Wright, Thomas C. Jr MD1; Massad, L. Stewart MD2; Dunton, Charles J. MD3; Spitzer, Mark MD4; Wilkinson, Edward J. MD5; Solomon, Diane MD6; for the 2006 ASCCP-Sponsored Consensus Conference
In 2001, the American Society for Colposcopy and Cervical Pathology (ASCCP) joined other professional societies and federal and international organizations to develop the 2001 Consensus Guidelines for Managing Women with Cytological Abnormalities . These were comprehensive evidenced-based guidelines developed to help clinicians of all subspecialties manage the approximately 4.8 million women who are diagnosed with cytological abnormalities annually in the United States . Before the introduction of the 2001 Consensus Guidelines, recommendations for managing women with cytological abnormalities varied considerably between different professional societies and government agencies. However, because most societies and organizations that deal with cytological screening participated in the development of the 2001 Consensus Guidelines, their introduction has led to considerable harmonization of management recommendations in the United States.
Since 2001, new information has become available, including the key follow-up results from the ASCUS/LSIL Triage Study (ALTS), sponsored by the National Cancer Institute [3, 4]. Moreover, molecular testing for high-risk types of human papillomavirus (HPV) has been approved for use with cervical cytology for screening in women 30 years and older. Although "interim guidance" for the use of HPV DNA testing in the screening setting was proposed in 2004, recommendations for how to manage combinations of HPV DNA and Pap test results have not formally been evaluated by a large multidisciplinary group . In addition, implementation of the 2001 guidelines in a variety of clinical settings made apparent the need for changes in a number of areas. This pertains particularly to "special populations" such as adolescents and postmenopausal women. Finally, there was also a desire to streamline the guidelines and make them more user-friendly. Therefore, in 2005, the ASCCP, together with its partner professional societies and federal and international organizations (listed in Appendix A), began the process of revising the guidelines. This culminated in the 2006 Consensus Conference that was held at the National Institutes of Health in September 2006. This report provides the recommendations developed for managing women with cytological abnormalities. Recommendations for managing women with cervical intraepithelial neoplasia (CIN) and adenocarcinoma in situ (AIS) will be published separately. A more comprehensive discussion of the recommendations and their supporting evidence will be made available on the ASCCP website (http://www.asccp.org/consensus.shtml).
GUIDELINE DEVELOPMENT PROCESS
The process used to develop the 2006 Consensus Guidelines was similar to that for the previous guidelines . Approximately 12 months before the conference, 6 working groups were formed, incorporating leaders in cervical cancer prevention. Groups identified problem areas in the 2001 guidelines and formulated questions that were posted on an open Internet bulletin board for discussion among the screening and reproductive health communities. At the same time, the working groups conducted MEDLINE searches of the English-language articles published since 2000. Abstracts were reviewed for relevance, and relevant articles were reviewed for validity and generalizability. Based on Internet discussions and literature reviews, draft guidelines were developed and posted on the Internet bulletin boards for public comment as well as discussed during conference calls among the committee members. After further revision, guidelines and supporting data were presented, discussed, modified if necessary, and voted on at the consensus conference. All guidelines were approved by at least a two-thirds majority vote.
Cervical cytological abnormalities are managed by clinicians of many specialties, some of whom spend only a limited amount of time dealing with gynecologic conditions. Therefore, the 2006 Consensus Guidelines mirror the 2001 Consensus Guidelines for situations where new information does not necessitate change. To maintain consistency, the terminology used in the new guidelines is identical to that which was used previously, as is the 2-part rating system (Table 1) . The terms recommended, preferred, acceptable, and unacceptable are used in the guidelines to describe various interventions. For example, in some clinical situations, there are multiple management options that have reasonable evidence of efficacy, but based on less-defined issues such as costs or patient convenience, one approach may be "preferred." The letters A through E are used to indicate "strength of recommendation" for or against the use of a particular option. The strength of the recommendation is based on consideration of several criteria, including potential for harm if an intervention did not occur, potential complications of a given intervention, as well as the "quality of the evidence." Therefore, an exact correlation does not exist between "strength of the recommendation" and the "quality of the evidence." "Quality of evidence" was designated using Roman numerals I to III as defined in Table 1. A number of terms that are used in the guidelines were specifically defined at the beginning of the Consensus Conference (Table 1). These include the terms recommended, preferred, acceptable, and unacceptable.
2006 CONSENSUS GUIDELINES
Although the guidelines are based on evidence whenever possible, for certain clinical situations, there is limited high-quality evidence, and in these situations, the guidelines have, by necessity, been based on consensus expert opinion. Acceptable management strategies provide what the participants considered an acceptable level of risk of failing to detect high-grade neoplasia or cancer in a given clinical situation. It is unreasonable for patients or clinicians to expect that this risk can be reduced to zero, and attempts to achieve zero risk could result in greater harm than good, including overtreatment. It is also important to recognize that these guidelines should never substitute for clinical judgment. Clinical judgment should always be used when applying a guideline to an individual patient because it is impossible to develop guidelines that apply to all situations.
The 2001 Bethesda System terminology is used for cytological classification . This terminology uses the terms low-grade squamous intraepithelial lesion (LSIL) and high-grade squamous intraepithelial lesion (HSIL) to refer to low-grade lesions and high-grade cervical cancer precursors, respectively. The histological classification used is a 2-tiered system that applies the terms CIN 1 to low-grade lesions and CIN 2,3 to high-grade precursors. It is important to note that cytological LSIL is not equivalent to histological CIN 1 and cytological HSIL is not equivalent to histological CIN 2,3. Algorithms detailing the different management recommendations are available at the ASCCP website (http://www.asccp.org/consensus.shtml). A glossary of terms used in the guidelines is in Appendix B.
There are several important points with respect to management strategies in general, and HPV DNA testing and colposcopy in particular, that apply whenever these modalities are recommended. Triage using either HPV testing or a program of repeat cytology is generally not considered an acceptable option if 75% or more of women tested would be referred to colposcopy because of a positive result. The current guidelines expand clinical indications for HPV testing based on studies using validated HPV assays. One cannot assume that management decisions that are based on results of HPV tests that have not been similarly validated will result in the outcomes that are intended by these guidelines. Instead, doing so may increase the potential for patient harm. The appropriate use of these guidelines requires that laboratories use only HPV tests that have been analytically and clinically validated with proven acceptable reproducibility, clinical sensitivity, specificity, and positive and negative predictive values for cervical cancer and verified precancer (CIN 2,3), as documented by Food and Drug Administration (FDA) approval and/or publication in peer-reviewed scientific literature. It is also important to stress that testing should be restricted to high-risk (oncogenic) HPV types (i.e., 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 66) . Testing for low-risk (nononcogenic) HPV types has no role in the evaluation of women with abnormal cervical cytological results. Therefore, whenever "HPV testing" is referred to in the guidelines, it applies only to testing for high-risk (oncogenic) HPV types.
There is increasing recognition that colposcopy is less sensitive than previously thought and that a single colposcopic examination misses approximately one third of women with CIN 2,3 [8-10]. An analysis of the performance of colposcopy in ALTS indicates that sensitivity is significantly greater when 2 or more biopsies are obtained . The utility of performing endocervical sampling in all women undergoing colposcopy is controversial . However, there is some evidence to suggest that endocervical sampling may be useful even in women with satisfactory colposcopy . One recent study of women with satisfactory colposcopy and CIN 2,3 or cancer found that the lesion was detected only by endocervical curettage in 5.5% of the women .
The exact same cytological result has a different risk of CIN 2,3 or cancer in various groups of women. Adolescent women (aged 20 and younger) are one such "special population." Adolescents have a very low risk for invasive cervical cancer. In 2002, there were only 12 cases of invasive cervical cancer in females 10 to 19 years old in the United States, and the age-specific incidence of invasive cervical cancer is only 1.5 per 100,000 for women 20 to 24 years old . For comparison, the incidence of invasive cervical cancer is 11.4 per 100,000 for women 30 to 34 years old. In contrast, minor-grade cytological abnormalities (ASC and LSIL) are more common in women 15 to 19 years old than in older women . This is because of the high prevalence of HPV infections in adolescent women . At any single period, approximately 20% to 25% of sexually active women younger than 21 years will be HPV DNA positive, and approximately 80% of sexually active young women will be HPV DNA positive at some point soon after initiating sexual activity . Although often associated with minor cytological abnormalities, most HPV infections spontaneously clear within 2 years after infection and are of little long-term clinical significance . Therefore, performing colposcopy for minor cytological abnormalities in adolescents should be discouraged, because it identifies considerable numbers of cervical lesions that have minimal long-term oncogenic significance and can potentially result in harm by prompting unnecessary treatment.
Pregnant women are also considered a "special population." The only indication for treatment of cervical neoplasia in pregnant women is invasive cancer. Therefore, it is reasonable to defer colposcopy in pregnant women at low risk for having cancer. Colposcopy is more difficult in pregnant patients because pregnancy accentuates both normal and abnormal colposcopic findings. Because of concern about bleeding, clinicians frequently do not biopsy pregnant patients [17, 18]. However, cervical biopsy has not been associated with serious bleeding or pregnancy losses in the large series, and failure to perform biopsies in pregnant women has been associated with missed cancers [17, 19]. Endocervical curettage is contraindicated in pregnant patients.
Atypical Squamous Cells
Atypical squamous cells (ASC) are subcategorized into atypical squamous cells of undetermined significance (ASC-US) and atypical squamous cells, cannot exclude HSIL (ASC-H). The median reporting rate of ASC-US in US laboratories is 4.7%, and the median rate of ASC-H is 0.4% . There are several factors to be taken into consideration when managing women with ASC. One is that a cytological diagnosis of ASC is the least reproducible of all cytological categories [20-22]. Another is that the prevalence of invasive cancer is low in women with ASC (approximately 0.1%-0.2%) . Finally, the prevalence of CIN 2,3 is higher among women with ASC-H than women with ASC-US. The prevalence of CIN 2,3 among women with ASC is 7% to 12% in the United States [3, 24, 25]. In contrast, the prevalence of CIN 2,3 among women with ASC-H ranges from 26% to 68% [26-29]. Rates of high-risk HPV DNA positivity are similarly discrepant: from 40% to 51% among women with ASC-US but 74% to 88% among women with ASC-H [3, 24, 25, 27, 28, 30]. Consequently, ASC-H should be considered to represent equivocal HSIL and a productive HPV infection.
Approaches to Managing Women With ASC-US.
Clinical data from ALTS and other studies have demonstrated that 2 repeat cytological examinations performed at 6-month intervals, testing for HPV, and a single colposcopic examination are all safe and effective approaches to managing women with ASC-US [3, 24, 25, 31]. Therefore, the 2001 Consensus Guidelines recognized that all 3 approaches were acceptable for managing women with ASC-US. The scientific basis for the 2001 recommendation has been strengthened during the last 5 years by additional clinical studies, additional analyses of the ALTS data, and meta-analyses of published studies [9, 25, 32-36]. A meta-analysis performed in 2004 reported that the pooled estimate of the sensitivity of HPV testing for detecting women with CIN 2,3 is considerably higher than that of a single repeat cytology . In ALTS, repeating cytology twice at 6-month intervals detected 95% of CIN 3 lesions using an ASC-US threshold for colposcopy and referred 67% of the women to colposcopy . For comparison, a single HPV test identified 92% of CIN 3 lesions and referred 53% to colposcopy. Therefore, 2 repeat cytology examinations are as sensitive as HPV testing for detecting CIN 3 but require 2 follow-up visits.
Although all 3 management approaches are considered acceptable for managing women with ASC-US, "reflex" HPV testing is preferred. Reflex testing refers to testing either the original liquid-based cytology residual specimen or a separate sample co-collected at the time of the initial screening visit for HPV testing. This approach is preferred because it eliminates the need for women to return for repeat testing, rapidly reassures many women that they do not have a significant lesion, and spares 40% to 60% of women from undergoing colposcopy. Cost-effectiveness analyses have shown that reflex HPV testing is less expensive and more effective at detecting CIN 2,3 than the other strategies [29, 37, 38].
Because a single colposcopic examination can miss significant lesions, women who are referred for colposcopy and found not to have CIN 2,3 require additional follow-up. ALTS evaluated different postcolposcopy follow-up strategies and found that HPV testing performed 12 months after the initial colposcopy detected 92% of the cases of CIN 2,3 that had not been detected at initial colposcopy and resulted in 55% of women undergoing a second colposcopy . Two repeat cytology examinations performed at 6-month intervals, at an ASC-US threshold for colposcopy, detected 88% of the missed cases and required that 64% of women undergo a second colposcopy. Combining cytology with HPV testing did not increase sensitivity and reduced specificity .
The prevalence of HPV DNA positivity changes with age among women with ASC-US. In ALTS, the prevalence of HPV DNA positivity was much higher in women 18 to 22 years old (71%) versus those older than 29 years (31%) . Similarly, in another study, the prevalence of HPV DNA positivity in adolescents 19 years old and younger with ASC-US was 77% versus 58% in women older than 25 years . Thus, using HPV testing to manage adolescents and young women with ASC-US would refer large numbers of women at low risk for having cancer to colposcopy. It is important to note that many adolescents experience multiple sequential HPV infections, and a repetitively positive HPV test in this age group may represent repeated transient infections rather than a persistent infection.
ASC-US is less common in postmenopausal than in premenopausal women, and the risk of significant pathology in postmenopausal women with a history of prior negative cervical cancer screening results is relatively low [14, 41, 42]. HPV testing is actually more efficient in older compared with younger women with ASC-US, because it refers a lower proportion to colposcopy [41, 43, 44]. In ALTS, only 20% of women 40 years and older with ASC-US were HPV DNA positive .
ASC-US is quite common in HIV-infected women. Two recent follow-up studies reported that 60% to 78% of HIV-infected women have ASC-US during 4 to 5 years of follow-up [45, 46]. Previously, it was recommended that all immunosuppressed women with ASC-US undergo colposcopy. This was based on studies that had reported a high prevalence of both HPV DNA positivity and significant cervical pathology in this population . However, more recent studies have found a lower prevalence of CIN 2,3 and HPV DNA positivity [47, 48].
The risk of cancer is relatively low among pregnant women with ASC-US, and some studies have found that antepartum colposcopic evaluation does not alter management .
Recommended Management of Women With ASC-US.
general management approaches.
A program of DNA testing for high-risk (oncogenic) types of HPV, repeat cervical cytological testing, or colposcopy are all acceptable methods for managing women older than 20 years with ASC-US (Figure 1). (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)
Women with ASC-US who are HPV DNA negative can be followed up with repeat cytological testing at 12 months. (BII) Women who are HPV DNA positive should be managed in the same fashion as women with LSIL and be referred for colposcopic evaluation. (AII) Endocervical sampling is preferred for women in whom no lesions are identified (BII) and those with an unsatisfactory colposcopy (AII) but is acceptable for women with a satisfactory colposcopy and a lesion identified in the transformation zone. (CII) Acceptable postcolposcopy management options of women with ASC-US who are HPV positive but in whom CIN is not identified are HPV DNA testing at 12 months and repeat cytological testing at 6 and 12 months. (BII) It is recommended that HPV DNA testing not be performed at intervals less than 12 months. (EIII)
When a program of repeat cytological testing is used for managing women with ASC-US, it is recommended that cytological testing be performed at 6-month intervals until 2 consecutive "negative for intraepithelial lesion or malignancy" results are obtained. (AII) Colposcopy is recommended for women with ASC-US or greater cytological abnormality on a repeat test. (AII) After 2 repeat "negative for intraepithelial lesion or malignancy" results are obtained, women can return to routine cytological screening. (AII)
When colposcopy is used to manage women with ASC-US, repeat cytological testing at 12 months is recommended for women in whom CIN is not identified. (BIII) Women found to have CIN should be managed according to the 2006 Consensus Guidelines for the Management of Cervical Intraepithelial Neoplasia.
Because of the potential for overtreatment, the routine use of diagnostic excisional procedures such as the loop electrosurgical excision is unacceptable for women with an initial ASC-US in the absence of histologically diagnosed CIN 2,3. (EII)
ASC-US in Special Populations.
In adolescents with ASC-US, follow-up with annual cytological testing is recommended (Figure 2). (BII) At the 12-month follow-up, only adolescents with HSIL or greater on the repeat cytology should be referred to colposcopy. At the 24-month follow-up, those with an ASC-US or greater result should be referred to colposcopy. (AII) HPV DNA testing and colposcopy are unacceptable for adolescents with ASC-US. (EII) If HPV testing is inadvertently performed, the results should not influence management.
immunosuppressed and postmenopausal women.
HIV-infected, other immunosuppressed women, and postmenopausal women with ASC-US should be managed in the same manner as women in the general population. (BII)
Management options for pregnant women older than 20 years with ASC-US are identical to those described for nonpregnant women, with the exception that is acceptable to defer colposcopy until at least 6 weeks postpartum. (CIII) Endocervical curettage is unacceptable in pregnant women. (EIII)
Recommended Management of Women With ASC-H.
The recommended management of women with ASC-H is referral for colposcopic evaluation (Figure 3). (AII) In women in whom CIN 2,3 is not identified, follow-up with HPV DNA testing at 12 months or cytological testing at 6 and 12 months is acceptable. (CIII) Referral to colposcopy is recommended for women who subsequently test positive for HPV DNA or who are found to have ASC-US or greater on their repeat cytological tests. (BII) If the HPV DNA test is negative or if 2 consecutive repeat cytological tests are "negative for intraepithelial lesion or malignancy," return to routine cytological screening is recommended. (AI)
Low-Grade Squamous Intraepithelial Lesion
The Bethesda System terminology uses low-grade squamous intraepithelial lesion to refer to cytological changes previously reported as mild dysplasia, CIN 1, HPV effects, and koilocytosis . During the last decade, the rate of LSIL has increased in the United States. In 1996, the median percentile reporting rate for US laboratories was 1.6%. This increased to 2.1% by 2003, whereas reporting rates for other cytological categories did not show similar increases . The increase seems to be because of the widespread switch to liquid-based cytology. The median percentile reporting rate of LSIL in US laboratories in 2003 was 1.4% for conventional cytology specimens and 2.4% for liquid-based specimens . A result of LSIL is highly predictive of HPV infection. A recent meta-analysis reported that the pooled estimate of high-risk (oncogenic) HPV DNA positivity among women with LSIL was 76.6% . Postmenopausal women are an exception, with lower HPV prevalence after an LSIL result. The prevalence of CIN 2,3 or cancer identified at initial colposcopy among women with LSIL is 12% to 17% [4, 51].
Approaches to Managing Women With LSIL.
Data from ALTS indicate that the risk of high-grade cervical neoplasia in women with LSIL is the same as in those with ASC-US who are high-risk (oncogenic) HPV DNA positive . This supports managing both groups of women in an identical manner, except in special populations such as postmenopausal women.
Prospective follow-up studies of adolescents with LSIL have shown very high rates of regression to normal. In one of the largest studies of adolescents with LSIL, the cumulative regression rate was 91% at 36 months . Moreover, it is not unusual for regression to take years to occur. Among adolescents with LSIL who had not regressed at 2 years, 60% still regressed to normal during the following 12 months . It is important to recognize, however, that a small proportion of adolescents with LSIL may have underlying CIN 3, although essentially none will have cancer before the age of 20 years. A recent study of adolescents undergoing colposcopy found that 7% of adolescents and young women 13 to 22 years old with LSIL had CIN 2,3 at colposcopy. Most of these lesions will be detected with repeat cytology . As with ASC-US, the high prevalence of HPV DNA positivity in adolescents with LSIL makes HPV testing of little value in this population.
Although in ALTS there was no age above which HPV testing became an attractive triage option for women with LSIL, interpretation was hampered by the small number of older women with LSIL . Other studies have found that the prevalence of both HPV DNA positivity and CIN 2,3 decline with age . This suggests that postmenopausal women with LSIL can be managed less aggressively than premenopausal women and that triage using HPV testing may be an efficient alternative to colposcopy.
Recommended Management of Women With LSIL.
Colposcopy is recommended for managing women with LSIL, except in special populations (see below, Figure 4). (AII) Endocervical sampling is preferred for nonpregnant women in whom no lesions are identified (BII) and those with an unsatisfactory colposcopy (AII) but is acceptable for those with a satisfactory colposcopy and a lesion identified in the transformation zone. (CII) Acceptable postcolposcopy management options for women with LSIL cytology in whom CIN is not identified are testing for high-risk (oncogenic) types of HPV at 12 months or repeat cervical cytological testing at 6 and 12 months. (BII) If the HPV DNA test is negative or if 2 consecutive repeat cytological tests are "negative for intraepithelial lesion or malignancy," return to routine cytological screening is recommended. (AI) If either the HPV DNA test is positive or if repeat cytology is reported as ASC-US or greater, colposcopy is recommended. (AI) Women found to have CIN should be managed according to the appropriate 2006 Consensus Guidelines on the Management of Cervical Intraepithelial Neoplasia. In the absence of histologically identified CIN, diagnostic excisional or ablative procedures are unacceptable for the initial management of patients with LSIL. (EII)
LSIL in Special Populations.
In adolescents with LSIL, follow-up with annual cytological testing is recommended (Figure 2). (AII) At the 12-month follow-up, only adolescents with HSIL or greater on the repeat cytology should be referred to colposcopy. At the 24-month follow-up, those with an ASC-US or greater result should be referred to colposcopy. (AII) HPV DNA testing is unacceptable for adolescents with LSIL. (EII) If HPV DNA testing is inadvertently performed, the results should not influence management.
Acceptable options for the management of postmenopausal women with LSIL include reflex HPV DNA testing, repeat cytological testing at 6 and 12 months, and colposcopy. (CIII) If the HPV DNA test is negative or if CIN is not identified at colposcopy, repeat cytology in 12 months is recommended. If either the HPV DNA test is positive or the repeat cytology is ASC-US or greater, colposcopy is recommended. (AII) If 2 consecutive repeat cytological tests are"negative for intraepithelial lesion or malignancy," return to routine cytological screening is recommended.
Colposcopy is preferred for pregnant nonadolescent women with LSIL cytology (Figure 5). (BII) Endocervical curettage is unacceptable in pregnant women. (EIII) Deferring the initial colposcopy until at least 6 weeks postpartum is acceptable. (BIII) In pregnant women who have no cytological, histological, or colposcopically suspected CIN 2,3 or cancer at the initial colposcopy, postpartum follow-up is recommended. (BIII) Additional colposcopic and cytological examinations during pregnancy are unacceptable for these women. (DIII)
High-Grade Squamous Intraepithelial Lesion
The Bethesda System terminology uses the term high-grade squamous intraepithelial lesion to refer to cytological findings previously reported as moderate dysplasia, severe dysplasia, carcinoma in situ, CIN 2, and CIN 3. The mean reporting rate of HSIL in US laboratories is 0.7% . The rate of HSIL varies with age. In one US center, the rate of HSIL in women 20 - 29 years old was 0.6%, compared with 0.2% and 0.1% in women 40 - 49 years and 50 - 59 years old, respectively . The finding of an HSIL result on cytology connotes a high risk for significant cervical disease. Recent studies have found that a single colposcopic examination identifies CIN 2,3 or cancer in 53% to 66% of women with HSIL cytological results and that CIN 2,3 or cancer is diagnosed in 84% to 97% of women evaluated using a loop electrosurgical excision [51, 53, 54]. Approximately 2% of women with HSIL have invasive cancer .
Approaches to Managing Women With HSIL.
Management of women with HSIL should incorporate several considerations. These include the considerable risk of a CIN 2,3 lesion or cancer and a high prevalence of HPV DNA positivity [28, 54-56]. Thus, intermediate triage using HPV testing or cytology is inappropriate. Management also needs to recognize that the sensitivity of colposcopy for detecting CIN 2,3 is more limited than previously appreciated [10, 11, 39]. Failure to detect CIN 2,3 at colposcopy in a woman with HSIL does not necessarily mean that a CIN 2,3 lesion is not present, although occult carcinoma is unlikely. As a result, most women with HSIL eventually undergo a diagnostic excisional procedure. Because of this, many have advocated "see-and-treat" approaches for managing women with HSIL, with a loop electrosurgical excision used for initial evaluation [53, 57, 58]. It should be noted, however, that most cases of CIN 2,3, especially in adolescents and young adults, spontaneously regress [59, 60]. Moreover, recent studies have highlighted the potential negative impact on subsequent pregnancies of loop electrosurgical excision [61-64]. Loop electrosurgical excision seems to approximately double the risk that a woman will subsequently have preterm delivery, a low-birth weight infant, or premature rupture of membranes . For this reason, careful observation of HSIL may be appropriate for women contemplating future childbearing.
Adolescents are at low risk for cervical cancer, and most CIN 2,3 lesions in adolescents spontaneously regress. This, coupled with the potential negative impact of loop electrosurgical excision on future pregnancies argues against see-and-treat approaches in this population.
Recommended Management of Women With HSIL
An immediate loop electrosurgical excision or colposcopy with endocervical assessment is an acceptable method for managing women with HSIL, except in special populations (see below, Figure 6). (BII) When CIN 2,3 is not identified histologically, either a diagnostic excisional procedure or observation with colposcopy and cytology at 6-month intervals for 1 year is acceptable, provided in the latter case that the colposcopic examination is satisfactory and endocervical sampling is negative. (BIII) In this circumstance, it is also acceptable to review the cytological, histological, and colposcopic findings; if the review yields a revised interpretation, management should follow guidelines for the revised interpretation. (BII) If observation with cytology and colposcopy is elected, a diagnostic excisional procedure is recommended for women with repeat HSIL cytological results at either the 6- or 12-month visit. (CIII) After 1 year of observation, women with 2 consecutive "negative for intraepithelial lesion or malignancy" results can return to routine cytological screening.
A diagnostic excisional procedure is recommended for women with HSIL in whom the colposcopic examination is unsatisfactory, except in special populations (e.g., pregnant women). (BII) Women with CIN 2,3 should be managed according to the appropriate 2006 Consensus Guideline for the Management of Women with Cervical Intraepithelial Neoplasia. Ablation is unacceptable in the following circumstances: colposcopy has not been performed, CIN 2,3 is not identified histologically, or the endocervical assessment identifies CIN of any grade. (EII) Triage using either a program of only repeat cytology or HPV DNA testing is unacceptable. (EII)
HSIL in Special Populations.
In adolescents with HSIL, colposcopy is recommended (Figure 7). Immediate LEEP (i.e., see-and-treat approach) is unacceptable in adolescent women. (AII) When CIN 2,3 is not identified histologically, observation for up to 24 months using both colposcopy and cytology at 6-month intervals is preferred, provided the colposcopic examination is satisfactory and endocervical sampling is negative. (BIII) In exceptional circumstances, a diagnostic excisional procedure is acceptable. (BIII) If during follow-up a high-grade colposcopic lesion is identified or HSIL cytology persists for 1 year, biopsy is recommended. (BIII) If CIN 2,3 is identified histologically, management should follow the 2006 Consensus Guideline for the Management of Women with Cervical Intraepithelial Neoplasia. (BIII) If HSIL persists for 24 months without identification of CIN 2,3, a diagnostic excisional procedure is recommended. (BIII) After 2 consecutive "negative for intraepithelial lesion or malignancy" results, adolescents and young women without a high-grade colposcopic abnormality can return to routine cytological screening. (BIII) A diagnostic excisional procedure is recommended for adolescents and young women with HSIL when colposcopy is unsatisfactory or CIN of any grade is identified on endocervical assessment. (BII)
Colposcopy is recommended for pregnant women with HSIL. (AII) It is preferred that the colposcopic evaluation of pregnant women with HSIL be conducted by clinicians who are experienced in the evaluation of colposcopic changes induced by pregnancy. (BIII) Biopsy of lesions suspicious for CIN 2,3 or cancer is preferred; biopsy of other lesions is acceptable (BIII). Endocervical curettage is unacceptable in pregnant women. (EIII) Diagnostic excision is unacceptable unless invasive cancer is suspected based on the referral cytology, colposcopic appearance, or cervical biopsy. (EII) Reevaluation with cytology and colposcopy is recommended no sooner than 6 weeks postpartum for pregnant women with HSIL in whom CIN 2,3 is not diagnosed. (CIII)
Atypical Glandular Cells
The 2001 Bethesda System classifies glandular cell abnormalities less severe than adenocarcinoma into 3 categories: atypical glandular cells (AGC; endocervical, endometrial, or "glandular cells" not otherwise specified [NOS]); AGC, either endocervical or "glandular cells" favor neoplasia (AGC favor neoplasia); and endocervical AIS . An AGC interpretation is poorly reproducible among observers . AGC results are relatively uncommon, with a mean reporting rate of only 0.4% in the United States in 2003 . In contrast to ASC, LSIL, and HSIL, which are more common in younger as opposed to older women, AGC is more common in women 40 years and older . Although AGC is frequently caused by benign conditions such as reactive changes and polyps, clinicians should be aware that it is not uncommon for AGC to be associated with a significant underlying neoplastic condition including adenocarcinomas of the cervix, endometrium, ovary, and fallopian tube. Recent series have reported that 9% to 38% of women with AGC have significant neoplasia (CIN 2,3, AIS, or cancer) and 3% to 17% have invasive cancer [66-69].
Approaches to Managing Women With AGC.
Although a variety of glandular lesions are associated with AGC, somewhat paradoxically, CIN is the most common significant finding identified in women with AGC. In various studies, CIN lesions have been found in 8% to 83% of women with AGC, of which 40% to 68% are CIN 2,3 . The frequency and nature of significant findings in women with AGC vary with age . In one recent study, 13% of women younger than 35 years with AGC had CIN 2,3, and none had a gynecologic malignancy . In contrast, 3% of those 35 years and older had a gynecologic malignancy, but only 2% had CIN 2,3. In addition, because approximately half of women with AIS have a coexisting CIN lesion, identification of a CIN lesion does not change the management of women with AGC . Pregnancy does not seem to change the underlying associations between AGC and gynecologic neoplasia, although studies are limited [72, 73].
The evaluation of women with AGC should be conducted by clinicians with experience in evaluating glandular disorders. Neither HPV testing nor repeat cervical cytology has the requisite sensitivity to be used alone as an initial triage test for women with AGC [69, 74, 75]. Because of the spectrum of neoplasia linked to AGC, initial evaluation must include multiple testing modalities [69, 74]. These include colposcopy, endocervical evaluation and sampling, HPV testing, and endometrial sampling. HPV testing seems to be quite sensitive for identifying women with CIN 2,3 and AIS, but it misses non-HPV-associated neoplasia arising from the endometrium or fallopian tube. However, HPV testing is useful once these upper tract lesions have been excluded. In one study, no significant lesions were subsequently identified in women with AGC who had an initial negative workup and were HPV DNA negative . Because of the high incidence of neoplasia and the poor sensitivity of all test modalities, diagnostic excisional procedures may be necessary, despite initial negative testing, for women with AGC "favor neoplasia," AIS, or repeat AGC cytology .
Other Glandular Abnormalities.
Benign-appearing endometrial cells in a woman 40 years and older and endometrial stromal cells or histiocytes are occasionally encountered cytologically. Approximately 0.5% to 1.8% of cervical cytology specimens from women 40 years and older will have endometrial cells . Benign-appearing exfoliated endometrial cells in premenopausal women identified during either the first or the second half of the menstrual cycle are rarely associated with significant pathology . Similarly, the presence of endometrial stromal cells/histiocytes rarely has clinical significance. In contrast, benign-appearing endometrial cells in postmenopausal women are not infrequently associated with significant endometrial pathology. In a study of postmenopausal women with benign-appearing endometrial cells on routine cytology who underwent endometrial biopsy, 8% had significant pathology identified including endometrial adenocarcinoma in 5% of the women . Although hormone replacement therapy can increase the rate of shedding of benign-appearing endometrial cells, the prevalence of significant pathology remains elevated in this setting [76, 77]. Benign-appearing glandular cells derived from small accessory ducts, foci of benign adenosis, or prolapse of the fallopian tube into the vagina are sometimes seen in cytology specimens after total hysterectomy and have no clinical significance.
Recommended Management of Women With AGC.
Colposcopy with endocervical sampling is recommended for women with all subcategories of AGC and AIS (Figure 8). (AII) Endometrial sampling is recommended in conjunction with colposcopy and endocervical sampling in women 35 years and older with all subcategories of AGC and AIS. (BII) Endometrial sampling is also recommended for women younger than 35 years with clinical indications suggesting they may be at risk for neoplastic endometrial lesions. These include unexplained vaginal bleeding or conditions suggesting chronic anovulation. It is recommended that women with atypical endometrial cells be initially evaluated with endometrial and endocervical sampling. Colposcopy can be either performed at the initial evaluation or deferred until the results are known. If no endometrial pathology is identified, colposcopy is recommended. (AII) If not already obtained, HPV DNA testing at the time of colposcopy is preferred in women with atypical endocervical, endometrial, or glandular cells NOS. (CIII) The use of HPV DNA testing alone or a program of repeat cervical cytology is unacceptable for the initial triage of all subcategories of AGC and AIS (EII).
subsequent evaluation or follow-up.
The recommended postcolposcopy management of women of known HPV status with either atypical endocervical, endometrial, or glandular cells NOS who do not have CIN 2,3 or glandular neoplasia identified histologically is to repeat cytological testing combined with HPV DNA testing at 6 months if they are HPV DNA positive and at 12 months if they are HPV DNA negative (Figure 9). (CII) Referral to colposcopy is recommended for women who subsequently test positive for high-risk (oncogenic) HPV DNA or who are found to have ASC-US or greater on their repeat cytological tests. If both tests are negative, women can return to routine cytological testing. (BII) The recommended postcolposcopy management of women of unknown HPV status with atypical endocervical, endometrial, or glandular cells NOS who do not have CIN 2,3 or glandular neoplasia identified histologically is to repeat cytological testing at 6-month intervals. After 4 consecutive "negative for intraepithelial lesion or malignancy" results are obtained, women can return to routine cytological testing. (CIII)
If CIN, but no glandular neoplasia, is identified histologically during the initial workup of a woman with atypical endocervical, endometrial, or glandular cells NOS, management should be according to the 2006 Consensus Guidelines for the Management of Women with Cervical Intraepithelial Neoplasia. If invasive disease is not identified during the initial colposcopic workup, it is recommended that women with atypical endocervical or glandular cells "favor neoplasia" or endocervical AIS undergo a diagnostic excisional procedure. (AII) It is recommended that the type of diagnostic excisional procedure used in this setting provide an intact specimen with interpretable margins. (BII) Concomitant endocervical sampling is preferred. (BII)
AGC in Special Populations.
In pregnant women, the initial evaluation of AGC should be identical to that of nonpregnant women, except that endocervical curettage and endometrial biopsy are unacceptable. (BII)
Other Forms of Glandular Abnormalities.
benign-appearing endometrial cells.
For asymptomatic premenopausal women with benign endometrial cells, endometrial stromal cells, or histiocytes, no further evaluation is recommended. (BII) For postmenopausal women with benign endometrial cells, endometrial assessment is recommended regardless of symptoms. (BII)
benign-appearing glandular cells posthysterectomy.
For posthysterectomy patients with a cytological report of benign glandular cells, no further evaluation is recommended. (BII)
HPV DNA Testing When Used for Screening
Despite its successes as a cervical cancer screening method, cytology has significant limitations, including limited sensitivity . These have led to considerable interest in using a combination of HPV testing and cytology for screening . In 2003, FDA approved the use of HPV testing as an adjunct to cervical cytology screening in women aged 30 years and older . Because newly acquired HPV infections clear spontaneously and the prevalence of HPV DNA positivity drops with age from a peak in adolescents and women in their 20s [16, 81], HPV testing should not be used for routine screening in women before the age of 30 years [5, 82]. Approval for use in screening was based on studies that demonstrated that adding "high-risk" HPV testing increases the sensitivity of cervical cancer screening. Table 2 includes results of the more recent studies that have directly compared cervical cytology alone (either liquid-based or conventional cytology) with HPV testing as well as with a combination of cytology and HPV testing [83, 84]. In all of the studies, HPV DNA testing was significantly more sensitive than cytology alone. A recent review of screening studies from North America and Europe reported that the pooled sensitivity and specificity of HPV testing for the detection of CIN 2, 3 or cancer (CIN2+) in women 35 years and older is 95% and 93%, respectively . For comparison, pooled sensitivity and specificity of cytology at a threshold of ASC-US are 60% and 97%, respectively. Sensitivity using a combination of HPV testing and cytology is significantly higher than that of either test alone with negative predictive values of 99% to 100% [85, 86].
Based on this and other data, the American Cancer Society concluded in the 2002 Guidelines for the Early Detection of Cervical Neoplasia and Cancer that it is "reasonable to consider" the use of HPV DNA testing with cytology for primary cervical cancer screening in women 30 years and older . It was also concluded that the frequency of combined cytology and HPV testing should not be more than every 3 years provided that both tests are negative. Similarly, the American College of Obstetricians and Gynecologists has recommended based on "level B" evidence that use of a combination of cervical cytology and HPV DNA testing for screening is "appropriate" for women 30 years and older . However, although combining HPV testing with cytology will improve the sensitivity of screening, there remains insufficient data to prove that a combination of cervical cytology and HPV DNA testing improves outcomes of a screening program or that it will reduce the costs of screening. Therefore, cytology alone continues to be an acceptable screening method in women 30 years and older.
Interim guidance on how to manage women with different combinations of screening results was developed by a joint National Cancer Institute, ASCCP, and American Cancer Society workshop in 2003 . The 2006 Consensus Conference formally reviewed and modified the previous interim guidance. The 2 controversial areas are when should women negative by both cytology and HPV testing be rescreened and how to manage cytology-negative, HPV-positive women. Women who are negative by both cytology and HPV testing have a less than 1 in 1,000 risk of having CIN 2+, and prospective follow-up studies have shown that the risk of developing CIN 3 during a 10-year period is quite low [5, 87, 88]. Less than 2% of cytology- and HPV-negative Danish women 40 to 50 years old developed CIN 3+ during 10 years of follow-up . Identical results have been reported for women 30 years and older in Portland, OR . Health policy modeling studies demonstrate that triennial screening using a combination of cytology and HPV testing in women 30 years and older provides equivalent or greater benefits than those provided by annual conventional cytology . Therefore, women who are negative by both cytology and HPV testing should not be rescreened before 3 years.
Many women in screened populations who test positive for HPV will have a negative cervical cytology. In a series of more than 213,000 women 30 years and older enrolled in Kaiser Northern California, the overall prevalence of HPV positivity was 6.5% and 58% of the HPV-positive women had a concurrent negative cytology . HPV-positive women require counseling with respect to their risk for CIN 2+, source of their infection, and their infectivity. The risk of having an undetected CIN 2+ is quite low in cytology-negative, HPV-positive women in screened populations, ranging from 2.4% to 5.1% [90-93]. For comparison, CIN 2+ was detected at enrollment colposcopy in 10.2% of women of unknown HPV status with ASC-US in ALTS . Even in women 30 years and older, most HPV-positive women become HPV negative during follow-up. In a prospective study from France, 60% of HPV-positive women became HPV negative after a median follow-up of 6 months . Based on these considerations, conservative follow-up with repeat cytology and HPV testing at 12 months seems to be the best management approach for cytology-negative, HPV-positive women. Women who on repeat testing are persistently HPV positive should undergo colposcopy, even if cytology negative, whereas women who are negative on both tests can be rescreened in 3 years, and those who develop cytological abnormalities can be managed according to the preceding guidelines
Emerging data suggest that infection with different types of high-risk (oncogenic) HPV confers a differing risk for the development of CIN 2+. Although epidemiological studies indicate that approximately 13 types of HPV should be classified as oncogenic, just 3 types of HPV, 16, 18, and 45, are associated with 77% of all cervical cancers [7, 94]. HPV-18 seems to be particularly important for invasive adenocarcinomas of the cervix because it is found in association with 32% of cervical adenocarcinomas .
One of the greatest barriers to incorporating HPV testing into screening of women 30 years and older is the management of cytology-negative, HPV-positive women. Several prospective follow-up studies have shown that infection with HPV-16 and HPV-18 accounts for most cases of CIN 2,3 subsequently identified in cytology-negative, high-risk HPV DNA-positive women [88, 96]. In the Kaiser Portland, OR, follow-up study of cytology-negative women 30 years and older, after 10 years of follow-up, CIN 3 was identified in 21% and 18% of women who were HPV-16 or HPV-18 positive at enrollment, respectively . The risk of CIN 3 among women infected with other high-risk HPV types in this study was only 1.5%. This suggests that using genotyping assays to identify which women are infected with HPV-16 and HPV-18 might be useful when managing cytology-negative, HPV-positive women.
Genotyping assays to determine specific high-risk HPV type(s) have not yet been approved by the FDA. However, once HPV genotyping assays are approved, it would be reasonable to apply genotyping to cytology-negative, HPV-positive women in the same manner as HPV testing is used in women with ASC-US. Samples from cytology-negative, HPV-positive women would be genotyped for specific high-risk types of HPV and women with HPV-16 or HPV-18 would be referred for colposcopy . Women with other types of HPV would be told to return in 12 months for retesting for both cytology and HPV. This approach would allow most women with CIN 2,3 lesions and false-negative cytology results to receive colposcopy and provide reassurance regarding the safety of follow-up without colposcopy for 12 months for women found not to have HPV-16 or HPV-18.
Recommended Management Different Combinations of Results.
It is recommended that HPV DNA testing target only high-risk (oncogenic) HPV types. There is no clinical utility in testing for other (non-oncogenic) types. (AI) Testing for other (non-oncogenic) HPV types when screening for cervical neoplasia or during the management and follow-up of women with abnormal cervical cytology or cervical neoplasia is unacceptable. (EI)
recommendations for women with different combinations of results.
For women 30 years and older who have a cytology result of "negative for an intraepithelial lesion or malignancy" but test positive for HPV, repeat cytology and HPV testing at 12 months is preferred (Figure 10). (BII) If on repeat testing HPV is detected, colposcopy is recommended. (AII) Women found to have an abnormal result on repeat cytology should be managed according to the appropriate 2006 Consensus Guidelines outlined earlier.
recommendations for hpv genotyping.
Until an FDA-approved assay becomes available, a recommendation for use of type-specific HPV genotyping cannot be made. Once such assays are FDA-approved, emerging data support the triage of women 30 years and older with a cytology result of "negative for an intraepithelial lesion or malignancy" but who are HPV positive with HPV genotyping assays to identify those with HPV-16 and HPV-18. (AII)
The authors thank all the participants and formal observers to the 2006 Consensus Conference who worked so hard to develop the guidelines. We also thank Ms Kathy Poole for administrative support during the development of the guidelines and Dr Anna Barbara Moscicki who chaired the Adolescent Working Group.
Text for this article was first published in Wright TC, Jr, Massad LS, Dunton CJ, Spitzer M, Wilkinson EJ, Solomon D. 2006 Consensus Guidelines for the Management of Women with Abnormal Cervical Cancer Screening Tests. AJOG 2007;197(4):346-355. ©Elsevier 2007.
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Appendix A: Participants and Participating Organizations
Organizer: American Society for Colposcopy and Cervical Pathology (Also on http://www.asccp.org/consensus.shtml)
Fadi Abdul-Karim, MD, University Hospitals of Cleveland, Cleveland, OH
Ronald D. Alvarez, MD, University of Alabama, Birmingham, AL†
Barbara Apgar, MD, MS, University of Michigan, Ann Arbor, MI†
Raheela Ashfaq, MD, University of Texas Southwestern, Dallas, TX*,†
R. Marshall Austin, MD, PhD, Magee-Women's Hospital of the University of Pittsburgh, Pittsburgh, PA†
Mark M. Bajorek, MD, Oregon Health Sciences University, Portland, OR
Jonathan Berek, MD, Stanford University School of Medicine, Los Angeles, CA*,†
Monique Bertrand, MD, London Health Sciences Center, London, Ontario, Canada†
Marluce Bibbo, MD, Thomas Jefferson University Hospital, Philadelphia, PA†
George Birdsong, MD, Grady Health System, Atlanta, GA
Lori A. Boardman, MD, ScM, Brown University Women and Infants Hospital, Providence, RI†
Fredrik F. Broekhuizen, MD, Medical College of Wisconsin, Milwaukee, WI
Carol L. Brown, MD, Memorial Sloan-Kettering Cancer Center, New York, NY*,†
S.C. Peter Bryson, MD, Queen's University, Kingston, Ontario, Canada‡
Louis Burke, MD, Beth Israel/Deaconness Medical Center, Harvard Medical School, Boston, MA‡
Robert A. Burger, MD, University of California Irvine, Irvine, CA*,†
Philip Castle, PhD, MPH, National Cancer Institute, Bethesda, MD†
David Chhieng, MBA, MD, University of Alabama, Birmingham, AL*
Carmel Cohen, MD, Columbia University, New York, NY†
Terrance Colgan, MD, Mount Sinai Hospital, Toronto, Ontario, Canada†
Terri Cornelison, MD, National Cancer Institute, Bethesda, MD†
J. Thomas Cox, MD, University of California-Santa Barbara, Santa Barbara, CA†
William Creasman, MD, Medical University of South Carolina, Charleston, SC‡
Christopher P. Crum, MD, Harvard Medical School, Boston, MA†
Vanessa Cullins, MD, Planned Parenthood Federation of America, New York, NY
Teresa M. Darragh, MD, University of California-San Francisco, San Francisco, CA
Diane D. Davey, MD, University of Kentucky, Lexington, KY†
Gordon D. Davis, MD, Maricopa Medical Center, St Joseph's Hospital and Medical Center, Phoenix, AZ
Linda Dominguez, CNP, RN, Planned Parenthood of New Mexico, Albuquerque, NM
Rebecca K. Donohue, PhD, RN, CS, Simmons College, Boston, MA
Charles Dunton, MD, Lankenau Hospital, Wynnewood, PA†
Juan C. Felix, MD, LAC-USC Medical Center, Los Angeles, CA
Francisco Garcia, MD, MPH, University of Arizona Health Sciences Center, Tucson, AZ†
Kim R. Geisinger, MD, Wake Forest University School of Medicine, Winston Salem, NC
Melvin V. Gerbie, MD, Northwestern University Medical School, Chicago, IL†
Michael A. Gold, MD, University of Oklahoma Health Sciences Center, Oklahoma City, OK†
David L. Greenspan, MD, Maricopa Medical Center, St Joseph's Hospital and Medical Center, Phoenix, AZ†
Benjamin Greer, MD, University of Washington Medical Center, Seattle, WA†
Richard Guido, MD, Magee-Women's Hospital of the University of Pittsburgh, Pittsburgh, PA†
Fernando Guijon, MD, University of Manitoba, Winnipeg, Manitoba, Canada
Hope K. Haefner, MD, University of Michigan, Ann Arbor, MI†
Kenneth D. Hatch, MD, University of Arizona Health Sciences Center, Arizona Cancer Center, Tucson, AZ*,†
Thomas J. Herzog, MD, Columbia University, New York, NY*,†
Christine Holschneider, MD, UCLA School of Medicine, Los Angeles, CA
Beth C. Huff, MSN, NP, Vanderbilt University Medical Center, Nashville, TN
Warner K. Huh, MD, University of Alabama at Birmingham, Birmingham, AL†
Verda J. Hunter, MD, Gynecologic Resource Center for Gynecologic Oncology, Kansas City, MO
Mujtaba Husain, MD, Wayne State University, Detroit, MI
Jose A. Jeronimo, MD, National Cancer Institute, Bethesda, MD
Howard W. Jones III, MD, Vanderbilt University, Nashville, TN†
Beth Jordan, MD, Association of Reproductive Health Professionals, Washington, DC
Thomas M. Julian, MD, University of Wisconsin, Madison, WI‡
Barbara F. Kelly, MD, AF Williams Family Medical Center, Denver, CO
Valerie J. King, MD, MPH, Oregon Health and Science University, Portland, OR
Walter Kinney, MD, University of California-Davis, Permanente Medical Group, Sacramento, CA†
Marina Kondratovich, PhD, Food and Drug Administration, Rockville, MD
Edward R. Kost, MD, Brooke Army Medical Center, Fort Sam Houston, TX*,†
Burton A. Krumholz, MD, Long Island, NY*,†
Robert J. Kurman, MD, Johns Hopkins Hospital, Baltimore, MD
Hershel W. Lawson, MD, Centers for Disease Control and Prevention, Atlanta, GA†
Neal M. Lonky, MD, MPH, Kaiser Permanente, Yorba Linda, CA†
Silvana Luciani, PhD, Pan-American Health Organization, Washington, DC
L. Stewart Massad, MD, Washington University School of Medicine, St Louis, MO†
Edward J. Mayeaux, MD, Louisiana State University Health Sciences Center, Shreveport, LA†
Alexander Meisels, MD, Laval University, Quebec City, Quebec, Canada‡
Kathleen McIntyre-Seltman, MD, Magee Women's Hospital, Pittsburgh, PA†
Anna-Barbara Moscicki, MD, University of California-San Francisco, San Francisco, CA†
Carolyn Y. Muller, MD, University of New Mexico, Albuquerque, NM
Gary R. Newkirk, MD, Family Medicine Spokane, Spokane, WA†
Hextan Y.S. Ngan, MBBS, MD, International Federation of Gynecology and Obstetrics, Hong Kong
Kenneth L. Noller, MD, Tufts University School of Medicine, Boston, MA†
Dennis M. O'Connor, MD, Clinical Pathology Associates, Inc., Louisville, KY†
Edward Partridge, MD, University of Alabama at Birmingham, Birmingham, AL†
Diane M. Provencher, MD, CHUM-Hôpital Notre-Dame, Montreal, Quebec, Canada
Stephen Raab, MD, Allegheny General Hospital, Pittsburgh, PA
Eddie Reed, MD, Centers for Disease Control and Prevention, Atlanta, GA‡
Max Robinowitz, MD, Food and Drug Administration, Rockville, MD
William Rodgers, MD, University of Maryland Medical System, Baltimore, MD†
Mary Rubin, RNC, PhD, CRNP, University of California-San Francisco, San Francisco, CA†
Mona Saraiya, MD, MPH, Centers for Disease Control and Prevention-US Public Health Service, Atlanta, GA
Debbie Saslow, PhD, American Cancer Society, Atlanta, GA*,†
Mark Schiffman, MD, MPH, National Cancer Institute, Bethesda, MD†
Volker Schneider, MD, International Academy of Cytology, Freiburg, Germany‡
Karen Shea, MSN, CRNP, Planned Parenthood Federation, New York, NY
Mark Sherman, MD, National Cancer Institute, Bethesda, MD†
Mary Sidawy, MD, George Washington University, Washington, DC
Diane Solomon, MD, National Cancer Institute, Bethesda, MD†
Mark Spitzer, MD, Brookdale University Hospital and Medical Center, Brooklyn, NY†
Mark Stoler, MD, University of Virginia Health Sciences Center, Charlottesville, VA†
Pamela Stratton, MD, National Institutes of Child Health and Human Development, Rockville, MD
Cornelia Trimble, MD, Johns Hopkins University, Baltimore, MD†
Edward G. Trimble, MD, MPH, National Cancer Institute, Bethesda, MD†
Leo B. Twiggs, MD, University of Miami School of Medicine, Miami, FL†
Elizabeth R. Unger, MD, PhD, Centers for Disease Control and Prevention (CEVC), Atlanta, GA
Jeffrey Waldman, MD, Planned Parenthood Shasta-Diablo, Concord, CA†
Alan G. Waxman, MD, Unversity of New Mexico, Albuquerque, NM†
Claudia L. Werner, MD, University of Texas Southwestern, Dallas, TX†
Edward Wiesmeier, MD, UCLA, Los Angeles, CA
David C. Wilbur, MD, Massachusetts General Hospital, Boston, MA
Edward J. Wilkinson, MD, University of Florida College of Medicine, Gainesville, FL†
Cheryl Wiseman, MPH, CT, Centers for Medicaid and Medicare Services, Baltimore, MD
Jason D. Wright, MD, Columbia University, New York, NY*,†
Thomas C. Wright, MD, Columbia University, New York, NY†
Shaheen Ahmed, MD, Blue Springs, MO
Andrea Abati, MD, National Cancer Institute, Bethesda, MD
Edward A. Barker, MD, Medical Laboratory Associates, Seattle, WA
Henry W. Buck, MD, University of Kansas, Lawrence, KS
Catherine Copenhaver, MD, Bethesda, MD
Julia Corrado, MD, Food and Drug Administration, Rockville, MD
Maria L. Diaz, MD, Davie, FL
Mary C. Eiken, SGO National Office, Chicago, IL
Tremel Faison, Food and Drug Administration, Rockville, MD
Sarah Feldman, MD, MPH, Harvard Medical School, Cambridge, MA
Lisa Flowers, MD, Emory University School of Medicine, Atlanta, GA
Patricia Lynn Fontaine, MD, MS, University Family Physicians-North Memorial Clinic, Minneapolis, MN
Julia C. Gage, MPH, Health Resources and Services Administration, Rockville, MD
Chad A. Hamilton, MD, Stanford University Medical Center, Stanford, CA
Vivien W. Hanson, MD, University of Washington School of Public Health, Seattle, WA
Robert D. Hilgers, MD, University of Louisville, Louisville, KY
Thomas M. Kastner, MD, Mayo Clinic, Rochester, MN
Jill Koshiol, PhD, National Cancer Institute, Bethesda, MD
Aimee R. Kreimer, PhD, National Cancer Institute, Bethesda, MD
Michelle D. Lavey, MS-FNP, Rockville, MD
Ronald D. Luff, MD, Quest Diagnostics, Teterboro, NJ
Louise E. Magruder, Food and Drug Administration, Rockville, MD
Sheila F. Mahoney, CNM, MPH, National Institute of Child Health and Human Development, Bethesda, MD
William J. Mann, Jr, MD, Jersey Shore University Medical Center, Neptune, NJ
Linda McWey-Price, MD, Carilion New River Valley Medical Center, Christiansburg, VA
Gabriele Medley, AM, MBBS, FRCPA, FIAC, University of Melbourne, Victoria, Australia
Melissa A. Merideth, MD, MPH, National Institutes of Health, Bethesda, MD
Brigitte E. Miller, MD, Wake Forest University Baptist Medical Center, Winston-Salem, NC
Mary F. Mitchell, American College of Obstetricians and Gynecologists-Department of Practice Activities, Washington, DC
Mary L. Nielsen, MD, University of Kansas School of Medicine, Wichita, KS
Catherine Platt, MD, Arlington, VA
Marianne U. Prey, MD, Quest Diagnostics Incorporated, St Louis, MO
Mahboobeh Safaeian, MD, MPH, National Cancer Institute, Bethesda, MD
Ellen E. Sheets, MD, Cytyc Corporation, Malborough, MA
Mario G. Sideri, MD, European Institute of Oncology, Milan, Italy
Albert Singer, MD, Whittington Hospital, London, United Kingdom
Diane R. Smith, NP, Arlington, VA
Karen K. Smith-McCune, MD, UCSF Comprehensive Cancer Center, San Francisco, CA
Nancy J. Swick, MSN, CRNP, Santa Rosa Memorial Hospital, Santa Rosa, CA
Candice A. Tedeschi, OGNP, North Shore-LIJ Health Systems, Lake Success, NY
Leslie A. Tyska, MD, California State Polytechnic University, Pomona, CA
Joanne P. Walenga, RN, Rockville, MD
Amy J. Wendel, SCT, MP, Mayo Clinic, Rochester MN
Donald S. Wiersma, MD, Potomac, MD
Barbara A. Winkler, MD, Quest Diagnostics Incorporated, Teterboro, NJ
Meggan Zsemlye, MD, University of New Mexico, Albuquerque, NM
All observers were either members or employees of the participating organizations and federal agencies.
American Academy of Family Physicians, American Cancer Society, American College Health Association, American College of Obstetricians and Gynecologists, American Social Health Association, American Society for Clinical Pathology, American Society for Colposcopy and Cervical Pathology, American Society of Cytopathology, Association of Reproductive Health Professionals, Centers for Disease Control and Prevention - Division of Viral and Rickettsial Disease, Centers for Disease Control and Prevention - Division of Cancer Prevention and Control, and Centers for Disease Control and Prevention - Division of Laboratory Systems, Centers for Medicaid and Medicare Services, College of American Pathologists, Food and Drug Administration, International Academy of Cytology, International Federation for Cervical Pathology and Colposcopy, International Federation of Gynecology and Obstetrics, International Gynecologic Cancer Society, International Society of Gynecological Pathologists, National Cancer Institute, National Association of Nurse Practitioners in Women's Health, Papanicolaou Society of Cytopathology, Pan American Health Organization, Planned Parenthood Federation of America, Society of Canadian Colposcopists, Society of Gynecologic Oncologists, Society of Gynecologic Oncologists of Canada, Society of Obstetricians and Gynaecologists of Canada.
APPENDIX B: Definitions Of Terms
Colposcopy is the examination of the cervix, vagina, and, in some instances the vulva, with the colposcope after the application of a 3% to 5% acetic acid solution coupled with obtaining colposcopically directed biopsies of all lesions suspected of representing neoplasia.
Endometrial sampling includes obtaining a specimen for histological evaluation using an endometrial biopsy or a "dilatation and curettage" or hysteroscopy.
Endocervical sampling includes obtaining a specimen for either histological evaluation using an endocervical curette or a cytobrush or for cytological evaluation using a cytobrush.
Endocervical assessment is the process of evaluating the endocervical canal for the presence of neoplasia using either a colposcope or endocervical sampling.
Diagnostic excisional procedure is the process of obtaining a specimen from the transformation zone and endocervical canal for histological evaluation and includes laser conization, cold-knife conization, loop electrosurgical excision, and loop electrosurgical conization.
Satisfactory colposcopy indicates that the entire squamocolumnar junction and the margin of any visible lesion can be visualized with the colposcope.
Adolescent women are women 13 to 20 years old (i.e., from 13th to 21st birthdays).
*Members of working groups who were unable to attend the conference. Cited Here...
†Conference participants who were members of the working groups. Cited Here...
‡Designated delegates who participated in the public comment review periods and delegate conference calls but were unable to attend the conference. Cited Here...