Pharmaceutical giants Merck & Co. and GlaxoSmithKline are racing to the marketplace with a vaccine to prevent cervical cancer. Both vaccines prevent early stage cervical cancer and precancerous lesions caused by human papillomavirus (HPV) types 16 and 18. The US Food and Drug Administration (FDA) is expected to approve both vaccines this year. At the same time, screening for cervical cancer has bubbled to the surface again with major medical organizations publishing revised screening recommendations that will have a more significant impact on the lab than the new vaccines.
The clinical basics of cervical cancer are clear and fairly positive. It is the most preventable cancer, and most cases are linked to HPV. For decades, conventional cytology and liquid-based Pap tests served as the standard of care for cervical cancer screening; now the HPV test is emerging as the standard of care for cervical cancer screening.
Mark Stoler, MD
Multiple major medical associations have recognized the new paradigm and issued revised recommendations for cervical cancer screening. “The current, somewhat tentative American College of Obstetrics and Gynecology (ACOG) guidelines recommend the use of HPV and PAP testing for women over the age of 30,” says Mark Stoler, MD, professor of pathology and clinical gynecology at University of Virginia Health Sciences Center (Charlottesville, Vir.). Indeed, the FDA has approved the combined HPV/Pap test model as the primary screening mechanism for women age 30 and older. Many providers, however, have not yet fully implemented the model, so labs have not seen the true impact of the revised guidelines.
Another aspect of cervical cancer that boosts the odds of survival is the long natural history of the disease; it takes several years to progress from HPV to cervical cancer. This fact accounts for another change in screening guidelines. Recently, both ACOG and the American Cancer Society (ACS) tailored their screening guidelines to the long natural history of the disease. If both the Pap and HPV tests are negative, there is no need to repeat either test for 3 years. That’s because the combination of the two tests is highly sensitive for the presence of HPV.
The increased sensitivity is good news for laboratories that perform cervical cytology. The test has the highest malpractice risk for labs; the country realized a 600% increase in cervical cytology lawsuits between 1987 and 1995. One reason for the high malpractice rate is the significant percentage of cervical cancer cases linked to Pap test detection failure. A recent study published in The Journal of the National Cancer Institute(1) found that 32% of cervical cancer cases can be attributed to Pap test detection failures. Labs on the cutting edge of screening may have a lower risk for lawsuit than others.
At the same time, cervical cancer screening remains in transition. Several companies are exploring new HPV tests as well as genotyping technology to further triage women at the highest risk for cervical cancer. Each of these developments has implications for labs and laboratory professionals.
The Changing Cervical Cancer Screening Landscape
“There are multiple ways to screen for cervical cancer, and they don’t all need to be used in the same way,” says Thomas Wright, MD, associate professor of pathology at Columbia University College of Physicians and Surgeons (New York City). The new guidelines are based on multiple clinical studies indicating the utility of the HPV-cervical cytology combination. According to ACOG, combined HPV testing with cervical cytology has a negative predictive value for cervical intraepithelial neoplasia (CIN) 2 and 3 of 99 to 100%. HPV testing can help predict whether women with normal cytology will develop CIN in the next few years, according to ACOG. The combined tests are more sensitive than and almost as specific as conventional Pap screening and can dramatically reduce the incidence of false negatives.
Despite the promising research, the combined HPV and Pap screens are not being implemented as widely as they should be, says Stoler. “It only makes sense to perform additional tests if they correlate with longer screening intervals [as is the case with HPV testing]. Longer screening intervals have a significant impact on both the doctor-patient relationship and practice flow,” explains Stoler. The other barrier to more widespread adoption may be cost. Double testing can cost $40 to $50 more than the Pap alone, a short-term cost increase that is more than compensated for by longer screening intervals. Nonetheless, providers need time and planning to manage the changes.
According to the Centers for Disease Control and Prevention (CDC) only 21% of Pap test providers order the HPV test as an adjunct to the Pap test for cervical cancer screening. J. Thomas Cox, MD, director of the gynecology and colposcopy clinic at the University of California Santa Barbara, says providers are headed toward fuller implementation of the new guidelines. He foresees an increase in HPV testing and a decrease in Pap testing. “If the Pap and HPV tests are done only every 3 years for the estimated 25 million women eligible for the combination, then the increase in HPV tests would be in the millions. If approximately four percent of these women are HPV positive and Pap negative, then they would have a repeat HPV test and Pap in 6 to 12 months. Another six percent would have an abnormal Pap with or without a positive HPV test. Many of these women also would have repeat Pap tests in an accelerated manner. But if clinicians follow the guidelines and lengthen the screening interval to 3 years for patients with negative results, the number of Pap tests will drop,” explains Cox.
The Lab’s Role
While the number of Pap tests is projected to decrease in coming years, HPV testing will undergo a substantial increase, and laboratories need to prepare for the road ahead. Wright says, “Labs should prep for a lower volume of cytology.” At the same time, the increasing use of HPV tests has consequences in the lab. Although most labs currently perform the HPV test and are outfitted with the necessary tools, the increase in testing could require that labs add staff. “Large labs with in-house HPV testing could scale up; smaller labs may need to add capabilities,” explains Stoler.
There are other factors to consider as labs gear up for increased HPV testing. Cleveland Clinic (Cleveland, Ohio) has a long history of HPV-based screening. The clinic began implementing the HPV test in 1995 as a reflex-test for ASCUS cytology and currently uses the test as part of cervical cancer screening recommendations from ACOG and ACS. The HPV test has been part of routine screening for women over the age of 30 at Cleveland Clinic Health Network since 2004. Consequently, HPV screening volume quadrupled from 7,000 tests in 2004 to approximately 28,000 in 2005.
Effective HPV screening implementation requires some clinician education on the part of the lab, says Belinda Yen-Lieberman, PhD, professor of pathology at Cleveland Clinic Lerner College of Medicine of Case Western Reserve University. “It’s difficult to complete a molecular HPV test if cells are fixed and clumped in an alcohol solution, including standard liquid Pap reagents,” explains Yen-Lieberman.
Digene Corp, developer of the current FDA-approved HPV test, offers a specimen transfer media (STM) to facilitate the process. The Cervical Sampler collecting kit contains STM and a brush that can be used as a co-collection process to eliminate the cell clumping that occurs with alcohol-fixed cells. Clinicians at Cleveland Clinic routinely use the STM for a second swab at the time of collection. Yen-Lieberman says, “The key to HPV screening is to use the co-collection cervical sampler model, which reduces the number of equivocal and indeterminate results.”
Yen-Lieberman achieved clinician compliance with the co-collection model with a comprehensive clinician education program. The effort began with a meeting and visit to the floors to introduce the cervical sampler for HPV testing. The initial visit also outlined the benefits of STM. The next arm of the program was a “show and tell” visit with clinicians and nurse practitioners from the laboratory personnel. As a final note, lab management and a reimbursement expert covered reimbursement for HPV as a screening test.
Future Directions
As labs gear up for the changing cervical cancer screening environment, it helps to look in the crystal ball and consider other changes coming down the pipeline.
Roche is working on a PCR-based HPV test, and Digene is focusing on a next-generation, fully automated HPV test, an advance that could remove the staff burden as HPV testing becomes the standard of care. “There is a lot of room for lab-friendliness in the market. There are labor implementation issues with the current HPV assay. Instrumentation and automation will become available. Different companies are taking different approaches based on their strengths,” says Stoler.
Also, researchers have recognized that HPV genotyping will play an important role in the fight against cervical cancer. “HPV genotyping is on the horizon,” says Yen-Lieberman. HPV types 16 and 18 account for the majority of cervical cancer cases. Currently, researchers at Cleveland Clinic and elsewhere are studying the use of Luminex technology with the Digene HPV test to further characterize the presence of high-risk HPV genotypes. Recent publications from the National Cancer Institute indicate that the use of HPV genotyping following a Hybrid Capture HPV DNA screening test likely will improve the clinical sensitivity for disease as well as maintain the high clinical sensitivity standard of HPV DNA screening.
Researchers also are evaluating P 16 and have developed a solid immunohistochemistry combined with conventional cytology. “This could become an ELISA format test,” notes Wright. Another possibility is the use of s-phase markers in conjunction with cytology. Cox says some providers have discussed primary screening with the HPV test, using the Pap only if the HPV result is positive. Whether or not that model is adopted remains to be seen. “All of these options need to be evaluated in large clinical studies,” concludes Wright. Regardless of which tests are implemented, this next level of testing would facilitate more specific triage among high-risk women.
Cervical cancer screening is a changing model. Major medical organizations have recognized the role of combined HPV testing and Pap testing and issued new guidelines recommending combined testing for women over the age of 30 as well as a 3-year screening interval for women with negative results. Health care providers are beginning to implement the new guidelines, but full implementation will take time. The lab can play an important role by evaluating processes and tools for HPV testing and sharing their findings with health care providers. Equally important, laboratorians can educate themselves about other upcoming advances, including HPV genotyping that will bring additional benefits to high-risk women and changes for the lab.
Lisa Fratt is a contributing writer for Clinical Lab Products.
Reference
1. Leyden WA, Manos MM, Geiger AM, et al. Cervical cancer in women with comprehensive health care access: attributable factors in the screening process. Journal of the National Cancer Institute. 2005; 97:675-683.
