L. Stewart Massad

2012 updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors.

A group of 47 experts representing 23 professional societies, national and international health organizations, and federal agencies met in Bethesda, MD, September 14-15, 2012, to revise the 2006 American Society for Colposcopy and Cervical Pathology Consensus Guidelines. The groups goal was to provide revised evidence-based consensus guidelines for managing women with abnormal cervical cancer screening tests, cervical intraepithelial neoplasia (CIN) and adenocarcinoma in situ (AIS) following adoption of cervical cancer screening guidelines incorporating longer screening intervals and co-testing. In addition to literature review, data from almost 1.4 million women in the Kaiser Permanente Northern California Medical Care Plan provided evidence on risk after abnormal tests. Where data were available, guidelines prescribed similar management for women with similar risks for CIN 3, AIS, and cancer. Most prior guidelines were reaffirmed. Examples of updates include: Human papillomavirus-negative atypical squamous cells of undetermined significance results are followed with co-testing at 3 years before return to routine screening and are not sufficient for exiting women from screening at age 65 years; women aged 21-24 years need less invasive management, especially for minor abnormalities; postcolposcopy management strategies incorporate co-testing; endocervical sampling reported as CIN 1 should be managed as CIN 1; unsatisfactory cytology should be repeated in most circumstances, even when HPV results from co-testing are known, while most cases of negative cytology with absent or insufficient endocervical cells or transformation zone component can be managed without intensive follow-up.

The effect of highly active antiretroviral therapy on cervical cytologic changes associated with oncogenic HPV among HIV-infected women

ObjectiveCervical intraepithelial neoplasia (CIN), a common condition among HIV-infected women, has been linked to HIV load and immune status. Highly active antiretroviral therapy (HAART) improves immunologic and virologic status. This study was undertaken to determine the relationship between HAART use and CIN. DesignCohort study. The Womens Interagency HIV Study (WIHS) in five cities in the USA (Bronx/Manhattan, New York; Brooklyn, New York; Chicago, Illinois; Los Angeles, California; San Francisco Bay area, California; Washington, District of Columbia). MethodsHIV-infected women were followed every 6 months with Papanicolaou smears and cervicovaginal lavage for human papillomavirus (HPV) DNA testing. To characterize exposures that changed over time and to capture the dynamic nature of cytologic changes, Papanicolaou smear findings from each participants consecutive visits were defined as a pair. We determined the proportion of all pairs that exhibited either regression or progression, according to HAART exposure, HPV results and Papanicolaou smear status. As participants could contribute multiple pairs, inferences were based on robust methods to adjust for correlated observations. ResultsWomen with persistent HPV infection were more likely to have progression of their lesions. After adjustment for CD4 cell count and Papanicolaou smear status, women on HAART were 40% (95% confidence interval, 4–81%) more likely to demonstrate regression and less likely (odds ratio, 0.68; 95% confidence interval, 0.52–0.88) to demonstrate progression ConclusionsHAART altered the course of HPV disease in HIV-infected women, reducing progression and increasing regression. As HPV disease is a common sex-specific manifestation of HIV disease this effect of HAART would be a major additional benefit from this modality of therapy.

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

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

Evolution of cervical abnormalities among women with HIV-1: Evidence from surveillance cytology in the Women's Interagency HIV Study

Objective: To determine incidence, progression, and regression rates for abnormal cervical cytology and their correlates among women with HIV. Methods: In a multicenter prospective cohort study conducted October 1, 1994, through September 30, 1999 at university, public, and private medical centers and clinics, 1639 HIV‐seropositive and 452 seronegative women were evaluated every 6 months for up to 5 years using history, cervical cytology, T‐cell subsets, and quantitative plasma HIV RNA. Human papillomavirus (HPV) typing at baseline was determined by polymerase chain reaction. Cytology was read using the Bethesda system, with any smear showing at least atypia considered abnormal. Poisson regression identified factors associated with incident cytologic abnormalities whereas logistic regression identified those associated with progression and regression after an abnormality. Results: At least one abnormal smear was found during all of follow‐up among 73.0% of HIV‐seropositive patients and 42.3% of seronegatives (p < .001). Only 5.9% of seropositives ever developed high‐grade lesions, and the proportion with high‐grade findings did not rise over time. Incidence of atypical squamous cells of uncertain significance (ASCUS) or more severe lesions among HIV‐seropositive patients and seronegative patients was 26.4 and 11.0/100 woman‐years (rate ratio [RR], 2.4; 95% confidence interval [CI], 1.9‐3.0), whereas that of at least low‐grade squamous intraepithelial lesions (SIL) was 8.9 and 2.2/100 (RR, 4.0; CI, 2.6‐6.1). HIV status, detection of the presence of human papillomavirus (HPV), CD4 lymphocyte count, and HIV RNA level predicted incidence of abnormal cytology (p < .05); HPV detection and HIV RNA level predicted progression (p < .01); and HPV detection, CD4 lymphocyte count, and HIV RNA level predicted regression (p < .001). Rates of incidence, progression, and regression of abnormal cytology did not differ between HIV seronegative women and seropositive women with CD4 lymphocyte counts >200/mm3 and HIV RNA levels <4000/ml of similar HPV status. Conclusions: Although HIV infected women were at high risk for abnormal cytology, high‐grade changes were uncommon. HIV status, HPV detection, CD4 lymphocyte count, and HIV RNA level predicted the incidence of cervical cytologic abnormalities. Progression was significantly increased only among the most immunosuppressed women, while regression was significantly reduced in all HIV seropositive women except those with the best controlled HIV disease.

Pregnancy rates and predictors of conception, miscarriage and abortion in US women with HIV.

Objective: To determine frequency and outcomes of pregnancy in US women with HIV before and after introduction of highly active antiretroviral therapy (HAART). Design: Prospective cohort study at six US centers. Methods: HIV seropositive and at-risk seronegative women reported pregnancy outcomes at 6-month intervals during the period 1 October 1994 to 31 March 2002. Outcomes were tabulated and pregnancy rates calculated. Logistic regression defined outcome correlates. Results: Pregnancy rates were 7.4 and 15.2 per 100 person-years in seropositive and seronegative women, respectively (P < 0.0001). Among seropositives, 119 (36%) pregnancies ended in live birth, six (2%) in stillbirth, 126 (36%) in abortion, 83 (24%) in miscarriage, 16 (5%) in ectopic pregnancy, and two (1%) in other outcomes (P = nonsignificant versus seronegatives). Independent baseline correlates of conception in seropositives included younger age [odds ratio (OR), 1.20; 95% confidence interval (CI), 1.16–1.23], prior abortion (OR, 1.79; 95% CI, 1.25–2.63), lower HIV RNA levels (OR, 1.30; 95% CI, 1.10–1.54 for each log decrease), and being unmarried (OR, 1.59; 95% CI, 1.02–2.44). Baseline antiretroviral use at baseline was linked to lower conception risk (OR, 0.34; 95% CI, 0.49–0.98 for mono- or combination therapy; OR, 0.34; 95% CI, 0.03–4.28 for HAART). Abortion was less likely during the HAART era, (OR, 0.68; 95% CI, 0.35–1.33 during the early HAART era; OR, 0.46; 95% CI, 0.23–0.90 during the later HAART era, compared with before HAART). Conclusions: Women with HIV were less likely to conceive than at-risk uninfected women, but pregnancy outcomes were similar. Abortion became less common after the introduction of HAART.

Strength of correlations between colposcopic impression and biopsy histology

OBJECTIVE The aim of this study was to determine the strength of the correlation between colposcopic impression and biopsy histology. METHODS In an urban referral clinic, colposcopy and directed biopsy were performed between July 1, 1996, and December 31, 1999, by residents supervised by board-certified attending obstetrician-gynecologists. Impression and biopsy were graded as benign, suggesting condyloma or koilocytosis, cervical intraepithelial neoplasia (CIN) grades 1-3, or cancer. The significance of association was assessed by chi(2) testing and the strength by kappa statistics. RESULTS Colposcopies were performed on 2825 women, with colposcopic impression and biopsy grade known for 2112. Exact agreement was found in only 893 (37%) women, but results agreed within one grade in 1203 (75%). The association between impression and histology was significant (P < 0.001), but the strength of the correlation was poor (0.20). The positive predictive value of any colposcopic abnormality for any histologic abnormality was 80%. The negative predictive value of a benign colposcopic impression was 68%. The sensitivity of colposcopy with a threshold of any lesion detected was 89%, and the specificity was 52%. The sensitivity for CIN 2/3 was 56%. CONCLUSION Colposcopy is imprecise, although useful in estimating lesion grade. Management decisions require biopsy.

The accuracy of colposcopic grading for detection of high-grade cervical intraepithelial neoplasia

Objective. To relate aspects of online colposcopic image assessment to the diagnosis of grades 2 and 3 cervical intraepithelial neoplasia (CIN 2+). Methods: To simulate colposcopic assessment, we obtained digitized cervical images at enrollment after acetic acid application from 919 women referred for equivocal or minor cytologic abnormalities into the ASCUS-LSIL Triage Study. For each, 2 randomly assigned evaluators from a pool of 20 colposcopists assessed images using a standardized tool online. We calculated the accuracy of these assessments for predicting histologic CIN 2+ over the 2 years of study. For validation, a subset of online results was compared with same-day enrollment colposcopic assessments. Results. Identifying any acetowhite lesion in images yielded high sensitivity: 93% of women with CIN 2+ had at least 1 acetowhite lesion. However, 74% of women without CIN 2+ also had acetowhitening, regardless of human papillomavirus status. The sensitivity for CIN 2+ of an online colpophotographic assessment of high-grade disease was 39%. The sensitivity for CIN 2+ of a high-grade diagnosis by Reid Index scoring was 30%, and individual Reid Index component scores had similar levels of sensitivity and specificity. The performance of online assessment was not meaningfully different from that of same-day enrollment colposcopy, suggesting that these approaches have similar utility. Conclusions. Finding acetowhite lesions identifies women with CIN 2+, but using subtler colposcopic characteristics to grade lesions is insensitive. All acetowhite lesions should be assessed with biopsy to maximize sensitivity of colposcopic diagnosis with good specificity.

Cancer risk among participants in the women's interagency HIV study.

Background:The HIV epidemic has been associated with an increased incidence of specific cancers. However, less is known about cancers occurring in HIV-infected women than men. Methods:To determine the risk of cancer among HIV-infected and at-risk HIV-uninfected women, cancer incidence data from the Women’s Interagency HIV Study (WIHS) were compared with data from the population-based United States Surveillance, Epidemiology, and End Results (SEER) registry. Age- and race-adjusted standardized incidence ratios (SIRs) were computed and exact statistical tests were used to measure significance. Results:Among the 1950 women participants (1554 HIV infected, 391 HIV uninfected, and 5 HIV seroconverters), 48 cancers were diagnosed during study follow-up. Among HIV-infected women, significantly (P < 0.05) increased incidence rates were observed for all cancer types (SIR = 1.9), Kaposi sarcoma (SIR = 213.5), non-Hodgkin lymphoma (NHL) (SIR = 19.0), and lung cancer (SIR = 6.3) when compared with SEER rates. Lung cancer incidence was also elevated (P = 0.07) among the HIV-uninfected women (SIR = 6.9), when compared with SEER rates, and was similar to the SIR for HIV-infected women. While the incidence rate of NHL among HIV-infected women was significantly lower during the era of highly active antiretroviral therapy (HAART) compared with the pre-HAART era (relative risk = 0.15, P = 0.005), the incidence of NHL among HIV-infected WIHS participants remained significantly higher than in the US population (SIR = 6.4, 95% CI = 1.3–15.5). Conclusion:In the HAART era, the higher rates of cancer among HIV-infected women, coupled with increased life expectancy, should lead to more intensive cancer screening and prevention efforts in this population.

Marginal and Mixed-Effects Models in the Analysis of Human Papillomavirus Natural History Data

Human papillomavirus (HPV) natural history has several characteristics that, at least from a statistical perspective, are not often encountered elsewhere in infectious disease and cancer research. There are, for example, multiple HPV types, and infection by each HPV type may be considered separate events. Although concurrent infections are common, the prevalence, incidence, and duration/persistence of each individual HPV can be separately measured. However, repeated measures involving the same subject tend to be correlated. The probability of detecting any given HPV type, for example, is greater among individuals who are currently positive for at least one other HPV type. Serial testing for HPV over time represents a second form of repeated measures. Statistical inferences that fail to take these correlations into account would be invalid. However, methods that do not use all the data would be inefficient. Marginal and mixed-effects models can address these issues but are not frequently used in HPV research. The current study provides an overview of these methods and then uses HPV data from a cohort of HIV-positive women to illustrate how they may be applied, and compare their results. The findings show the greater efficiency of these models compared with standard logistic regression and Cox models. Because mixed-effects models estimate subject-specific associations, they sometimes gave much higher effect estimates than marginal models, which estimate population-averaged associations. Overall, the results show that marginal and mixed-effects models are efficient for studying HPV natural history, but also highlight the importance of understanding how these models differ. Cancer Epidemiol Biomakers Prev; 19(1); 159–69

Low incidence of invasive cervical cancer among HIV-infected US women in a prevention program.

Objective: To measure the incidence of invasive cervical cancer (ICC) in US women infected with HIV. Design: Multicenter prospective cohort study, conducted between October 1994, and September 2001. Setting: HIV research centers operating as six urban consortia in the Womens Interagency HIV Study. Subjects: A total of 2131 women (462 HIV seronegative, 1661 HIV seropositive, and eight seroconverters). Women with a history of hysterectomy or of cervical cancer at baseline evaluation were excluded. Intervention: Cervical cytology obtained at 6-month intervals, with a colposcopy referral threshold of atypia, followed by individualized treatment. Main outcome measure: ICC diagnoses obtained from study databases and regional cancer registries and confirmed by a gynecologic pathologist. Results: No incident ICC were observed in HIV seronegative women during 2375 woman-years of observation. During 8260 woman-years of observation, eight putative incident cases of cervical cancer were identified in HIV seropositive women, but only one was confirmed, yielding an incidence rate of 1.2/10 000 woman-years (95% confidence interval, 0.3–6.7/10 000 woman-years). The difference in incidence between HIV seropositive and seronegative women was not significant (P = 1.0). Conclusion: ICC is uncommon in HIV-infected US women participating in a regular prevention program.