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2006 Consensus Guidelines for the Management of Women With Cervical Intraepithelial Neoplasia or Adenocarcinoma In Situ

Wright, Thomas C. Jr. MD1; Massad, L. Stewart MD2; Dunton, Charles J. MD3; Spitzer, Mark MD4; Wilkinson, Edward J. MD5; Solomon, Diane MD6for the 2006 American Society for Colposcopy and Cervical Pathology-sponsored Consensus Conference

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Journal of Lower Genital Tract Disease: October 2007 - Volume 11 - Issue 4 - p 223-239
doi: 10.1097/LGT.0b013e318159408b
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Cervical cancer, once one of the leading causes of cancer death in women in the United States, is now relatively uncommon. This decline is frequently attributed to cervical cancer screening programs, but the appropriate management of women with cervical 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 problem, especially in women of reproductive age. Laboratory 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 somewhat 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) joined other 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 guidelines. Since 2001, considerable new information has become available on the natural history of CIN, particularly in adolescents and young women [6-8]. Our understanding of how to manage women with cervical adenocarcinoma in situ (AIS), a human papillomavirus (HPV)-associated precursor to invasive cervical adenocarcinoma, 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 recommendations 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].


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 discussions 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 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 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.

Table 1
Table 1:
Rating the Recommendations


General Comments

Although the 2006 Consensus Guidelines are "evidenced 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 preferences. Guidelines should never be considered a substitute for clinical judgment, and it is impossible to develop guidelines comprehensive enough to apply to all clinical situations. Finally, both clinicians and patients need to realize that although cervical cancer can often be prevented through a program of screening and treatment of cervical cancer precursor lesions, no screening or treatment modality is perfect, and unfortunately, invasive cervical cancer can develop in women who participate in such programs.

The 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 squamous intraepithelial lesion (HSIL) is not equivalent to histological CIN 2,3.

Treatment Methods.

Both ablative treatment methods 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, electrofulguration, 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 endocervical 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 electrosurgical needle conization. Excisional methods are considered 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 with unsatisfactory colposcopic examinations, positive endocervical curettage, and large lesions with a high-grade colposcopic appearance [12]. It is also often recommended 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 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 "see-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 thought to reduce patient anxiety while they wait for biopsy results [15]. It does, however, result in some overtreatment 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 histologically 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 CIN and reducing a woman's risk of future invasive cervical cancer [15, 20-22]. 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, 25-27].

It has been recognized for some time that cold-knife conization increases a woman's risk of future preterm labor, 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, 29-31]. 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 was found 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, 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 on 8,210 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 cytology and treatment history, and history of default from follow-up, operator experience, and nonvisualization of the transformation zone.

Posttreatment Follow-up.

The reported treatment failure rate using either ablative or excisional methods varies between 1% and 25% [10, 20, 35-37]. 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 treatment [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]. A recent 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-risk HPV 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 identifying 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 13-20 years) and young women are considered a "special population." There is a very low risk for invasive cervical cancer in this group, but cytologically diagnosed squamous intraepithelial lesions are common [2, 43]. Squamous intraepithelial lesions in adolescents have a very high rate of spontaneous 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 spontaneous regression postpartum is relatively high [44, 45]. In fact, many oncologists follow early-stage cervical cancer 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 both histopathology and cytology are relatively poor predictors 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 the standard for determining clinical management. Literature cited at the time of the 2001 Consensus Conference recognized that CIN 1 represents a heterogeneous group of lesions [51]. This heterogeneity is due to several factors including the poor reproducibility of a histological diagnosis of CIN 1 [52]. In the National Cancer Institute's ASCUS/LSIL Triage 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 "downgraded" to normal by the study pathologists. This occurred in 41% of cases. Nonconcordance in the opposite direction was less common, but did occur. Twelve percent of CIN 1 lesions were "upgraded" 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 of HPV [53]. However, HPV-6 or -11 was detected in only 12% of the HPV DNA-positive 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 Netherlands found that over a 4-year period all women with LSIL who were infected with non-high-risk types of HPV 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 2,3 or 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 histological 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 "negative for intraepithelial lesion or malignancy," return to routine cytological screening is recommended (AII).

Figure 1
Figure 1

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 endocervical 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 unsatisfactory 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 unacceptable (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 diagnosis of CIN 1 preceded by HSIL or AGC-NOS (atypical glandular cells not otherwise specified) cytology, 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).

Figure 2
Figure 2

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 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 cytological 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 colposcopy. At the 24-month follow-up, those with an ASC-US or greater result should be referred to colposcopy (AII). Follow-up with HPV DNA testing is unacceptable (EII).

Figure 3
Figure 3
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% will progress to carcinoma in situ or become invasive [60]. For CIN 3 lesions, the rates of regression, persistence, and progression were 32%, 56%, and 14%, respectively. 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 associated 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 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 a satisfactory colposcopic examination. However, excisional 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 examination 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 [67-70]. 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, 71-74]. Although a number 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 with involved 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 recommended 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 [72-74]. 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 appropriate in selected instances.

Recommended Management of Women With CIN 2,3.

initial management.

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 histological diagnosis of CIN 2,3 and unsatisfactory colposcopy (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
Figure 4
follow-up after treatment.

Acceptable posttreatment 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 also acceptable (BII). Colposcopy with endocervical sampling 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 "negative 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 2,3 not 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 diagnosis of CIN 2 is specified, observation is preferred but treatment is acceptable. When a histological diagnosis of CIN 3 is specified or when colposcopy is unsatisfactory, treatment is recommended (BIII).

Figure 5
Figure 5

If the colposcopic appearance of the lesion worsens or if HSIL cytology or a high-grade colposcopic lesion persists for 1 year, repeat biopsy is recommended (BIII). After 2 consecutive "negative for intraepithelial lesion or malignancy" results, adolescents and young women with normal colposcopy can return to routine cytological 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 cytological 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 postpartum is acceptable (BII). A diagnostic excisional procedure is recommended only if invasion is suspected (BII). Unless invasive cancer is identified, treatment is unacceptable (EII). Re-evaluation with cytology and colposcopy 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 1991-1995, the overall incidence of squamous carcinoma in situ of 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 challenging and controversial. Many of the assumptions that are used to justify conservative management approaches inwomen with CIN 2,3 lesions do not apply to AIS. For example, the colposcopic changes associated withAIS 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 difficult. AIS is also frequently multifocal and frequently has "skip 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 continues to be the treatment of choice for AIS in women who have completed childbearing. However, AIS often occurs 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% [79-83]. 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 [84-87]. 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 should remember 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 Adenocarcinoma 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 future fertility 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
Figure 6


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 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 management of women with cervical intraepithelial neoplasia or adenocarcinoma in situ. Am J Obstet Gynecol 2007;197:340-45. © Elsevier/2007.


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Appendix A: Participants and Participating Organizations

Organizer: American Society for Colposcopy and Cervical Pathology (ASCCP) (Also on

  • 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*

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 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.

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, 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, 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, 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 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.

Endometrial sampling includes obtaining a specimen for histological evaluation using an endometrial biopsy or a "dilatation 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 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 of age (i.e., from 13th to 21st birthdays).

*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 and delegate conference calls but were unable to attend the conference.


cervical intraepithelial neoplasia; treatment; loop electrosurgical excision procedure; cryotherapy; adenocarcinomas in situ of the cervix

©2007The American Society for Colposcopy and Cervical Pathology