When it comes to cervical cancer, the attention is centred on the vaccine for Human Papillomaviruses (HPV). It’s an incredible development, and I am hopeful that one day the HPV vaccine could render cervical cancer a killer of the past. But there’s another innovation – called the HPV test – that could be harnessed immediately to improve cervical cancer screening.
Before I get into the HPV test, I need to explain what’s wrong with the 70-year-old Pap test, our current cervical cancer screening method. For the Pap test to produce an accurate reading, cervical cells have to be properly spread and stained on a glass slide that’s viewed under a microscope. The sample of exfoliated cells has to be representative, which means the health care provider has to properly collect the sample for an accurate diagnosis to be made. Then, the technologist who is viewing the slide has to interpret it correctly. Looking at samples under a microscope is a monotonous task; it can lead to mental fatigue and errors as a result. Whether because of health worker or technologist error or a mix of both, we know that Pap tests give false negative results – meaning that they don’t detect the presence of precancerous or cancerous cells. Even in Canada, where we have rigorous quality control, a study I conducted found that the false negative rate of Pap tests is 45%. (Don’t be too alarmed by this, cervical cancer develops very slowly and the test is performed frequently, every two to three years depending on the jurisdiction. So even with the high false negative rate, most cervical pre-cancerous cells are detected in time when provincial screening protocols are followed.)
There is another screening option that is increasingly being used in other countries, including the US, UK and Netherlands. It’s called the HPV test and it’s been available since 2003. Economic models show the introduction of this test will make cervical cancer screening more efficient and affordable, in addition to making cervical cancer screening more convenient for the majority of women.
Before we get into why HPV testing (combined with Pap smears) is superior to Pap tests alone, I need to explain some key information. Cervical cancer is caused by some strains of HPV, which are sexually transmitted viruses. Most genital HPV infections in women (and men) are asymptomatic, even if they involve carcinogenic (or cancer-causing) HPV types. Most – even the carcinogenic types – eventually clear and are no longer detectable after one year. But a small proportion of the carcinogenic HPV infections that persist may progress to precancerous lesions of the uterine cervix. If untreated, these lesions may progress to cervical cancer. The entire process from acquisition of an HPV infection until development of cervical cancer may take 15 to 25 years. Although most sexually active women (and men) eventually acquire an HPV infection, the proportion of women that eventually develop cervical cancer over a lifetime in Canada is about 0.5-1%.
HPV screening can detect the strains of the HPV virus that research shows are most likely to cause cervical cancer. In an HPV test, a sample is gathered from the cervix, but unlike in the Pap test, it doesn’t have to be highly representative. And the sample is then extracted, processed, and read by a machine – taking human error out of the interpretation. With HPV tests, the false negative rate is only 5%.
Here’s how HPV testing would work. Up until around age 30 (experts differ slightly as to the appropriate age), women would be screened using Pap tests. That’s because young women tend to have more sexual partners and are exposed to HPV at a high rate. But, as mentioned, the virus doesn’t tend to stick around and cause problems. So a positive HPV test may not mean much.
After 30, however, HPV can be the dominant screening method. If the HPV test is negative, a Pap test wouldn’t be required and the HPV test wouldn’t have to be repeated for another five years. If an HPV test is positive, that’s concerning, because that suggests the woman has a persistent HPV infection that may have already developed into a precancerous lesion or will in the future. So for these women, we do a Pap test to see if the infection has already become associated with cellular changes in the cervix indicative of developing cancer. If the Pap tests are also found to be positive, women would then be referred for colposcopy for a final diagnostic confirmation and eventually treatment.
For women who are positive with the HPV test but not with the Pap test, they would have to repeat the HPV and/or the Pap tests within one year. If the infection persists or the Pap test became positive then their physician will want to refer them for a colposcopy.
The combination of HPV and Pap test screening would be beneficial for many reasons. Firstly, only those who are found to have infections with carcinogenic HPV types would be referred for Pap testing. Only about 6% to 10% of women above 30 have HPV infections, so more than 90% of women would be able to move from Pap tests every three years to HPV tests every five years. Secondly, Pap tests would only be done when there is a high concern that pre-cancerous lesions could be present. So technologists would be viewing 10-fold less Pap test slides, meaning the interpretation would be less prone to mental fatigue. Because technologists know that HPV has been detected in the samples they view, they would be more vigilant in looking for abnormal cells. Finally, combination testing would be cheaper – because HPV tests are automated and don’t require the expertise of high-salaried technologists, they’re not as expensive as Pap tests.
There is overwhelming evidence for the superiority of HPV testing as the primary technology in cervical cancer screening, all from large-scale randomized controlled trials, including two in Canada (available here and here).
You may be wondering why I’m concentrating on the need to detect HPV viruses when the HPV vaccine is available. Publicly funded, school-based HPV vaccination of teenage girls (and now also boys in some provinces) has been a reality in Canada since 2007. Although HPV vaccination will bring enormous benefits in reducing the incidence of cervical cancer, the vaccines do not prevent an existing infection from progressing to cervical cancer. It will be another 30-40 years before we can even hope to end cervical cancer screening. And in the meantime, as the vaccination reduces the risk of HPV infections, the Pap test could become less and less effective. Why? If a technologist is looking at higher and higher rates of normal smears, there’s a high risk that the technologists could become complacent, and miss the odd abnormal test. In other words, as HPV comes down, HPV testing will become even more important.
So why then haven’t we adopted HPV screening in Canada? Part of the reason comes down to short-term thinking on cost. As of today, HPV tests are more expensive than Pap cytology. However, this is because HPV testing has been used in a limited capacity, such as to provide additional information when a Pap smear isn’t clear, which is not the best use of this technology. In the high-volume scenario of primary screening and with the pricing control measures of centralized procurement, the HPV test will be reduced to be about half of that of Pap tests currently. The extension of screening intervals to every five years that comes from a change to HPV screening will lower the cost of cervical cancer control even further for provinces.
Using the HPV test as the primary method of screening is the best from a clinical, economic and patient convenience perspective. We have the opportunity to make screening better and cheaper right now.
Dr. Franco’s research into HPV and cervical cancer is publicly funded. He has no financial interest in companies that make the HPV test. He has consulted for biotech companies, for which he has received expenses and honoraria.