Evan R. Myers

Accuracy of the Papanicolaou Test in Screening for and Follow-up of Cervical Cytologic Abnormalities: A Systematic Review

Since the implementation of widespread screening with the Papanicolaou (Pap) test, rates of cervical cancer in the United States have decreased from 14.2 per 100 000 in 1973 to 7.8 per 100 000 in 1994. Nevertheless, cervical cancer is still the ninth-leading cause of cancer deaths among U.S. women (1). Most of these deaths occur in women who have never had a Pap test, but some occur in women who recently received negative test results. Approximately two thirds of false-negative results are caused by sampling error, and the rest are caused by detection error. Sampling error occurs when abnormal cells are not collected or are not transferred to the Pap slide, and detection error occurs when abnormal cells on the Pap slide are missed or misinterpreted. The most common sampling error is lack of cells from the cervical transformation zone. To reduce sampling error, an endocervical cytobrush and a spatula can be used instead of a cotton swab. However, a recent meta-analysis found that the Pap test did not differ in sensitivity or specificity when different sampling devices were used (2). The Food and Drug Administration (FDA) has approved another potential solution: liquid-based monolayer preparation (ThinPrep, Cytyc Corp., Boxborough, Massachusetts). With this technique, the sample is collected as in the conventional Pap test, but cells are then placed in a fixative solution. The cells are dispersed, collected onto a filter, and transferred to a microscopic slide for interpretation. Because samples are fixed immediately after collection, fewer cellular morphologic artifacts occur. Fewer cells on the slide are obscured because the process reduces the amounts of other sampled material, such as blood and mucus, and deposits cells on the slide in a monolayer. To reduce detection error, some researchers advocate rescreening slides initially reported to be normal. The Clinical Laboratory Improvement Amendments of 1988 mandate rescreening of a 10% random sample of normal slides as a quality assurance measure. Rescreening can also be performed on a higher proportion of slides by using computerized technologies. The FDA has approved two such systems, one that is algorithm-based (AutoPap QC System, TriPath Imaging, Inc., Redmond, Washington), and one that uses neural networks (PAPNET, Neuromedical Systems, Inc., Suffern, New York). PAPNET uses neural network computerized imaging of Papanicolaou smear slides to identify cells or clusters of cells that require review; it then displays up to 128 images per slide that are likely to contain abnormalities. A cytotechnologist reviews these images and decides whether to review the actual slide using light microscopy. AutoPap uses its algorithm-based decision-making technology to identify slides that exceed a certain threshold for the likelihood of abnormal cells. The laboratory can select different thresholds, corresponding to 10%, 15%, or 20% review rates. In contrast to random rescreening, AutoPap selects a sample of slides that is enriched with abnormalities, thereby including most of the slides that contain abnormalities missed by manual screening. Another approach to reducing detection error is improving the sensitivity of the initial screening step. The FDA has recently approved a new method (AutoPap Primary Screening System, TriPath Imaging) for this indication. AutoPap Primary Screening System uses proprietary computerized algorithms to identify slides that exceed a certain threshold for the likelihood of abnormal cells. A cytotechnologist then reviews these slides. The system allows laboratories to concentrate on the 75% of slides that most likely contain abnormal cells while immediately archiving the remainder. Sampling and detection errors are reduced when Pap test screening is repeated frequently. However, cost-effectiveness analyses have concluded that if persons are screened more than every 3 years, cost-effectiveness ratios exceed

American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer

50 000 per life-year saved (3, 4). Precise estimates of cytologic test sensitivity and specificity are important because they may be used to determine policy decisions, such as recommendations for optimal frequency of screening, management of mild abnormalities, and use of newer methods. Our primary objective was to systematically review the operating characteristics of conventional and new methods (computer screening and monolayer slide preparation) of Pap testing in the detection of cervical cancer and its precursors. We also evaluated test performance among women with previous cytologic abnormalities. The Agency for Healthcare Research and Quality (AHRQ), under contract to Duke University (Durham, North Carolina), funded the study. An AHRQ-approved advisory panel assisted in the design, conduct, and reporting of this work, and the evidence report on which this manuscript is based was reviewed by an external peer review panel (5). Methods Data Sources Data sources, including MEDLINE (from 1966), EMBASE (from 1980), HealthStar (from 1975), CancerLit (from 1983), and CINAHL (from 1983) were searched through October 1999 by using a strategy developed with a medical librarian (Table 1). Searches were limited to English-language studies in humans. We manually searched newly published relevant journal issues, bibliographies of included studies, and recent systematic reviews (6-9). To locate unpublished studies, we also contacted relevant professional societies and manufacturers of cytologic devices. Table 1. Search Strategy Study Selection We identified studies of conventional Pap testing (with or without manual rescreening), Pap testing using monolayer slide preparation (ThinPrep), Pap testing with primary computer screening (AutoPap or PAPNET), and Pap testing with computer rescreening (AutoPap or PAPNET). Other recently developed methods, the AutoCyte PREP System and the AutoCyte SCREEN system (TriPath Imaging, Inc., Burlington, North Carolina), had not been approved by the FDA at the time of our review and were not evaluated in this study. Study samples included women undergoing Pap testing for primary screening and those undergoing evaluation for previous cytologic abnormalities. The main outcome measures were the sensitivity and specificity of the cytologic test for detecting cases. Cytologic abnormality was defined by one of three thresholds: atypical squamous cells of undetermined significance (ASCUS), low-grade squamous intraepithelial lesions (LSIL), and high-grade squamous intraepithelial lesions (HSIL). Cases were defined as histologic diagnosis of cervical intraepithelial neoplasia (CIN), grades I to III, or carcinoma. Equivalent categories in other classification schemes (10-14) were also used (Figure). Figure. Map of classification schemes for cervical cytology. We included studies of the conventional Pap test if a reference standard of histologic examination or colposcopy was reasonably concurrent to the cytologic screening test (within 3 months) and if sufficient data were reported to complete all four cells of a 2 2 table. Comparison with such a reference standard provides a more relevant outcome for clinical decision makers because colposcopic or histologic diagnoses form the basis of most clinical management decisions. Only one study of ThinPrep (15) provided enough information to allow us to extract data on sensitivity and specificity compared with a gold standard of histologic examination or colposcopy. We therefore used a separate set of screening criteria for studies of the new methods, based on cytology society guidelines (16, 17) and FDA documents [18]: 1) The study must prospectively compare screening tests or test and reference standard on the same set of patients or slides; 2) if cytologic examination is the reference standard, discordant results from the two study tests must be adjudicated by an independent panel of experienced cytology professionals; 3) at least 50% of patients testing positive for HSIL must be verified by histologic examination or colposcopy; and 4) the study design must allow for separate analyses of sensitivity (or relative true-positive rate) and specificity (or relative false-positive rate). Data based on a cytologic reference standard cannot be integrated with data based on a histologic reference standard (19-23). However, when negative test results are not verified with the reference standard, information about incremental characteristics of test performance may be obtained by directly comparing independently applied conventional and new tests (21). In this case, both tests must be applied independently to all patients, and all positive results on either test must be verified with the reference standard. A relative true-positive rate and a relative false-positive rate, which can be used to determine relative estimates of the performance of the new test, can then be calculated. Two investigators independently screened each study. Differences of opinion were reconciled by consensus. The title and abstract of each citation were screened first, and the full report was screened second. Of the 1193 bibliographic references we reviewed, 761 (approximately 64%) were excluded on the basis of title or abstract. We reviewed the full reports of 346 studies of the conventional Pap test and 86 studies of the new methods (18 on AutoPap, 42 on PAPNET, and 26 on ThinPrep). We developed a numeric quality score to evaluate included citations. Nine members of the studys working group (6 clinicians, 2 economists, and 1 health policy analyst) initially identified more than 12 evaluation criteria on the basis of previously reported criteria (6, 24, 25). We used a consensus process to narrow this list to 7. Blinded to the rest of the group, each participant then independently assigned numerical weights to the criteria. The means of these votes were calculated. Each participant received a copy of his or her responses, depicted graphically in relation to the mean for each criterion, and was requested to confirm or

American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer.

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.

Acute Myocardial Infarction in Pregnancy. A United States Population-Based Study

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.

Incidence and risk factors for stroke in pregnancy and the puerperium.

Background— The purpose of this study was to determine the incidence, mortality, and risk factors for pregnancy-related acute myocardial infarction in the United States. Methods and Results— The Nationwide Inpatient Sample for the years 2000 to 2002 was queried for all pregnancy-related discharges. A total of 859 discharges included a diagnosis of acute myocardial infarction, for a rate of 6.2 (95% confidence interval [CI] 3.0 to 9.4) per 100 000 deliveries. Among these, there were 44 deaths, for a case fatality rate of 5.1%. The odds of acute myocardial infarction were 30-fold higher for women aged 40 years and older than for women <20 years of age. Single independent variables that were statistically and clinically significant, including age, race, and certain medical conditions and obstetric complications, were entered into a multivariable logistic regression model. Hypertension (odds ratio [OR] 21.7, 95% CI 6.8 to 69.1), thrombophilia (OR 25.6, 95% CI 9.2 to 71.2), diabetes mellitus (OR 3.6, 95% CI 1.5 to 8.3), smoking (OR 8.4, 95% CI 5.4 to 12.9), transfusion (OR 5.1, 95% CI 2.0 to 12.7), postpartum infection (OR 3.2, 95% CI 1.2 to 10.1), and age 30 years and older remained as significant risk factors for pregnancy-related acute myocardial infarction. Black race was eliminated as a risk factor in the multivariable analysis, which suggests that the increased incidence among black women is explained by an increased prevalence of other cardiovascular risk factors. Conclusions— Although acute myocardial infarction is a rare event in women of reproductive age, pregnancy increases the risk 3- to 4-fold. Certain medical conditions and complications of pregnancy increase the risk further and are potentially modifiable risk factors.

Forecasting the prevalence of pelvic floor disorders in U.S. Women: 2010 to 2050.

Objective: To estimate the incidence, mortality, and risk factors for pregnancy-related stroke in the United States. Methods: The Nationwide Inpatient Sample from the Healthcare Cost and Utilization Project of the Agency for Healthcare Research and Quality, for the years 2000–2001 was queried for International Classification of Diseases, 9th Revision, codes for stroke among all pregnancy-related discharges. Results: A total of 2,850 pregnancy-related discharges included a diagnosis of stroke for a rate of 34.2 per 100,000 deliveries. There were 117 deaths or 1.4 per 100,000 deliveries. Twenty-two percent of survivors were discharged to another facility. The risk of stroke increased with age, particularly ages 35 years and older. African-American women were at a higher risk, odds ratio (OR) 1.5 (95% confidence interval [CI] 1.2–1.9). Medical conditions that were strongly associated with stroke included migraine headache, OR 16.9 (CI 9.7–29.5), thrombophilia, OR 16.0 (CI 9.4–27.2), systemic lupus erythematosus, OR 15.2 (CI 7.4–31.2), heart disease, OR 13.2 (CI 10.2–17.0), sickle cell disease, OR 9.1 (CI 3.7–22.2), hypertension, OR 6.1(CI 4.5–8.1) and thrombocytopenia, OR 6.0 (CI 1.5–24.1). Complications of pregnancy that were significant risk factors were postpartum hemorrhage, OR 1.8 (CI 1.2–2.8), preeclampsia and gestational hypertension, OR 4.4 (CI 3.6–5.4), transfusion OR 10.3 (CI 7.1–15.1) and postpartum infection, OR 25.0 (CI 18.3–34.0). Conclusion: The incidence, mortality and disability from pregnancy related-stroke are higher than previously reported. African-American women are at an increased risk, as are women aged 35 years and older. Risk factors, not previously reported, include lupus, blood transfusion, and migraine headaches. Specific strategies, not currently employed, may be required to reduce the devastation caused by stroke during pregnancy and the puerperium. Level of Evidence: II-2

Four year efficacy of prophylactic human papillomavirus quadrivalent vaccine against low grade cervical, vulvar, and vaginal intraepithelial neoplasia and anogenital warts: randomised controlled trial.

OBJECTIVES: To estimate the number of women who will have symptomatic pelvic floor disorders in the United States from 2010 to 2050. METHODS: We used population projections from the U.S. Census Bureau from 2010 to 2050 and published age-specific prevalence estimates for bothersome, symptomatic pelvic floor disorders (urinary incontinence [UI], fecal incontinence, and pelvic organ prolapse [POP]) from the 2005 National Health and Nutrition Examination Survey. We abstracted data regarding the number of women aged 20 years or older in 20-year age groups. We assumed that the age-specific prevalences for these disorders and the population distribution of risk factors remained unchanged thru 2050. We also conducted sensitivity analyses that varied both the prevalence estimates and the population projections. RESULTS: The number of American women with at least one pelvic floor disorder will increase from 28.1 million in 2010 to 43.8 million in 2050. During this time period, the number of women with UI will increase 55% from 18.3 million to 28.4 million. For fecal incontinence, the number of affected women will increase 59% from 10.6 to 16.8 million, and the number of women with POP will increase 46% from 3.3 to 4.9 million. The highest projections for 2050 estimate that 58.2 million women will have at least one pelvic floor disorder, with 41.3 million with UI, 25.3 million with fecal incontinence, and 9.2 million with POP. CONCLUSION: The prevalence of pelvic floor disorders will increase substantially given the changing demographics in the United States. This increase has important implications for public health and the field of gynecology. LEVEL OF EVIDENCE: III

Incidence and risk factors for stroke in pregnancy and the puerperium

Objectives To evaluate the prophylactic efficacy of the human papillomavirus (HPV) quadrivalent vaccine in preventing low grade cervical, vulvar, and vaginal intraepithelial neoplasias and anogenital warts (condyloma acuminata). Design Data from two international, double blind, placebo controlled, randomised efficacy trials of quadrivalent HPV vaccine (protocol 013 (FUTURE I) and protocol 015 (FUTURE II)). The trials were to be 4 years in length, and the results reported are from final study data of 42 months’ follow-up. Setting Primary care centres and university or hospital associated health centres in 24 countries and territories around the world. Participants 17 622 women aged 16-26 years enrolled between December 2001 and May 2003. Major exclusion criteria were lifetime number of sexual partners (>4), history of abnormal cervical smear test results, and pregnancy. Intervention Three doses of quadrivalent HPV vaccine (for serotypes 6, 11, 16, and 18) or placebo at day 1, month 2, and month 6. Main outcome measures Vaccine efficacy against cervical, vulvar, and vaginal intraepithelial neoplasia grade I and condyloma in a per protocol susceptible population that included subjects who received all three vaccine doses, tested negative for the relevant vaccine HPV types at day 1 and remained negative through month 7, and had no major protocol violations. Intention to treat, generally HPV naive, and unrestricted susceptible populations were also studied. Results In the per protocol susceptible population, vaccine efficacy against lesions related to the HPV types in the vaccine was 96% for cervical intraepithelial neoplasia grade I (95% confidence interval 91% to 98%), 100% for both vulvar and vaginal intraepithelial neoplasia grade I (95% CIs 74% to 100%, 64% to 100% respectively), and 99% for condyloma (96% to 100%). Vaccine efficacy against any lesion (regardless of HPV type) in the generally naive population was 30% (17% to 41%), 75% (22% to 94%), and 48% (10% to 71%) for cervical, vulvar, and vaginal intraepithelial neoplasia grade I, respectively, and 83% (74% to 89%) for condyloma. Conclusions Quadrivalent HPV vaccine provided sustained protection against low grade lesions attributable to vaccine HPV types (6, 11, 16, and 18) and a substantial reduction in the burden of these diseases through 42 months of follow-up. Trial registrations NCT00092521 and NCT00092534.

A Pooled Analysis of Continued Prophylactic Efficacy of Quadrivalent Human Papillomavirus (Types 6/11/16/18) Vaccine against High-grade Cervical and External Genital Lesions

OBJECTIVE To estimate the incidence, mortality, and risk factors for pregnancy-related stroke in the United States. METHODS The Nationwide Inpatient Sample from the Healthcare Cost and Utilization Project of the Agency for Healthcare Research and Quality, for the years 2000-2001 was queried for International Classification of Diseases, 9th Revision, codes for stroke among all pregnancy-related discharges. RESULTS A total of 2,850 pregnancy-related discharges included a diagnosis of stroke for a rate of 34.2 per 100,000 deliveries. There were 117 deaths or 1.4 per 100,000 deliveries. Twenty-two percent of survivors were discharged to another facility. The risk of stroke increased with age, particularly ages 35 years and older. African-American women were at a higher risk, odds ratio (OR) 1.5 (95% confidence interval [CI] 1.2-1.9). Medical conditions that were strongly associated with stroke included migraine headache, OR 16.9 (CI 9.7-29.5), thrombophilia, OR 16.0 (CI 9.4-27.2), systemic lupus erythematosus, OR 15.2 (CI 7.4-31.2), heart disease, OR 13.2 (CI 10.2-17.0), sickle cell disease, OR 9.1 (CI 3.7-22.2), hypertension, OR 6.1(CI 4.5-8.1) and thrombocytopenia, OR 6.0 (CI 1.5-24.1). Complications of pregnancy that were significant risk factors were postpartum hemorrhage, OR 1.8 (CI 1.2-2.8), preeclampsia and gestational hypertension, OR 4.4 (CI 3.6-5.4), transfusion OR 10.3 (CI 7.1-15.1) and postpartum infection, OR 25.0 (CI 18.3-34.0). CONCLUSION The incidence, mortality and disability from pregnancy related-stroke are higher than previously reported. African-American women are at an increased risk, as are women aged 35 years and older. Risk factors, not previously reported, include lupus, blood transfusion, and migraine headaches. Specific strategies, not currently employed, may be required to reduce the devastation caused by stroke during pregnancy and the puerperium. LEVEL OF EVIDENCE II-2.

A national study of the complications of lupus in pregnancy

Quadrivalent human papillomavirus (HPV) vaccine has been shown to provide protection from HPV 6/11/16/18–related cervical, vaginal, and vulvar disease through 3 years. We provide an update on the efficacy of the quadrivalent HPV vaccine against high-grade cervical, vaginal, and vulvar lesions based on end-of-study data from three clinical trials. Additionally, we stratify vaccine efficacy by several baseline characteristics, including age, smoking status, and Papanicolaou (Pap) test results. A total of 18,174 females ages 16 to 26 years were randomized and allocated into one of three clinical trials (protocols 007, 013, and 015). Vaccine or placebo was given at baseline, month 2, and month 6. Pap testing was conducted at regular intervals. Cervical and anogenital swabs were collected for HPV DNA testing. Examination for the presence of vulvar and vaginal lesions was also done. Endpoints included high-grade cervical, vulvar, or vaginal lesions (CIN 2/3, VIN 2/3, or VaIN 2/3). Mean follow-up time was 42 months post dose 1. Vaccine efficacy against HPV 6/11/16/18–related high-grade cervical lesions in the per-protocol and intention-to-treat populations was 98.2% [95% confidence interval (95% CI), 93.3-99.8] and 51.5% (95% CI, 40.6-60.6), respectively. Vaccine efficacy against HPV 6/11/16/18–related high-grade vulvar and vaginal lesions in the per-protocol and intention-to-treat populations was 100.0% (95% CI, 82.6-100.0) and 79.0% (95% CI, 56.4-91.0), respectively. Efficacy in the intention-to-treat population tended to be lower in older women, women with more partners, and women with abnormal Pap test results. The efficacy of quadrivalent HPV vaccine against high-grade cervical and external anogenital neoplasia remains high through 42 months post vaccination.