A Revised System for Reporting Pap Test Results

Early Detection of Cancer through Screening

Magazine article

By: Caroline McNeil and Nicole Gottlieb

Date: April 24, 2002

Source: Caroline McNeil and Nicole Gottlieb. "Bethesda 2001: A Revised System for Reporting Pap Test Results." BenchMarks 2 (April 24, 2002). 〈http://www.cancer.gov/newscenter/benchmarks-vol2-issue4〉 (accessed February 21, 2006).

About the Author: This article was written by contributors to BenchMarks, the magazine of the U.S. National Cancer Institute (NCI). The NCI is a component of the National Institutes of Health (NIH), one of eight agencies that compose the Public Health Service (PHS) in the Department of Health and Human Services (DHHS). Established under the National Cancer Act of 1937, it is the federal government's principal agency for cancer research and training.

INTRODUCTION

The cervical smear was introduced by the Greek-American pathologist George Papanicolaou (1883–1962) (hence the name 'Pap' smear). In the 1920s, Papanicolaou began to study cellular abnormalities in samples taken from women with cancer of the cervix (the neck of the uterus). The technique that Papanicolaou developed for taking a cervical smear has changed little since his time. The physician or nurse spreads the walls of the vagina using an instrument called a speculum and then takes a sample of cells from the cervix by inserting a wooden spatula or brush through the speculum. The sample is then "smeared" onto a glass slide and examined under a microscope for abnormalities in the cells. Sometimes these abnormalities are slight and if the smear is repeated the cells are found to have reverted to a normal appearance. At other times the abnormality reveals a pre-cancerous condition that needs treating or even cancer itself—which has a much greater chance of being cured if found at this early stage.

In 1943, Papanicolaou published an account of his work in Diagnosis of Uterine Cancer by the Vaginal Smear. Following this publication, the cervical smear started to become a routine health screening test for women both in the U.S. and elsewhere. Before this, cervical cancer was once of the most common causes of cancer death among American women. The number of cases began to fall sharply once screening for cervical cancer with the Pap smear became well established. Cervical cancer is now considered rare. American Cancer Society statistics indicate about 10,000 new cases per year of cervical cancer occur; up to 4,000 of which will prove fatal. Women who have never been screened are most at risk of death from cervical cancer.

No screening test is 100 percent accurate. Cervical smears are examined by pathology technicians under a microscope, so there is inevitably an objective element in the result. Faulty handling or inadequate sampling also may contribute to inaccuracy. In addition, there is sometimes confusion as to how results should be interpreted. Thus, a few women receive either a false positive or a false negative result. A false positive means a woman is thought to have pre-cancer or cancer when she is, in fact, healthy. False-positive test results can cause a great deal of anxiety and unnecessary medical investigation. A false negative means that a cancer has been missed, and this may place a woman's life at risk if the missed cancer spreads. The article below describes recommendations, called the Bethesda 2001 System, for the manner in which pathologists should describe smear results.

PRIMARY SOURCE

BenchMarks interviewed Diane Solomon, M.D., of the Division of Cancer Prevention at the National Cancer Institute (NCI), who is the first author on the JAMA article titled "The 2001 Bethesda System: Terminology for Reporting Results of Cervical Cytology." Dr. Solomon has worked extensively in the field of cervical cytology and coordinated the development of The Bethesda System in 1988, as well as its revision in 1991 and the current 2001 revision. Dr. Solomon talked to BenchMarks about the changes included in Bethesda 2001 and what the revised system will mean for women and their doctors.

Why is the publication of these two papers considered a "milestone"?

Dr. Solomon: This is a milestone because it's the first time, to my knowledge, that we have collaborative development of terminology that the lab uses and management guidelines for clinicians based on that terminology. I think that in this collaborative development, each process improved the other—there was cross-fertilization. The involvement of clinicians in the revisions to the Bethesda terminology as well as the participation of pathologists in the development of clinical guidelines will result in better communication between the laboratory and clinicians because both groups are invested in the terminology and the guidelines.

How, specifically, will these publications improve care of patients with Pap test abnormalities?

Dr. Solomon: It will improve the care of women because these guidelines are based on the most up-to-date information we have from research and clinical trials in the area of cervical abnormalities.

A specific example would be in the area of ambiguous test results. We have information from a clinical trial sponsored by the National Cancer Institute that identified a group of women with ambiguous test results that are at higher risk of having an underlying high-grade lesion, or abnormality, that needs to be treated. That finding led to a new term in the new 2001 Bethesda System called "atypical squamous cells cannot exclude HSIL" (ASC-H), which identifies this small number of women.

The guidelines, in turn, recommend that these women be managed differently based on this increased risk. That would be an example of how we have research coming together to inform terminology, and which then becomes the basis for the development of clinical management guidelines.

In addition, the terminology clarifies the communication between the laboratory and the clinician, so that there's less confusion about what the Pap test findings mean—their clinical significance. For instance, in the previous version of Bethesda, there was a category known as benign cellular changes. This caused a lot of confusion amongst clinicians who really weren't quite sure whether this was "Negative" or whether this reflected something that really required management—was this woman at increased risk? In the 2001 version of Bethesda, benign changes are more clearly identified as negative for atypical cervical changes. Even if there's inflammation that's causing some cellular changes, the findings are categorized as negative. Hopefully this will reduce concern and confusion in communications between the laboratory and clinician.

The fact that this is a uniform terminology that has been adopted by the vast majority of laboratories in the United States means that no matter where a woman is undergoing cervical screening, the terms will be the same.

Are you confident that most laboratories will use the new system?

Dr. Solomon: If past versions of The Bethesda System are any guide, over 90 percent of laboratories in the United States will use some form of the 2001 Bethesda System….

How does Bethesda 2001 reflect our current knowledge of the biology of cervical cancer?

Dr. Solomon: We've learned a lot over the past 10 to 15 years about the biology of cervical cancer. We know that cervical cancer is clearly related to infection with a virus known as human papillomavirus, or HPV. While HPV is the main cause of cervical cancer, having an HPV infection does not necessarily lead to cervical cancer. In fact, HPV infection is very, very common, while cervical cancer is not. We understand that most people who are infected with HPV have the infection, but only transiently—it goes away on its own. The person's immune system responds to the presence of the virus and, over the course of a year or so the infection resolves and the virus is no longer found. In some small number of cases the virus persists and cell changes occur that may lead to a precursor lesion to cancer. If not treated such precursor lesions may eventually lead to cancer.

The Bethesda terminology reflects our understanding of the role of HPV and cellular changes in the development of cervical cancer by emphasizing the fact that there is a dichotomy of low-grade lesions and high-grade lesions in the spectrum of squamous cell changes. Low-grade lesions are, by and large, transient infections with HPV that may cause some cellular changes. But in most cases the infection will go away on its own.

Uncommonly, HPV persists and you may have more abnormal cell changes known as a high-grade squamous intraepithelial lesion, or HSIL. This indicates that the HPV infection has not gone away on its own. This is the lesion that needs to be recognized and treated so that cancer never even develops.

The low-grade and high-grade dichotomy in the spectrum of squamous changes is not something new in Bethesda 2001. It actually was introduced in earlier versions of Bethesda but there has been controversy as to whether this was the proper categorization of the spectrum of squamous changes. What we've learned over the past ten years is that yes, the low-grade/high-grade dichotomy is actually the best way to translate what we know about the development of cervical cancer precursors and cervical cancer into terminology for cervical cancer screening. So sometimes we use knowledge to change things and sometimes our new findings actually just reinforce what we had before. In this case, our new knowledge has confirmed the terminology in earlier versions of Bethesda.

Were there concerns about previous Bethesda Systems?

Dr. Solomon: The original Bethesda System introduced a term known as "Atypical Squamous Cells of Undetermined Significance," which is a very long way of saying that the laboratory is not quite sure what the findings represent. This term has been shortened to an acronym known as ASCUS, which clinicians as well as laboratories have found very frustrating because it's not quite clear how to manage women who have this ambiguous ASCUS result.

And in fact the National Cancer Institute sponsored a clinical trial of women who have ASCUS, as well as low-grade squamous findings, to ask the question "What is the best way to manage women with these types of test results?" We've certainly learned a lot based on ALTS [ASCUS/LSIL Triage Study], which in fact has now informed the development of guidelines for managing women with these findings. So this is a case where the Bethesda terminology really prompted a clinical trial that has provided data that in turn was used in the development of clinical management guidelines.

It's a frustrating fact for laboratorians, clinicians, doctors, and women that there are limitations to any medical test. No screening test is perfect, and one of the limitations in terms of the Pap test, or cervical cytology, is that the findings are not always crystal clear. There are cell changes that are ambiguous and we have to recognize that. We have to try to reduce that ambiguous category to the lowest possible number, but we also have to acknowledge that that's one of the limitations of the test. I think the ALTS findings help us deal with that reality of the limitation of cervical screening.

Do you foresee another revision of The Bethesda System?

Dr. Solomon: Not immediately! However, it is true that The Bethesda System is a living document, and that means that it is flexible and can incorporate new developments or new findings based on research. But I think that with this third revision that we have reached a point where we have incorporated all that we currently know about HPV, about the development of cervical precancers and cancers. But I think it's also important to recognize that should there be new data that comes to light, The Bethesda System is ready to evolve and incorporate new findings….

What do you see as the next steps related to cervical cancer screening?

Dr. Solomon: We need to continue efforts to reach women who have not been screened. Unscreened women are among those at highest risk for cervical cancer.

We also need to reevaluate screening recommendations for how often women should have Pap tests done, when they should begin having Pap tests done, and if they ever reach a point at which Pap tests are no longer needed. I think one of the key areas that we need to address with regard to screening, is the question of how we incorporate new technologies into new cervical cancer screening recommendations.

What do you see as the next steps in terms of research in cervical cancer screening?

Dr. Solomon: I think one of the most exciting areas in cervical cancer research is the work on developing vaccines against human papillomavirus, or HPV, which we know is the cause of cervical cancer. I think that this is extremely promising and has the potential for having a tremendous impact in terms of women's health—both in the United States, as well as worldwide.

In the United States we're fortunate to have a strong cervical cancer screening infrastructure, where women have, by and large, access to Pap testing. But in many parts of the world that lack such an infrastructure, cervical cancer is the number one cause of cancer deaths among women. Development of a vaccine would have a significant impact on reducing deaths due to cervical cancer worldwide.

SIGNIFICANCE

The Pap smear was the earliest example of cancer screening, and it is now possible to screen for various other cancers. However, the value and applicability of screening varies with the type of cancer. Many experts agree that breast and colon cancer screening should be recommended to the general population, while screening for ovarian cancer is best applied to higher risk groups. Prostate cancer screening using the prostate specific antigen (PSA) test is popular with the public and some physicians recommend it, but there is some debate over its value in predicting disease when no symptoms are present.

Screening is a means of detecting cancer early, before symptoms arise. Tests are, therefore, given to many people who do not actually have cancer and will not develop it. It is important that screening tests are as non-invasive as possible to minimize any health risk from the test and also to encourage people to receive them. Some tests rely on physical examination and pose no risk to the patient (unless an inaccurate result is given). For instance, a dentist should always check for oral cancer during a routine exam, and physicians and nurses can check a woman's breasts for lumps that may indicate that cancer is present.

Some screens depend upon imaging techniques, such as mammography for breast cancer and computed tomography for lung cancer. Colon cancer screening can be done by a lab test known as the fecal occult blood test or by colonoscopy, where the colon is examined by inserting a thin tube equipped with a miniature camera. This carries a small risk of perforating the colon, and may eventually be superseded by "virtual" colonoscopy where computed tomography images of the colon are collected.

Laboratory screening tests are generally based on measuring levels of cancer-related substances in the blood called biomarkers. The best known is the PSA test for prostate cancer risk. Another is the CA125 test for women at risk of ovarian cancer, which is usually combined with ultrasound imaging. Many biomarker tests are under development for bladder and other cancers. The estimates of the number of cancers that can be avoided by screening vary between 3 and 35 percent. More research is still needed to determine the optimal frequency of screening and to develop new and more accurate tests.

FURTHER RESOURCES

Periodicals

Solomon, D., et al. "The 2001 Bethesda System: Terminology for Reporting Results of Cervical Cytology." Journal of the American Medical Association 287 (2002): 2114-2119.

Web sites

American Cancer Society. "Overview: Cervical Cancer. How Many Women Get Cancer of the Cervix?" 〈http://www.cancer.org/docroot/CRI/content/CRI_2_4_1X_What_are_the_key_statistics_for_cervical_cancer_8.asp?rnav=cri〉 (accessed December 3, 2005).

National Cancer Institute. "Cancer Screening Overview. Health Professional Version." 〈http://www.cancer.gov/cancertopics/pdq/screening/overview/healthprofessional〉 (accessed December 3, 2005).