The shift from Papanicolaou (Pap) cytology to direct testing for the human papillomavirus (HPV) represents a major advance in cervical cancer screening. Nevertheless, some experts like Emily Delpero, MD, of Mount Sinai Hospital in Toronto, Canada, expect significant initial pushback from patients and physicians alike.
Others like Marc Steben, MD, co-director of HPV Global Action, and professor in the School of Public health at the University of Montreal, argue that the problems that other countries encountered on introducing HPV testing have been solved. With good public education, the sailing should be much smoother once the test is introduced in Canada, he told Medscape Medical News.
“HPV polymerase chain reaction [PCR] testing of cervical samples is better at detecting precancer or cancer than Pap testing and would decrease the overall cost of screening,” write Delpero and Mount Sinai colleague Amanda Selk, MD, MSc, in a commentary published online May 2 in the Canadian Medical Association Journal.
“However,” they add, “shifting to this new screening modality will mean overhauling existing algorithms for age and screening intervals, changing resource allocation, and educating physicians and patients.” Clinicians should discuss why and how cervical screening will change when Canada adopts the new test, she added.
First, recommended screening intervals will become significantly longer — probably as long as 5 years between HPV tests. Though the Pap test has a specificity approaching 97%, it has a low sensitivity of between 55 to 60%, so it misses almost half of all significant lesions. Its accuracy is “about the same as flipping a coin,” said Steben.
Indeed, in the landmark HPV for Cervical Cancer or FOCAL trial, over 19,000 women in British Columbia were randomly assigned to primary screening with either HPV testing or routine cytology. At the end of the study, all women underwent existing HPV screening and cytology testing. The risk ratio of finding a high-grade lesion was 0.42 for those randomized to up-front HPV test screening, compared with routine care.
“This finding suggests that many lesions were missed by initial cytology testing and reinforces HPV testing as the better screening method,” write Delpero and Selk. By having women undergo repeat Pap testing every 2 to 3 years, starting at a fairly young age of between 21 and 25 years, “subsequent testing is likely to detect previously missed pathology in populations with relatively high disease prevalence,” she added.
Fewer False Positives
However, a significant shortcoming of Pap cytology is that it was developed to detect squamous cell carcinoma, not adenocarcinoma. “Squamous and adenocarcinoma are very different,” said Steben. “The Pap test is not good at identifying adenocarcinoma, which is increasing in younger women,” he added.
Moreover, cytology highly depends on the quality of the specimen and the expertise of the technician who is reading the slides — neither of which is a given, said Steben. Testing a cervical sample for HPV subtypes relies on PCR technology that is more reliable than human judgment. HPV testing also has a high negative predictive value that is far superior to that achieved with, for example, breast mammography or colonoscopy, Steben added.
Organizations can safely lengthen the interval between HPV tests to 10 years because if no virus is present at the time of the test, it is unlikely that disease will develop for many years to come. In a long-term follow-up of FOCAL participants, the probability of finding a high-grade lesion 10 years after a single negative HPV test was less than 1%, with most lesions detected after 7 years or more. Screening could also start between the ages of 25 and 30 years, write Delpero and Selk.
On the other hand, at least during the initial stages of the rollout, a greater proportion of unvaccinated women would be expected to receive a positive HPV test result. But with increasing HPV vaccine uptake and decreasing prevalence of high-risk HPV types 16 and 18, HPV testing is expected to lead to far fewer false positives than Pap testing.
At-Home Testing
Another major advantage of HPV testing over cytology is that women can collect a sample at home. “We have a group of women who are not reached by the health system,” Steben explained. “In fact, we know that about 1 out of 7 women in Canada has never received a Pap test in her life, and the main reason for this is that she cannot connect with the healthcare system or she is not in the right place to get the right advice to get the test done,” he added. The availability of home testing is thus an advantage.
The major disadvantage of replacing cytology with the HPV test, both Delpero and Steben agreed, is that it changes the paradigm for physicians and for patients. First, experts are no longer looking for precancerous lesions. They are testing the cervix for a sexually transmitted virus, which could add to the stigma around HPV testing, said Steben.
“Raising the age of initial screening and reducing screening frequency could be viewed [by women] as a governmental cost-cutting measures, with no benefit for patients,” Delpero and Selk add. This occurred when the HPV test was first introduced in Australia.
Thus, significant initiatives will be needed to counter mistrust among physicians and the public about the new test, “It always takes time to change habits and established practice,” Delpero told Medscape Medical News. “But supporting HPV testing would be a huge gain for Canadian women with a cervix,” she added. “Hopefully…when new guidelines come out, we will have widespread adoption and a smoother transition to the HPV test than Australia had,” Delpero said.
Steben is convinced that the obstacles that Australia and other countries encountered have been resolved and that the Canadian transition will be smoother. “One of the World Health Organization’s goals is to eliminate cervical cancer, but we need new tools to do it,” Steben said. “Cytology has been good — it’s the only thing we had for a very long time — but now it’s time to turn the corner and head into the 21st century,” he added. “HPV testing is clearly the way forward.”
Delpero received an honorarium from Searchlight Pharma for a speaker introduction. Selk is president of the Society of Canadian Colposcopists (no payment received) and co-author of upcoming national colposcopy guidelines from the SCC and Society of Gynecologic Oncology of Canada. Steben has potential conflicts of interest with most vaccine, therapeutic, and testing companies.
CMAJ. Published online May 2, 2022. Full text
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