Guía 2006 Seguimiento mujeres con lesiones cervicales por VPH

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  • 8/3/2019 Gua 2006 Seguimiento mujeres con lesiones cervicales por VPH

    1/17Copyright @ 2007 American Society for Colposcopy and Cervical Pathology. Unauthorized reproduction of this article is prohibited.

    2006 Consensus Guidelines for the

    Management of Women With

    Cervical Intraepithelial Neoplasiaor Adenocarcinoma In Situ

    Thomas C. Wright Jr., MD,1 L. Stewart Massad, MD,2 Charles J. Dunton, MD,3

    Mark Spitzer, MD,4 Edward J. Wilkinson, MD,5 Diane Solomon, MD;6

    for the 2006 American Society for Colposcopy and

    Cervical PathologyYsponsored Consensus Conference1Department of Pathology, College of Physicians and Surgeons of Columbia University,New York, NY, 2Department of Obstetrics and Gynecology, Washington University School

    of Medicine, St Louis, MO, 3Department of Obstetrics and Gynecology, Lankenau Hospital,Wynnewood, PA, 4Department of Obstetrics and Gynecology, Brookdale University Hospitaland Medical Center, Brooklyn, NY, 5Department of Pathology, University of Florida College

    of Medicine, Gainesville, FL, and6National Institutes of Health and National Cancer Institute,Bethesda, MD

    h Abstract

    Objective. To provide updated consensus guidelinesfor the management of women with cervical intraepithe-lial neoplasia (CIN) or adenocarcinoma in situ (AIS).

    Participants. A group of 146 experts including repre-sentatives from 29 professional organizations, federalagencies, and national and international health organiza-tions met on September 18Y19, 2006, in Bethesda, MD, todevelop the guidelines.

    Major Changes in the Guidelines. The management ofwomen with CIN grade 1 (CIN 1) has been modifiedsignificantly. In the earlier guidelines, managementdepended on whether the colposcopic examination wassatisfactory and treatment using ablative or excisionalmethods was acceptable for women with CIN 1. In the

    new guidelines, cytological follow-up is the only recom-mended management option, regardless of whether thecolposcopic examination is satisfactory, for women withCIN 1 who have a low-grade referral cervical cytology.Treatment of CIN 1 is particularly discouraged in adoles-cents. The basic management of women in the generalpopulation with CIN 2,3 underwent only minor modifica-tions, but options for the conservative management ofadolescents with CIN 2,3 have been expanded. Moreover,management recommendations for women with biopsy-confirmed AIS are now included.

    Conclusion. Updated evidenced-based guidelineshave been developed for the management of womenwith CIN or AIS. These guidelines reflect recent changes inour understanding of human papillomavirusYassociateddiseases of the cervix and the potential impact oftreatment on future pregnancies. h

    Key Words: cervical intraepithelial neoplasia, treatment,

    loop electrosurgical excision procedure, cryotherapy, adeno-

    carcinomas in situ of the cervix

    Cervical cancer, once one of the leading causes ofcancer death in women in the United States, is nowrelatively uncommon. This decline is frequently attrib-

    uted to cervical cancer screening programs, but the

    appropriate management of women with cervical

    Reprint requests to: Thomas C. Wright Jr., MD, Room 16-404 P&S Bldg,

    630 W 168th St, New York, NY 10032. E-mail: [email protected]

    These evidenced-based Consensus Guidelines reflect recent changes in

    our understanding of how to manage women with cervical intraepithelial

    neoplasia and adenocarcinoma in situ of the cervix.

    These guidelines were developed with funding from the American

    Society for Colposcopy and Cervical Pathology and the National Cancer

    Institute. Its contents are solely the responsibility of the authors and the

    American Society for Colposcopy and Cervical Pathology and do not

    necessarily represent the official views of the National Cancer Institute.

    2007, American Society for Colposcopy and Cervical Pathology

    Journal of Lower Genital Tract Disease, Volume 11, Number 4, 2007, 223Y239

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    2/17Copyright @ 2007 American Society for Colposcopy and Cervical Pathology. Unauthorized reproduction of this article is prohibited.

    intraepithelial neoplasia (CIN) is as critical a component

    of cervical cancer prevention programs as screening and

    managing abnormal screening test results. Cervical

    intraepithelial neoplasia is a relatively common pro-

    blem, especially in women of reproductive age. Labora-tory surveys from the mid-1990s from the College of

    American Pathologists suggest that more than 1 million

    women are diagnosed each year with low-grade cervical

    intraepithelial lesions, referred to as CIN grade 1 (CIN

    1), and that approximately 500,000 are diagnosed with

    high-grade cervical cancer precursor lesions, referred to

    as CIN 2,3 [1]. Since the mid-1990s, the rate of

    abnormal cervical cytology has increased in the United

    States, suggesting that the number of women with CIN is

    continuing to increase [1]. A report from the Kaiser

    Permanente Northwest health plan indicates a some-

    what lower rate of CIN among women enrolled in a

    prepaid health plan, with a projected annual incidence

    per 1,000 women of 1.2 for CIN 1 and 1.5 for CIN 2,3

    [2]. Improper management of CIN can increase risk of

    cervical cancer on the one hand and can result in

    complications from overtreatment on the other. It is

    becoming increasingly clear that loop electrosurgical

    excision, which is widely used to treat CIN, produces a

    small, but significant, negative impact on subsequent

    pregnancy [3, 4].

    Approximately 5 years ago, the American Society for

    Colposcopy and Cervical Pathology (ASCCP) joinedother professional societies and federal and international

    organizations to develop the 2001 Consensus Guidelines

    for Managing Women with Cervical Intraepithelial

    Neoplasia [5]. The goal was to improve the care of

    women with CIN by weighing the best available

    evidence and developing consensus management guide-

    lines. Since 2001, considerable new information has

    become available on the natural history of CIN, par-

    ticularly in adolescents and young women [6Y8]. Our

    understanding of how to manage women with cervical

    adenocarcinoma in situ (AIS), a human papillomavirus

    (HPV)Yassociated precursor to invasive cervical adeno-carcinoma, also has progressed. Therefore, in 2005,

    the ASCCP and its partner organizations (listed in

    Appendix A), began the process of revising the 2001

    Consensus Guidelines. This culminated in a consensus

    conference held at the National Institutes of Health in

    September 2006. This report provides the recommenda-

    tions developed with respect to managing women with

    CIN and AIS. Recommendations for managing women

    with abnormal cervical cancer screening tests appear in

    an accompanying article [9].

    GUIDELINE DEVELOPMENT PROCESS

    The process used to develop the 2006 guidelines was

    similar to that for the 2001 guidelines and is described in

    depth elsewhere [5, 9]. Guidelines were developed

    through a multistep process. Nationally recognized

    experts in cervical cancer prevention were recruited to

    working groups. These groups met initially to define

    areas where modifications to the existing guidelines

    might be needed, establishing each as a research

    question. They then performed literature reviews and

    retrieved and rated articles published since 2000 on each

    question. They next conducted Internet-based discus-

    sions open to the professional community at large that

    focused on the research questions. The working groups

    presented draft guidelines and supporting evidence to

    the full Consensus Conference, which voted on each,with revision as needed. All guidelines were passed by

    at least 66% of participants.

    The terminology utilized for the new guidelines is

    identical to that used previously, as is the 2-part rating

    system and is provided in the Table 1. The terms

    recommended, preferred, acceptable, and unacceptable

    Table 1. Rating the Recommendations

    Strength of recommendationa

    A Good evidence for efficacy and substantial clinical

    benefit support recommendation for use

    B Moderate evidence for efficacy or only limited

    clinical benefit supports recommendation for use

    C Evidence for efficacy is insufficient to support a

    recommendation for or against use, but

    recommendations may be made on other grounds

    D Moderate evidence for lack of efficacy or for adverse

    outcome supports a recommendation against use

    E Good evidence for lack of efficacy or for adverse

    outcome supports a recommendation against use

    Quality of evidencea

    I Evidence from at least 1 randomized controlled trial

    II Evidence from at least 1 clinical trial without

    randomization, from cohort or case-control

    analytic studies (preferably from more than one

    center), or from multiple time-series studies,

    or dramatic results from uncontrolled experiments

    III Evidence from opinions of respected authorities based

    on clinical experience, descriptive studies, or reports

    of expert committees

    Terminology used for recommendationsb

    Recommended Good data to support use when only one option

    is available

    Preferred Option is the best (or one of the best) when there are

    multiple other options

    Acceptable One of multiple options either when there are data

    indicating that another approach is superior or when

    there are no data to favor any single option

    Unacceptable Good data against use

    aModified from Gross et al. [89] and Kish [90].bTheassignment of these terms representsan opinion ratifiedby voteby the ConsensusConference.

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    are used in the guidelines to describe various interven-

    tions. 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 maybe Bpreferred.[ The letters A through E are used to

    indicate Bstrength 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 Bquality of the evidence.[

    Therefore, an exact correlation does not exist between

    Bstrength of the recommendation[ and the Bquality of

    the evidence.[ Quality of evidence is 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,

    and those definitions are provided in Appendix B.

    2006 CONSENSUS GUIDELINES

    General Comments

    Although the 2006 Consensus Guidelines are Bevidenced

    based,[ in many instances there was a limited amount of

    evidence available on which to base recommendation for

    a particular management decision, or the evidence

    which was available to inform the development of a

    guideline was quite limited. This resulted in instances in

    which the guidelines had to be based on either relatively

    small descriptive studies or simply on expert opinion. It

    is also important to recognize that although the 2006

    Consensus Guidelines are designed to provide guidance

    to clinicians caring for women with cervical cancer

    precursors in the United States, management approaches

    will frequently need to be individualized to take into

    account individual patients clinical findings and pre-

    ferences. Guidelines should never be considered a

    substitute for clinical judgment, and it is impossible to

    develop guidelines comprehensive enough to apply to allclinical 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, inva-

    sive cervical cancer can develop in women who

    participate in such programs.

    The histological classification incorporated into

    these guidelines is a 2-tiered system that applies the

    terms CIN 1 to low-grade lesions and CIN 2,3 to high-

    grade precursors. Cytological low-grade squamous

    intraepithelial lesion (LSIL) is not equivalent to

    histological CIN 1, and cytological high-grade squa-

    mous intraepithelial lesion (HSIL) is not equivalent to

    histological CIN 2,3.Treatment Methods. Both ablative treatment meth-

    ods that destroy the affected cervical tissue in vivo and

    excisional modalities that remove the affected tissue are

    widely utilized for treating CIN lesions [10]. Ablative

    methods include cryotherapy, laser ablation, electro-

    fulguration, and cold coagulation. Ablative methods are

    usually recommended only for women who have a

    satisfactory colposcopic examination and in whom

    invasive cervical cancer has been ruled out through a

    combination of colposcopy and endocervical sampling

    with cytological correlation [11, 12]. Pretreatment

    endocervical sampling can help identify women with

    occult invasive cervical cancer [13]. In one study of 391

    women undergoing a diagnostic excisional conization,

    none of the women with a negative endocervical

    curettage before conization were found to have an

    occult invasive lesion in the conization specimen,

    whereas all of the 17 found to have invasive disease

    had a positive endocervical sampling [13]. Studies of

    patients diagnosed with invasive disease after ablative

    therapy have found that many either did not have an

    endocervical sampling before treatment or underwent

    an ablative procedure despite having a positive endo-cervical sampling [14].

    Excisional methods that provide a tissue specimen for

    pathological examination include cold-knife conization,

    loop electrosurgical excision procedures (widely referred

    to as LEEP or LLETZ [large loop excision of the

    transformation zone]), laser conization, and electrosur-

    gical needle conization. Excisional methods are con-

    sidered preferable in situations where invasive cervical

    cancer cannot be ruled out through a combination of

    colposcopy and endocervical sampling with cytological

    correlation and in situations where the risk of occult

    cervical cancer is high. Examples include women withunsatisfactory colposcopic examinations, positive endo-

    cervical curettage, and large lesions with a high-grade

    colposcopic appearance [12]. It is also often recom-

    mended that women with posttreatment recurrence of

    CIN 2,3 be treated using an excisional as opposed to an

    ablative method [12]. Many recurrent or persistent CIN

    lesions are found in the endocervical canal, where they

    are not colposcopically visible and therefore are not

    suitable for ablative therapy. Cold-knife conization was

    the original conservative method for treating CIN, but

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    today, cold-knife conization has been largely replaced by

    other excisional methods that do not require general

    anesthesia. Cold-knife conization is also associated with

    a higher rate of complications, and there is clear

    evidence that it produces pregnancy-related morbidity.Therefore, today, cold-knife conization is usually

    restricted to selected patients such as older women in

    whom there is a suspicion of microinvasion or those who

    have glandular neoplasia that can be located deep in the

    endocervical canal [15]. Hysterectomy is a radical

    procedure which is infrequently used today for the

    treatment of intraepithelial lesions [15]. Hysterectomy

    carries a substantially greater risk of morbidity, and even

    mortality, when compared with excisional and ablative

    procedures. This usually outweighs any potential benefit

    of using hysterectomy as primary therapy for women

    with CIN 2,3.

    Simple outpatient excisional methods such as loop

    excision offer the potential to be used as part of a Bsee-

    and-treat[ approach in which both evaluation and

    treatment are performed at the same visit [16]. See-

    and-treat has a number advantages, especially for

    women with an HSIL referral cytology, most of whom

    will eventually undergo treatment irrespective of the

    findings at colposcopy. Performing a loop excision at the

    time at the initial colposcopic examination reduces the

    number of office visits, reduces the potential for women

    being lost to follow-up before treatment, and is thoughtto reduce patient anxiety while they wait for biopsy

    results [15]. It does, however, result in some over-

    treatment of women without CIN 2,3. This can be

    minimized by only performing see-and-treat when

    women have an HSIL referral cytology [12]. One study

    of see-and-treat found that when limited to women

    referred with HSIL cytology, 84% of the treated patients

    had histologically identified CIN 2,3 in the loop excision

    specimens [17]. Another study reported that 94% of

    loop excisions specimens obtained using a see-and-treat

    approach in women referred with HSIL had histologi-

    cally identified CIN 2,3 [18].All of the treatment methods listed above are widely

    utilized for treating CIN lesions, and each of the

    different modalities has its proponents [19]. Only a

    relatively limited number of randomized trials have

    directly compared the different treatment modalities. A

    Cochrane Database Systematic Review evaluated 28

    individual trials that in aggregate compared a total of 7

    treatment modalities [10]. Many of the trials were not

    randomized controlled trials. Data were extracted from

    the published reports by 2 investigators independently.

    The primary conclusion of the Cochrane Review was

    that there is no significant difference in the success rate

    of the different modalities [10]. Other reviews have also

    concluded that both ablative and excisional modalities

    have a similar efficacy with respect to eliminating CINand reducing a womans risk of future invasive cervical

    cancer [15, 20Y22]. It should be cautioned, however,

    that the number of randomized controlled trials directly

    comparing any 2 treatment modalities is limited, and

    most trials are only powered to identify large differences

    in outcomes. Moreover, there are difficulties inherent in

    interpreting the pooled data for very diverse trials that

    have different enrollment criteria, depth of excision, and

    other variables associated with treatment [12].

    Several randomized clinical trials and clinical case

    series have directly compared the efficacy of cold-knife

    conization with loop excisional procedures in women

    requiring conization [23, 24]. These trials have reported

    equivalent success rates and comparable rates of

    complications for both methods. It remains unclear,

    however, whether there is a significant difference

    between cold-knife conization and loop excision with

    respect to pathologic margins. Some, but not all, studies

    have found that pathologic margins are less frequently

    involved by CIN and are easier to interpret when cold-

    knife conization is used [23, 25Y27].

    It has been recognized for some time that cold-knife

    conization increases a womans risk of future pretermlabor, low-birth-weight infant, and cesarean section

    [28]. Other treatment methods such as loop excision

    were thought to have no adverse effects on future

    pregnancies since most of the studies published in the

    early 1990s showed little impact on obstetric outcomes.

    This has changed. Over the last few years, several large

    retrospective series have reported that all forms of

    excisional procedures present obstetrical risks [3, 15,

    29Y31]. A recent systematic review of the published

    literature on obstetric outcomes after treatment of CIN

    found that all types of excisional procedures result in

    pregnancy-related morbidity [3]. Loop excision wasfound to have a significant association with preterm

    delivery (11% risk in treated women versus 7% risk in

    untreated women), low-birth-weight infants (8% in

    treated women versus 4% in untreated women), and

    premature rupture of membranes (5% in treated women

    versus 2% in untreated women). Although there were no

    significant increases in neonatal intensive care unit

    admissions or perinatal mortality in women who had

    undergone loop excision versus those who had not,

    nonsignificant increases were observed. In most studies,

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    ablative methods have not been shown to be associated

    with a similar adverse effect on pregnancy outcome;

    however, it is difficult to measure small effects on

    pregnancy outcome [3, 30, 31]. A large record linkage

    study from Finland that evaluated national data on8,210 subsequent singleton births among 25,827

    women who had been treated for CIN has recently

    reported that any form of treatment including ablative

    methods and loop excision increases the risk of preterm

    delivery [32]. Thus, it is possible that ablative methods

    may also have an adverse effect on future pregnancies.

    Of interest, a recent Australian study showed that both

    treated and untreated women with CIN were at

    increased risk for preterm birth compared with the

    general population, suggesting that treatment may be a

    proxy for other risks [31].

    There are no accepted nonsurgical therapies for CIN

    [33]. Several topical agents have been either evaluated or

    are in clinical trials, but none has been proven as

    effective as excision or ablation. Similarly, although

    there is considerable interest in therapeutic HPV

    vaccines, none has been proven effective [34].

    These considerations indicate that the decision as to

    which therapeutic option to use in an individual patient

    depends on considerations such as patient age, parity,

    desire for future childbearing, preferences, prior cytol-

    ogy and treatment history, and history of default from

    follow-up, operator experience, and nonvisualization ofthe transformation zone.

    Posttreatment Follow-up. The reported treatment

    failure rate using either ablative or excisional methods

    varies between 1% and 25% [10, 20, 35Y37].

    Systematic reviews indicate overall pooled failure

    rates of 5% to 15% for the different modalities,

    with no significant difference between the modalities

    [20]. Most failures occur within 2 years after treat-

    ment [35, 38]. In addition to developing recurrent/

    persistent CIN, women who have been treated for CIN

    2,3 remain at increased risk for developing invasive

    cervical cancer for a protracted period [22, 39]. Arecent systematic review reported that the incidence of

    invasive cervical disease in treated women remains

    about 56 per 100,000 for at least 20 years after

    treatment, substantially greater than that in the general

    US population (5.6/100,000 woman-years) [22, 40].

    Therefore, decades-long follow-up is essential.

    A number of posttreatment follow-up protocols have

    been recommended [41, 42]. These include cytology,

    colposcopy, combinations of cytology and colposcopy,

    and testing for high-risk (oncogenic) types of HPV,

    performed at a variety of intervals. None of the follow-

    up protocols has been evaluated in randomized clinical

    trials, and because the various follow-up approaches are

    so different, it is difficult to compare them [38].

    Systematic reviews of the performance of high-riskHPV DNA testing for posttreatment follow-up have

    found that its performance is quite good and exceeds

    that of cytological follow-up [38, 42]. Overall, the

    pooled sensitivity of high-risk HPV testing for identify-

    ing recurrent/persistent CIN reaches 90% by 6 months

    after treatment and has been shown to remain at this

    level for at least 24 months. In contrast, the pooled

    sensitivity of cytology is approximately 70% [38]. In

    some studies, but not others, use of a combination of

    HPV testing and cytology resulted in an increased

    sensitivity [38].

    Special Populations. Adolescents (aged 13Y20 years)

    and young women are considered a Bspecial population.[

    There is a very low risk for invasive cervical cancer in this

    group, but cytologically diagnosed squamous intraepithe-

    lial lesions are common [2, 43]. Squamous intraepithelial

    lesions in adolescents have a very high rate of sponta-

    neous regression [8].

    Pregnant women are another special population. The

    risk of progression of CIN 2,3 to invasive cervical cancer

    during pregnancy is minimal, and the rate of sponta-

    neous regression postpartum is relatively high [44, 45].

    In fact, many oncologists follow early-stage cervicalcancer during pregnancy until fetal viability is achieved

    [46]. Treatment of CIN during pregnancy is associated

    with a high rate of complications including severe

    intraoperative hemorrhage [47]. Moreover, there is a

    high rate of incomplete excision which results in a high

    rate of recurrence or persistence [48, 49]. Therefore,

    treatment for CIN during pregnancy should be avoided,

    and the only indication for therapy of cervical neoplasia

    in pregnant women is invasive cancer.

    Cervical Intraepithelial Neoplasia Grade 1

    It is important for clinicians to recognize that bothhistopathology and cytology are relatively poor pre-

    dictors of the biological potential of an individual lesion.

    Based on biomarkers as well as biological behavior

    during long-term follow-up, it is now clear that some

    lesions that are histologically and cytologically low-

    grade have biological features of a high-grade lesion.

    Moreover, some lesions that are histologically and

    cytologically high-grade behave biologically like low-

    grade lesions, with substantial rates of regression [50].

    Nevertheless, the histological diagnosis of CIN remains

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    the standard for determining clinical management.

    Literature cited at the time of the 2001 Consensus

    Conference recognized that CIN 1 represents a hetero-

    geneous group of lesions [51]. This heterogeneity is due to

    several factors including the poor reproducibility of ahistological diagnosis of CIN 1 [52]. In the National

    Cancer Institutes ASCUS/LSILTriage Study (ALTS), it was

    found that less than half of lesions diagnosed as CIN 1 by

    the clinical site pathologists were subsequently classified as

    CIN 1 when reviewed by a study pathologist [52]. In most

    instances, this was attributable to lesions initially classified

    as CIN 1 being Bdowngraded[ to normal by the study

    pathologists. This occurred in 41% of cases. Nonconcor-

    dance in the opposite direction was less common, but did

    occur. Twelve percent of CIN 1 lesions were Bupgraded[

    by the study pathologist to CIN 2,3. There also is more

    heterogeneity with respect to associated HPV types for

    CIN 1 lesions than for CIN 2,3 lesions.

    Although most CIN 1 lesions are associated with

    high-risk types of HPV, the distribution of high-risk

    types in CIN 1 is different than that seen in CIN 2,3 [53].

    A meta-analysis of HPV types associated with CIN 1

    found that HPV-16 was the single most common

    genotype identified. HPV-16 is found in 26.3% of all

    HPV-positive CIN 1 [53]. HPV-31, -51, and -53 were the

    next most commonly identified HPV types. Each type is

    identified in 10% to 12% of CIN 1 lesions. CIN 1

    lesions can also be associated with low-risk types ofHPV [53]. However, HPV-6 or -11 was detected in only

    12% of the HPV DNAYpositive CIN 1. In addition to

    being heterogeneous with respect to HPV types, CIN 1

    lesions are also heterogeneous with respect to ploidy

    status and other markers of neoplasia [54].

    Low-grade cervical lesions have a high rate of

    spontaneous regression in the absence of treatment. A

    prospective study of Brazilian women with a cytological

    result of LSIL found that more than 90% regressed

    within 24 months [55]. Another study from the Nether-

    lands found that over a 4-year period all women with

    LSIL who were infected with nonYhigh-risk types ofHPV regressed to normal cytology, as did 70% of those

    infected with high-risk types of HPV [56]. Even higher

    rates of regression occur in adolescents and young

    women. Moscicki et al. [8] found that 91% of

    adolescents and young women with LSIL spontaneously

    cleared their lesions with 36 months, irrespective of

    associated HPV type.

    Recent data suggest that CIN 1 uncommonly

    progresses to CIN 2,3, at least within 24 months of

    being diagnosed. In ALTS, the risk for having a CIN 2,3

    lesion identified during the subsequent 2 years after

    initial colposcopy was nearly identical in women with a

    histological diagnosis of CIN 1 (13%) and in women

    whose initial colposcopy and biopsy were negative

    (12%) [57]. The risk of having an undetected CIN 2,3or AIS lesion is expected to be greater in women with

    CIN 1 preceded by an HSIL or atypical glandular cells

    (AGC) cytology result than for women with CIN 1

    preceded by an ASC or LSIL cytology result. CIN 2,3 is

    identified in 84% to 97% of women with HSIL cytology

    evaluated using a LEEP [17, 18, 58]. Therefore, in the

    2006 guidelines, separate recommendations are made

    for women with CIN 1 preceded by an HSIL or AGC

    cytology result.

    Recommended Management of Women With CIN 1.

    CIN 1 PRECEDED BY ASC-US, ASC-H, OR LSIL CYTOLOGY. The

    recommended management of women with a histologi-

    cal diagnosis of CIN 1 preceded by an ASC-US (atypical

    squamous cells of undetermined significance), ASC-H

    (atypical squamous cells, cannot exclude HSIL), or LSIL

    cytology is follow-up with either HPV DNA testing

    every 12 months or repeat cervical cytology every 6 to

    12 months (BII) (Figure 1). If the HPV DNA test is

    positive or if repeat cytology is reported as ASC-US or

    greater, colposcopy is recommended. If the HPV test is

    negative or 2 consecutive repeat cytology tests are Bnega-

    tive for intraepithelial lesion or malignancy,[ return to

    routine cytological screening is recommended (AII).If CIN 1 persists for at least 2 years, either continued

    follow-up or treatment is acceptable (CII). If treatment is

    selected and the colposcopic examination is satisfactory,

    either excision or ablation is acceptable (AI). A

    diagnostic excisional procedure is recommended if the

    colposcopic examination is unsatisfactory, the endocer-

    vical sampling contains CIN, or the patient has been

    previously treated (AIII).

    Treatment modality should be determined by the

    judgment of the clinician and should be guided by

    experience, resources, and clinical value for the specific

    patient (A1). In patients with CIN 1 and an unsatisfac-tory colposcopic examination, ablative procedures are

    unacceptable (EI). Podophyllin or podophyllin-related

    products are unacceptable for use in the vagina or on the

    cervix (EII). Hysterectomy as the primary and principal

    treatment for histologically diagnosed CIN 1 is unac-

    ceptable (EII).

    CIN 1 PRECEDED BY HSIL OR AGC-NOS CYTOLOGY. Either a

    diagnostic excisional procedure or observation with

    colposcopy and cytology at 6 month intervals for one

    year is acceptable for women with a histological

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    diagnosis of CIN 1 preceded by HSIL or AGC-NOS

    (atypical glandular cells not otherwise specified) cytol-

    ogy, provided in the latter case that the colposcopic

    examination is satisfactory and endocervical sampling is

    negative (Figure 2) (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 recom-

    mended 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 Bnegative for

    intraepithelial lesion or malignancy[ results can return

    to routine cytological screening. A diagnostic excisional

    procedure is recommended for women with CIN 1

    preceded by an HSIL or AGC-NOS cytology in whom

    the colposcopic examination is unsatisfactory, except in

    special populations (e.g., pregnant women) (BII).

    CIN 1 in Special Populations.

    ADOLESCENT WOMEN. Follow-up with annual cytolo-

    gical assessment is recommended for adolescents

    with CIN 1 (Figure 3) (AII). At the 12-month

    follow-up, only adolescents with HSIL or greater

    on the repeat cytology should be referred to colpo-

    scopy. At the 24-month follow-up, those with an

    ASC-US or greater result should be referred to

    Figure 1.

    Figure 2.

    2006 Consensus GuidelinesVHistology & 229

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    colposcopy (AII). Follow-up with HPV DNA testing

    is unacceptable (EII).

    PREGNANT WOMEN. The recommended management of

    pregnant women with a histological diagnosis of CIN 1

    is follow-up without treatment (BII). Treatment of

    pregnant women for CIN 1 is unacceptable (EII).

    Cervical Intraepithelial Neoplasia Grade 2,3

    In the 2001 Consensus Guidelines, a decision was made

    to utilize CIN 2,3 as the threshold for treatment

    decisions. CIN 2,3 includes lesions previously referred

    to as moderate dysplasia (i.e., CIN 2) and severe

    dysplasia/carcinoma in situ (i.e., CIN 3) [54]. There

    are a number of reasons for combining CIN 2 with CIN

    3 for treatment decisions. Follow-up studies have shown

    that despite marginal relative differences in behavior,

    both of these lesions are more likely to persist or

    progress than to regress [50, 59, 60]. A systematic

    review of published follow-up studies found that 43% of

    untreated CIN 2 lesions regress in the absence of

    treatment, whereas 35% will persist, and 22% willprogress to carcinoma in situ or become invasive [60].

    For CIN 3 lesions, the rates of regression, persistence,

    and progression were 32%, 56%, and 14%, respec-

    tively. Another reason for combining CIN 2 with CIN 3

    for clinical management decisions is that a histological

    diagnosis of CIN 2 is poorly reproducible [61, 62]. In

    ALTS, only 43% of lesions histologically diagnosed as

    CIN 2 by the clinical site pathologists were subsequently

    classified as CIN 2 when reviewed by a study pathologist

    [62]. Twenty-seven percent of all lesions originally

    diagnosed as CIN 2 were upgraded to CIN 3 by the

    study pathologists. Nonconcordance in the opposite

    direction was also common. The study pathologists

    downgraded 29% of lesions initially classified as CIN 2

    to CIN 1 or normal.

    Although CIN 2 lesions are more likely to regress

    during long-term follow-up than are CIN 3 lesions,

    CIN 2 and CIN 3 lesions share a number of biological

    characteristics usually associated with true cervical

    cancer precursors [54]. In contrast to CIN 1 lesions,

    almost all CIN 2 and CIN 3 lesions are monoclonal

    proliferations of cells that show evidence of genetic

    instability [54, 63]. The majority of CIN 2 and CIN 3

    lesions are aneuploid and have loss of heterozygosity

    at nonrandom chromosomal loci that may be asso-

    ciated with neoplastic development [54, 64]. CIN 2

    and CIN 3 lesions also have much less heterogeneity

    with respect to associated HPV types than do CIN 1

    lesions. A meta-analysis recently reported that just 5

    high-risk types of HPV (16, 18, 31, 33, and 58) are

    associated with 75% of high-grade cervical lesions[65]. Therefore, CIN 2 is generally utilized as the

    threshold for treatment in the United States to provide

    an added measure of safety [54, 62].

    Treatment of Women With Biopsy-Confirmed CIN

    2,3. There is widespread agreement that treatment of

    CIN 2,3 reduces both incidence and mortality from

    invasive cervical cancer. To be effective, treatment

    needs to remove the entire transformation zone,

    rather than selectively targeting the colposcopically

    identified lesion [66]. As discussed previously, data

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    from clinical trials have generally failed to show

    significant differences in outcome after treatment

    using different modalities. Therefore, both ablative

    and excisional methods can be utilized to treat

    women with biopsy-confirmed CIN 2,3 and asatisfactory colposcopic examination. However, exci-

    sional methods allow pathological assessment of the

    excised tissue and should reduce the risk that a

    microinvasive or occult invasive carcinoma is treated

    as a noninvasive lesion. This is particularly an issue

    for women with large high-grade lesions or lesions

    extending into the endocervical canal and for women

    who have been previously treated for CIN. Up to 7%

    of women with an unsatisfactory colposcopic exam-

    ination and CIN 2,3 have an occult carcinoma

    detected when they undergo a diagnostic excisional

    conization [13, 23]. Therefore, a diagnostic excisional

    conization that allows pathological assessment of the

    excised tissue should be used in these instances.

    Pathologic margin status is generally considered to be

    a risk factor for the development of recurrent or

    persistent CIN [67Y70]. When performed at the time

    of a diagnostic excisional procedure, endocervical

    sampling correlates with endocervical margin status

    and a positive endocervical sampling is predictive of

    residual disease [13, 70]. Rates of recurrent or persistent

    CIN when the margin is involved have ranged from 10%

    to 33% in recent studies [68, 71Y

    74]. Although anumber of studies have reported that recurrent or

    persistent CIN is more frequent in women with involved

    resection margins, relatively few studies have been able

    to control for other variables that might account for the

    higher failure rates in these patients. The few studies that

    have utilized multivariate analysis to adjust for other

    potential contributing factors have found that margin

    status is not an independent predictor of residual disease

    [75, 76]. It must be emphasized that most women withinvolved margins will not develop recurrent or persistent

    CIN and that up to 40% of all women undergoing loop

    excision have pathologic margin involvement [77, 78].

    Based on these considerations, it is generally recom-

    mended that women with positive margins be counseled

    about their elevated risk for recurrent or persistent CIN,

    but that in most instances they should be closely

    followed up rather than receive immediate treatment

    [72Y74]. For cases in which further treatment is decided

    upon, repeat excision offers a balance between the risk

    of treatment complications and the desire to eradicate

    potential residual CIN. Hysterectomy may be appro-

    priate in selected instances.

    Recommended Management of Women With CIN 2,3.

    INITIAL M ANAGEMENT. Both excision and ablation are

    acceptable treatment modalities for women with a

    histological diagnosis of CIN 2,3 and satisfactory

    colposcopy, except in special circumstances (see below)

    (Figure 4) (AI). A diagnostic excisional procedure is

    recommended for women with recurrent CIN 2,3 (AII).

    Ablation is unacceptable and a diagnostic excisional

    procedure is recommended for women with a histolo-

    gical diagnosis of CIN 2,3 and unsatisfactory colpo-scopy (AII). Observation of CIN 2,3 with sequential

    cytology and colposcopy is unacceptable, except in

    special circumstances (see below) (EII). Hysterectomy is

    unacceptable as primary therapy for CIN 2,3 (EII).

    Figure 4.

    2006 Consensus GuidelinesVHistology & 231

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    FOLLOW-UP AFTER TREATMENT. Acceptable posttreat-

    ment management options for women with CIN 2,3

    include HPV DNA testing at 6 to 12 months (BII).

    Follow-up using either cytology alone or a combination

    of cytology and colposcopy at 6 months intervals is alsoacceptable (BII). Colposcopy with endocervical sam-

    pling is recommended for women who are HPV DNA

    positive or have a repeat cytology result of ASC-US or

    greater (BII). If the HPV DNA test is negative or if 2

    consecutive repeat cytology tests are Bnegative for

    intraepithelial lesion or malignancy,[ routine screening

    for at least 20 years commencing at 12 months is

    recommended (AI). Repeat treatment or hysterectomy

    based on a positive HPV DNA test is unacceptable (EII).

    If CIN 2,3 is identified at the margins of a diagnostic

    excisional procedure or in an endocervical sample

    obtained immediately after the procedure, reassessment

    using cytology with endocervical sampling at 4 to 6

    months posttreatment is preferred (BII). Performing a

    repeat diagnostic excisional procedure is acceptable

    (CIII). Hysterectomy is acceptable if a repeat diagnostic

    procedure is not feasible.

    A repeat diagnostic excision or hysterectomy is

    acceptable for women with a histological diagnosis of

    recurrent or persistent CIN 2,3 (BII).

    CIN 2,3 in Special Populations.

    ADOLESCENT AND YOUNG WOMEN. For adolescents and

    young women with a histological diagnosis of CIN 2,3not otherwise specified, either treatment or observation

    for up to 24 months using both colposcopy and cytology

    at 6-month intervals is acceptable, provided colposcopy

    is satisfactory (Figure 5) (BIII). When a histological di-

    agnosis of CIN 2 is specified, observation is preferred

    but treatment is acceptable. When a histological diag-

    nosis of CIN 3 is specified or when colposcopy is

    unsatisfactory, treatment is recommended (BIII).

    If the colposcopic appearance of the lesion worsensor if HSIL cytology or a high-grade colposcopic lesion

    persists for 1 year, repeat biopsy is recommended (BIII).

    After 2 consecutive Bnegative for intraepithelial lesion or

    malignancy[ results, adolescents and young women

    with normal colposcopy can return to routine cytologi-

    cal screening (BII). Treatment is recommended if CIN 3

    is subsequently identified or if CIN 2,3 persists for 24

    months (BII).

    PREGNANT WOMEN. In the absence of invasive disease or

    advanced pregnancy, additional colposcopic and cyto-

    logical examinations are acceptable in pregnant women

    with a histological diagnosis of CIN 2,3 at intervals no

    more frequent than every 12 weeks (BII). Repeat biopsy

    is recommended only if the appearance of the lesion

    worsens or if cytology suggests invasive cancer (BII).

    Deferring re-evaluation until at least 6 weeks postpar-

    tum is acceptable (BII). A diagnostic excisional proce-

    dure is recommended only if invasion is suspected (BII).

    Unless invasive cancer is identified, treatment is unac-

    ceptable (EII). Re-evaluation with cytology and colpo-

    scopy is recommended no sooner than 6 weeks

    postpartum (CIII).

    Adenocarcinoma In Situ

    Adenocarcinoma in situ (AIS) is much less commonly

    encountered than is CIN 2,3. In 1991Y1995, the

    overall incidence of squamous carcinoma in situ of

    Figure 5.

    232 & W R I G H T E T A L .

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    the cervix in white women in the United States was

    41.4 per 100,000, whereas the incidence of AIS was

    only 1.25 per 100,000 [40]. Although the overall

    incidence of AIS remains rather low, the incidence

    increased by approximately 6-fold from the 1970s to

    1990s [40].

    Management of women with AIS is both challen-

    ging and controversial. Many of the assumptions

    that are used to justify conservative management

    approaches in women with CIN 2,3 lesions do notapply to AIS. For example, the colposcopic changes

    associated with AIS can be minimal, so it can be

    difficult to determine the extent of a lesion. AIS

    frequently extends for a considerable distance into the

    endocervical canal, making complete excision dif-

    ficult. AIS is also frequently multifocal and frequently

    has Bskip lesions.[ Thus, negative margins on a

    diagnostic excisional specimen do not necessarily

    mean that the lesion has been completely excised.

    Because of these considerations, hysterectomy con-

    tinues to be the treatment of choice for AIS in women

    who have completed childbearing. However, AIS oftenoccurs in women who wish to maintain their fertility.

    A number of studies have now clearly demonstrated

    that an excisional procedure is curative in the

    majority of these patients. The failure rate after an

    excisional procedure (e.g., recurrent/persistent AIS or

    invasive adenocarcinoma) ranges from 0% to 9%

    [79Y83]. A comprehensive review of the published

    literature conducted in 2001 identified 16 studies that

    included a total of 296 women with AIS who had

    been treated with a diagnostic excisional procedure

    [82]. The overall failure rate was 8% [82]. Margin

    status is one of the most clinically useful predictors of

    residual disease [84Y87]. Recent data suggest that

    endocervical sampling at the time of an excisional

    biopsy is also predictive of residual disease [84].

    Some, but not all, studies have suggested that there is

    an increased recurrence rate as well as an increase in

    positive margins when a loop excision procedure, as

    opposed to cold-knife conization, is used [81, 82, 88].

    Irrespective of conization method, clinicians shouldremember that margin status and interpretability of

    the margins are important for future treatment

    planning and management. Moreover, it should be

    emphasized that a diagnostic excisional procedure is

    required in all women with AIS before making any

    subsequent management decisions.

    Recommended Management of Women With Adeno-

    carcinoma In Situ. Hysterectomy is preferred for

    women who have completed childbearing and have a

    histological diagnosis of AIS on a specimen from a

    diagnostic excisional procedure (Figure 6) (CIII).

    Conservative management is acceptable if futurefertility is desired (AII). If conservative management is

    planned and the margins of the specimen are involved

    or endocervical sampling obtained at the time of

    excision contains CIN or AIS, re-excision to increase

    the likelihood of complete excision is preferred. Re-

    evaluation at 6 months using a combination of cervical

    cytology, HPV DNA testing, and colposcopy with

    endocervical sampling is acceptable in this circumstance.

    Long-term follow up is recommended for women who do

    not undergo hysterectomy (CIII).

    Figure 6.

    2006 Consensus GuidelinesVHistology & 233

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    Acknowledgments

    The authors thank all of the participants and formal

    observers to the 2006 Consensus Conference who

    worked so hard to develop the guidelines. Their names

    and organizations can be viewed at www.asccp.org. The

    authors 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, Wilkerson EJ,

    Solomon D. 2006 Consensus guidelines for the manage-

    ment of women with cervical intraepithelial neoplasia

    or adenocarcinoma in situ. Am J Obstet Gynecol

    2007;197:340Y45. Elsevier/2007.

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    APPENDICES

    Appendix A: Participants and ParticipatingOrganizations

    Organizer: American Society for Colposcopyand Cervical Pathology (ASCCP) (Also onhttp://www.asccp.org/consensus.shtml)Participants.

    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. MarshallAustin, MD, PhD,Magee-Womens 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, Queens University, Kingston, Ontario, Canada

    Louis Burke, MD, Beth Israel/Deaconess 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 CaliforniaYSanta 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 CaliforniaYSan Francisco, San

    Francisco, CA

    Diane D. Davey, MD, University of Kentucky, Lexington, KY*

    Gordon D. Davis, MD, Maricopa Medical Center, St Josephs Hospital and

    Medical Center, Phoenix, AZ

    Linda Dominguez, CNP, RN, Planned Parenthood of New Mexico,

    Albuquerque, NMRebecca 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 Josephs Hospital

    and Medical Center, Phoenix, AZ*

    Benjamin Greer, MD, University of Washington Medical Center, Seattle,

    WA*

    Richard Guido, MD, Magee-Womens Hospital of the University of

    Pittsburgh, Pittsburgh, PA*

    Fernando Guijon, MD, University of Manitoba, Winnipeg, Manitoba, CanadaHope 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

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    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 CaliforniaYDavis, Permanente Medical

    Group, Sacramento, CA*

    Marina Kondratovich, PhD, Food and Drug Administration, Rockville, MDEdwardR. Kost, MD,BrookeArmy Medical Center, Fort SamHouston, 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 Womens Hospital, Pittsburgh, PA*

    Anna-Barbara Moscicki, MD, University of CaliforniaYSan 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 (FIGO), Hong Kong

    Kenneth L. Noller, MD, Tufts University School of Medicine, Boston, MA*

    Dennis M. OConnor, MD, Clinical Pathology Associates, Inc, Louisville, KY*

    Edward Partridge, MD, University of Alabama at Birmingham, Birmingham, AL*

    Diane M. Provencher, MD, CHUM-Hopital 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 CaliforniaYSan Francisco, San

    Francisco, CA*

    Mona Saraiya, MD, MPH, Centers for Disease Control and PreventionVUS

    Public Health Service, Atlanta, GA

    Debbie Saslow, PhD, American Cancer Society, Atlanta, GA*,

    Mark Schiffman, MD, MPH, National Cancer Institute, Bethesda, MD*VolkerSchneider, MD, InternationalAcademy 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, Charlottes-

    ville, 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, Universityof 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*

    *Conference participants who were members of the working groups.Members of working groups who were unable to attend the conference.Designated delegates who participated in the public comment review periods anddelegate conference calls but were unable to attend the conference.

    Formal Observers*.

    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 PhysiciansYNorth

    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 Institute of Health, Bethesda, MD

    Brigitte E. Miller, MD, Wake Forest University Baptist Medical Center,

    Winston-Salem, NC

    Mary F. Mitchell,ACOGYDepartment of Practice Activities, Washington, DC

    Mary L. Nielsen, MD, University of Kansas School of Medicine, Wichita, KS

    Catherine Platt, MD, Arlington, VAMarianne 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, UK

    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 ShoreYLIJ 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 organizationsand federal agencies.

    Participating Organizations

    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,

    238 & W R I G H T E T A L .

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    17/17

    Association of Reproductive Health Professionals,

    Centers for Disease Control and PreventionVDivision

    of Viral and Rickettsial Disease, Centers for Disease

    Control and PreventionVDivision of Cancer Preven-

    tion and Control, Centers for Disease Control andPreventionVDivision of Laboratory Systems, Centers

    for Medicaid and Medicare Services, College of

    American Pathologists, Food and Drug Administra-

    tion, 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

    Womens Health, Papanicolaou Society of Cytopathol-

    ogy, Pan-American Health Organization, Planned Par-

    enthood Federation of America, Society of Canadian

    Colposcopists, Society of Gynecologic Oncologists,

    Society of Gynecologic Oncologists of Canada, and

    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.

    Endocervical samplingincludes obtaining a specimen

    for either histological evaluation using an endocervicalcurette 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.

    Endometrial sampling includes obtaining a specimen

    for histological evaluation using an endometrial biopsy

    or a Bdilatation and curettage[ or hysteroscopy.

    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 (i.e., LEEP), and loop electro-

    surgical 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 of age

    (i.e., from 13th to 21st birthdays).

    2006 Consensus GuidelinesVHistology & 239