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Castle P.E.,American Society for Clinical Pathology Institute | Schiffman M.,U.S. National Cancer Institute
Journal of Clinical Microbiology | Year: 2012

High-risk human papillomavirus (HR-HPV) testing is increasingly important. We therefore examined the impact on accuracy of repeated versus one-time testing, type-specific versus pooled detection, and assay analytic sensitivity. By using a nested casecontrol design from the ASCUS-LSIL Triage Study, we selected women with incident cervical intraepithelial neoplasia grade 2 or grade 3 (CIN2/3; n = 325) and a random sample of women with


Saslow D.,Breast and Gynecologic Cancer | Solomon D.,U.S. National Institutes of Health | Lawson H.W.,Emory University | Killackey M.,Sloan Kettering Cancer Center | And 15 more authors.
CA Cancer Journal for Clinicians | Year: 2012

An update to the American Cancer Society (ACS) guideline regarding screening for the early detection of cervical precancerous lesions and cancer is presented. The guidelines are based on a systematic evidence review, contributions from 6 working groups, and a recent symposium cosponsored by the ACS, the American Society for Colposcopy and Cervical Pathology, and the American Society for Clinical Pathology, which was attended by 25 organizations. The new screening recommendations address age-appropriate screening strategies, including the use of cytology and high-risk human papillomavirus (HPV) testing, follow-up (eg, the management of screen positives and screening intervals for screen negatives) of women after screening, the age at which to exit screening, future considerations regarding HPV testing alone as a primary screening approach, and screening strategies for women vaccinated against HPV16 and HPV18 infections. CA Cancer J Clin 2012. © 2012 American Cancer Society. Copyright © 2012 American Cancer Society, Inc.


Darragh T.M.,University of California at San Francisco | Tokugawa D.,Kaiser Permanente | Castle P.E.,American Society for Clinical Pathology Institute | Follansbee S.,Kaiser Permanente | And 7 more authors.
Cancer Cytopathology | Year: 2013

BACKGROUND: The majority of anal cancers are caused by persistent infections with carcinogenic human papillomaviruses (HPV). Similar to cervical carcinogenesis, the progression from HPV infection to anal cancer occurs through precancerous lesions that can be treated to prevent invasion. In analogy to cervical cytology, anal cytology has been proposed as a screening tool for anal cancer precursors in high-risk populations. METHODS: The authors analyzed the interobserver reproducibility of anal cytology in a population of 363 human immunodeficiency virus (HIV)-infected men who have sex with men (MSM). Liquid-based cytology (LBC) specimens were collected in the anal dysplasia clinic before the performance of high-resolution anoscopy on all patients. Papanicolaou-stained LBC slides were evaluated by 2 cytopathologists, each of whom was blinded to the clinical outcome and the other pathologist's results, using the revised Bethesda terminology. RESULTS: Overall agreement between the 2 observers was 66% (kappa, 0.54; linear-weighted kappa, 0.69). Using dichotomizing cytology results (atypical squamous cells of undetermined significance [ASC-US] or worse vs less than ASC-US), the agreement increased to 86% (kappa, 0.69). An increasing likelihood of testing positive for markers associated with HPV-related transformation, p16/Ki-67, and HPV oncogene messenger RNA was observed, with increasing severity of cytology results noted both for individual cytologists and for consensus cytology interpretation (P value for trend [ptrend] < .0001 for all). CONCLUSIONS: Moderate to good agreement was observed between 2 cytopathologists evaluating anal cytology samples collected from HIV-positive MSM. A higher severity of anal cytology was associated with biomarkers of anal precancerous lesions. Anal cytology may be used for anal cancer screening in high-risk populations, and biomarkers of HPV-related transformation can serve as quality control for anal cytology.


Guan Y.,Johns Hopkins University | Castle P.E.,American Society for Clinical Pathology Institute | Wang S.,Peking Union Medical College | Li B.,Peking Union Medical College | And 5 more authors.
Sexually Transmitted Infections | Year: 2012

Objective: To assess the acceptability of using self-collection as a method of sampling for human papilloma virus testing in rural China. Methods: 174 women from the national cervical cancer screening programme in Xiangyuan County, China, were enrolled in our study and underwent self-collection, clinician collection, colposcopy examination and were administered questionnaire. The questionnaire assessed the patients' preference and acceptability of collection method. Results: The mean overall acceptability score for self-collection, although significantly less than the overall score for clinician collection (p<0.01), still is well above 4 (4.33 of 5), indicating high acceptability. The acceptability scores for self-collection and clinician collection were not significantly different on scales measuring comfort and convenience (p>0.05). The scores were significantly lower for self-collection on scales measuring trust, ability to collect specimen and perceived effects of testing compared with clinician collection (p<0.01). 74% of participants preferred clinician collection, and of these participants, 86% preferred it because they thought the results were more accurate. Conclusions: The study shows that self-collection was highly acceptable and that self-collection and clinician collection were equally comfortable and convenient; however, the participants still preferred clinician collection because of lack of trust in the results of self-collection. This indicates that self-collection is an acceptable potential method for screening but education programmes about the validity of self-collection that target general population may be needed prior to implementation.


Castle P.E.,American Society for Clinical Pathology Institute | Stoler M.H.,University of Virginia | Wright T.C.,Columbia University | Sharma A.,Hoffmann-La Roche | And 2 more authors.
The Lancet Oncology | Year: 2011

Background: The ATHENA study was designed to assess the performance of carcinogenic human papillomavirus (HPV) testing and HPV16 or HPV18 genotyping compared with liquid-based cytology for cervical cancer screening in a large US population aged 21 years and older. We did a subanalysis of this population to compare the screening performance of the cobas HPV test versus liquid-based cytology in women aged 25 years and older, and assess management strategies for HPV-positive women. Methods: Women aged 25 years or older who were attending routine cervical screening were enrolled from 61 clinical centres in 23 US states. Cervical specimens were obtained for liquid-based cytology and HPV DNA testing with two first-generation assays (Amplicor HPV test and Linear Array HPV genotyping test) and the second-generation cobas HPV test (with individual HPV16 and HPV18 detection). Colposcopy and diagnostic biopsies were done on women with atypical squamous cells of undetermined significance (ASC-US) or worse cytology, those who tested positive with either first-generation HPV test, and a random sample of women who tested negative for HPV and cytology. All women not selected for colposcopy received their results and exited the study. Participants and colposcopists were masked to cytology and HPV test results until the colposcopy visit was completed. The primary endpoint for this substudy was histologically confirmed cervical intraepithelial neoplasia grade 3 (CIN3) or worse. This study is registered with ClinicalTrials.gov, number NCT00709891; the study is in the follow-up phase, which is due to be completed in December, 2012. Findings: From May 27, 2008, to Aug 27, 2009, 47 208 women were enrolled, of whom 41 955 met our eligibility criteria. Valid cobas HPV and liquid-based cytology test results were available for 40 901 women (97%), who were included in this analysis. Of these, 4275 women (10%) tested cobas HPV positive and 2617 (6%) had abnormal cytology. 431 women were diagnosed with CIN2 or worse and 274 with CIN3 or worse. In women who had colposcopy, the cobas HPV test was more sensitive than liquid-based cytology for detection of CIN3 or worse (252/274 [92·0%, 95% CI 88·1-94·6] vs 146/274 [53·3%, 95% CI 47·4-59·1]; difference 38·7%, 95% CI 31·9-45·5; p<0·0001). Addition of liquid-based cytology to HPV testing increased sensitivity for CIN3 or worse to 96·7% (265/274, 95% CI 93·9-98·3), but increased the number of screen positives by 35·2% (5783/40 901 vs 4275/40 901) compared with HPV testing alone. As a triage test to identify CIN3 or worse in HPV-positive women, detection of HPV16, HPV18, or both alone was equivalent to detection of ASC-US or worse alone in terms of sensitivity (150/252 [59·5%] vs 133/252 [52·8%]; p=0·11) and positive predictive value (PPV) (150/966 [15·5%] vs 133/940 [14·1%]; p=0·20). Among HPV-positive women, detection of HPV16, HPV18, or both or low-grade squamous intraepithelial lesion or worse cytology had better sensitivity (182/252 [72·2%]; p<0·0001) and similar PPV (182/1314 [13·9%]; p=0·70) for detection of CIN3 or worse than ASC-US or worse cytology alone. Furthermore, detection of HPV16, HPV18, or both or high-grade squamous intraepithelial lesion or worse cytology had higher sensitivity (165/252 [65·5%]; p=0·0011) and PPV (165/1013 [16·3%]; p=0·031) for detection of CIN3 or worse than ASC-US or worse cytology alone. Interpretation: HPV testing with separate HPV16 and HPV18 detection could provide an alternative, more sensitive, and efficient strategy for cervical cancer screening than do methods based solely on cytology. Funding: Roche Molecular Systems. © 2011 Elsevier Ltd.


Zhao F.-H.,Chinese Academy of Sciences | Lewkowitz A.K.,Mount Sinai School of Medicine | Chen F.,Chinese Academy of Sciences | Lin M.J.,Beth Israel Deaconess Medical Center | And 12 more authors.
Journal of the National Cancer Institute | Year: 2012

Background Worldwide, one-seventh of cervical cancers occur in China, which lacks a national screening program. By evaluating the diagnostic accuracy of self-collected cervicovaginal specimens tested for human papillomavirus (HPV) DNA (Self-HPV testing) in China, we sought to determine whether Self-HPV testing may serve as a primary cervical cancer screening method in low-resource settings. Methods We compiled individual patient data from five population-based cervical cancer-screening studies in China. Participants (n = 13140) received Self-HPV testing, physician-collected cervical specimens for HPV testing (Physician-HPV testing), liquid-based cytology (LBC), and visual inspection with acetic acid (VIA). Screen-positive women underwent colposcopy and confirmatory biopsy. We analyzed the accuracies of pooled Self-HPV testing, Physician-HPV testing, VIA, and LBC to detect biopsy-confirmed cervical intraepithelial neoplasia grade 2 or more severe (CIN2+) and CIN3+. All statistical tests were two-sided. Results Of 13004 women included in the analysis, 507 (3.9%) were diagnosed as CIN2+, 273 (2.1%) as CIN3+, and 37 (0.3%) with cervical cancer. Self-HPV testing had 86.2% sensitivity and 80.7% specificity for detecting CIN2+ and 86.1% sensitivity and 79.5% specificity for detecting CIN3+. VIA had statistically significantly lower sensitivity for detecting CIN2+ (50.3%) and CIN3+ (55.7%) and higher specificity for detecting CIN2+ (87.4%) and CIN3+ (86.9%) (all P values < .001) than Self-HPV testing, LBC had lower sensitivity for detecting CIN2+ (80.7%, P = .015), similar sensitivity for detecting CIN3+ (89.0%, P = .341), and higher specificity for detecting CIN2+ (94.0%, P < .001) and CIN3+ (92.8%, P < .001) than Self-HPV testing. Physician-HPV testing was more sensitive for detecting CIN2+ (97.0%) and CIN3+ (97.8%) but similarly specific for detecting CIN2+ (82.7%) and CIN3+ (81.3%) (all P values <.001) than Self-HPV testing. Conclusions The sensitivity of Self-HPV testing compared favorably with that of LBC and was superior to the sensitivity of VIA. Self-HPV testing may complement current screening programs by increasing population coverage in settings that do not have easy access to comprehensive cytology-based screening. © 2012 The Author. Published by Oxford University Press. All rights reserved.


Castle P.E.,American Society for Clinical Pathology Institute | Gravitt P.E.,Johns Hopkins University | Wentzensen N.,U.S. National Institutes of Health | Schiffman M.,U.S. National Institutes of Health
American Journal of Clinical Pathology | Year: 2012

Cervical intraepithelial neoplasia grade 3 (CIN 3) is the best proxy in research and screening for invasive cancer risk. Yet the timing of CIN 3 development is uncertain because of measurement errors integral to its diagnosis. We were interested in estimating the proportions of prevalent vs incident CIN 3 within 2 years of finding a minor cytologic abnormality. We estimate that only 17 (2.8%) of 613 CIN 3 cases diagnosed during the 2-year duration of the atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intraepithelial lesion (LSIL) triage study (ALTS) were incident CIN 3 following an incident human papillomavirus (HPV) infection that persisted until the CIN 3 diagnosis was made. Using prevalent high-grade cytology as a marker of prevalent CIN 3, we estimated that another approximately 23% of CIN 3 cases were incident CIN 3 following a prevalently detected HPV infection that persisted until the CIN 3 diagnosis was made. We concluded that most CIN 3 cases diagnosed within the 2-year time frame were prevalent cases, and most incident CIN 3 cases followed a prevalently detected HPV infection. Copyright© by the American Society for Clinical Pathology.


Campos N.G.,Center for Health Decision Science | Campos N.G.,University of Miami | Castle P.E.,American Society for Clinical Pathology Institute | Schiffman M.,U.S. National Institutes of Health | Kim J.J.,Center for Health Decision Science
Medical Decision Making | Year: 2012

Background. Although the randomized controlled trial (RCT) is widely considered the most reliable method for evaluation of health care interventions, challenges to both internal and external validity exist. Thus, the efficacy of an intervention in a trial setting does not necessarily represent the real-world performance that decision makers seek to inform comparative effectiveness studies and economic evaluations. Methods. Using data from the ASCUS-LSIL Triage Study (ALTS), we performed a simplified economic evaluation of age-based management strategies to detect cervical intraepithelial neoplasia grade 3 (CIN3) among women who were referred to the study with low-grade squamous intraepithelial lesions (LSIL). We used data from the trial itself to adjust for 1) potential lead time bias and random error that led to variation in the observed prevalence of CIN3 by study arm and 2) potential ascertainment bias among providers in the most aggressive management arm. Results. We found that using unadjusted RCT data may result in counterintuitive cost-effectiveness results when random error and/or bias are present. Following adjustment, the rank order of management strategies changed for 2 of the 3 age groups we considered. Conclusions. Decision analysts need to examine study design, available trial data, and cost-effectiveness results closely in order to detect evidence of potential bias. Adjustment for random error and bias in RCTs may yield different policy conclusions relative to unadjusted trial data.


Wheeler C.M.,University of New Mexico | Hunt W.C.,University of New Mexico | Cuzick J.,Queen Mary, University of London | Langsfeld E.,University of New Mexico | And 5 more authors.
International Journal of Cancer | Year: 2013

Currently, two prophylactic human papillomavirus (HPV) vaccines targeting HPV 16 and 18 have been shown to be highly efficacious for preventing precursor lesions although the effectiveness of these vaccines in real-world clinical settings must still be determined. Toward this end, an ongoing statewide surveillance program was established in New Mexico to assess all aspects of cervical cancer preventive care. Given that the reduction in cervical cancer incidence is expected to take several decades to manifest, a systematic population-based measurement of HPV type-specific prevalence employing an age- and cytology-stratified sample of 47,617 women attending for cervical screening was conducted prior to widespread HPV vaccination. A well-validated polymerase chain reaction (PCR) method for 37 HPV genotypes was used to test liquid-based cytology specimens. The prevalence for any of the 37 HPV types was 27.3% overall with a maximum of 52% at age of 20 years followed by a rapid decline at older ages. The HPV 16 prevalences in women aged ≤20 years, 21-29 years or a;̂yen30 years were 9.6, 6.5 and 1.8%, respectively. The combined prevalences of HPV 16 and 18 in these age groups were 12.0, 8.3 and 2.4%, respectively. HPV 16 and/or HPV 18 were detected in 54.5% of high-grade squamous intraepithelial (cytologic) lesions (HSIL) and in 25.0% of those with low-grade SIL (LSIL). These baseline data enable estimates of maximum HPV vaccine impact across time and provide critical reference measurements important to assessing clinical benefits and potential harms of HPV vaccination including increases in nonvaccine HPV types (i.e., type replacement). Copyright © 2012 UICC.


Castle P.E.,American Society for Clinical Pathology Institute | Castle P.E.,U.S. National Institutes of Health | Castle P.E.,University of New Mexico | Gage J.C.,American Society for Clinical Pathology Institute | And 8 more authors.
Obstetrics and Gynecology | Year: 2011

Objective: To determine whether the diagnosis of cervical intraepithelial neoplasia (CIN) grade 1 increases the risk of CIN 3 above what is observed for human papillomavirus (HPV) infection. Methods: Using data from the atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intraepithelial lesions (LSIL) triage study, we compared the 2-year cumulative risk of CIN 3 for women with an enrollment diagnosis of CIN 1 (n=594) (median age 23 years) compared with those with negative histology or no biopsy taken at colposcopy ("no CIN 1," n=570) (median age 24 years). Baseline cervical specimens were tested for carcinogenic HPV by a clinical HPV test and HPV genotypes by polymerase chain reaction. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) as a measure of association of enrollment status, including CIN 1 compared with no CIN 1 diagnosis, with 2-year worst outcomes of CIN 3. Results: The two-year risks of CIN 3 were 10.3% (95% CI 7.9-13.0) for women with CIN 1, 7.3% (95% CI 4.6-10.9) for negative histology, and 6.4% (95% CI 3.8-9.9) for women referred to colposcopy and no biopsies were taken (P=.1). The 2-year risks of CIN 3 for women positive for HPV16, HPV18, or other carcinogenic HPV genotypes were 19.1%, 13.9%, and 5.7%, respectively, and did not differ significantly by the baseline cytology interpretation (ASCUS or LSIL). Taking HPV genotypes into account, having a CIN 1 (compared with no CIN 1) was not a risk factor for developing CIN 3 (OR 0.99, 95% CI 0.54-1.8). Conclusion: A CIN 1 diagnosis does not represent a significant risk factor for CIN 3 above the risk attributed to its molecular cause, genotype-specific HPV infection. © 2011 by The American College of Obstetricians and Gynecologists. Published by Lippincott Williams & Wilkins.

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