New guidance supports HPV primary screening for cervical cancer
Interview by Steve Halasey
This January, the use of human papilloma virus (HPV) primary screening for cervical cancer received a significant boost, as the American Society for Colposcopy and Cervical Pathology (ASCCP) and the Society for Gynecologic Oncology (SGO) released a new interim guidance for healthcare professionals.
Published online simultaneously in Gynecologic Oncology, Journal of Lower Tract Genital Disease, and Obstetrics and Gynecology, the newly issued guidance supports HPV primary screening using an FDA-approved test in women 25 and older as an effective alternative to previous screening recommendations with the Pap smear alone or cotesting with the Pap smear and HPV testing.1–3 The guidance was developed by ASCCP and SGO, with input from representatives of the American Cancer Society, American College of Obstetricians and Gynecologists, American Society for Clinical Pathology, American Society of Cytopathology, and the College of American Pathologists.
Also published in Gynecologic Oncology at the beginning of the month, end-of-study data from the Addressing the Need for Advanced HPV Diagnostics (Athena) trial helped to inform the interim guidance.4 Athena trial data showed that HPV primary screening using the Cobas HPV test by Roche Diagnostics Corp, Basel, Switzerland, detected significantly more cervical disease than a Pap test alone. Compared to a woman with a negative Pap result, a woman with a negative result from the Cobas HPV test had less than half the risk of developing cervical precancer within 3 years.
Persistent infection with human papillomavirus (HPV) is the principal cause of cervical cancer, with HPV implicated in more than 99% of cervical cancers worldwide. According to the National Cancer Institute, there are more than 12,000 new cases of cervical cancer in the United States annually and 4,210 deaths due to the disease. The World Health Organization estimates there are more than 500,000 new cases of cervical cancer annually.
Launch of the new interim guidance was not without some controversy, as expressed in three additional articles published in Obstetrics and Gynecology.5–7 In a self-described “minority viewpoint,” Kinney et al. express concern over the reduced level of cancer protection afforded by currently recommended screening at 3-year intervals. “It is our opinion that the decision to consider the level of cancer protection provided by cytology at 3-year intervals as acceptable should be reconsidered, and that we should return to using the level of cancer protection provided by annual cytology as the benchmark,” they write.
Among a half dozen recommendations for encouraging “trust in and compliance with future screening recommendations,” the authors suggest that patients and practitioners be permitted access to “a range of acceptable screening options.” Specifically, they write, the options of screening at 3-year intervals using either an FDA-approved HPV test alone, or cotesting with cytology and an FDA-approved HPV test, “should be available to all patients and providers who want to maintain a level of cervical cancer protection similar to what was previously available with annual cytology.”
To find out how practitioners are approaching the adoption and implementation of the new ASCCP/SGO guidance, CLP spoke with Ryan R. Fortna, MD, PhD, director of molecular pathology at Northwest Pathology, Bellingham, Wash. A regional pathology group that performs “the whole gamut” of anatomic and molecular pathology associated with women’s health, Northwest Pathology was among the first labs in the nation to offer HPV primary screening, says Fortna.
“We had an interest in the possibility of HPV for primary cervical cancer screening even before Roche got FDA approval for it, just because our evaluation of the data in the literature was pretty similar to what ended up being shown by the Athena trial,” says Fortna. “We had suspected that HPV as the primary test would be coming into play soon, so we were excited to see that it was approved.”
“Until now, because there have been no national guidelines that included it, adoption of HPV primary screening by clinicians has been relatively low,” adds Fortna. “But I think that may change now, with the publication of these new guidelines.”
CLP: The new ASCCP/SGO guidelines on the use of high-risk HPV screening for the early detection of cervical cancer replace guidelines that are only 4 years old. What new evidence supports the new guidelines’ recommendations?
Fortna: The primary new evidence reviewed by the panel was from Roche’s Athena trial, which involved more than 47,000 patients. That trial looked at the sensitivity of HPV-only testing versus cytology or cotesting. The panel also reviewed a number of other studies, including some smaller studies and a large study from Kaiser Permanente that involved more than a million patients.
The HPV testing guidelines from 2011 recommended cotesting with both cytology and HPV for women 30 years of age or older, and permitted less-frequent intervals for testing. The reason for longer testing intervals was that someone with negative cytology and a negative HPV test was unlikely to develop a high-grade lesion within a short time.
The newer data reviewed by the panel—including data from the Athena trial—shows that most of the negative predictive value of a negative cotest comes from the negativity of the HPV test. In other words, if you perform only the HPV test, and the results of that test are negative, that is essentially as sensitive as doing both cytology and HPV testing together. Comparing HPV-only versus cytology-only, the HPV test is much more sensitive, meaning that the negative predictive value of HPV-only testing is significantly greater than cytology-only testing.
Even though the earlier guidelines are not very old, the new research demonstrates that permitting longer intervals between rescreening is acceptable because of the negative predictive value of the HPV test. I think that’s the main piece of evidence that supports the updating of the guidelines.
CLP: The previous guidelines identified several areas of concern that prevented a recommendation for screening by hrHPV testing alone. Have those concerns now been addressed?
Fortna: One of the concerns that some have raised is the fact that there are some malignancies, actual invasive squamous cell carcinomas of the cervix, in which HPV cannot be detected. There are a variety of theories about why this is the case. In very rare instances, the malignancies simply are not HPV-associated. In others, it may be that the HPV has mutated during tumorigenesis, to the point that even if it is still there it is no longer detectable by routine methods.
Those who don’t like the idea of HPV-only testing may use these instances as an argument against it, and this does seem to be an area of legitimate concern. But these are very rare cases. Most malignancies either should have been preceded by earlier Pap tests that were positive, or would have produced other clinical signs and symptoms to alert the clinician that something is worth biopsying.
Without any particular data on the subject, I would predict that the number of cases of invasive squamous cell carcinoma that will be missed because of using HPV primary screening instead of cotesting will be very, very low. Nevertheless, that’s one area of concern that probably hasn’t been entirely addressed by the most recent studies.
CLP: Compared to the other trials reviewed by the panel, how important were the results of the Athena trial for supporting the use of hrHPV screening without cytology cotesting?
Fortna: That question would be best answered by someone involved in updating the guidelines. However, I believe that the results of the Athena trial were the primary driver for both FDA’s approval of HPV primary screening and for the development of the new interim guidelines by ASCCP and SGO.
CLP: In answering its two main questions, the panel concluded that hrHPV testing is at least as effective as cytology at the same screening intervals, and that primary hrHPV screening can be considered an alternative to cytology-based screening. Do you see those conclusions as controversial in any way?
Fortna: Apart from the issue of very rare malignancies that can’t be detected by HPV testing, there is no reason that the panel’s conclusions should be controversial. They are fully supported by the studies that the panel reviewed.
Where controversy over the panel’s conclusions exists, it seems to arise from areas unrelated to HPV testing for cervical cancer screening. For instance, some clinicians are reluctant to abandon Pap testing because of its potential to provide ancillary benefits, such as the detection of other malignancies like endometrial carcinoma, or detection of infectious processes like candida vaginitis or bacterial vaginosis. Although detecting those conditions is not the primary purpose of a Pap test, some clinicians are reluctant to adopt a molecular-only test because those conditions won’t be identified. Others may prefer to continue using the Pap test because both clinicians and patients have a historical and psychological attachment to the test as the primary driver for regular gynecological care—another ancillary benefit.
But if we are talking about data and the effectiveness of HPV as a cervical cancer screen, I don’t think there are any good reasons for controversy over the new HPV testing guidelines, even though other issues may have caused it to seem controversial.
CLP: In a roughly equivalent scenario several years ago, the US Preventive Services Task Force (USPSTF) recommended reduced frequency for mammography screening, and effectively caused a firestorm of opposition to its recommendation. In the case of hrHPV, the scientific support for changing the guidelines—and especially the involvement of so many specialty societies in compiling the new guidelines—seem likely to minimize the potential for controversy. Would you agree?
Fortna: Having strong scientific support has the potential to reduce controversy, but I don’t know that it necessarily will. One difference between the HPV testing guidelines compared to the USPSTF recommendations on mammography is that the new interim HPV guidelines are not intended to replace the old guidelines, but rather to be a separate option for clinicians.
From a patient perspective, at least, the HPV testing guidelines should be less controversial. Compared to the USPSTF mammography recommendations, they don’t change nearly as much about the screening methodology. The recommendation is still to screen approximately every 3 years, which is pretty similar to what the cotesting recommendation was previously. Since this is really just a difference in testing methodology, it shouldn’t be as controversial among patients.
However, the new guidelines are more likely to be controversial among clinicians—in particular, some gynecologists and cytologists who have built their practice around the Pap test as the primary reason that patients come in to be seen at all. Of course, HPV testing is still a good reason for patients to come in and be seen. But it is a little different and doesn’t have the term “Pap” attached to it, and clinicians will get different information from it.
Involving numerous societies in updating the HPV guidelines will certainly have an effect on clinicians. Nevertheless, it will be difficult for some clinicians to let go of the Pap test, which has come to occupy such a central place in the practice of gynecology. And there are some side benefits of doing a Pap test, beyond just screening for cervical cancer. Cytologists and cytotechnologists may also have trouble letting go of the Pap test to some degree, because it’s one of their primary responsibilities.
In any case, I don’t think the new guidelines require clinicians to let go of Pap testing. Instead, they offer a viable and legitimate option for clinicians who choose to adopt it.
CLP: The panel noted a need for further trial data to guide the management of hrHPV-positive women. Do the new guidelines offer practitioners enough direction in the interim?
Fortna: I think so, because both the Roche algorithm (which was used in the Athena trial and in Roche’s premarket approval application) and the updated ASCCP/SGO guidelines provide a very specific next step to be performed if a patient’s result is HPV positive.
If a patient tests positive for HPV, the next step is to look at which HPV genotype is involved. If it’s HPV 16 or 18, the patient should undergo colposcopy. That’s a very definite step.
If the genotype involved is not HPV 16 or 18, an examination of the cytology should be performed to determine whether colposcopy is needed.
For HPV-positive women as a group, these steps are pretty unambiguous. And for clinicians, these steps actually simplify the algorithm when compared to the older ASCCP algorithms that required cotesting.
CLP: Do you then agree with the panel’s recommendation that HPV testing should begin at age 25, with rescreening after a negative result no sooner than every 3 years?
Fortna: Yes, I do. But the question of whether screening should start at age 25 or 30 may still be the most debatable point in the entire guidelines. And, of course, some of this is subjective, depending on what level of disease we think is worthwhile to screen for.
The results of the Athena trial indicate that there is a significant incidence of high-grade cervical lesions among patients aged 25 to 30, and a particularly low sensitivity of cytology for those lesions. So, if what we care about is detecting high-grade lesions among women in this age range, then the Athena data support the panel’s recommendation.
CLP: What do you expect the long-term outcome of hrHPV testing will be for patients?
Fortna: Adoption of hrHPV testing should decrease the number of undetected cancers. Although cotesting was one of the recommendations included in the older algorithms, many clinicians have still been performing Pap-only testing, even among women over 30 years of age.
There are certain cancers that clearly go undetected when using cytology alone—especially adenocarcinomas, but also high-grade squamous cell lesions. HPV testing has a very high sensitivity for those cancers (with the rare caveats noted earlier for some invasive squamous carcinomas). Consequently, if clinicians adopt HPV testing as either their primary modality or as cotesting, the number of undetected cancers will be reduced.
Another outcome to be hoped for, in my opinion, is that the availability of hrHPV testing will become the first step toward reaching patient populations that currently aren’t getting tested at all. For this goal, the alternative of conducting primary screening with a ThinPrep test won’t have much of an effect, because the patient still has to undergo a pelvic exam and go through essentially the same process as a Pap test. But I expect that sometime in the next decade, we will begin to see primary screening by way of swab-based HPV testing in the clinic, as well as at-home, patient-directed swab-based HPV testing. Together, these methods could bring in patients who are currently afraid of getting pelvic exams, or could create ways for patients who won’t come in at all to be tested at home. This is already being done in some other countries. Obviously, this is somewhat speculative, but it’s my hope that adoption of hrHPV testing with these new guidelines will be a first step in that direction.
CLP: Will having fewer undetected cancers—and catching cancers at an earlier, more treatable stage—ultimately result in a significant drop in the incidence of cervical cancer?
Fortna: Yes. With an increased acceptance of HPV screening, I think we should see a reduced incidence of actual invasive carcinoma. But an even greater reduction will be seen, I think, when we can reach out to populations that are currently underserved.
As a pathologist, I can tell you that it’s not very common to see an invasive cervical cancer these days. But when we do see them, a large proportion of those patients simply haven’t had a Pap smear at any time in the past 5 years or more. In my opinion, many of the actual carcinomas that we see nowadays—perhaps the majority of them—have developed because some patients haven’t been getting tested at all.
The combination of the higher sensitivity of HPV testing and finding a way to reach out to people who aren’t currently getting tested at all will reduce the incidence of cervical cancer.
CLP: Overall, how do you expect that implementing the new guidelines will change your practice?
Fortna: That will probably depend on what percentage of clinicians ultimately decide to use HPV as primary screening versus cotesting. If all of the patients that we now see were converted to HPV primary screening, we would definitely see a lower number of cytology cases, because only about 10% of those cases would need to be reflexed to cytology for that triage step in the algorithm.
So, if HPV primary screening becomes widely adopted, it will definitely reduce the number of Pap tests we see. Some practices might see that as a negative.
Apart from evaluating fewer Pap smear morphology cases, I don’t think that implementing the new guidelines will bring about a huge change in our particular pathology practice. The definitive diagnostic step is still colposcopy with biopsy, which remains very much a part of the new guidelines.
CLP: Nationwide, are there many other practices at the same stage as yours, or will most see a bigger change when they implement the guidelines in their practice?
Fortna: Our practice was among the first in the nation to offer HPV primary screening. In our particular region, there are still not very many groups that are offering it to my knowledge. Most pathology groups, I think, have been waiting for the national specialty societies to provide guidelines before incorporating new procedures into their practice. So it’s not at all surprising that there hasn’t been a huge movement toward adoption yet.
Whether it was right or wrong for our group to adopt HPV primary screening as early as we did is a matter of opinion. I believe it was the right thing to do, because the test had received FDA approval, it made scientific sense and had good data behind it, and it made sense for us to offer it to our clinicians as an option. Medical practitioners don’t necessarily need to wait for a national society to tell them what to do, although, of course, I completely understand that many clinicians prefer to wait and follow national society guidelines when they are published.
Now that the updated guidelines have been published, I expect they will quickly have an impact on what pathology groups are offering. That may happen because a particular group reviews the guidelines and determines that HPV primary screening is something they should offer. Or it may happen because there is pressure from clinicians saying, “We want to have that as an option; please offer it.”
Steve Halasey is chief editor of CLP.
- Huh WK, Ault KA, Chelmow D, et al. Use of primary high-risk human papillomavirus testing for cervical cancer screening: interim clinical guidance. Gynecol Oncol. 2015; available at http://dx.doi.org/10.1016/j.ygyno.2014.12.022.
- Huh WK, Ault KA, Chelmow D, et al. Use of primary high-risk human papillomavirus testing for cervical cancer screening: interim clinical guidance. J Low Genit Tract Dis. 2015; available at http://dx.doi.org/10.1097/LGT.0000000000000103.
- Huh WK, Ault KA, Chelmow D, et al. Use of primary high-risk human papillomavirus testing for cervical cancer screening: interim clinical guidance. Obstet Gynecol. 2015;125(2):330–337; available at http://dx.doi.org/0.1097/AOG.0000000000000669.
- Wright TC, Stoler MH, Behrens CM, et al. Primary cervical cancer screening with human papillomavirus: end of study results from the Athena study using HPV as the first-line screening test. Gynecol Oncol. 2015; available at http://dx.doi.org/10.1016/j.ygyno.2014.11.076.
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- Kinney W, Wright TC, Dinkelspiel HE, et al. Increased cervical cancer risk associated with screening at longer intervals. Obstet Gynecol. 2015;125(2):311-315; available at http://dx.doi.org/10.1097/AOG.0000000000000632.
- Silver MI, Rositch AF, Burke AE, et al. Patient concerns about human papillomavirus testing and 5-year intervals in routine cervical cancer screening. Obstet Gynecol. 2015;125(2):317-329; available at http://dx.doi.org/10.1097/AOG.0000000000000638.