The recent publication of final U.S. Preventive Services Task Force (USPSTF) recommendations for cervical cancer screening has pushed the issue of co-testing back into the spotlight. Some women's health and cytopathology experts hope it stays there—leading to more conversations about who should be co-tested with Pap smear and liquid-based cytology and when.
The task force published updated final guidelines for cervical cancer screening in August, for the first time recommending the option of standalone or combination screening for high-risk types of human papillomavirus (hrHPV) in women aged 30-65 years every 5 years. The task force continued its earlier recommendation for screening every 3 years with cytology alone in women aged 21-29 years. This document is available at the USPSTF site here: https://bit.ly/2nXrM2I.
Specifically, the USPSTF gave Grade A recommendations to the following:
- For women aged 21-29 years, cervical cancer screening every 3 years with cervical cytology alone.
- For women aged 30-65 years, screening every 3 years with cervical cytology alone, every 5 years with high-risk human papillomavirus (hrHPV) testing alone, or every 5 years with hrHPV testing in combination with cytology (co-testing).
The American College of Obstetricians and Gynecologists, Society of Gynecologic Oncology, and the ASCCP issued a joint statement soon after the guidelines were released, noting that women should have access to the testing they desire.
“With the number of screening options now available, the new guidelines emphasize the importance of the patient-provider shared decision-making process to assist women in making an informed choice about which screening method is most suitable for them,” the organizations noted. “However, more importantly, there needs to be a continued effort to ensure all women are adequately screened because a significant number of women in this country are not. It's also essential for women to have access to all of the tests and that they are appropriately covered by insurance companies.”
The release of the USPSTF guidelines coincided with publication of a new study supporting the clinical value of using liquid-based cytology (LBC) to screen for cervical cancer and cervical cancer risk.
Evidence for Co-Testing
The research was led by R. Marshall Austin, MD, PhD, Medical Director of Cytopathology at University of Pittsburgh Magee-Womens Hospital, where he is also a staff pathologist focused on gynecologic and breast surgical pathology. He is Professor of Pathology at the University of Pittsburgh School of Medicine. Austin's study, published in August in the American Journal of Clinical Pathology (2018; doi:10.1093/ajcp/aqy114), found that LBC-enhanced co-testing identified cervical cancer and cervical disease more effectively than conventional Pap smear and HPV co-testing.
Austin and his coinvestigators undertook the study after reading the results of a Kaiser Permanente analysis of cervical cancer screening results (J Natl Cancer Inst 2018;110:501-508). The Kaiser Permanente Northern California (KPNC) system relied exclusively on conventional Pap smears until 2009 and thus may have been among the last large health systems to incorporate LBC. Because this study questioned the contribution of cytology to detection by co-testing of cervical cancer and precancer, Austin and colleagues decided to analyze their extended clinical experience with co-testing utilizing the most widely employed FDA-approved LBC methods and FDA-approved from-the-vial HPV co-testing.
“You need to look at your own data to see how you're doing and to understand the contribution of cytology as well as HPV testing with regard to cervical cancer and dysplasia,” Austin said. The study analyzed cervical screening data collected from 270,263 women aged 30 years and older between January 2005 and August 2017 at Magee-Womens Hospital.
A total of 748,947 LBC test results were analyzed. The database reflected test results generated from widely used screening technologies, including LBC using the ThinPrep Pap test, computer-assisted LBC imaging using the ThinPrep Imaging System, and the from-the-PreservCyt vial testing for the presence of hrHPV using the Hybrid Capture 2 HPV test, the Cervista HPV HR test, or the Aptima HPV test. Cytology results were reported utilizing the 2001 Bethesda System. Pap tests reporting epithelial cell abnormalities at the level of atypical squamous cells of undetermined significance were considered abnormal or “positive” cytology results, as were more severe cytologic abnormalities.
The study found that among patients 30 years and older who underwent co-testing, more cervical cancers and precancerous changes were detected with LBC than with from-the-LBC vial HPV testing. This differed from KPNC findings that HPV co-testing along with large-scale use of conventional Pap smears identified more women subsequently diagnosed with cervical cancer and precancer.
“Numerous large datasets comparing high-grade squamous intraepithelial lesions and cervical cancer detection rates utilizing LBC versus conventional Pap smears have consistently documented increased detection of significant abnormalities with LBC,” Austin and colleagues wrote. “Enhanced detection of abnormalities with LBC has been attributed to both increased harvesting of cells from Pap collection devices and the interpretive advantage of immediate wet fixation, as well as the opportunity to perform adjunctive molecular testing from residual LBC vial fluids.”
Approximately 13 percent of cervical cancer diagnoses and 7 percent of precancer diagnoses examined in the UPMC Magee-Womens analysis had positive cytology results when the HPV test specimen gathered at the same time was negative.
“Our study showed that we were making more contribution to detecting cervical cancer and high-grade precancer in our system than had been reported in the Kaiser system,” Austin said. “Our data is strong evidence that co-testing provides the patient with the greatest protection, the greatest likelihood that a woman who is developing cervical cancer will have a red flag thrown up, and that a woman developing cervical dysplasia will have a red flag thrown up. Patients are best served by this combined method of HPV co-testing.”
When asked about the updated USPSTF guidelines, Austin said he hopes the panel's support for high-risk HPV testing will lead to more in-depth provider-patient conversations and subsequent action. He also expressed the need for greater attention to cervical cancer risk among women whose HPV testing is negative for high-risk strains.
“Few people are aware of the data showing that someone developing cervical cancer may have a negative HPV test,” Austin said. “The Kaiser data showed that among women who will get cancer in 1-3 years, the chance of having a negative HPV test existed in one-third of cases. That generally is not recognized. USPSTF says that women who have a negative HPV test should have repeat testing in 5 years. To me, the extended screening intervals are inconsistent with this data.”
Austin also noted that clinical experience and data are suggesting that a woman's cervical cancer risk may benefit from earlier analysis. Although HPV screening of women in their 20s is not recommended by any guideline, Austin said he is concerned that HPV infection rates are high in this age group.
“The cervical cancers that develop in young women tend to be rapidly progressive cancers,” he said. “About 95 percent of these rare but rapidly progressive cancers diagnosed in younger women are caused by a small number of genotypes: 16 and 18, with a smaller proportion caused by genotype 45.
“I believe we should be looking a lot more at women in their 20s,” he continued. “I think young women would be well-served to have periodic co-testing for these three types. All studies show that our ability to prevent those is significantly lower than older age groups because cancers in younger women appear to more difficult to detect in the precancerous stage. ... I think we have not been aggressive enough in addressing this issue in younger women.”
On the other end of the age spectrum, Austin also has concerns about the screening needs of older women. “The task force says that women over 65 don't need screening if they have been screened adequately,” Austin said. “But the screening history of an older woman is, in most cases, not completely known to the doctor's office. If a woman's screening was significantly abnormal in her 20s, she's at high risk later in life. Few women have clear recollection of their testing results over time. We believe a lot of older women are being exited from screening prematurely and that their cervical cancer risk is not being fully appreciated.”
The lack of adequate history will become a greater concern as the U.S. population ages, Austin predicted. “A woman who had high-grade dysplasia in her 20s and 30s has a different immune system when she is older. We believe that these HPV infections may become reactivated. The activation of previous infection is the cause—not a new infection. ... We need to pay more attention to these patients. They certainly need to have cytology and HPV co-testing before they are exited from screening.”
Michelle Perron is a contributing writer.