By Judy Foreman, Globe Staff, 02/22/00

The Pap smear, used to detect cervical cancer, is done 50 million times each year in the United States and remains one of the best cancer-detection tools doctors have.

In the 50 years since it was introduced in the United States, the death rate from cervical cancer has dropped by 70 percent. In poor countries that don't yet do Pap screening, cervical cancer is a leading cause of cancer death in women.

But the Pap test, which involves scraping cells from the cervix and examining them under a microscope, is far from perfect. About 25 percent of the time, it misses abnormalities. And 3 million times a year, it yields such ambiguous findings that doctors aren't sure how to proceed.

That's where a relatively new test - to detect human papilloma virus or HPV - may help significantly.

Though many women don't realize it, scientists now know that 99 percent of cases of cervical cancer are caused by persistent infection with certain high-risk strains of HPV.

Many women - in fact, a majority of young women - are at least transiently infected with HPV, which is transmitted sexually. In many, a vigorous immune response fights off the virus before it can trigger the genetic changes that lead to cervical cancer. But, in others, HPV infection does lead to cervical cancer, which strikes 13,000 American women a year and kills 5,000.

The mildly abnormal Pap tests that have long had doctors - and women - in a quandary, are typically low-grade lesions that probably would never become cancer. They're often dubbed ASCUS, for "atypical squamous cells of undetermined significance."

There's agood chance that these mild abnormalities will go away by themselves in a year or so.

But since the lesions may be a precursor to cancer, doctors never know whether it's better to send a woman for more invasive - and expensive - testing and treatment, or just repeat the Pap test in six months.

Hopefully the answer to that will come next year when results of a trial of 5,000 women with mild cervical abnormalities conducted by the National Cancer Institute are in. In the meantime, some doctors are already urging women with mildly abnormal Pap tests to have the HPV test.

The test, made by the Digene company of Beltsville, Md., was approved for use in conjunction with Pap smears a year ago by the US Food and Drug Administration and has been shown to be a highly sensitive test.

The new thinking goes like this: If the Digene test shows no HPV infection in a woman with a mildly abnormal Pap smear, it's probably safe to just repeat the Pap test in six months.

If the Digene test does show HPV infection, it may make sense to have a more invasive procedure called colposcopy, in which the doctor examines the cervix with a high-powered microscope and takes a small sample of tissue. If that biopsy is precancerous, the woman would go back to have her cervix treated by freezing or have the abnormal cells cut out with a wire loop. If it is outright cancer, she would probably need a hysterectomy or radiation treatments.

Some gynecologists, like Dr. Diane McGrory of Dedham Medical Associates and Newton-Wellesley Hospital, already use HPV testing routinely in women with mildly abnormal Pap tests. Several medical centers, including those at Yale, Johns Hopkins and the Cleveland Clinic, are also working with Digene to expand HPV testing.

McGrory, who serves on the medical advisory board for Digene, says that just by identifying women who do not need colposcopy, HPV testing serves a major purpose. Colposcopy costs several hundred dollars and can cause pain and anxiety as well.

Adding the HPV test to Pap testing does add $35 to $50 to the costs, she noted, and some insurers do not pay for the HPV test. But doing the HPV test is cheaper than sending women for unnecessary colposcopies, she argued.

Furthermore, it's increasingly easy to combine the HPV test with a relatively new Pap test called ThinPrep because the same sample of cervical cells can be used for both tests.

(ThinPrep is part of an emerging type of Pap testing called liquid-based cytology, in which cells from the cervix are put into a vial of solution instead of being spread immediately on a microscope slide. The vial is shaken to separate cervical cells from mucus and blood. The cells are then spread in a thin layer - one cell thick - on the slide, making it easier to read than the often-lumpy traditional smear. Researchers are now working on ways to get computers to read the thinner Pap tests.)

To some cancer specialists, however, it's too soon to urge HPV tests at the first sign of a mildly abnormal Pap test. It simply won't be known whether this is the best or most cost-effective approach until the NCI study is completed next year, said Dr. Diane Solomon, who co-directs that study.

The American College of Obstetricians and Gynecologists is also holding off on recommendations on HPV testing, as is the National Women's Health Network, a Washington-based advocacy group.

Still others, like Dr. Robert Burk, a medical geneticist at the Albert Einstein College of Medicine in New York, take a middle course. The issue, as Burk sees it, is whether a woman has a transient or persistent infection with HPV.

Many women - and men, too - become temporarily infected with HPV during sex, he said, even if they use condoms, because the virus can be spread by mere contact with genital skin, not just with intercourse. Though there is no treatment for HPV, infections often disappear in nine months as the immune system fights off the virus. (In men, the virus only rarely leads to penile cancer.)

If the infection persists, genes from the virus may integrate into the DNA of cervical cells, though this can take 10 years or more. The virus then churns out proteins called E6 and E7 that bind to proteins called p53 and Rb, which block cancer. Once binding occurs and this cancer protection is lost, cervical cells may accumulate other genetic changes that lead them to grow uncontrollably. Some strains of HPV - notably HPV-16 - are especially dangerous, Burk said.

To tell whether a woman who has one positive HPV test has a persistent or transient infection, doctors could re-test for HPV in six to 12 months. If the same strain of HPV is present on both tests, she may have a persistent infection that could trigger cancer. If she tests negative, or has a different strain on the second test, she may not have a persistent infection.

But Burk, and many other researchers, do not yet recommend HPV testing in all women with mildly abnormal Pap tests, in part because HPV infection is so common, especially in young women, that the test wouldn't mean much. In one study of 608 female college students in New Jersey, for instance, 70 percent were infected with HPV.

Instead, Burk believes a wise course would be to use the HPV test in older women who have mildly abnormal Pap tests. For younger women, repeating the Pap test in six months is fine.

Ultimately, the HPV test could even replace the Pap test, some researchers say, especially in countries where women don't get Pap tests now. Two studies, published in January in the Journal of the American Medical Association, support this.

One study, by National Cancer Institute researchers, looked at 8,554 women in Costa Rica who were screened with the HPV test. It found HPV testing was more sensitive than conventional Pap testing.

The other, by researchers at Columbia University, studied 1,415 women in South Africa and found that even when women collected their own cervical samples for HPV testing, the test was as sensitive as Pap smears at detecting high-risk cervical disease.

Ultimately, the HPV test could be used as a screening test in the United States, too, and could even be sold over the counter so that women could test themselves for HPV infection.

Even before then, one thing already seems clear: Women who are faced with an ambiguous finding on a Pap test should at least ask their doctors about HPV testing before agreeing to more invasive procedures like colposcopy.

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