Advances in technology and the latest information from clinical trials have led to revisions in the system used to classify results of Pap smears and to new guidelines for the management of abnormal cytology results.
In what is considered a milestone, an expert group of clinicians, pathologists, researchers, and patient advocates worked for a year to produce a document that spells out how laboratories should report results of Pap smears. A second group folded that new terminology into updated guidelines for managing abnormal results. The revised reporting standard, called the 2001 Bethesda System, and the new evidence-based management guidelines, prepared under the sponsorship of the American Society for Colposcopy and Cervical Pathology (ASCCP), were published in the April 24 issue of the Journal of the American Medical Association.
Cervical cancer was one of the leading cancer killers of American women before screening was first launched in the 1950s, when George Papanicolaou, M.D., a Cornell University physician, developed a cervical smear screening test that bears his name. Now only about 13,000 cases of cervical cancer are diagnosed each yearand half of those are usually diagnosed in women who have not been screened adequately.
Critical to the success of standardizing how Pap smear results are read was the original Bethesda System, which spells out terminology that should be used to report the results of cervical cytology tests. For many years, most laboratories had relied on a numeric system (usually 1 to 5) to convey the extent of the abnormality. As successful as this system was, it did not provide sufficient guidance to the patient and clinician.
The Bethesda System, the product of a 1988 National Cancer Institute workshop, allowed laboratories to provide descriptive reports of the results that clinicians could use to help them make treatment decisions. Within 2 years, the system had been adopted by the majority of U.S. screening laboratories. The system was later revised in 1991.
Today, more than 50 to 55 million Pap smears are analyzed each year, and more than 90% of the laboratories in the United States use the Bethesda System, said Diane Solomon, M.D., a senior investigator at the National Cancer Institute who has coordinated the Bethesda System from the beginning. The Pap test has a 60% to 80% sensitivity for identifying high-grade lesions, usually years before it develops into cancer. "Its astonishing that it actually works as well as it does because cytotechnologists have to pick up a dozen or so abnormal cells out of the up to 100,000 cells on a slide," Solomon said.
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Still, the Bethesda System needed to be updated for a number of reasons, said Solomon. For one, technology has changed in the last decade. The technique of smearing cells on a glass slide is being replaced in many clinics by liquid-based collection techniques that distribute cells evenly across the glass slide, easing detection of abnormalities by laboratory technologists, and, more recently, by computers.
Second, researchers now have a better understanding of the development of cervical cancer, which is caused by infection with human papillomavirus (HPV). HPV infection does not necessarily lead to cervical cancer, and while HPV infection is very common, cervical cancer is not, said Solomon. "We understand now that most people who are infected with HPV have it only transientlyit resolves on its own," she said. "In some small number of cases, the virus persists and cell changes occur that may lead to a precursor lesion, and then, sometimes, to cancer."
The earlier Bethesda System included distinct categories for low-grade squamous intraepithelial lesions (LSIL) and high-grade squamous intraepithelial lesions (HSIL). But the evidence is now much stronger that most LSIL is usually the result of a transient HPV infection and that HSIL is an HPV infection that should be treated.
And, finally, evidence-based clinical research conducted over the past decade has given clinicians improved insight into how to treat women whose cytologic evaluations find atypical squamous cells of undetermined significance (ASCUS) and LSIL. Of major benefit were the results of a National Cancer Institute trial, the ASCUS/LSIL Triage Study (ALTS) that provided informative data for the management of women whose Pap smears showed ambiguous findings.
Updating Terminology
The most important changes in the 2001 Bethesda System have to do with cytology findings that are "ambiguous," or those that may or may not indicate a precancerous condition. Of the 50 million women who undergo cervical cancer screening each year, about 4% to 7% have such ambiguous results.
The new Bethesda System subdivided the pool of ambiguous findings that had all been previously labeled as atypical squamous cells of undetermined significance (ASCUS) so that atypical squamous cells are classified as "of undetermined significance" (ASC-US) or "cannot exclude a high-grade lesion" (ASC-H).
Women with ASC-H results have cells with slightly enlarged nuclei and reduced amounts of cytoplasm, and clinical research shows that these women are at higher risk of ultimately developing a high-grade lesion, said Columbia University pathologist Thomas Wright Jr., M.D. These women are referred for an immediate colposcopy, an examination of the vagina and cervix with a magnifying instrument.
ASC-US results identify women who are at a higher risk of precancerous lesions than those judged "negative," but who are at a lower risk than those with ASC-H results. Research has shown these women have a one-in-eight chance of developing a high-grade lesion. Wright, the lead author of the consensus guidelines, said such women should be followed up with either repeat cytology tests, an HPV test, or a colposcopy.
The 2001 Bethesda System also made changes in diagnostic terminology to better identify higher-risk women. First, it eliminated the category "benign cellular changes" because clinicians were confused about whether women in this category were at higher risk of cervical cancer. In the 2001 version, benign changes are more clearly identified as "negative for atypical cervical changes." Also dropped are the phrases "favor reactive processes" and "favor benign processes," in women who had ambiguous findings. "That had the effect of providing false assurance," Solomon said.
The new management guidelines are much more rigorous than the last set, because "this is the first time they are really based on clinical evidence," including evidence from the ALTS trial as well as other published and unpublished data, said Wright. "Before this, no one ever looked closely at the data."
The guidelines also incorporate use of new technology, and they represent diverse opinions from both clinicians and patient advocates, Wright said. "The real benefit is that it makes it much clearer to both providers and patients what their next steps are," he said.
Collaborative Efforts
The 2001 Bethesda System was developed through a process that combined a series of Internet-based discussion groups and a major workshop held on the NCI campus in May 2001.
The management guidelines were also developed using open Internet bulletin boards, and the 121 experts who attended that consensus meeting in September included 29 participating professional and health organizations. "We received input from people who have never had a voice in the process before, and some very valid points were made," said Wright. "It makes the guidelines much stronger."
"I didnt expect that we would make as many drastic changes as we did," said Diane Davey, M.D., a pathologist at the University of Kentucky Medical Center, and a co-author of 2001 Bethesda System. But the Internet consensus process produced a lot of feedback on how to redefine the adequate categories and the criteria they are based on, she said.
Pap smears are good but not perfect, Solomon said. But the vast majority of American women believe in the ability of a Pap smear to detect precancerous conditions, she said. "Women understand that mammography is not perfect," said Solomon. "But many women have an unrealistic expectation that Pap smears should be 100% accurate. Its an excellent screening test, but like all medical tests, it has its limitations."
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