened cotested patients in the United States. The increasing HSIL rates with older age and high rates of cervical cancer diagnoses noted at OGHFU appear to be best explained by the absence of consistent intraepithelial lesion ablation achievable with frequent screening and treatment. Cancer Cytopathol 2017;125:947-53. © 2017 American Cancer Society., (© 2017 American Cancer Society.)

Objectives: This study on human papillomavirus (HPV) testing in China's largest independent laboratory accredited by the international Laboratory Accreditation Program of the College of American Pathologists extends previous reports on cervical screening test results from this Chinese facility., Methods: A retrospective laboratory database search from 2007 to 2014 documented high-risk HPV test results using either Hybrid Capture 2 (HC2; Qiagen, Hilden, Germany) or multiplex polymerase chain reaction fluorescence testing (MPFT) methods., Results: During the study period, HPV testing steadily increased, with 643,702 HC2 and 27,641 MPFT HPV tests performed. The mean ages of the tested women were 35.0 years using HC2 and 38.3 years using MPFT. The HC2 HPV-positive rate was 21.7%, significantly higher than 15.7% with MPFT (P < .0001), with bimodal peak incidence in adolescents and women aged 60 to 69 years., Conclusions: Use of HPV testing in cervical screening is increasing in China. HC2 HPV-positive rates around 20% in all age groups from more than 500,000 tested Chinese women are consistent with previous reports from China and significantly higher than published HC2 HPV-positive rates in populations with more widespread cervical screening. MPFT HPV-positive rates were slightly lower in every age group. The high HPV-positive rate likely reflects limited routine cervical screening and high cervical cancer incidence in China., (© American Society for Clinical Pathology, 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: Cervical cancer affects 12 000 women in the United States annually. However, despite its prevalence, there remains no good methodology to detect its recurrence., Objective: To identify the role of cervicovaginal high-risk human papilloma virus (hr-HPV) testing in predicting cervical cancer recurrence., Design: This is a retrospective study of patients who underwent hr-HPV testing as part of their routine surveillance for cervical cancer. Standard statistical analyses, including χ² test and multivariable logistic regression, were performed with IBM SPSS 19.0., Results: A total of 133 patients were identified, of whom 107 (80%) had squamous cell carcinoma. Ninety patients (68%) had bulky disease and were treated primarily with chemoradiation and brachytherapy. Of patients whose disease recurred, 5 patients (42%) had tested positive for hr-HPV during their surveillance period, compared to 13 patients (11%) for whom disease did not recur (relative risk: 3.88, P = .002). On multivariate logistic regression, hr-HPV status remained significantly predictive of disease recurrence (odds ratio: 12.3, P = .02, 95% confidence interval: 1.5-99.6). Using 2 × 2 table analysis, we found that while cervicovaginal cytology has limited specificity (5.7%) in predicting recurrence, the combination of cytology with hr-HPV testing increases the specificity of testing to 89.3%., Conclusions: Persistence of hr-HPV is a risk factor for disease recurrence. High-risk-HPV testing is not routinely used during surveillance for cervical cancer, but this study suggests that large, prospective trials investigating the role of hr-HPV testing in cervical cancer surveillance are needed.

Screening for cervical cancer with cytology testing has been very effective in reducing cervical cancer in the United States. For decades, the approach was an annual Pap test. In 2000, the Hybrid Capture 2 human papillomavirus (HPV) test was approved by the U.S. Food and Drug Administration (FDA) for screening women who have atypical squamous cells of underdetermined significance (ASCUS) detected by Pap test to determine the need for colposcopy. In 2003, the FDA approved expanding the use of the test to include screening performed in conjunction with a Pap test for women over the age of 30 years, referred to as "cotesting." Cotesting allows women to extend the testing interval to 3 years if both tests have negative results. In April of 2014, the FDA approved the use of an HPV test (the cobas HPV test) for primary cervical cancer screening for women over the age of 25 years, without the need for a concomitant Pap test. The approval recommended either colposcopy or a Pap test for patients with specific high-risk HPV types detected by the HPV test. This was based on the results of the ATHENA trial, which included more than 40,000 women. Reaction to this decision has been mixed. Supporters point to the fact that the primary-screening algorithm found more disease (cervical intraepithelial neoplasia 3 or worse [CIN3+]) and also found it earlier than did cytology or cotesting. Moreover, the positive predictive value and positive-likelihood ratio of the primary-screening algorithm were higher than those of cytology. Opponents of the decision prefer cotesting, as this approach detects more disease than the HPV test alone. In addition, the performance of this new algorithm has not been assessed in routine clinical use. Professional organizations will need to develop guidelines that incorporate this testing algorithm. In this Point-Counterpoint, Dr. Stoler explains why he favors the primary-screening algorithm, while Drs. Austin and Zhao explain why they prefer the cotesting approach to screening for cervical cancer., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

Background: In the United States, human papillomavirus (HPV) and Papanicolaou (Pap) testing (cotesting) for cervical screening in women ages 30 to 65 years is the preferred strategy, and cytology alone is acceptable. Recently, a proprietary automated test for identifying high-risk HPV types for primary cervical screening was approved by the US Food and Drug Administration. The objective of the current study was to document extensive cervical screening among these screening options., Methods: To investigate the sensitivity of various testing options for biopsy-proven cervical intraepithelial neoplasia grade 3 or worse (≥ CIN3) and cancer, the authors reviewed 256,648 deidentified results from women ages 30 to 65 years at the time of cotest who had a cervical biopsy specimen obtained within 1 year of the cotest., Results: A positive cotest result was more sensitive (98.8%; 4040 of 4090 cotests) for diagnosing ≥ CIN3 than either a positive HPV-only test (94%; 3845 of 4090 HPV-only tests) or a positive Pap-only test (91.3%; 3734 of 4090 Pap-only tests; P < .0001). A positive Pap-only result was more specific (26.3%; 66,145 of 251,715 Pap-only tests) for diagnosing ≥ CIN3 than a positive HPV-only test (25.6%; 64,625 of 252,556 HPV-only tests) or a positive cotest (10.9%; 27,578 of 252,558 cotests; P < .0001). Of 526 cervical cancers, 98 (18.6%) were HPV-only negative, 64 (12.2%) were Pap-only negative, and 29 (5.5%) were cotest negative., Conclusions: Compared with HPV-only testing, cotesting was more sensitive for the detection of ≥ CIN3 in women ages 30 to 65 years. The current data suggest that approximately 19% of women with cervical cancer may be misdiagnosed by an HPV-only cervical screen. It is important to consider these data as the guidelines for cervical cancer screening undergo revision. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made., (© 2015 The Authors. Cancer Cytopathology published by Wiley Periodicals, Inc. on behalf of American Cancer Society.)

Objectives: Cervical screening guidelines now recommend repeat cotesting of patients aged 30 years and older having a human papillomavirus (HPV)-negative low-grade squamous intraepithelial lesion (LSIL) in 1 year as preferred management. Only limited follow-up data on patients with HPV-negative LSILs are available from routine US clinical practice settings., Methods: In total, 680 patients with Hybrid Capture 2 (Qiagen, Hinden, Germany) high-risk HPV-negative LSIL ThinPrep (Hologic, Marlborough, MA) results were identified. Patients' ages and histopathologic, cytologic, and HPV follow-up results were identified., Results: Among 680 patients with HPV-negative LSILs, 468 had follow-up within 1 year. During the study period, 14 (3.0%) of 468 had follow-up high-grade squamous intraepithelial lesion (HSIL) and 184 (39.3%) LSIL findings. No diagnoses of cervical carcinoma were documented. There were no significant follow-up differences between age groups. Of the 321 patients who had follow-up HPV testing, 271 (84.4%) had negative and 50 (15.6%) had positive HPV results., Conclusions: This is the largest study documenting follow-up results for patients with HPV-negative LSIL results based on prevalent US FDA-approved co-testing methods from one collection vial. These data document that risk for follow-up HSILs in these patients is low and also that no cervical cancers were diagnosed. These findings support recent recommendations for repeat co-testing after 1 year as an appropriate option for patients with HPV-negative LSIL results., (Copyright© by the American Society for Clinical Pathology.)

Objectives: To examine data correlating high-risk human papillomavirus (hrHPV) results in patients with both low-grade squamous intraepithelial lesion (LSIL) and atypical squamous cells cannot exclude high-grade squamous intraepithelial lesion (ASC-H) cytology findings (LSIL-H) with follow-up histopathology., Methods: A total of 494 LSIL-H ThinPrep (Hologic, Marlborough, MA) cases with hrHPV testing were identified. Histopathologic follow-up was available in 347 patients., Results: Among 347 patients with follow-up histopathology after LSIL-H cytology and hrHPV testing, 90.5% tested hrHPV positive. Cervical intraepithelial neoplasia (CIN) 2/3 was diagnosed in 29.4% and CIN 1 in 53.6%. CIN 2/3 was diagnosed in significantly more patients with hrHPV-positive LSIL-H than following hrHPV-negative LSIL-H results. Compared with published institutional data, LSIL-H had significantly lower hrHPV and histopathologic CIN 2/3+ rates (90.5% and 29.4%, with no cervical cancers) than high-grade squamous intraepithelial lesion (HSIL) (95.7% and 70.5%, with 2.4% cervical cancers) but higher rates than LSIL (80.2% and 12.9%) or atypical squamous cells/cannot exclude HSIL (ASC-H) (54.3% and 17.2%). Whereas CIN 2/3 detection rates were similar in HPV-positive LSIL-H and HPV-positive ASC-H, CIN 2/3 findings were more likely with HPV-negative LSIL-H than with HPV-negative ASC-H., Conclusions: LSIL-H is a unique category of cytologic abnormality associated with distinctive hrHPV and CIN 2/3+ diagnostic rates.

Objectives: To document screening test histories of women with histopathologic cervical glandular neoplasia (CGN) in a large integrated health system using new methods of cervical screening., Methods: Cervical screening test results were reviewed for 265 patients with histopathologic diagnoses of CGN, including 168 adenocarcinoma in situ, 80 invasive cervical adenocarcinoma, and 17 invasive cervical adenosquamous carcinoma cases., Results: Among 222 cases with known triggers of diagnostic studies, 211 (95%) had recent abnormal Papanicolaou (Pap) test results. Glandular cell abnormalities were the most common recent abnormal Pap test finding in 130 (61.6%) of 211; squamous cell abnormalities alone were documented in 81 (38.4%) of 211, reflecting coexisting cervical intraepithelial neoplasia (CIN) in 60% of CGN cases. Among 114 CGN cases with additional Pap tests more than 4 months to 3 years before CGN diagnosis, 70 (61.4%) had only earlier negative Pap test results. Among 72 CGN cases with recent human papillomavirus (HPV) test results, 70 (97.2%) tested HPV positive. Among 29 CGN cases with HPV test results more than 4 months to 3 years before CGN diagnosis, 25 (86.2%) tested HPV positive., Conclusions: Conservative cytologic screening practices and HPV cotesting can facilitate early diagnoses of CGN.

Context: Cervical screening in the United States increasingly involves newer US Food and Drug Administration-approved cytologic methods and adjunctive high-risk human papillomavirus (hrHPV) DNA testing., Objective: To document cervical screening test performance preceding histopathologic cervical intraepithelial neoplasia (CIN) 2/3 diagnoses., Design: Preceding screening test results with computer-imaged, liquid-based cytology (LBC) and hrHPV results were analyzed for 2827 patients with histopathologic CIN 2/3 diagnoses., Results: Of 2827 patients with CIN 2/3 diagnoses, 2074 (73.4%) had system LBC findings within 4 months of CIN 2/3 diagnoses: high-grade squamous intraepithelial lesion (n = 862; 41.6%), low-grade squamous intraepithelial lesion (n = 464; 22.4%), atypical squamous cells of undetermined significance (n = 445; 21.5%), atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion (n = 288; 13.9%), and atypical glandular cells/adenocarcinoma in situ (n = 15; 0.7%). Of the 2827 patients, 1488 (52.6%) also had earlier system LBC results at more than 4 months to 3 years before CIN 2/3 diagnoses: one or more abnormal LBC results (n = 978; 65.7%), one or more negative LBC results (n = 911; 61.2%), both abnormal and negative LBC (n = 401; 26.9%). Of 807 patients with hrHPV cotest results within 4 months of CIN 2/3 diagnoses, 786 (97.4%) had hrHPV(+) results. Of 454 patients who also had earlier hrHPV results at more than 4 months to 3 years before CIN 2/3 diagnoses: 377 (83.0%) had one or more hrHPV(+) result, 110 (24.2%) had one or more hrHPV(-) result, and 33 (7.3%) had both positive and negative HPV results., Conclusion: Patients with histopathologic CIN 2/3 had recent abnormal LBC results, most often, high-grade squamous intraepithelial lesions. Among cotested patients, 97.4% (786 of 807) tested hrHPV(+). However, a significant number of patients tested during an extended period of several years had earlier negative Papanicolaou or negative HPV test results, suggesting the recent development of some CIN 2/3 lesions and supporting the value of cotesting for enhanced detection of other developing, small, inaccessible, or nondiagnostic precursor lesions.

Recently updated cervical screening guidelines have proposed a 5-year screening interval for women aged 30 years and older with "double-negative" Papanicolaou (Pap) and high-risk human papillomavirus (hrHPV) results (DNR); however, published US follow-up data on women with DNR tested with US Food and Drug Administration (FDA) - approved HPV testing are limited to studies from Kaiser Permanente using conventional Pap smear cytology. Between July 2005 and June 2006, 4,112 patients with DNR who were screened with computer-imaged liquid-based cytology (LBC) (ThinPrep) and Hybrid Capture 2 (HC2) hrHPV tests of LBC vial fluid were identified. Cytologic or histopathologic data were available for 3,211 patients who were followed up for a mean 44 months. Among 2,960 patients aged 30 years and older with DNR, follow-up cervical abnormalities of cervical intraepithelial neoplasia (CIN) 3 or more severe (CIN3+) were documented in 5 (0.17%), including 1 endocervical adenocarcinoma. After DNR, CIN+ diagnoses were significantly more likely in women younger than 50 years than in older women. These data are consistent with previously published US and international studies that have consistently documented low rates of histopathologic CIN3+ during years of follow-up after DNR. Large-scale nationwide data are needed to further assess the level of risk of invasive cervical cancer after DNR using different available hrHPV testing methods.

Limited follow-up data are available on patients with cervical cytology results of atypical squamous cells, cannot exclude a high-grade intraepithelial lesion (ASC-H), who test negative for high-risk human papillomavirus (hrHPV). Between June 2005 and December 2010, 885 patients were identified with ThinPrep results of Hybrid Capture 2 (HC2) hrHPV-negative cervical ASC-H liquid-based cytology and follow-up histopathology or cytology results extending to September 2011. Of the 885 patients with available follow-up results, 549 (62.0%) had at least 1 histopathologic result during the entire follow-up period, whereas 336 (38.0%) had only cytologic follow-up documented. In an average follow-up period of 29 months, 14 (1.6%) of 885 patients with HPV-negative ASC-H results showed evidence of high-grade cervical intraepithelial neoplasia (CIN2/3). No cases of invasive cervical cancer were diagnosed. Four of 14 patients with HPV-negative ASC-H results with follow-up diagnoses of CIN2/3 had a history of earlier CIN2/3 diagnoses before HPV-negative ASC-H results. Follow-up of patients with HPV-negative ASC-H results using methods specified in this study yielded low rates of detectible CIN2/3 and no diagnoses of cervical cancer. Triage of study patients with HPV-negative ASC-H results to routine HPV and cytology cotesting at 1 year was a safe follow-up option.

Background: The study documents histopathologic outcomes and high-risk (hr) human papillomavirus (HPV) test results in a large cohort of patients with high-grade squamous intraepithelial lesion (HSIL) liquid-based cytology (LBC) Pap test results., Methods: A total of 352 patients with HSIL results (338 cervical and 14 vaginal) who had hrHPV testing and 290 patients with biopsy follow-up were studied. hrHPV detection rates were compared at different ages, with or without an endocervical/transformation zone sample (EC/TZS), and for cervical and vaginal HSIL Pap smears. Histopathologic follow-up findings were also compared. hrHPV-negative HSIL slides were re-evaluated in a blinded manner., Results: A total of 325 of 338 (96.2%) cervical HSIL and 12 of 14 (87.5%) vaginal HSIL tested hrHPV-positive. A total of 271 of 281 (96.4%) EC/TZS-positive cervical HSIL and 54 of 57 (94.7%) EC/TZS-negative cervical HSIL tested hrHPV-positive. The percentage of hrHPV-positive HSIL declined slightly with increasing age. 197 of 273 (72.3%) hrHPV-positive cervical HSIL had histopathologic cervical intraepithelial neoplasia (CIN) 2/3+ follow-up, including 8 squamous carcinomas, compared with 4 of 12 (33.3%) hrHPV-negative HSIL with CIN2/3 (no carcinomas). 167 of 241 (69.2%) EC/TZS-positive HSIL had CIN2/3+ follow-up, compared with 34 of 44 (77.3%) EC/TZS-negative HSIL. Equivocal HSIL morphology characterized some HPV-negative HSIL without CIN2/3+ follow-up., Conclusions: hrHPV was detected in LBC vials from 96.2% of 338 cervical HSIL and 85.7% of 14 vaginal HSIL. CIN2/3+ was significantly more likely with hrHPV-positive cervical HSIL than with hrHPV-negative cervical HSIL. Presence or absence of an EC/TZS did not significantly impact HSIL hrHPV or CIN2/3+ rates. Some hrHPV-negative HSIL cases may represent HSIL cytologic mimics., (Copyright © 2011 American Cancer Society.)

Context: Data on cytologic screening and follow-up disproportionately reflect findings from frequently screened younger women, and data from screened women 50 years and older using newer screening technologies remain limited., Objective: To better understand the utility of adjunctive high-risk human papillomavirus (hrHPV) testing for disease risk stratification in women 50 years and older with a range of liquid-based cytology, abnormal, squamous cell Papanicolaou test results., Design: Liquid-based cytology cases interpreted as high-grade squamous intraepithelial lesion (HSIL); low-grade squamous intraepithelial lesion (LSIL); atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion (ASC-H); and atypical squamous cells of undetermined significance (ASC-US) at Magee-Womens Hospital (Pittsburgh, Pennsylvania) were retrospectively identified for a 36-month period between July 1, 2005, and June 30, 2008, from women 50 years and older who also had hrHPV DNA test results. Histopathologic follow-up diagnoses were analyzed., Results: During the study period, 4855 women 50 years and older had HSIL, LSIL, ASC-H, or ASC-US Papanicolaou test results and hrHPV testing. In 89.3% of HSIL cases, 71.0% of LSIL cases, 38.9% of ASC-H cases, and 14.2% of ASC-US cases, hrHPV test results were positive. The positive predictive value of a positive hrHPV test for histopathologic cervical intraepithelial neoplasia 2/3(+) detection was 90.5% with HSIL, 15% with ASC-H, 9.8% with LSIL, and 3.2% with ASC-US. A negative hrHPV test result had a 100% negative predictive value for histopathologic cervical intraepithelial neoplasia 2/3(+) in both LSIL and ASC-H cases., Conclusions: In women 50 years and older, a positive hrHPV test result significantly increased the likelihood of follow-up histopathologic diagnoses of cervical intraepithelial neoplasia 2 /3(+) in patients with HSIL, LSIL, and ASC-H Papanicolaou test results compared with women with negative hrHPV test results. No cervical intraepithelial neoplasia 2/3(+) diagnoses were documented in women 50 years and older with LSIL or ASC-H Papanicolaou test results and negative hrHPV test results.

Objective: To review the cytology category atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion (ASC-H), with human papillomavirus (HPV) and other ancillary testing results and according to age group., Methods: A literature search was performed on the ASC-H category, and studies analyzing ASC-H according to ancillary testing modalities or patient age groups during the past 4 years were emphasized., Results: The ASC-H category accounts for less than 1% of cytology reports, and 33% to 84% will test positive for oncogenic HPV. The number of patients with cervical intraepithelial neoplasia 2/3 and cancer on biopsy is quite variable, from about 12% to more than 70%, averaging about 40%. The variation reflects patient population as well as local laboratory practices, but older subgroups are more likely to have negative HPV results and negative follow-up. Both the sensitivity of HPV testing for cervical intraepithelial neoplasia 2/3 detection and the negative predictive value for a patient with ASC-H and negative HPV testing average more than 95%. Additional studies evaluating other types of ancillary testing for the ASC-H category are needed., Conclusions: Atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion, is an uncommon cytology result, and HPV testing results and biopsy follow-up show variation according to patient age group and local laboratory practices. A negative HPV result in ASC-H offers a high negative predictive value and could be considered as a management strategy in mature women as well as women 30 years and older receiving combined cytology and HPV screening.

Objective: The purpose of this study was to document the prevalence of high-risk HPV DNA (HPV) in the largest cohort of woman studied to date with negative ThinPrep Imaging system (TIS)-imaged Pap tests., Methods: Women with negative (TIS)-imaged ThinPrep Pap Tests (TPPT) who also were tested for HPV were identified between July 1, 2005 and December 31, 2007 from a large women's hospital practice. HPV detection rates were compared for women with either presence or absence of a transformation zone/endocervical cell sample (EC/TZS)., Results: 26,558 negative TPPT also underwent HPV testing. HPV detection was higher in women younger than 30 and sharply declined in women 30-39 (P<0.001). Declining HPV detection rates continued in the 40-49 age group (age 30-39 vs. 40-49; 2.8% vs. 1.7%, P<0.001) and then levelled off. No statistically significant difference for HPV prevalence was identified comparing women with and without a TZ/ECS., Conclusion: This is the largest study to date documenting very low HPV detection rates in women screened cytology negative with computer-imaged liquid-based Pap methods now representing a major portion of the U.S. cervical cytology market. Findings of very low rates of HPV detection in 490 (1.9%) of 25,259 cytology negative women 30 and older extend and confirm previously reported findings in smaller study populations. Because HPV testing provides an objective measure of relative residual risk for cervical neoplasia after screening, these data are relevant to discussions on how best to combine cytology and HPV testing in screening low risk populations.

Context: Reflex human papillomavirus (HPV) testing has been designated in consensus guidelines as "preferred" for women with atypical squamous cells of undetermined significance (ASC-US) liquid-based cytology (LBC) results, and colposcopy is currently recommended for patients with HPV-positive ASC-US results. Data from large clinical practices using newer screening methods and current cytology terminology are limited., Objectives: We analyzed data from patients with ASC-US LBC and positive HPV test results. We also assessed the impact of the presence or absence of an endocervical cell/ transformation zone sample (EC/TZS) on biopsy diagnoses., Design: The information system of a large women's hospital serving an older-than-average population was searched over a 21-month period between July 1, 2005, and March 31, 2007, for HPV-positive cases interpreted as ASC-US (Bethesda System 2001) using computer-imaged LBC. Histologic diagnoses, patient ages, and presence or absence of an EC/TZS were analyzed. The average follow-up period was 7.5 months., Results: Among 4273 women with HPV-positive ASC-US results, the cumulative cervical intraepithelial neoplasia 2 or 3 (CIN 2/3) and CIN 1 rates for 2192 women with available biopsies were 5.1% and 43.6%, respectively. Cervical intraepithelial neoplasia 2/3 and CIN 1 rates for women with HPV-positive ASC-US results were not significantly different for women with and without an EC/TZS., Conclusions: The risk of CIN 2/3 in the study population was significantly lower than reported in widely cited trial data. Neither presence nor absence of an EC/TZS, nor the age of the patient, had a statistically significant impact on the likelihood of biopsy diagnoses of CIN 2/3 and CIN 1 for patients with HPV-positive ASC-US test results.

Objectives: This study assesses whether high-risk human papillomavirus (HPV) DNA test results from residual vial fluid of unsatisfactory liquid-based cytology(LBC) samples might provide useful information on disease risk., Materials and Methods: Patients with unsatisfactory imaged ThinPrep Pap test results and available Hybrid Capture 2 high-risk HPV results were identified at an academic women's hospital laboratory between July 1, 2005, and July 31, 2007. Follow-up repeat cytology results, HPV results, and available biopsy results were analyzed., Results: Three hundred four patients with unsatisfactory cytology results and HPV test results were studied. Eleven (3.6%) of 304 tested positive for HPV DNA, and 293 tested HPV negative. Five (45%) of 11 HPV-positive patients had detectible low-grade squamous intraepithelial/cervical intraepithelial neoplasia 1 during a mean follow-up period of almost 6 months. Among 293 women with negative HPV results, only 1 case of cervical intraepithelial neoplasia 1 was identified during roughly the same follow-up period., Conclusions: A positive high-risk HPV result associated with an unsatisfactory ThinPrep Pap test result identified patients at risk for diagnosis of an undetected squamous intraepithelial/cervical intraepithelial neoplasia. Negative high-risk HPV results associated with an unsatisfactory LBC had high negative predictive value in this limited study. The overall low detection rate for significant disease on follow-up of all patients with unsatisfactory imaged LBC is similar to findings reported in another LBC study but differs from studies reporting increased risk for undetected disease in women screened with unsatisfactory conventional Pap smears.

Background: The prevalence of high-risk Human Papillomavirus DNA (hrHPV DNA) in women with negative Papanicolaou (Pap) test results provides a measure of residual risk for cervical neoplasia after cytology screening. The purpose of this study was to document the prevalence of hrHPV DNA in several thousand women ages > or =30 years with negative ThinPrep Imaging System (TIS)-imaged Pap test results in a large academic hospital cytology laboratory., Methods: All cytology-negative TIS-imaged ThinPrep Pap tests (TPPT) with hrHPV DNA tests that were performed by the United States Food and Drug Administration (FDA)-approved Hybrid Capture 2 (HC2) method from May 1, 2005 to November 20, 2006 were identified and reviewed. Imaged-negative Pap test slides associated with a positive hrHPV DNA test result were rescreened manually. Variation in hrHPV DNA prevalence was assessed for different age and ethnic groups., Results: Of 8070 imaged cytology-negative TPPT from women ages 11 to 90 years, hrHPV DNA test results were also available. Among 7426 women ages > or =30 years with a cytology-negative, TIS-imaged, Pap test, a significant age-associated decline in hrHPV DNA prevalence was noted, 3.4% in 3050 women ages 30-45 years, 2.4% in 7426 women ages 30-90 years, and 1.8% in 5491 women ages 40-90 years. The hrHPV DNA-positive rate was 2.3% in 6012 imaged cytology-negative white women and 4.1% in 739 imaged cytology-negative black women., Conclusions: Very low HC2 hrHPV DNA rates in 7426 women ages > or =30 years with cytology-negative, TIS-imaged, ThinPrep, Pap tests were similar to recently published data from 1 other academic center and lower than rates reported in previous studies on cytology-negative North American or European women screened manually with conventional or liquid-based Pap tests. These data may impact assessments of how best to combine cytology and HPV testing.

Risk management efforts in the cytology laboratory must address the gap between what can be achieved with medical history's most effective cancer screening test, the Papanicolaou (Pap) test, and even higher entrenched public expectations. Data from the Atypical Squamous Cells of Undetermined Significance (ASCUS)/Low-Grade Squamous Intraepithelial Lesion Triage Study (ALTS) now provide level I clinical evidence from a large, randomized, controlled, multicenter clinical trial that reflex human papillomavirus (HPV) DNA testing of ASCUS cases is generally the preferred method for initial assessment of the most prevalent category of abnormal Pap interpretation. The proposed combination of HPV DNA testing with cytologic Pap testing, the DNA Pap test, further shows the potential to nearly eliminate false-negative screening results, based on sensitivity and negative predictive values reported in available studies. Human papillomavirus DNA testing also appears to represent a significant enhancement for detection of endocervical adenocarcinomas, which are difficult to detect and prevent. Human papillomavirus DNA testing, when used in conjunction with cervical cytology, can significantly reduce risk to both the patient and the laboratory.