Michelle J. Khan

Socioeconomic status and the risk of cervical intraepithelial neoplasia grade 3 among oncogenic human papillomavirus DNA‐positive women with equivocal or mildly abnormal cytology

Low socioeconomic status (SES) is a reported risk factor for cervical carcinoma, but few studies have taken into account adequately the possibly confounding effects of oncogenic human papillomavirus (HPV) infection as well as access to screening and subsequent treatment.

Diagnostic Utility of Endocervical Curettage in Women Undergoing Colposcopy for Equivocal or Low-Grade Cytologic Abnormalities

OBJECTIVE: To estimate the diagnostic yield of endocervical curettage (ECC) when performed as part of a colposcopic procedure in the multicenter ASCUS-LSIL Triage Study (ALTS), a randomized trial of management strategies for women with equivocal or mildly abnormal cytology. METHODS: A total of 1,119 women in ALTS had colposcopic examinations that included an ECC performed at the discretion of the colposcopist. We compared the results of ECC and concurrent cervical colposcopic evaluation, with or without biopsy, in prediction of final histopathologic diagnosis. This was defined as the worst histopathologic result from that colposcopy or any subsequent procedure during 2 years of follow-up. RESULTS: Overall, 3.7% of ECCs yielded a diagnostic abnormality of cervical intraepithelial neoplasia (CIN) 2+ compared with 21.7% of colposcopically directed biopsies. In women ultimately found to have CIN 2+ in the trial, the overall sensitivity of colposcopically directed biopsy was 72.5%, compared with 12.2% for ECC. In women under 40, the marginal contribution of ECC, independently of biopsy, was only 2.2%. By contrast, among women 40 and older, the sensitivity of biopsy dropped while the sensitivity of ECC improved, resulting in 13.0% increased detection with ECC, independently of biopsy. However, in women 40 and older, the combined sensitivity of ECC and biopsy was only 47.8% for a single colposcopy procedure. CONCLUSION: As an ancillary diagnostic technique to colposcopically directed biopsy, ECC is of questionable value in younger women. However, in women aged 40 and older, the sensitivity of colposcopic biopsy decreased and the sensitivity of ECC increased. Thus, ECC may be useful in older women undergoing colposcopy for equivocal or mildly abnormal cytology.

Screening for Anal Cancer in Women.

Objective The incidence of anal cancer is higher in women than men in the general population and has been increasing for several decades. Similar to cervical cancer, most anal cancers are associated with human papillomavirus (HPV), and it is believed that anal cancers are preceded by anal high-grade squamous intraepithelial lesions (HSIL). Our goals were to summarize the literature on anal cancer, HSIL, and HPV infection in women and to provide screening recommendations in women. Methods A group of experts convened by the American Society for Colposcopy and Cervical Pathology and the International Anal Neoplasia Society reviewed the literature on anal HPV infection, anal SIL, and anal cancer in women. Results Anal HPV infection is common in women but is relatively transient in most. The risk of anal HSIL and cancer varies considerably by risk group, with human immunodeficiency virus–infected women and those with a history of lower genital tract neoplasia at highest risk compared with the general population. Conclusions While there are no data yet to demonstrate that identification and treatment of anal HSIL leads to reduced risk of anal cancer, women in groups at the highest risk should be queried for anal cancer symptoms and required to have digital anorectal examinations to detect anal cancers. Human immunodeficiency virus–infected women and women with lower genital tract neoplasia may be considered for screening with anal cytology with triage to treatment if HSIL is diagnosed. Healthy women with no known risk factors or anal cancer symptoms do not need to be routinely screened for anal cancer or anal HSIL.

Treatment of cervical precancers: back to basics.

Both ablative (cervical cryotherapy, laser ablation) and excisional methods (loop electrosurgical excision procedure, cold knife conization) can be effective at treating cervical precancer. Excisional procedures are associated with adverse obstetric outcomes including preterm delivery and perinatal mortality with the depth of excision potentially contributing to the adverse outcomes. Ablative therapies are now used much less commonly than loop electrosurgical excision procedure but have less of an effect on adverse obstetric outcomes and hence are effective alternatives for treating cervical precancer in reproductive-aged women. Morphometric data indicate that the vast majority of precancerous lesions are less than 5 mm deep, suggesting that treatments that reach 6–7 mm below the epithelium are adequate in women with satisfactory colposcopy. Cone biopsies, “top-hat” loop electrosurgical excision procedures, or the use of loop electrodes greater than 10 mm are therefore unnecessary for the majority of reproductive-aged women and increase risk of adverse obstetric outcomes. New consensus guidelines allow observation instead of treatment in appropriately selected young women. Until the association of excisional methods with adverse obstetric outcomes is clarified with more data, ablative methods should be revitalized and used by health care providers in appropriately selected patients. Treatment should be individualized based on patient’s age, fertility desires, and colpopathologic findings.

Evidence-based Consensus Recommendations for Colposcopy Practice for Cervical Cancer Prevention in the United States

The American Society for Colposcopy and Cervical Pathology (ASCCP) Colposcopy Standards recommendations address the role of colposcopy and directed biopsy for cervical cancer prevention in the United States (US). The recommendations were developed by an expert working group appointed by ASCCPs Board of Directors. An extensive literature review was conducted and supplemented by a systematic review and meta-analysis of unpublished data. In addition, a survey of practicing colposcopists was conducted to assess current colposcopy practice in the US. Recommendations were approved by the working group members, and the final revisions were made based on comments received from the public. The recommendations cover terminology, risk-based colposcopy, colposcopy procedures, and colposcopy adjuncts. The ASCCP Colposcopy Standards recommendations are an important step toward raising the standard of colposcopy services delivered to women in the US. Because cervical cancer screening programs are currently undergoing important changes that may affect colposcopy performance, updates to some of the current recommendations may be necessary in the future.

Preparing for the Next Round of Asccp-sponsored Cervical Screening and Management Guidelines

T he American Society for Colposcopy and Cervical Pathology (ASCCP), in collaboration with the National Cancer Institute, has begun to prepare for the next update to its cervical screening and management consensus guidelines. Here, we describe the current plans for this multiyear process. Since 2001, the ASCCP has sponsored several rounds of cervical consensus guidelines; each has made extensive use of epidemiologic data from clinical trials and epidemiologic studies from the National Cancer Institute and other sources. The recommendations have been developed by expert representatives of many cooperating clinical societies after extensive public comment periods. Initially, the ASCCP-sponsored guidelines concentrated on the management of cytologic and histologic abnormalities found during screening. More recently, the ASCCP has cooperated with the American Cancer Society (ACS) and more than 20 other clinical organizations to consider general population screening issues as well. The next round of guidelines might continue to consider both cervical screening and management of abnormal results, pending discussion and in cooperation with other groups. Although it is undesirable to change clinical recommendations unless necessary, revision is needed soon for several reasons. The introduction of human papillomavirus (HPV) testing into US screening programs almost 15 years ago was a major change; initially, it was not possible to judge how repeated rounds of screening would perform. There are now enough data to judge and guide the realistic clinical performance of multiple rounds of “co-testing” combining HPV testing with cytology. We can also estimate howmultiple rounds of primary screening with HPV tests alonewould perform. Second, young women vaccinated prophylactically against HPV have reached the age of screening, and HPV vaccination will increasingly and profoundly affect screening performance. Given the postvaccination prevalence of precancer, cytology and pooled HPV tests perform less effectively (e.g., they are less predictive of cervical precancer) in vaccinated populations than in unvaccinated populations. In addition, new tests and strategies for triage of screen-positive women have been introduced and evaluated sufficiently to consider their role in new recommendations. Finally, the current guidelines are already very complex but still incomplete. As we strive for even greater precision to maximize the benefits andminimize the harms of screening, producing more algorithm trees is not a practical answer. Given available evidence, it is possible, as explained hereafter, to push simultaneously toward greater precision and simplicity, supported by a computer-based decision tool. The risk database will be publicly available, permitting access to those wishing to use it to create such tools. In preparing for the next round of guidelines, we recognize that several groups offer cervical screening and management recommendations, most prominently the US Preventive Services Task Force, ACS, and the American College of Obstetrics and Gynecology. Consistency in recommendations, preferably unanimity regarding the important issues, is very important. Nonetheless, the ASCCP-sponsored guidelines provide a unique perspective in the following ways. The guidelines aim to be as comprehensive as possible, covering such a large number of specific clinical situations that reliance on data from the reference standard of evidence, randomized clinical trials addressing individual questions, are not conceivable for most recommendations. Less emphasis will be on formal review of individual published studies with grading of the published literature provided by a separate group of evaluators. Instead, observational “big data” as well as trial data, pooled from all available sources, will form the basis of the updated recommendations. Epidemiologic research targeted specifically to support the guidelines will be conducted and reviewed by cervical screening and management experts. The most recent set of ASCCP-sponsored consensus guidelines introduced risk of cervical intraepithelial neoplasia (CIN) 2, CIN 3, adenocarcinoma in situ, and cancer as the unifying principle of the many recommendations and algorithm “trees.” Regardless of the screening test or algorithm (e.g., screening followed by triage), there should be equal management of equal risk. A prime example is the equal management of cytologic low-grade squamous intraepithelial lesion (LSIL) and HPVpositive atypical squamous cells of undetermined significance (atypical squamous cells of undetermined significance [ASC-US]). Anticipated improvements planned for the next set of ASCCP-sponsored guidelines will include the following: A) More detailed risk estimates, for greater numbers of test combinations, and for a greater number of clinical scenarios, such that the guidelines better address the variety of clinical situations EDITORIAL

ASCCP Colposcopy Standards: Risk-Based Colposcopy Practice

Objectives The American Society for Colposcopy and Cervical Pathology (ASCCP) Colposcopy Standards recommendations address the role of and approach to colposcopy for cervical cancer prevention in the United States. Materials and Methods The recommendations were developed by an expert working group appointed by ASCCPs Board of Directors. This article describes the rationale, evidence, and recommendations related to risk-based colposcopy practice. Results Women referred to colposcopy have a wide range of underlying precancer risk, which can be estimated by referral screening tests including cytology and human papillomavirus testing, in conjunction with the colposcopic impression. Multiple targeted biopsies, at least 2 and up to 4, are recommended to improve detection of prevalent precancers. At the lowest end of the risk spectrum, untargeted biopsies are not recommended, and women with a completely normal colposcopic impression can be observed. At the highest end of the risk spectrum, immediate treatment is an alternative to biopsy confirmation. Conclusions Assessing the risk of cervical precancer at the colposcopy visit allows for modification of colposcopy procedures consistent with a womans risk. Implementation of these recommendations is expected to lead to improved detection of cervical precancers at colposcopy, while providing more reassurance of negative colposcopy results.

Genotyping for human papillomavirus types 16 and 18 in women with minor cervical lesions: A systematic review and meta-analysis

Background High-risk human papillomavirus (hrHPV) testing to triage women with minor cervical lesions generates many referrals. Purpose To evaluate the accuracy of genotyping for HPV types 16 and 18 and its utility as a second triage step after hrHPV testing in women with minor cervical lesions. Data Sources Searches of 4 bibliographic databases, without language restrictions, from 1 January 1999 to 1 February 2016. Study Selection Studies involving women with atypical squamous cells of undetermined significance (ASC-US) or low-grade squamous intraepithelial lesions (LSIL) who were triaged with tests for hrHPV and HPV 16/18 to find cervical intraepithelial neoplasia (grade ≥2 [CIN2+] or grade ≥3 [CIN3+]). Data Extraction Independent study selection, extraction of data, and quality assessment by 2 reviewers. Data Synthesis Twenty-four moderate- to good-quality studies involving 8587 women with ASC-US and 5284 with LSIL were found. The pooled sensitivity of HPV 16/18 genotyping for CIN3+ was about 70% for women with either ASC-US or LSIL. The pooled specificity (with a threshold of grade <2 CIN) was 83% (95% CI, 80% to 86%) for women with ASC-US and 76% (CI, 74% to 79%) for those with LSIL. The average risk for CIN3+ was 17% and 19% in HPV 16/18-positive women with ASC-US and LSIL, respectively, and was 5% in hrHPV-positive but HPV 16/18-negative women with either ASC-US or LSIL. Limitation Methodological and technical heterogeneity among studies; insufficient data to assess accuracy of separate assays. Conclusion Testing for HPV 16/18 to triage women with minor abnormal cytology is poorly sensitive but may be useful as a second triage test after hrHPV testing, with direct referral if the woman is positive for HPV 16/18. Whether colposcopy or repeated testing is recommended for hrHPV-positive but HPV 16/18-negative women depends on local decision thresholds that can be derived from pretest-posttest probability plots. Primary Funding Source 7th Framework Programme of the European Commission.

Does treatment for cervical and vulvar dysplasia impact women's sexual health?

Human papillomavirus-associated disease represents an immense public health burden worldwide. Persistent human papillomavirus infection can lead to the development of cervical dysplasia and vulvar dysplasia, both of which have been increasing in incidence in women in recent years. Numerous studies have focused on methods for screening and diagnosis of cervical dysplasia, but few have looked at the effects of treatment on womens psychological and sexual health. Even fewer studies have addressed these issues in women with vulvar dysplasia. The aim of this article was to provide a comprehensive review of the existing evidence concerning the impact of therapy for cervical and vulvar precancers on womens sexual function and sexual relationships. We performed a search of the medical literature for the time period up to and including August 2013 on PubMed. The findings from a limited number of studies to date indicate that psychosexual vulnerability increases after diagnosis and treatment of both cervical and vulvar dysplasia. More in-depth research is needed to better understand the effects of different treatment modalities on womens sexual health and relationships during and following treatment.

Evaluation of Human Papillomavirus as a Risk Factor for Preterm Birth or Pregnancy-related Hypertension

OBJECTIVE: To compare rates of preterm birth and pregnancy-related hypertension in women with and without human papillomavirus (HPV) infection. METHODS: We performed a retrospective cohort study of all women delivered at our institution in 2013 who had cervical cancer screening test results within 3 years before delivery. Patients were excluded if they had prior procedure(s) for cervical dysplasia other than biopsy. There were two primary outcomes: preterm birth (less than 37 weeks of gestation) and pregnancy-related hypertension (gestational hypertension, preeclampsia, or eclampsia). Multivariable logistic regression was performed to adjust for confounders including demographic variables, diabetes, prior preterm birth, chronic hypertension, and other genital infections. Assuming a 10% prevalence of HPV, a rate of 12% in the HPV-negative group for both preterm birth and pregnancy-related hypertension, &agr; of 0.05, and &bgr; of 0.2, we needed 2,207 patients to detect a 60% increase in the rate of either outcome in the HPV-positive group. RESULTS: A total of 3,958 patients delivered in 2013, of whom 2,321 met eligibility criteria, 242 (10.4%) of whom were HPV-positive and 2,079 (89.2%) of whom were HPV-negative. In multivariate analyses, the rate of preterm birth was not significantly different between HPV-positive and HPV-negative women (16.5% compared with 12.2%, adjusted odds ratio [OR] 1.3, 95% confidence interval [CI] 0.9–1.9); rates of pregnancy-related hypertension also were not significantly different between HPV-positive and HPV-negative women (17.0% compared with 16.4%, adjusted OR 1.0, 95% CI 0.7–1.5). CONCLUSION: Maternal HPV infection is not an independent risk factor for preterm birth or pregnancy-related hypertension.