An interim report developed with input from multiple medical organizations and published simultaneously in three leading gynecological journals last week provides guidance to health-care providers who want to offer a test for the human papillomavirus (HPV) as first-line screening for cervical cancer. The HPV test would take the place of the Pap test, which has been the standard since the 1950s.
“All the data that have been collected so far show that the performance of HPV [testing] as a primary screening test is likely to be as good or better overall than relying on Pap smears,” said Dr. Stephen Schwartz, a Fred Hutchinson Cancer Research Center epidemiologist who studies HPV immunogenetics but was not involved in the report.
The Pap test involves a technician examining a swab of cervical cells under a microscope to look for precancerous changes in the cells of the cervix which, if not treated, could develop into cancer. The HPV test puts the cervical sample into an automated machine to detect the DNA of the virus that can cause those changes.
Current cervical cancer screening guidelines, last updated in 2012 by the U.S. Preventive Services Task Force, recommend the Pap test for women beginning at age 21 with the option of adding a second test for HPV from ages 30 to 65. Women with normal Pap results should be re-tested every three years; those with negative results for both tests can extend the screening interval to five years.
Since 2012, additional studies have shown that the HPV test outperforms the Pap test, the report’s authors said. Last spring, the U.S. Food and Drug Administration for the first time approved a stand-alone HPV test, triggering the need for interim guidance until the major medical societies revisit the formal guidelines.
The interim report calls for the Pap test to continue as the primary screen for women under age 25. After that, stand-alone HPV testing could begin at 25 and continue at three-year intervals as long as results were negative. The report included direction on what to do if an HPV test is positive, including using a Pap test as a follow-up.
The cervical screening specialists who wrote the interim guidance were well aware that women could find the evolving recommendations confusing. Lest such confusion deter women from getting screened altogether, Dr. Warner Huh, director of gynecologic oncology at the University of Alabama at Birmingham and co-author of the interim report, released a statement along with the report.
“What is most important,” it said, “is that women need to be screened with any strategy, as many women in the United States with cervical cancer are either unscreened or underscreened.”
Each year, about 12,000 women get cervical cancer in the United States and about 4,000 die of the disease. More than half of new cases occur in women who have never, or rarely, been screened. Cervical cancer is highly treatable when detected early, but a report released in November by the U.S. Centers for Disease Control and Prevention found that about 8 million U.S. women in the recommended 21- to 65-year-old age group have not been screened in the last five years.
Since its introduction 60 years ago, the Pap test has been one of the great success stories in cancer prevention, leading to a dramatic decrease in what used to be the top cause of cancer deaths in U.S. women.
Over the last three decades, a team of researchers from Fred Hutch and the University of Washington, led by Fred Hutch’s Dr. Denise Galloway, played a pivotal role in another breakthrough: identifying how HPV, which is sexually transmitted, perpetrates nearly all genital-tract and some head and neck cancers.
Nearly 80 million people in the United States, most in their late teens and early 20s, are infected with at least one of many strains of HPV; it is the most common sexually transmitted infection. Most do not know they’re infected, and usually the immune system clears the virus within two years. But a tiny portion became infected persistently, and persistent infection with certain types of HPV is associated with multiple cancers — Cervical cancer being the most common.
Galloway and her colleagues were also instrumental in laying the groundwork for a vaccine that prevents HPV infection. But the number of U.S. adolescents receiving the vaccine has stalled well below goals set by public health experts, who recommend routine HPV vaccination of children aged 11 or 12 years old, with catch-up vaccinations up to age 26.
So in addition to serving as a reminder for women to get screened for cervical cancer, the interim guidance report underscores the importance of the vaccine as a primary prevention measure to reduce cervical cancer cases and deaths.
In the meantime, it will likely take several years to fully update guidelines as physicians and scientists collect additional data, especially on the best way to address women who test positive to the HPV test.
The interim guidance suggests that if a woman tests positive for HPV genotypes 16 or 18, the two types associated with a higher risk of future disease, she should be referred for a colposcopy, which allows a doctor to examine the cervix under illumination and magnification. If a woman is positive for 12 other lower-risk HPV genotypes, she should get a Pap smear.
“HPV is required to have cancer, but it doesn’t mean you’re going to get cancer,” said Dr. Barbara Goff, director of gynecologic oncology at University of Washington Medicine and an affiliate researcher at Fred Hutch. “What’s attractive about [the interim guidance] is that it identifies the people who have the virus that puts them at risk of having cancer, then cytology [the Pap test] comes in and says, yes, your HPV is causing you problems. Cytology as a secondary screen – to me that just makes so much sense.”
Another advantage of the HPV test is that the Pap test misses a fair number of adenocarcinomas, one of the two common types of cervical cancer representing up to a quarter of the cases seen in the United States, Goff said. Studies have also shown that a negative HPV test is better at predicting that a woman will be free of lesions for the next three years than a negative Pap test. And while the experience for the patient is the same for both tests, the HPV test requires less material from the cervix to detect an infection so there’s less concern that a sample will be inadequate.
Goff said the guidance will affect the way she practices.
“I would definitely offer HPV screening to patients 25 and older that we’re currently offering cytology to,” she said. “Cytology doesn’t have the same sensitivity that HPV screening does. For younger people, incorporating HPV into testing is an important step to reducing cervical cancer.”
For Dr. Connie Mao, an associate professor at University of Washington School of Medicine and director of Harborview Women’s Colposcopy Clinic, the big question is when, not if, women should start HPV screening. Her concern is how to balance increased detection with the likelihood that most younger women who test positive will likely not progress to cancer.
The interim guidelines suggest dropping the age to begin HPV screening from 30 to 25.
“One of the risks of testing women under 30 with HPV test is we’re going to have a lot of people test positive, and we’re not going to know what to do with that,” Mao said. “There are still many questions about what impact this is going to have for women who test positive and get really early treatment for lesions that may or may not be cancer.”
Mao predicts that it will take a few years for consensus to form. Until then, her advice is for women to talk with their doctors and she echoed the interim report’s authors in stressing the importance of any kind of screening as well as preventive vaccination.
“There are two definite messages [from the report],” she said. “Half of the cancers that we see in this country are women who have not been screened in three to five years. Most of them could have been prevented if they’d just gotten screened. And with vaccination, we will eventually need much less screening because cervical cancer will be so rare."
The interim guidance report was published simultaneously in Gynecologic Oncology, Journal of Lower Genital Tract Disease and Obstetrics and Gynecology. Input came from representatives of the Society of Gynecologic Oncology, American Society for Colposcopy and Cervical Pathology, American College of Obstetricians and Gynecologists, American Cancer Society, American Society of Cytopathology, College of American Pathologists and American Society for Clinical Pathology.
Mary Engel is a former staff writer at Fred Hutchinson Cancer Research Center. Previously, she covered medicine and health policy for the Los Angeles Times, where she was part of a team that won a Pulitzer Prize for Public Service. She was also a fellow at the Knight Science Journalism Program at MIT. Follow her on Twitter @Engel140.