2001 consensus guidelines for the management of women with cervical intraepithelial neoplasia

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2001 consensus guidelines for the management of women with cervical intraepithelial neoplasia
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  295 Once a leading cause of cancer death in the UnitedStates, invasive cervical cancers are now relatively uncom-mon. This shift is often attributed to the adoption of cyto-logic screening, but cervical cytology alone is insufficient to prevent cervical cancer. Prevention requires the eradi-cation of cancer precursor lesions referred to as cervical in-traepithelial neoplasia, or CIN, and these constitute one of the most commonly encountered significant health prob-lems among women of reproductive age in the UnitedStates. Although exact figures are not available, laboratory surveys from the College of American Pathologists (CAP)indicate that more than 1 million women each year are di-agnosed with low-grade intraepithelial lesions, referred toas cervical intraepithelial neoplasia (CIN) grade 1, and500,000 will be found to have high-grade cervical cancerprecursor lesions, referred to as CIN-2 and CIN-3. 1 During the past decade, new data on the epidemiology,natural history, and treatment of CIN have become avail-able, but efforts to integrate this information into clinicalmanagement have been limited. In September 2001, the American Society for Colposcopy and Cervical Pathology (ASCCP) held a consensus workshop to develop evi-dence-supported consensus-based guidelines for themanagement of women with cytologic abnormalities andcervical cancer precursors. This meeting had representa-tives from 29 participating professional organizations,federal agencies, and national and international healthorganizations. Input from the professional community  was obtained through a novel approach that incorpo-rated internet-based discussion groups. This report pro- vides a summary of recommendations from that meeting with respect to managing biopsy-confirmed cervical can-cer precursors. Management guidelines for cytologic ab-normalities from the 2001 Consensus Conference havealready been published. 2  From the Department of Pathology, College of Physicians and Surgeons of Columbia University, New York  a  ; Student Health Services, University of California—Santa Barbara, Calif, and American Social Health Associ- ation, Durham, NC  b  ; Department of Obstetrics and Gynecology, South- ern Illinois University School of Medicine, Springfield  c  ; Department of Obstetrics and Gynecology, Walter Reed Army Medical Center, Washing- ton, DC  d  ; Institute of Women’s Health, University of Miami, Fla  e  ; and  Department of Pathology, University of Florida, Gainesville.  f  This set of guidelines was supported by grant number 1 R13 CA96190- 01 from the National Cancer Institute. Its contents are solely the responsibility of the authors and do not neces- sarily represent the official views of the National Cancer Institute or the  participating societies and organizations.Received for publication January 28, 2003; revised April 1, 2003; ac- cepted May 31, 2003.Reprint requests: Thomas C. Wright, Jr, MD, Room 16-404, P&S Build- ing, 630 W 168th St, New York, NY 10032. E-mail: tcw1@columbia.edu doi:10.1067/mob.2003.633  2001 Consensus Guidelines for the Management of Women withCervical Intraepithelial Neoplasia Thomas C. Wright, Jr, MD, a   J. Thomas Cox, MD, b L. Stewart Massad, MD, c  Jay Carlson, DO, d Leo B. Twiggs, MD, e and Edward J. Wilkinson, MD, f for the 2001 ASCCP-sponsored Consensus Workshop New York, NY; Durham, NC; Springfield, Ill; Washington, DC; Miami and Gainesville, Fla  OBJECTIVE: The study was undertaken to provide consensus guidelines for the management of womenwith histologically confirmed cervical intraepithelial neoplasia (CIN) that can act as a precursor to invasivecervical cancer and represents one of the most common significant gynecologic diseases of women of repro-ductive age. PARTICIPANTS: An independent panel of 121 experts in various aspects of the diagnosis and managementof cervical cancer precursors, including representatives from 29 participating professional organizations, fed-eral agencies, national and international health organizations, and others were invited by the American Soci-ety for Colposcopy and Cervical Pathology (ASCCP). CONSENSUS PROCESS: Guidelines for the management of women with CIN were developed through amultistep process.Draft management guidelines were developed by working groups who performed formalliterature reviews and obtained input from the professional community at large by way of an interactive inter-net-based bulletin board.At the ASCCP Consensus Conference, September 6 through 8, 2001, in Bethesda,Md, all guidelines were discussed, revised, and adopted by formal vote. CONCLUSION: Evidence-based guidelines have been developed for the management of women withbiopsy-confirmed CIN.(Am J Obstet Gynecol 2003;189:295-304.) Key words: Cervical intraepithelial neoplasia, LEEP, colposcopy   296Wright et al  July 2003 Am J Obstet Gynecol General comments The 2001 Consensus Conference and the process usedto develop the Consensus Guidelines have previously been reported. 2 Each guideline is rated by using a 2-part grading system. 3,4 The “strength of recommendation” foror against the use of a particular option is indicated by the letters A through E. It is important to recognize that several criteria that included the possibility for harm to apatient if a specific intervention did not take place, thepossible complications that could be associated with agiven intervention, as well as the quality of the evidencefor a specific recommendation, were all taken into ac-count when determining the “strength of recommenda-tion.” Therefore, an exact correlation does not exist between the “quality of evidence” and the “strength of arecommendation.” “Quality of evidence” was designatedby using roman numerals I through III as defined inTable I. A number of terms that are used in the guidelines were specifically defined at the beginning of the Consen-sus Conference, Table I. These include the terms recom- mended  ,  preferred  , acceptable  , and unacceptable  . The 2001 Consensus Guidelines are designed to helpstandardize the management of women with cytologic ab-normalities and cervical intraepithelial neoplasia. It is im-portant to recognize, however, that it is impossible forguidelines to apply to all clinical situations and thereforeclinical discretion is critical when developing a manage-ment plan for a specific patient. A full discussion of thelimitations inherent in the use of clinical guidelines anddefinitions of terms used in the 2001 Consensus Guide-lines have been published and are also available at  www.asccp.org. 2 Cervical intraepithelial neoplasia grade 1 (CIN-1) General comments.  Women with a diagnosis of CIN-1on a colposcopically directed biopsy represent a hetero-geneous group. Numerous studies have documented ahigh level of intraobserver and interobserver variability inthe histologic diagnosis of CIN-1. 5-7 In the National Can-cer Institute’s ASCUS/LSIL Triage Study (ALTS) clinicaltrial, only 43% of the cervical biopsies initially diagnosedas CIN-1 were classified as CIN-1 by the expert pathology review committee, 41% were downgraded to normal, and13% were upgraded to CIN-2 and CIN-3. 7 In addition, acolposcopically directed biopsy represents a limited sam-pling of the cervix that may be influenced by a number of factors, including the skill of the colposcopist and only moderate specificity of colposcopic findings. 7 Studies of  women with CIN-1 diagnosed on a colposcopically di-rected biopsy, who undergo a loop electrosurgical exci-sion procedure (LEEP), have identified CIN-2 and CIN-3in 23% to 55% of the excised specimens. 8 The natural history of untreated CIN-1 is characterizedby high rates of spontaneous regression and low rates of progression to cancer. A comprehensive literature review that included information on 4504 patients with CIN-1found that spontaneous regression occurs in 57% of pa-tients and 11% progress to CIN-2 and CIN-3 or cancer. 9 Overall, the rate of progression to invasive cervical cancerobserved in these studies was 0.3%. A recent meta-analysisof the natural history of CIN-1 arrived at similar conclu-sions. 10 Similar rates of detection of CIN-2 and CIN-3 havebeen noted in the 2-year follow-up of biopsy-confirmedCIN-1 in the National Cancer Institute’s ALTS (MarkSchiffman, written communication, Sept 7, 2001). There isno definitive method to identify which CIN-1 lesions willspontaneously regress and which will persist or progress.Loss of heterozygosity at specific chromosomal loci,  FHIT  (a candidate tumor-suppressor gene) expression, telom-erase activity, DNA ploidy, Ki-67 expression, human papil-lomavirus (HPV) type and variants, and p16 expressionhave been evaluated as potential biomarkers of clinicaloutcome. 11-16  Although the available data are promising,there is currently insufficient information to support theroutine clinical use of any of these biomarkers.The poor reproducibility of the histologic diagnosis of CIN-1, as well as the uncertain biologic potential of le-sions that are classified on the basis of their histologic ap-pearance as CIN-1, makes management of these womenproblematic. It is also important to note that with the useof either cytologic or histologic methods alone, it is im-possible to determine whether a CIN-1 that appears to bepersistent is a truly persistent lesion or represents a new lesion. Approaches to managing women with CIN-1 Follow-up of biopsy-confirmed CIN-1. Because most casesof CIN-1 spontaneously regress without therapy, many ex-perts advocate follow-up without treatment if the colpo-scopic examination is satisfactory. 17,18 It is important torecognize, however, that although invasive cancers havebeen observed in most large series, these have usually oc-curred among women who were lost to follow-up. 19-21 Follow-up protocols for women with CIN-1 vary andhave not been compared in prospective trials. Some pro-tocols use cytology alone, others a combination of cytol-ogy and periodic colposcopy. Follow-up intervals vary from 3 to 12 months, and the length of time during which women are followed with CIN-1 before treatment is recommended varies from months to years. Prospec-tive follow-up studies indicate that the risk a woman withbiopsy-confirmed CIN-1 undergoing conservative follow-up will subsequently develop, or will be subsequently found to have, biopsy-confirmed CIN-2 and CIN-3 is 9%to 16%. 19,22 This is approximately the same risk that a woman with a cytologic result of atypical squamous cellsof undetermined significance (ASC-US) has of havingbiopsy-confirmed CIN-2 and CIN-3. 23-25 This suggeststhat women with biopsy-confirmed CIN-1 can be safely followed by using a program of repeat cervical cytology similar to that considered acceptable for women with a   Volume 189, Number 1 Wright et al297  Am J Obstet Gynecol cytologic diagnosis of ASC-US. 2  ALTS longitudinal fol-low-up data confirmed that testing for HPV at 12 monthsis an alternative to 2 repeat cervical cytology tests in thefollow-up of women with CIN-1. 26 HPV DNA testing de-tected 95% of the CIN-3 found over the 2-year follow-up, with re-referral of 55% of women. In contrast, repeat cy-tology at 6 and 12 months cumulatively detected 85% of the CIN-3 with re-referral of 60% of women to col-poscopy and an extra office visit for all. This data, com-bined with evidence that only persistent HPV progressesto CIN-3, and that testing for high-risk HPV detects most CIN-3, indicates that HPV DNA testing at 12 months pro- vides an acceptable follow-up approach for women withCIN-1. 27 Incorporating periodic colposcopic examinations dur-ing follow-up would help assure that CIN-2 and CIN-3 arenot missed, but would be expected to increase the costs of follow-up and necessitates access to colposcopic services.However, there are no studies demonstrating the superi-ority of follow-up protocols incorporating colposcopy asopposed to cytology alone. Follow-up of women with CIN-1 beyond 24 months has been shown to result in both in-creased cumulative rates of spontaneous regression, as well as higher rates of progression to CIN-2 and CIN-3. 28 However, there are no data to suggest that follow-up of patients with persistent CIN-1 for more than 24 months isunsafe in compliant populations.  A conservative follow-up protocol is more controversial when patients with biopsy-confirmed CIN-1 have an un-satisfactory colposcopic examination because these pa-tients may have occult disease of higher grade within theendocervical canal. One series of women undergoingcone biopsies for CIN-1 reported that for those women with an unsatisfactory colposcopy, regardless of the endo-cervical sampling results, the rate of detection of CIN-2and CIN-3 in the conization specimen was about 10%. 29 Because data are limited and the consequences of miss-ing an occult invasive cancer are significant, a diagnosticexcisional procedure is more appropriate than follow-up without treatment for women with biopsy-confirmed CIN-1 and an unsatisfactory colposcopic examination, regard-less of the endocervical sampling results. Treatment options: Both ablative modalities that destroy the effected cervical tissue in vivo and excisional modali-ties that remove the effected tissue and allow pathologicexamination have been widely used to treat CIN-1 in women with satisfactory colposcopic examinations. 30,31  Although several topical agents are currently being evalu-ated for efficacy and tolerance in the treatment of women with biopsy-confirmed CIN-1, at the current time there isinsufficient published data to develop recommendationseither for or against their use. Ablative modalities include cryotherapy, electrofulgu-ration, laser ablation, and cold coagulation. Ablative pro-cedures have usually been 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 endocervicalsampling with cytologic correlation. 29 This is because anumber of studies have shown that pretreatment endo-cervical sampling can help identify women with occult in- vasive cervical cancer. 32,33 In 1 study of 391 women Table I. Rating the recommendations* Strength of recommendation† AGood evidence for efficacy and substantial clinical benefit support recommendation for use. BModerate evidence for efficacy or only limited clinical benefit supports recommendation for use. CEvidence for efficacy is insufficient to support a recommendation for or against use, but recommendations may be made on other grounds.DModerate evidence for lack of efficacy or for adverse outcome supports a recommendation against use. EGood evidence for lack of efficacy or for adverse outcome supports a recommendation against use. Quality of evidence†IEvidence from at least 1 randomized, controlled trial.IIEvidence from at least 1 clinical trial without randomization, from cohort or case-controlled analytic studies (preferably from more than 1 center), or from multiple time-series studies, or dramatic results from uncontrolled experiments.IIIEvidence from opinions of respected authorities based on clinical experience, descriptive studies, or reports of expert committees.Terminology‡Recommended:Good data to support use when only 1 option is available.Preferred:Option is the best (or 1 of the best) when there are multiple other options.  Acceptable:One of multiple options when there are either data indicating that another approach is superior or when there are no data to favor any single option. Unacceptable:Good data against use.*Used with permission from Wright et al. 2 †Modified from Kish 4 and Gross et al. 90 ‡The assignment of these terms represents an opinion or vote by the Consensus Conference and the assignment is not directly linkedto the “strength of evidence” or “quality of evidence.”  298Wright et al  July 2003 Am J Obstet Gynecol undergoing a diagnostic excisional conization, none of the women with a negative endocervical curettage weresubsequently found to have invasive disease, whereas allthe 17 with invasive disease had positive endocervicalsampling. 32 Studies of patients presenting with invasivecervical cancer after ablative therapy have shown that many either did not have endocervical disease excludedby endocervical sampling before treatment or underwent an ablative procedure despite a positive endocervicalsampling. 34-36 Excisional modalities include LEEP, laser, and cold-knife conization (ie, diagnostic excisional procedures).It is often recommended that posttreatment recurrenceof CIN be treated by using excisional as opposed to abla-tive methods. 37 This is because recurrent/persistent CINfrequently occurs in the endocervical canal where it isnot colposcopically detectable and therefore not suitablefor ablative therapy. In addition, many women with re-current CIN are considered unsuitable for ablative ther-apy either because their colposcopic findings, a suspicionof invasive disease, or because they are considered to beat high-risk for having occult invasive disease. 38-41 Hys-terectomy carries a substantially greater risk of morbid-ity, and even mortality, when compared with excisionaland ablative procedures, and this outweighs any poten-tial benefit to its use as primary therapy for women withCIN-1. A randomized clinical trial comparing cryotherapy,laser ablation, and LEEP as treatment for CIN of allgrades reported no significant difference in complica-tion or clearance rates associated with the different treatment modalities. 42 Other studies comparingcryotherapy with laser vaporization have also reportedsimilar success rates for both modalities, as have studiescomparing laser vaporization with LEEP. 43,44  A system-atic review of published controlled and randomized tri-als reported no significant difference in outcomes withrespect to recurrence of CIN between cryotherapy, laserablation, or LEEP, in women with satisfactory colpo-scopic examinations. 45 Similarly, all the approachesused for diagnostic excisional procedures (ie, LEEP,laser conization, and cold-knife conization) have beenshown to be effective. Although loop electrosurgicalconizations have been associated with lower blood loss,better posttreatment colposcopic visualization, andshorter operative times than cold-knife conizations insome studies, pathologic margins are often more fre-quently involved and more difficult to interpret than with cold-knife conizations. 46-48 Therefore, a decision asto which therapeutic option is best for an individual pa-tient depends on factors such as the training and expe-rience of the clinician, the preferences of the patient,the resources available, the expected clinical value of agiven treatment modality for that patient, and whethercancer has been excluded. Recommendations for managing women withbiopsy-confirmed CIN-1 Women with satisfactory colposcopic examination. Man-agement options for women with biopsy-confirmed CIN-1are follow-up without treatment or treatment with the useof ablative or excisional modalities, Table II. Follow-up with a program of either repeat cervical cytology, at 6 and12 months, or HPV DNA testing for high-risk types of HPV at 12 months, is the preferred management ap-proach for women with biopsy-confirmed CIN-1 and a sat-isfactory colposcopic examination (AII). When follow-upis used, referral to colposcopy is preferred if a repeat cy-tology is reported as ASC or greater or the woman is high-risk HPV DNA positive at 12 months (AII). After 2negative, consecutive cervical cytology tests or a negativeDNA test for high-risk types of HPV at 12 months, it is pre-ferred that patients return to annual cytologic screening(BII). In clinical settings where colposcopy is available, acombination of repeat cytology and colposcopic exami-nation at 12 months is an acceptable approach to follow-up (AII). Women found to have cytologic or combinedcytologic and colposcopic regression during follow-upcontinue to be at higher risk, and it is recommended that they have follow-up with repeat cytology at 12 months(BIII).The decision to treat persistent CIN-1 should bebased on patient and provider preferences (BIII).Provided the colposcopic examination is satisfactory andtreatment is selected, the following treatment modalitiesfor biopsy-confirmed CIN-1 are considered acceptable:cryotherapy, electrofulguration, laser ablation, cold coagu-lation, and LEEP (AI).If treatment is selected, the choiceof treatment should be determined by the judgment of theclinician and should be guided by experience, resources,and clinical value for the specific patient (AI).It is recom-mended that endocervical sampling be performed beforeablation of CIN-1 (AII). Excisional modalities are pre-ferred for patients who have recurrent biopsy-confirmedCIN-1 after undergoing previous ablative therapy (BII). Women with unsatisfactory colposcopic examination. The preferred treatment for patients with biopsy-con-firmed CIN-1 and an unsatisfactory colposcopic examina-tion is a diagnostic excisional procedure (ie, LEEP, laserconization, or cold-knife conization) (AII). Exceptions where follow-up are acceptable are pregnant and im-munosuppressed women (see CIN-2 and CIN-3 specialcircumstances), and adolescent women in whom, basedon limited experience, CIN-2 and CIN-3 are rare in thesetting of biopsy-confirmed CIN-1 and an unsatisfactory colposcopy (CIII). Unacceptable treatment approaches.  Ablative proce-dures are unacceptable for CIN-1 in patients with an un-satisfactory colposcopic examination (EII). Podophyllinor podophyllin-related products are unacceptable for usein the vagina or on the cervix (EII). Hysterectomy as the   Volume 189, Number 1 Wright et al299  Am J Obstet Gynecol primary and principal treatment for biopsy-confirmedCIN-1 is unacceptable (EII). CIN-2 and CIN-3 General comments. The term CIN-2,3  is used to refer tolesions previously referred to as moderate dysplasia (ie,CIN-2) and severe dysplasia/carcinoma in situ (ie, CIN-3). 49  Although natural history studies of untreated mod-erate dysplasia, severe dysplasia, and carcinoma in situhave reported differences in the behavior of these lesionsduring long-term follow-up, the histologic diagnosis of these entities is poorly reproducible. 5-7,45 Moreover, fol-low-up studies have found that despite marginal relativedifferences, all these lesions are more likely to persist orprogress than to regress. Review of the published naturalhistory literature indicates that 43% of untreated CIN-2 le-sions will regress in the absence of treatment, whereas35% will persist and 22% progress to carcinoma in situ orinvasive cervical cancer. 50 For comparison, 32% of CIN-3lesions spontaneously regress, 56% persist, and 14% Table II. Synopsis of management guidelines for biopsy-confirmed CIN StrengthQualityTerminology   Women with biopsy-confirmed CIN-1  When colposcopy is satisfactory:Options are follow-up without treatment or treatment using ablative or excisional modalities.Follow-up without treatment Follow-up with repeat Pap test at 6 and 12 mo or  HPV testing at 12 mo is preferred.AIIPreferredRefer to colposcopy if repeat cytology of ≥  ASC or high-risk HPV DNA positive.AIIPreferred After 2 negative cytology results or a negative HPV test, return to annual screening.BIIPreferred A combination of repeat cytology and colposcopy at 12 mo is also acceptable for follow-up.AIIAcceptableIt is recommended that women with regression during follow-up have repeat cytology at 12 mo.BIIIRecommendedDecision to treat persistent CIN-1 should be based on patient and provider preferences.BIIITreatment Cryotherapy, laser ablation, and LEEP are all acceptable treatment modalities.AIAcceptableTreatment modality should be determined by the judgment of the clinician.AIEndocervical sampling is recommended before ablation of CIN-1.AIIRecommendedExcisional modalities are preferred for recurrent CIN-1 occurring after previous ablative therapy.BIIPreferred When colposcopy is unsatisfactory:The preferred treatment is a diagnostic excisional procedureAIIPreferredFollow-up is acceptable in pregnant, immunosuppressed women, and adolescent women.CIIIAcceptable  Women with biopsy-confirmed CIN-2,3 Initial management Both excision and ablation are acceptable for women with CIN-2,3 and a satisfactory colposcopy.AIAcceptableIn patients with recurrent CIN-2,3, excisional modalities are preferred.AIIPreferredDiagnostic excisional procedures are recommended for CIN-2,3 and unsatisfactory colposcopy.AIIRecommendedObservation of CIN-2,3 with sequential cytology and colposcopy is unacceptable, except in special circumstances.EIIUnacceptableHysterectomy is unacceptable as primary therapy for CIN-2,3.EIIUnacceptableFollow-up after treatment Follow-up using either cytology or combination of cytology and colposcopy at 4- to 6-mo intervals until at least 3 cytologic results are negative is acceptable.AIIAcceptableDuring cytologic follow-up, the recommended threshold for referral to colposcopy is ≥  ASC.AIIRecommended Annual cytology follow-up is recommended after 3 negative cytologic results are obtained.AIIRecommendedHPV DNA testing performed at least 6 mo after treatment is acceptable for surveillance.BIIAcceptableIf high-risk types of HPV are identified, colposcopy is recommended.BIIIRecommendedIf HPV testing is negative, triage to annual cytology follow-up is recommended.BIIRecommendedRepeat conization or hysterectomy based on a single positive HPV test is unacceptable.DIIIUnacceptableIf CIN is identified at the margins of a diagnostic excisional procedure or in a postprocedure endocervical sampling. A colposcopic examination and an endocervical sampling is preferred at the 4- to 6-mo follow-up.BIIPreferred A repeat diagnostic excisional procedure is acceptable in this setting.AIIAcceptableHysterectomy is acceptable in this situation when a repeat diagnostic excision is not feasible.BIIAcceptable
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