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Abnormal Pap Smears: Critical New Guidelines Clinician Reviews 12(8):53-60, 2002. © 2002 Clinicians Group, LLC Posted 10/15/2002
Abstract and IntroductionAbstractOf the 50 to 60 million American women who undergo Papanicolaou testing each year, approximately 3.5 million will have a cervical cytologic abnormality that requires further evaluation. In the past, how best to manage these women has been both controversial and confusing. It is expected, then, that revisions made to the Bethesda System -- the widely used standard for interpreting laboratory results -- and the recently issued, evidence-based guidelines from the American Society for Colposcopy and Cervical Pathology will help clinicians better care for women with cervical cytologic abnormalities. IntroductionTwo consensus statements published earlier this year in JAMA are expected to make a significant impact on the practice of gynecology. One is from the American Society for Colposcopy and Cervical Pathology (ASCCP) on the management of women with cervical cytologic abnormalities; the other, from the National Cancer Institute, outlines the revised terminology of the Bethesda System.* Both were prompted by a better understanding of the potential for human papillomavirus (HPV) as a cervical cancer precursor and the increased use of advanced technologies (eg, liquid-based cervical cytology and HPV DNA testing). The ASCCP guidelines are the first to incorporate the language of the newly updated Bethesda System and represent an effort to simplify what can be a complicated clinical situation. *This clinical feature is based on: Wright TC Jr, Cox JT, Massad LS, et al, for the 2001 ASCCP-Sponsored Consensus Conference. 2001 consensus guidelines for the management of women with cervical cytological abnormalities. JAMA. 2002;287:2120-2129; and Solomon D, Davey D, Kurman R, et al, for the Forum Group Members and the Bethesda 2001 Workshop. The 2001 Bethesda System: terminology for reporting results of cervical cytology. JAMA. 2002;287:2114-2119. Most of the remaining references were cited in these consensus statements.
The Bethesda SystemKey to understanding the ASCCP guidelines is a grasp of the language of the Bethesda System, which, in some form, is currently used by more than 90% of laboratories in the United States to report cervical cytology.[1] The statement that appeared in JAMA summarizes the system's most clinically relevant changes (see Table 1). "Adequacy" RedefinedWhat may be the Bethesda System's "most important quality assurance component" is the evaluation of cervical cell specimens for adequacy. According to the 2001 consensus statement, specimens are deemed either satisfactory or unsatisfactory for evaluation. Gone is the potentially confusing category satisfactory but limited by..., which may have prompted clinicians to perform unnecessary repeat testing. For the first time, the Bethesda System takes into consideration the technology of liquid-based cervical cytology (ie, cells collected from the cervix during the pelvic examination that are suspended in a liquid fixative rather than placed onto a slide). An adequate specimen now comprises at least 8,000 to 12,000 well-visualized squamous cells for conventional smears and 5,000 for liquid-based preparations. General Categories SimplifiedThe optional general category headings -- within normal limits and benign cellular changes -- have been combined into a single designation: negative for intraepithelial lesion or malignancy. This wording will make it clearer to the clinician that no dangerous changes have occurred. The heading other has been added to indicate findings suggesting increased risk, such as benign-appearing endometrial cells in women 40 years or older. In the event that several findings can be applied to a sample, the most clinically significant result will determine the interpretation. Interpretation, Not DiagnosisThe term diagnosis is no longer part of the Bethesda System vocabulary, as its use in the past may have been misleading. Papanicolaou (Pap) test specimens are collected for the purpose of screening and diagnosis, maintain the statement authors, and findings must be integrated into a clinical context. Therefore, the heading descriptive diagnosis has been renamed interpretation results. General interpretation results now fall into two main categories. The first -- negative for intraepithelial lesions or malignancy -- may include findings of bacterial, fungal, and viral organisms, and non-neoplastic findings, such as inflammation or atrophy. The second category is epithelial cell abnormalities. These involve squamous cells or glandular cells. Squamous Cells. Two types of atypical squamous cells may be found. One is the familiar ASC-US (atypical squamous cells of undetermined significance). The other is new: ASC-H (atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion [SIL]). This new subdivision may include 5% to 10% of ASC cases overall.[2-4] The following key terms for squamous cell abnormalities (ie, cervical cancer precursors) have remained unchanged:
Glandular Cells. For findings of atypical glandular cells (AGC), the old qualifier AGUS (atypical glandular cells of undetermined significance) has been eliminated to avoid confusing this finding with that of ASC-US -- especially in light of the higher risk of underlying high-grade disease associated with AGC. The term favor reactive has also been eliminated; samples that previously would have belonged in the favor reactive and AGUS categories are now categorized as AGC. Categories of AGC include endocervical, endometrial, and not otherwise specified (AGC NOS); favor neoplasia; and endocervical adenocarcinoma in situ.
Managing Women With ASCThe authors of the ASCCP consensus statement point out that women whose Pap test results yield findings of ASC have a 5% to 17% chance of having CIN 2,3 confirmed by biopsy and those with ASC-H, 24% to 99%.[2,3,5-9] Yet the risk of invasive cervical cancer is 0.1% to 0.2%.[10,11] While follow-up is warranted, unnecessary inconvenience, anxiety, cost, and discomfort should be avoided. Studies suggest that immunosuppressed women with ASC are at increased risk for CIN 2,3[12,13] and that postmenopausal women have a lower risk of CIN than do premenopausal women.[14-16] The common practices of performing repeat cytology until a patient has several consecutive negative results for SIL or malignancy (see Figure 1) or of performing immediate colposcopy are both acceptable methods of managing women with ASC-US, according to the ASCCP guidelines. However, repeat cytology can delay diagnosis of CIN 2,3 and also poses the problem of patient adherence to multiple follow-up visits. In addition, cytologic tests have a low sensitivity for detecting CIN 2,3.[5,17-21] Immediate colposcopy gives quick results and is 0.96 sensitive in distinguishing between normal and abnormal tissue;[22] women who receive a negative result for CIN can resume their routine Pap test screening program at 12 months. However, use of colposcopy can lead to overdiagnosis and overtreatment. Furthermore, many women find the procedure uncomfortable, and scheduling it may raise false concerns in patients about cervical disease.
A less stressful approach -- and one that would eliminate unnecessary repeat gynecologic visits -- is the ASCCP recommendation of "reflex" HPV DNA testing. To conduct this preferred method of screening, liquid-based cytology (or co-collection of a traditional smear for HPV DNA testing) is performed as part of the routine pelvic examination; HPV DNA testing of the original sample is then initiated only if the cytology test yields an interpretation of ASC-US. Research has found that the sensitivity of HPV DNA testing is 0.83 to 1.0 higher than that of a single repeat cervical cytologic test, with a negative predictive value for high-risk types of HPV of 0.98 or greater.[17-21, 23] Management subsequent to reflex HPV DNA testing is outlined in Figure 2 (see also "Cost Comparisons Among ASC-US Management Options."[24] page 58).
Pregnant women with ASC-US should receive the same management as nonpregnant women. Women with HIV and those who are otherwise immunosuppressed (regardless of CD4-cell count, HIV viral load, or antiretroviral therapy) should receive colposcopy following an interpretation of ASC-US. For postmenopausal women with ASC-US and evidence of atrophy and no contraindications, a course of intravaginal estrogen should be given and repeat Pap tests performed in one week and at four to six months. If both tests yield negative results, regular screening can be resumed. If results of ASC-US or greater are returned, colposcopy is indicated. A loop electrosurgical excision procedure (LEEP) should not be used routinely to treat women with ASC in the absence of biopsy-confirmed CIN. For women with ASC-H, immediate colposcopy is recommended. If no lesion is found, a review of the cytology, colposcopy, and histologic results should be performed to confirm the diagnosis of ASC-H. If the diagnosis is upheld, cytology at six and 12 months is acceptable. If the diagnosis is revised, clinicians should follow appropriate treatment guidelines. LSILFifteen percent to 30% of women with LSIL on cervical cytology will have CIN 2,3 identified on subsequent cervical biopsy.[10, 11] The recommended management option for women with LSIL is immediate colposcopy, which will reduce the risk that women with significant disease are lost to follow-up. For women with LSIL, the benefits of immediate colposcopy outweigh any of the aforementioned disadvantages. Diagnostic excisional procedures such as LEEP or ablation are unacceptable initial management options. Postmenopausal women and adolescents with LSIL can be managed more conservatively. Pregnant women should be referred to clinicians who are experienced in evaluating colposcopic changes in pregnant women. HSILWhile a cytologic finding of HSIL may account for only 0.45% of interpretations,[25] women with this test interpretation have a 70% to 75% chance of having biopsy-confirmed CIN 2,3 and a 1% to 2% chance of having invasive cervical cancer.[25-27] Colposcopy with endocervical assessment has been the traditional treatment modality and remains the recommended option for women with HSIL. However, there remains considerable risk of undiagnosed CIN 2,3 lesions among women in whom a high-grade cervical or vaginal lesion is not identified through colposcopy. Research has shown that as many as 35% of women with a colposcopy-confirmed diagnosis of CIN 1 and a Pap test result of HSIL have later been found to have biopsy-confirmed CIN 2,3.[28, 29] Therefore, it is recommended that negative test results be reviewed. If results are later revised, treatment according to current guidelines should be initiated. If negative findings are upheld or a review is not possible, a diagnostic excisional procedure (LEEP or ablation) should be performed on nonpregnant women. For pregnant women, colposcopic biopsy of lesions suspicious for high-grade disease or cancer is preferred; endocervical curettage is not acceptable. Again, pregnant women should be under the care of a specialized clinician. Management of AGCAn interpretation of atypical glandular cells is associated with a substantially greater risk for cervical neoplasia than are interpretations of ASC or LSIL.[30] Premenopausal women with AGC have a higher risk of CIN 2,3 than do postmenopausal women, but premenopausal women with AGC have lower risk of endometrial hyperplasia or cancer. Repeat cytology, colposcopy, and endocervical sampling are traditional methods used to evaluate AGC or endocervical adenocarcinoma in situ. Cytology testing has only a 50% to 72% sensitivity for identifying glandular neoplasia,[30-36] and many cases of biopsy-confirmed endocervical adenocarcinoma in situ have had no observed colposcopic abnormalities.[37] There is little evidence to show that any of these methods alone is sensitive to detect cancer. Except for women with aytpical endometrial cells (who should initially be evaluated with endometrial sampling), women with all subcategories of AGC should undergo colposcopy with endocervical sampling. If no invasive disease is found in women with an initial interpretation of "favor neoplasia" or endocervical adenocarcinoma in situ, these women should undergo a diagnostic excisional procedure, preferably cold-knife conization. For women with AGC NOS in whom no neoplasia is found, appropriate management includes repeat Pap testing every four to six months until four consecutive negative for intraepithelial lesions or malignancy results are returned; findings of ASC or LSIL warrant repeat colposcopy or referral to a clinician experienced in the management of complex cytologic situations.
ConclusionRecent discoveries about the precursors of cervical cancer and the availability of new cytologic testing methods -- such as liquid cytology and HPV DNA testing -- now make it possible to incorporate new approaches into managing women with cytologic abnormalities. CME InformationThe print version of this article was originally certified for CME credit. For accreditation details, contact the publisher. (link to publisher contact information: Clinicians Group, 2 Brighton Road, Suite 300, Clifton, NJ 07012, telephone: (973) 916-1000; fax (973) 916-1919) DisclosuresDisclosures for authors of the two articles summarized in this continuing education activity can be found in the original articles (Solomon D, Davey D, Kurman R, et al, for the Forum Group Members and the Bethesda 2001 Workshop. The 2001 Bethesda System: terminology for reporting results of cervical cytology. JAMA. 2002;287:2114-2119; and Wright TC Jr, Cox JT, Massad LS, et al, for the 2001 ASCCP-Sponsored Consensus Conference. 2001 consensus guidelines for the management of women with cervical cytological abnormalities. JAMA. 2002;287:2120-2129). This article does not address off-label use of any prescription drugs.
TablesTable 1. Key Changes in the Bethesda System Terminology
References
Sidebar: Cost Comparisons Among ASC-US Management OptionsIn a cost-effectiveness analysis published in JAMA shortly after these consensus guidelines, Kim and colleagues[24] conclude that biennial screening using liquid-based cervical cytology followed by reflex HPV-DNA testing for women with ASC-US is more effective and less costly than yearly conventional cervical cytology followed by repeat cervical cytology or colposcopy. Screening with liquid-based cytology and reflex HPV DNA testing costs $174,200 per year of life gained when conducted every two years, and $59,600 when conducted every three years.
Funding Information
This continuing education activity is jointly sponsored by the International Center for Postgraduate Medical Education and Clinicians Group, as well as The NPA. |
