2001 Consensus Guidelines for the Management of Women with Cervical Cytological Abnormalities

Each year in the United States, approximately 3.3 million Pap tests are interpreted as having some degree of cytological abnormality [1]. Identifying which of these women are at risk for having a clinically significant cervical abnormality, performing a diagnostic evaluation, and treating clinically significant abnormalities once identified presents a serious clinical and public health problem that has been estimated to cost billions of dollars [2]. This challenge is amplified by the fact that Pap tests are obtained in a variety of clinical settings, including school-based health clinics, sexually transmitted disease clinics, family planning clinics and private physician offices, as well as hospitals and emergency rooms. A spectrum of health care providers is responsible for cervical cancer screening in these various settings, and many of these clinicians have little expertise in managing cervical cytological abnormalities. Because of the magnitude of the clinical problem, there is a clear need for comprehensive, evidence-based guidelines for the management of cervical cytological abnormalities and cervical cancer precursors. There are a number of other reasons why new management guidelines are needed. In May 2001, the National Cancer Institute held a consensus workshop to revise the cervical cytological classification system used in the United States, which is now referred to as the 2001 Bethesda System. The 2001 Bethesda System changes the criteria used by cytologists to render an interpretation of atypical squamous cells (ASC), provides new subcategories of ASC, and changes the subcategories of atypical glandular cells (AGC) [3]. The ASC category is the most common cervical cytological abnormality in the United States, and management guidelines need to be revised to incorporate these changes in terminology. Other reasons for developing new management guidelines are a better understanding of the pathogenesis and natural history of human papillomavirus (HPV) and cervical cancer precursors and the availability of data from the large National Cancer Institute's Atypical Squamous Cells of Undetermined Significance/Low-grade Squamous Intraepithelial Lesion Study (ALTS) clinical trial [3a]. This $25 million, multisite, randomized clinical trial was designed specifically to address the best management approaches for women with a cytological result of ASC and low-grade squamous intraepithelial lesions (LSIL). The results of this trial need to be incorporated into clinical care of women in the United States. It is also important to recognize that current guidelines were developed before sensitive molecular methods for detecting high-risk types of HPV and liquid-based cytology methods became widely available. There is now compelling data that combining these two new technologies provides an attractive alternative to the more traditional management approaches for certain types of cytological abnormalities [4–6]. As a result, the use of these new technologies is increasing, and clinicians need clear, unbiased guidelines delineating the strengths and weakness of different management approaches and the best use of the new technologies. To develop comprehensive management strategies for women with cytological abnormalities and cervical cancer precursors, the American Society of Colposcopy and Cervical Pathology (ASCCP) sponsored a National Consensus Conference in Bethesda, MD, on September 6–8, 2001. This meeting had representatives from 29 national and international health organizations, professional societies, and federal agencies. Throughout the development of the guidelines, input was obtained from the professional community at large through a novel approach that incorporated Internet-based discussion groups. This report provides a summary of the key recommendations and algorithms for managing women with cytological abnormalities. A description of the evidence supporting the guidelines and the guidelines themselves have previously been published [7]. Comprehensive literature reviews of the evidence base supporting the recommendations will be published by each of the four Consensus Conference working groups [atypical squamous cells (ASC); atypical glandular cells (AGC); low-grade squamous intraepithelial lesion (LSIL); and high-grade squamous intraepithelial lesion (HSIL)] at a later date in the Journal of Lower Genital Tract Disease. In addition, separate 2001 Consensus Guidelines for the Management of Women with Cervical Histological Abnormalities will also be published at a later date. OVERVIEW OF GUIDELINE DEVELOPMENT PROCEDURES ASCCP began developing the 2001 Consensus Guidelines in the fall of 2000. To ensure that the guidelines reflect the needs of the diverse array of health care providers, federal agencies and national and international health organizations involved in the health care of women were invited to participate in the guideline development process. Twenty-nine different agencies and organizations agreed to formally participate, or in some instances to formally observe, the Consensus Conference and to send 2 to 4 representatives (seeAppendix 1). In total, 121 representatives attended the Consensus Conference. These included cytopathologists, cytotechnologists, epidemiologists, family physicians, gynecologists, gynecological oncologists, health policy experts, lawyers, nurse clinicians, social scientists, and pathologists. All are recognized experts in various aspects of the diagnosis and management of cervical cancer precursors. Approximately 6 months before the conference, four working groups composed of 10 to 11 participants each began developing draft guidelines through a multistep process. First, a list of key questions that needed to be addressed by literature reviews and comment from the professional community was prepared. These questions were posted on an open Internet bulletin board (http://www.asccp.org) for public discussion. Working groups also conducted MEDLINE searches of English-language, peer-reviewed articles published between at least 1988 and 2001 to identify articles pertaining to the key questions. Abstracts of articles were reviewed by members of the working group to determine their relevancy, and the relevant articles were reviewed to determine whether they fulfilled a minimum scientific standard. Data from articles that fulfilled this standard was extracted using data extraction forms, and summary data tables were prepared for many of the specific topics. Based on the literature review, draft management guidelines were developed. In instances in which published data pertaining to a key issue was either conflicting, scant, or simply missing, information provided by participants of the Internet bulletin boards or expert opinions of members of the working group were used to help formulate the guidelines. Draft guidelines were posted on the open Internet bulletin board for public comment and discussion. Once the discussion period was closed, the draft guidelines were revised by the working groups in light of the public comments and distributed to each of the Consensus Conference participants for review. At the conference, each participant was provided with an electronic numeric keypad that allowed “real-time” voting. Review and adoption of the guidelines took place in three stages. Initially, the draft guidelines and supporting evidence were presented by the working group to the entire Consensus Conference for discussion and voting. Any recommendation that was approved by 66% of the conference participants was accepted. Recommendations that were not approved underwent revision in open working sessions, and the revised recommendations were again discussed and voted on. If the revised recommendation was not accepted, it underwent a second round of revision and was again presented to the Consensus Conference for a third vote. All guidelines were accepted by a two-thirds majority vote. All recommendations are graded using a grading system based on one that has been successfully used for a number of years by the Infectious Disease Society of America (IDSA) for evidence-based practice guidelines [8,9]. More than 30 practice guidelines have been produced by the IDSA using this grading system (with or without minor modifications). Recent important guidelines that have used this grading system include the 1999 Guidelines for the Prevention of Opportunistic Infections in Persons with HIV (and the as yet unreleased 2001 update), produced by a joint panel of the National Institute of Allergy and Infectious Disease, the Centers for Disease Control and Prevention, and the IDSA. The two-part grading system is also almost identical to the one utilized by the US Preventative Services Task Force in its Guide to Clinical Preventative Services. The grading system that was used for the 2001 Consensus Guidelines is a two-part grading system [10]. In this system, the letters A–E reflect the “strength of the recommendation” for or against the use of a particular option (i.e., good, moderate, or insufficient) (Table 1). Roman numerals I–III were used to indicate the “quality of evidence” supporting the recommendation (Table 1). In addition, the terms “recommended,” “preferred,” “acceptable,” and “unacceptable” were specifically defined at the Consensus Conference (Table 1). It was felt that providing an indication of the strength of the evidence supporting each guideline was particularly important in a field in which clinical opinion or small case studies are frequently all that's available to guide a recommendation. Giving the strength of the evidence for a given guideline also provides the additional benefit of highlighting areas in which research is needed. It is expected that the 2001 Consensus Guidelines will be updated on a regular basis; and it is hoped that, with each revision, the data in support of a given practice guideline will become stronger as a result of the grading system.Table 1: Rating the Recommendations2001 CONSENSUS GUIDELINES FOR MANAGING WOMEN WITH CYTOLOGICAL ABNORMALITIES General Comments Although the 2001 Consensus Guidelines are “evidenced-based,” in many instances the evidence that was available to inform the development of a particular guideline was quite limited. This resulted in instances in which the guidelines had to be based on either relatively small studies or simply on expert opinion. It is also important to recognize that, although the 2001 Consensus Guidelines are designed to provide guidance to clinicians caring for women with cytological abnormalities and cervical cancer precursors in the United States, management approaches will frequently need to be individualized to take into account individual patients' clinical findings and preferences. There is a general consensus that guidelines should never be considered a substitute for clinical judgment and that it is impossible to develop guidelines comprehensive enough to apply to all clinical situations. Finally, both clinicians and patients need to realize that, although cervical cancer can often be prevented through a program of screening and treatment of cervical cancer precursor lesions, no screening or treatment modality is perfect and, unfortunately, invasive cervical cancer can develop in women who participate in such programs. The 2001 Bethesda System for cytological classification, which uses the terms low-grade squamous intraepithelial lesion (LSIL) and high-grade squamous intraepithelial lesion (HSIL) to refer to cervical cancer precursors, is used for the guidelines. The 2001 Consensus Guidelines have utilized a two-tiered terminology for the histopathological classification that uses the terms cervical intraepithelial neoplasia–grade 1 (CIN 1) and CIN 2,3 to refer to low-grade and high-grade precursors, respectively [11]. Several terms are used throughout the guidelines, and these have been clarified in Appendix 2. Atypical Squamous Cells General Comments. The 2001 Bethesda System subcategorizes ASC into two categories: atypical squamous cells of undetermined significance (ASC-US) and atypical squamous cells–cannot exclude HSIL (ASC-H) [3]. The prevalence of ASC varies considerably between laboratories and patient populations [1]. In 1997 the median ASC rate of laboratories participating in the College of American Pathologists Interlaboratory Comparison Program in Cervicovaginal Cytology (PAP) was 4.4% [1]. Several points need to be understood to interpret the consensus guidelines for the management of ASC. The first is that even with expert cytologists, the diagnosis of ASC is poorly reproducible [12–14]. For example, in the recent ALTS trial, only 55% of the cytology specimens originally diagnosed as ASC were subsequently given a diagnosis of ASC by the pathology quality control group [5]. Many of the slides initially interpreted as ASC were subsequently classified as normal. Second, a woman with a cytological diagnosis of ASC has a 5% to 17% chance of having biopsy-confirmed CIN 2,3 [5,15–17]. However, the risk that a woman with ASC has invasive cervical cancer is low (approximately 0.1%–0.2%) [18,19]. The prevalence of CIN 2,3 is considerably higher (24%–94%) among women referred for colposcopy (seeAppendix 2) for the evaluation of ASC-H compared with women referred for the evaluation of ASC-US [20–24]. Therefore, a woman with an ASC result requires some form of additional evaluation, but clinicians should attempt to minimize anxiety, cost, inconvenience, and patient discomfort during workup or follow-up. Recommendations for Managing Women with ASC. Management of Women with Atypical Squamous Cells—Undetermined Significance. A program of repeat cervical cytology, or colposcopy, or DNA testing for high-risk types of HPV are all acceptable methods for managing women with ASC-US (AI). When liquid-based cytology is used, or when co-collection for HPV DNA testing can be done, “reflex” HPV DNA testing is the preferred approach (AI). * DNA testing for high-risk types of HPV should be performed using a sensitive molecular test, and all women who are HPV DNA positive should be referred for colposcopic evaluation (AII). Women with ASC-US who are high-risk HPV DNA negative can be followed up with repeat cytology at months management for women who are positive for high-risk types of HPV but who not have biopsy-confirmed CIN include with repeat cytology at 6 and months with to colposcopy a result of ASC-US or is or HPV DNA testing at months with to colposcopy of all HPV DNA positive women Management of Women with Atypical Squamous Cells of Undetermined a program of repeat cervical cytology is used, women with ASC-US should repeat cytological testing or at to two for intraepithelial lesion or results are obtained (AII). Women diagnosed with ASC-US or cytological abnormality on the repeat tests should be referred for colposcopy (AII). two for intraepithelial lesion or repeat cytology tests are women can be to cytological screening (AII). When colposcopy is used to women with women who are referred to colposcopy and not to have CIN should be followed up with repeat cytology at months Women with ASC-US who are referred for colposcopy and to have biopsy-confirmed CIN should be to the 2001 Consensus for the Management of Women with Cervical Histological Abnormalities for Because of the for diagnostic (seeAppendix 2) such as should not be used to women with ASC in the of biopsy-confirmed CIN ASC-US in a of followed by a repeat cervical cytology obtained approximately a the is an acceptable option for women with ASC-US who have clinical or cytological evidence of and no to using If the repeat cervical cytology is for intraepithelial lesion or the cervical cytology should be in 4 to 6 If both repeat cytology tests are for intraepithelial lesion or the patient can to cytological but either repeat cytology is as ASC-US or the patient should be referred for colposcopy Management of Women with Atypical Squamous Cells of Undetermined (ASC-US) In for colposcopy is for all patients with ASC-US This all of HIV or It is that women with ASC-US be in the as women Management of Women with The management of women with ASC-H obtained using either or liquid-based cervical cytology is for colposcopic evaluation Management of Women with Atypical Squamous no lesion is identified colposcopy in women with it is that, when a of the cytology, colposcopy and be performed If the a revised management should guidelines for the revised a cytological interpretation of ASC-H is either cytological at 6 and months or HPV DNA testing at months is acceptable Women who are to have ASC or on their repeat cervical cytology or who are subsequently high-risk HPV DNA positive should be referred for Atypical Cells and In General Comments. abnormalities than are classified into three in the 2001 Bethesda System [3]. These are atypical glandular cells or not atypical glandular cells or and in [3]. In the median rate of laboratories in the United was [1]. most women with not have a significant cervical this category is of risk than the category of ASC or CIN is in of women with biopsy-confirmed is identified in and invasive cervical are identified in The majority of in women the of with are in of into two and women at different for having high-grade or invasive or CIN 2,3 have been in of women with compared with of women with women with a cytological result of will have either biopsy-confirmed or invasive cervical Recommendations for Managing Women with and Colposcopy with (seeAppendix 2) is for women with all subcategories of with the that women with atypical cells should initially be with (seeAppendix should be performed in with colposcopy in women the of with and women with who have Colposcopy with is also for women with a cytological result of Management of women with an result of or using a program of repeat cervical cytology is There is data to an of the use of HPV DNA testing in the management of women with or Management of Women with Atypical Cells and If invasive disease is not identified during the colposcopic it is that women with or a diagnostic (AII). The preferred diagnostic for women with or is If biopsy-confirmed CIN is identified during the workup of a woman with management should be to the 2001 Consensus for the Management of Women with Cervical Histological Abnormalities for If no is identified during the workup of a woman with it is that the woman be followed using a program of repeat cervical cytology at to four for intraepithelial lesion or cytology results are which the woman be to screening If an ASC or result is obtained on of the Pap acceptable include a repeat colposcopic or to a in the management of cytological If an or HSIL result is obtained on of the Pap acceptable include a diagnostic or to a in the management of cytological Squamous Intraepithelial Lesion General Comments. The median rate in the United in was However, as as have been from laboratories high-risk populations There is a relatively between the of lesion identified by cervical cytology and the of lesion that is identified on a CIN 2,3 is identified in approximately of women colposcopy for a cytological result of Recommendations for Managing Women with General Management Colposcopy is the preferred management of women with management on whether a lesion is whether the colposcopic is and whether the patient is or Management of Women with Squamous Intraepithelial is acceptable for women with a colposcopy (seeAppendix 2) and a lesion identified in the but it is preferred for women in no lesions are identified If biopsy-confirmed CIN is not identified and the colposcopy is acceptable management include with repeat cytology at 6 and months with a to colposcopy a result of ASC-US or is or HPV DNA testing at months with to colposcopy of all HPV DNA positive women is preferred for women with an colposcopy (AII). If biopsy-confirmed CIN is not identified and the colposcopy is acceptable management include with repeat cytology at 6 and or HPV DNA testing at months Women with who are to have biopsy-confirmed CIN should be to the 2001 Consensus Management in In without colposcopy using a of with repeat cytology at 6 and months with a to colposcopy of ASC, or HPV DNA testing at months is an acceptable option Management of Women with Squamous Intraepithelial In a of followed by a repeat cervical cytology obtained approximately a the is acceptable for women with ASC-US who have clinical or cytological evidence of with ASC-US and no to using is an acceptable If the repeat cervical cytology is for squamous intraepithelial lesion or the cervical cytology should be in 4 to 6 If both repeat cytology tests are for squamous intraepithelial lesion or the patient can to cytological but either repeat cytology is as ASC or the patient should be referred for In without colposcopy using a of up with repeat cytology at 6 and months with a to colposcopy of ASC, or HPV DNA testing at months is an acceptable option Management of Women with Squamous Intraepithelial In in in Women with The use of diagnostic or is for the management of patients with and either a or colposcopy in the of a biopsy-confirmed Squamous Intraepithelial Lesion to Managing Women with A cytological diagnosis of HSIL is relatively The median rate of HSIL in the United in was only to a College of American Pathologists A cytological result of HSIL is a significant it a of women who are at relatively high-risk for a CIN 2,3 or invasive cervical Approximately of women with HSIL will be at colposcopy to have a biopsy-confirmed CIN and will be to have invasive cervical cancer Recommendations for Managing Women with General Management Colposcopy with (seeAppendix 2) is the management of women with management on whether a lesion is whether the colposcopic is whether the patient is and whether is Management of Women with Squamous Intraepithelial When no lesion or only biopsy-confirmed CIN 1 is identified colposcopy in women with HSIL and a colposcopy, it is that, when a of the cytology, colposcopy and be If the a revised management should guidelines for the revised a cytological interpretation of HSIL is or is not a diagnostic is preferred in A colposcopic with is acceptable in HSIL in When no lesion is identified colposcopy in women with HSIL and an colposcopy, a of the cytology, colposcopy and should be performed when If the a revised management should guidelines for the revised If a cytological interpretation of HSIL is is not or a biopsy-confirmed CIN 1 is a diagnostic is in is of is acceptable when a diagnostic is In women with HSIL and a colposcopic of a high-grade evaluation a diagnostic is also an acceptable either a program of repeat cytology or HPV DNA testing is Women with HSIL who are to have biopsy-confirmed CIN should be the 2001 Consensus for the Management of Women with Cervical Histological Abnormalities for HSIL in It is preferred that the colposcopic evaluation of women with HSIL be conducted by clinicians who are in the evaluation of colposcopic changes by of lesions for high-grade disease or cancer is of other lesions is is in colposcopy become as the it is that women with an colposcopy a repeat colposcopic in 6 to In the of invasive additional colposcopic and cytological are with only the of the lesion or cytology invasive invasive cancer is treatment is A diagnostic is only is with cytology and colposcopy is no than 6 Women of When biopsy-confirmed CIN 2,3 is not identified in a woman with a HSIL cytology, with colposcopy and cytology at to for one year is provided colposcopy is is and the patient the risk of If a lesion to to a colposcopic high-grade lesion or HSIL cytology a diagnostic is The development of the 2001 Consensus Guidelines was by ASCCP and a 1 from the National Cancer The of the guidelines is the of the and not the of the National Cancer The ASCCP to for support for the conference and the development of the guidelines.