Pap Test Accuracy

by Food and Drug Administration (FDA)

Early detection means everything with cervical cancer. There are no early-warning symptoms or physical changes that a woman can detect. The only defense is an accurate Pap test.

The Food and Drug Administration has recently approved three new automated systems that show promise of substantially improving the accuracy of Pap tests.

A Silent Cancer

Unlike many cancers that cause pain, noticeable lumps, or other early symptoms, cervical cancer has no telltale symptoms until it is so advanced that it is usually unresponsive to treatment. Symptoms may even be absent at that point, although they often include abnormal vaginal bleeding, such as following intercourse or douching, between menstrual periods, or after menopause. Only in its late stages does cervical cancer cause pain in the lower abdominal or back regions.

But because the cervix, or neck of the uterus, can be easily accessed through the vagina, doctors can test for cervical cancer as well as for precancerous changes in the cervix. Most cervical cancers grow slowly over several years and often are preceded by abnormal cells. Cervical cancer can often be prevented by the removal of these abnormal cells.

To detect abnormal or cancerous cervical cells, George Papanicolaou, M.D., Ph.D., of Cornell University developed in the 1940s what is known today as the Pap test. In this test, a sample of cells is taken from in and around the cervix with a wooden scraper, cotton swab, or small cervical brush. The specimen is smeared on a glass slide, preserved with alcohol, and then sent to a laboratory. There cytotechnologists, specially trained in identifying abnormal cells, scrutinize the cervical cells under the microscope for any abnormal features associated with cancerous or precancerous cervical cells. These features include dark or irregularly shaped cell nuclei, or small or deformed cells.

The Pap test became a routine part of gynecological exams. As a result, there was a 70 percent drop in the number of women dying from cervical cancer between 1950 and 1970, according to the National Cancer Institute. But the problem of errors remained. Such errors are understandable when considering the magnitude of the task set before the cytotechnologist examining Pap slides. These standard-sized laboratory slides are lined with between 50,000 to 300,000 cervical cells. Lurking in these cells may be as few as a dozen abnormal cells. Finding such telltale cells is akin to finding a needle in a haystack, especially at the end of the day when cytotechnologists are likely to have examined nearly 100 Pap slides. In addition, abnormalities in cell shape may be slight and difficult for even the trained eye to detect, or may be masked by infection.

Improving Detection

A new slide preparation method may improve the accuracy of the initial screening.

The ThinPrep Processor Model 2000 is an automated slide preparation system for Pap smears that may make it easier to screen for atypical cells. Safety and effectiveness data submitted by the manufacturer to FDA demonstrated that slides prepared with the ThinPrep system are significantly more effective in a variety of patient populations for detecting low-grade squamous intraepithelial lesions (SILs) and some of the more severe lesions. In addition, the ThinPrep Processor is as safe and effective as the conventional method of preparing slides by hand for detecting all categories of atypical and diseased cervical cells.

In this system, improved quality comes from an automated process that concentrates the cellular material and filters out a lot of blood and other unneeded material.

The other new systems are computerized rescreening methods. In both systems, computers scan the slides for abnormal-looking cells.

One system, called PAPNET, uses neural net computer technology, which its manufacturer claims was originally created to detect flying missiles in what is known as the "Star Wars" defense strategy. PAPNET detects abnormal cervical cells with a computer system that essentially has learned by example. This system was created by feeding a series of digitized images of Pap slides to a computer. From these examples, the computer developed the guidelines for predicting abnormal cells.

PAPNET scans each Pap slide cytotechnologists have classified as normal and chooses the 128 cells or cell clusters that are most likely to be abnormal. Enlarged color images of these cells are then returned to the cytotechnologist for review.

Studies have used PAPNET rescreening to reexamine previous negative Pap smears taken from women with high-grade cervical cell abnormalities or cervical cancers. These studies found that in about one-third of these women, PAPNET testing detected abnormalities missed by manual screening on previous Pap smears.

The other Pap test rescreening system is called AutoPap 300 QC. This computerized system uses image interproduction and pattern recognition techniques to classify cells as abnormal. Hundreds of features — such as size, shape, density, and texture — are considered for each cell. Sophisticated statistical screens use this visual information to predict which cervical cells are abnormal. Following routine screening by a cytotechnologist, all "normal" slides are rescreened by AutoPap 300 QC, which selects 10 to 20 percent of slides with the highest probability of having abnormal cells. These are then rescreened manually by the cytotechnologist.

In one study, cytotechnologists randomly rescreening 10 percent of more than 4,000 Pap slides they originally classified as normal detected only about 1 of every 10 false negatives present. Cytotechnologists using AutoPap 300 QC to select the 10 percent of slides the system deemed as being most abnormal detected up to half of all the missed abnormals.

All three products are available for use by laboratories, but some labs may not yet be fully familiar with these new systems.

"Laboratories are starting to evaluate these devices and determine if and how they will use them," said Louise Magruder, of FDA's division of clinical laboratory devices.

Although use of ThinPrep, PAPNET and AutoPap 300 QC will considerably decrease the likelihood of missing a diagnosis of cervical cancer, none of these systems is perfect. Even if the rescreening systems could detect every abnormal cell on a Pap slide, some women with cervical cancer would still be told their Pap tests were normal because there were too few cells on the slide or the cell samples were not taken from both the inside and surface of the cervix. Douching or using vaginal spermicides or medicines a day or two before a Pap test can also wash away abnormal cells and thus reduce the test's accuracy.

Also, there is a small percentage of women who develop a rare form of aggressive cervical cancer that can develop to an advanced stage in less than a year. In addition, cervical cancer will continue to occur in women who don't receive regular gynecological exams and Pap tests. Most health professionals recommend that all women who are or have been sexually active or have reached age 18 have a Pap smear and gynecological exam as frequently as each year, but at least every three years, depending on their risk factors for cervical cancer.

There may be one exception to this recommendation: Researchers at Louisiana State University, writing in the Nov. 21, 1996, issue of the New England Journal of Medicine, found that the benefits of Pap tests for most women who have had hysterectomies are limited. The Pap test in such women is used to detect abnormal vaginal cells, and the researchers found the tests of little value for this use in women who had had hysterectomies for reasons other than cancer.

About the Author

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FDA is A United States government body that oversees medical devices, including contact lenses, intraocular lenses, excimer lasers and eyedrops. In the US, these products must be approved by the FDA before they can be marketed.