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New Bethesda Terminology and Evidence-Based Management Guidelines for Cervical Cytology Findings

New Bethesda Terminology and Evidence-Based Management Guidelines for Cervical Cytology Findings In women's health, a remarkable convergence of events in 2001 has produced new information and direction to foster systematic improvement in cervical cancer screening. The Atypical Squamous Cells of Undetermined Significance–Low-grade Squamous Intraepithelial Lesion (ASCUS-LSIL) Triage Study (ALTS), which is sponsored by the National Cancer Institute, has published several articles presenting long-awaited data regarding the utility of human papillomavirus (HPV) testing in the context of the most common forms of cytological abnormality.1-4 These data supported the effort to revise the Bethesda System terminology used for reporting results of cervical cytology screening. Both the new Bethesda terminology and the ALTS data directly influenced management guidelines produced by the American Society of Colposcopy and Cervical Pathology (ASCCP)–sponsored consensus conference. The efforts of the Bethesda System group and the ASCCP are all the more noteworthy because they used the World Wide Web as a platform for long-term and broad-based consensus building and debate prior to the conferences. Following an extremely vigorous and open debate at these conferences, the organizers for both groups again revised their documents. This consensus building process establishes a new model for future similar efforts. The 2 initial articles5,6 summarizing the fruits of these labors are presented in this issue of THE JOURNAL and represent required reading for all clinicians who care for women. These 2 articles contain several key points. First, the reports reaffirm that ". . . cervical cytology is primarily a screening test, which in some instances may serve as a medical consultation by providing an interpretation that contributes to a diagnosis."5 A Papanicolaou (Pap) smear is a highly complex laboratory test that requires careful patient preparation, skill in clinical specimen collection, highly skilled and controlled laboratory processing, and professional interpretation. The primary purpose of the Pap smear is to identify patients who have cellular changes that place them at risk for the development of cervical cancer. Like all laboratory tests, Pap smears are not perfect. A Pap smear is best viewed as a moderately sensitive, highly specific test that can have a small false-negative rate. Second, the articles acknowledge that HPV testing has been clinically validated and can become integral to both screening and clinical management. The ALTS trial and other studies have extensively evaluated the performance of HPV DNA testing using commercially available, highly sensitive molecular methods to detect high-risk types of HPV for the management of women with equivocal cytology results. Table 2 of the ASCCP article6 highlights these data, which had a tremendous impact on the deliberations of the consensus groups. Because of these studies, the bar has been raised for evaluating newer HPV diagnostic tests. Well-established positive and negative predictive values for the current test, which are applicable to most populations, along with the cervical cytology interpretation, allow for clear reporting of disease probabilities. Any new test must document its performance relative to this standard because many of the proposed management guidelines are based on data derived from the specific combination of cervical cytology with follow-up HPV DNA testing on the same sample. This extraction of more information from the same sample, the "superscreen" concept, improves predictive values and clinicopathologic correlations and enables pathologists and laboratories to provide more definitive interpretations. Third, and despite some pressure to the contrary, the 2001 Bethesda System retains and clarifies the category of atypical squamous cells (ASC). Indeed, some laboratories have mandated that pathologists reclassify ASC up or down to eliminate equivocal diagnoses. Follow-up studies have shown that this approach may be neither feasible nor desirable because of sensitivity issues, particularly in the group reinterpreted as normal, which may harbor a significant fraction with high-grade SIL (HSIL).7 Because of the clinical (and unfortunately medicolegal) need for high sensitivity, the most common result of a Pap smear is an ASC interpretation,1,2,5 a statement that the morphological changes are equivocal and are either quantitatively or qualitatively insufficient for a specific diagnosis of SIL or cancer. A similar definition applies for the numerically much less frequent, but more problematic (because of its higher clinical yield), atypical glandular cell (AGC) category.8,9 Pathologists and clinicians have long struggled to deal with equivocal diagnoses because the significance to the patient of an ASC/AGC diagnosis was uncertain; hence, the appended phrase "uncertain significance." Based on the findings from ALTS, ASC is in essence a 50-50 proposition. With minor provisos for age and population risk factors, approximately half of women with ASC actually have a lesion (LSIL or greater) and half do not.1,6 The half with lesions have positive results using highly sensitive and well-characterized HPV DNA testing, whereas those without lesions have HPV-negative test results. The performance of HPV testing allows for clear statements regarding the meaning of an ASC interpretation. Patients with equivocal cervical cytology who have positive HPV test results have double the probability (approximately 15%) of a prevalent HSIL compared with patients whose HPV status is unknown.1,6 More important, because of the high sensitivity and negative predictive value of the HPV assay used in ALTS, patients with a negative HPV test result have a 1% or lower chance of prevalent HSIL.1,6 The evidence-based approach of the ASCCP guidelines refers to HPV testing throughout the consensus document, with specific guidelines regarding when and when not to use this test. Based on the ALTS trial and other related studies, several strategies that use HPV testing in the ASCCP document are strongly recommended. This is in marked contrast with the prior generation of consensus opinions, which could not make clear distinctions among the different options because of the lack of evidence.10 No classification system or set of management guidelines will be accepted without some degree of controversy. However, during the next few years, the process started in 2001 will evolve and potentially improve even more. Longitudinal data from ALTS will fuel more debate and hopefully further clarify parameters of the cervical cancer screening system. The utility of HPV testing in both primary screening and surgical management will be explored and defined. The first phase 3 results of HPV vaccine trials will become available. But now, women can have better cervical cancer screening, clearer and more meaningful cytological interpretations, more rational and easier evidence-based management algorithms, and molecular diagnostics that can increase predictive power in ways that can improve outcomes and potentially reduce costs. While the new Bethesda classification system and new ASCCP guidelines mark a new beginning for reporting and treatment of cytological abnormalities, hopefully they will also mark the beginning of the end of cervical cancer. References 1. Solomon D, Schiffman M, Tarone R. Comparison of three management strategies for patients with atypical squamous cells of undetermined significance: baseline results from a randomized trial. J Natl Cancer Inst.2001;93:293-299.Google Scholar 2. Stoler MH, Schiffman M.for the Atypical Squamous Cells of Undetermined Significance–Low-grade Squamous Intraepithelial Lesion Triage Study (ALTS) Group. Interobserver reproducibility of cervical cytologic and histologic interpretations: realistic estimates from the ASCUS-LSIL Triage Study. JAMA.2001;285:1500-1505.Google Scholar 3. Sherman ME, Solomon D, Schiffman M.for the ALTS Group. Qualification of ASCUS: a comparison of equivocal LSIL and equivocal HSIL cervical cytology in the ASCUS-LSIL Triage Study. Am J Clin Pathol.2001;116:386-394.Google Scholar 4. Sherman ME, Schiffman M, Cox JT.and The ALTS Group. HPV testing for colposcopy triage: data on viral load and age effects from the ASCUSLSIL Triage Study (ALTS). J Natl Cancer Inst.2002;94:102-107.Google Scholar 5. 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.Google Scholar 6. Wright Jr TC, Cox JT, Massad LS, Twiggs LB, Wilkinson EJ.for the 2001 ASCCP-Sponsored Consensus Conference. 2001 Consensus guidelines for the management of women with cervical cytological abnormalities. JAMA.2002;287:2120-2129.Google Scholar 7. Pitman BM, Cibas ES, Powers CN, Frable WJ. Consequences of eliminating ASCUS. Cancer Cytopathol.In press.Google Scholar 8. Veljovich DS, Stoler MH, Anderson WA, Covell J, Rice LW. Atypical glandular cells of undetermined significance (AGUS): a five-year retrospective histopathologic study. Am J Obstet Gynecol.1998;179:382-390.Google Scholar 9. Ronnett BM, Manos MM, Ransley JE. et al. Atypical glandular cells of undetermined significance (AGUS): cytopathologic features, histopathologic results, and human papillomavirus DNA detection. Hum Pathol.1999;30:816-825.Google Scholar 10. Kurman RJ, Henson DE, Herbst AL, Noller KL, Schiffman MH. Interim guidelines for management of abnormal cervical cytology: the 1992 National Cancer Institute workshop. JAMA.1994;271:1866-1869.Google Scholar http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA American Medical Association

New Bethesda Terminology and Evidence-Based Management Guidelines for Cervical Cytology Findings

JAMA , Volume 287 (16) – Apr 24, 2002

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Publisher
American Medical Association
Copyright
Copyright © 2002 American Medical Association. All Rights Reserved.
ISSN
0098-7484
eISSN
1538-3598
DOI
10.1001/jama.287.16.2140
Publisher site
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Abstract

In women's health, a remarkable convergence of events in 2001 has produced new information and direction to foster systematic improvement in cervical cancer screening. The Atypical Squamous Cells of Undetermined Significance–Low-grade Squamous Intraepithelial Lesion (ASCUS-LSIL) Triage Study (ALTS), which is sponsored by the National Cancer Institute, has published several articles presenting long-awaited data regarding the utility of human papillomavirus (HPV) testing in the context of the most common forms of cytological abnormality.1-4 These data supported the effort to revise the Bethesda System terminology used for reporting results of cervical cytology screening. Both the new Bethesda terminology and the ALTS data directly influenced management guidelines produced by the American Society of Colposcopy and Cervical Pathology (ASCCP)–sponsored consensus conference. The efforts of the Bethesda System group and the ASCCP are all the more noteworthy because they used the World Wide Web as a platform for long-term and broad-based consensus building and debate prior to the conferences. Following an extremely vigorous and open debate at these conferences, the organizers for both groups again revised their documents. This consensus building process establishes a new model for future similar efforts. The 2 initial articles5,6 summarizing the fruits of these labors are presented in this issue of THE JOURNAL and represent required reading for all clinicians who care for women. These 2 articles contain several key points. First, the reports reaffirm that ". . . cervical cytology is primarily a screening test, which in some instances may serve as a medical consultation by providing an interpretation that contributes to a diagnosis."5 A Papanicolaou (Pap) smear is a highly complex laboratory test that requires careful patient preparation, skill in clinical specimen collection, highly skilled and controlled laboratory processing, and professional interpretation. The primary purpose of the Pap smear is to identify patients who have cellular changes that place them at risk for the development of cervical cancer. Like all laboratory tests, Pap smears are not perfect. A Pap smear is best viewed as a moderately sensitive, highly specific test that can have a small false-negative rate. Second, the articles acknowledge that HPV testing has been clinically validated and can become integral to both screening and clinical management. The ALTS trial and other studies have extensively evaluated the performance of HPV DNA testing using commercially available, highly sensitive molecular methods to detect high-risk types of HPV for the management of women with equivocal cytology results. Table 2 of the ASCCP article6 highlights these data, which had a tremendous impact on the deliberations of the consensus groups. Because of these studies, the bar has been raised for evaluating newer HPV diagnostic tests. Well-established positive and negative predictive values for the current test, which are applicable to most populations, along with the cervical cytology interpretation, allow for clear reporting of disease probabilities. Any new test must document its performance relative to this standard because many of the proposed management guidelines are based on data derived from the specific combination of cervical cytology with follow-up HPV DNA testing on the same sample. This extraction of more information from the same sample, the "superscreen" concept, improves predictive values and clinicopathologic correlations and enables pathologists and laboratories to provide more definitive interpretations. Third, and despite some pressure to the contrary, the 2001 Bethesda System retains and clarifies the category of atypical squamous cells (ASC). Indeed, some laboratories have mandated that pathologists reclassify ASC up or down to eliminate equivocal diagnoses. Follow-up studies have shown that this approach may be neither feasible nor desirable because of sensitivity issues, particularly in the group reinterpreted as normal, which may harbor a significant fraction with high-grade SIL (HSIL).7 Because of the clinical (and unfortunately medicolegal) need for high sensitivity, the most common result of a Pap smear is an ASC interpretation,1,2,5 a statement that the morphological changes are equivocal and are either quantitatively or qualitatively insufficient for a specific diagnosis of SIL or cancer. A similar definition applies for the numerically much less frequent, but more problematic (because of its higher clinical yield), atypical glandular cell (AGC) category.8,9 Pathologists and clinicians have long struggled to deal with equivocal diagnoses because the significance to the patient of an ASC/AGC diagnosis was uncertain; hence, the appended phrase "uncertain significance." Based on the findings from ALTS, ASC is in essence a 50-50 proposition. With minor provisos for age and population risk factors, approximately half of women with ASC actually have a lesion (LSIL or greater) and half do not.1,6 The half with lesions have positive results using highly sensitive and well-characterized HPV DNA testing, whereas those without lesions have HPV-negative test results. The performance of HPV testing allows for clear statements regarding the meaning of an ASC interpretation. Patients with equivocal cervical cytology who have positive HPV test results have double the probability (approximately 15%) of a prevalent HSIL compared with patients whose HPV status is unknown.1,6 More important, because of the high sensitivity and negative predictive value of the HPV assay used in ALTS, patients with a negative HPV test result have a 1% or lower chance of prevalent HSIL.1,6 The evidence-based approach of the ASCCP guidelines refers to HPV testing throughout the consensus document, with specific guidelines regarding when and when not to use this test. Based on the ALTS trial and other related studies, several strategies that use HPV testing in the ASCCP document are strongly recommended. This is in marked contrast with the prior generation of consensus opinions, which could not make clear distinctions among the different options because of the lack of evidence.10 No classification system or set of management guidelines will be accepted without some degree of controversy. However, during the next few years, the process started in 2001 will evolve and potentially improve even more. Longitudinal data from ALTS will fuel more debate and hopefully further clarify parameters of the cervical cancer screening system. The utility of HPV testing in both primary screening and surgical management will be explored and defined. The first phase 3 results of HPV vaccine trials will become available. But now, women can have better cervical cancer screening, clearer and more meaningful cytological interpretations, more rational and easier evidence-based management algorithms, and molecular diagnostics that can increase predictive power in ways that can improve outcomes and potentially reduce costs. While the new Bethesda classification system and new ASCCP guidelines mark a new beginning for reporting and treatment of cytological abnormalities, hopefully they will also mark the beginning of the end of cervical cancer. References 1. Solomon D, Schiffman M, Tarone R. Comparison of three management strategies for patients with atypical squamous cells of undetermined significance: baseline results from a randomized trial. J Natl Cancer Inst.2001;93:293-299.Google Scholar 2. Stoler MH, Schiffman M.for the Atypical Squamous Cells of Undetermined Significance–Low-grade Squamous Intraepithelial Lesion Triage Study (ALTS) Group. Interobserver reproducibility of cervical cytologic and histologic interpretations: realistic estimates from the ASCUS-LSIL Triage Study. JAMA.2001;285:1500-1505.Google Scholar 3. Sherman ME, Solomon D, Schiffman M.for the ALTS Group. Qualification of ASCUS: a comparison of equivocal LSIL and equivocal HSIL cervical cytology in the ASCUS-LSIL Triage Study. Am J Clin Pathol.2001;116:386-394.Google Scholar 4. Sherman ME, Schiffman M, Cox JT.and The ALTS Group. HPV testing for colposcopy triage: data on viral load and age effects from the ASCUSLSIL Triage Study (ALTS). J Natl Cancer Inst.2002;94:102-107.Google Scholar 5. 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.Google Scholar 6. Wright Jr TC, Cox JT, Massad LS, Twiggs LB, Wilkinson EJ.for the 2001 ASCCP-Sponsored Consensus Conference. 2001 Consensus guidelines for the management of women with cervical cytological abnormalities. JAMA.2002;287:2120-2129.Google Scholar 7. Pitman BM, Cibas ES, Powers CN, Frable WJ. Consequences of eliminating ASCUS. Cancer Cytopathol.In press.Google Scholar 8. Veljovich DS, Stoler MH, Anderson WA, Covell J, Rice LW. Atypical glandular cells of undetermined significance (AGUS): a five-year retrospective histopathologic study. Am J Obstet Gynecol.1998;179:382-390.Google Scholar 9. Ronnett BM, Manos MM, Ransley JE. et al. Atypical glandular cells of undetermined significance (AGUS): cytopathologic features, histopathologic results, and human papillomavirus DNA detection. Hum Pathol.1999;30:816-825.Google Scholar 10. Kurman RJ, Henson DE, Herbst AL, Noller KL, Schiffman MH. Interim guidelines for management of abnormal cervical cytology: the 1992 National Cancer Institute workshop. JAMA.1994;271:1866-1869.Google Scholar

Journal

JAMAAmerican Medical Association

Published: Apr 24, 2002

Keywords: guidelines,cervical cytology,evidence-based practice

References