Charna Albert
February 2025—Eric Huang, MD, PhD, is the first to admit that when it came time to switch to primary HPV testing, his laboratory at the University of Washington faced fewer obstacles than most.
Dr. Huang joined the university in 2018 as director of the cytopathology laboratory. At the time, primary HPV screening was approved by the FDA but not recommended by the guidelines as the preferred screening test for cervical cancer. “But I knew that was the direction that cervical cancer screening was moving toward,” says Dr. Huang, who is also director of HPV molecular pathology and professor in the Department of Laboratory Medicine and Pathology.
His colleagues were similarly minded, and the institution was supportive. Moreover, the laboratory already used a platform that was FDA approved for primary screening, and thanks to the cytopathology laboratory’s former director, an HPV researcher who developed the laboratory’s original homebrew HPV test, HPV testing had always been with cytopathology rather than microbiology. It’s done in a standalone laboratory that performs only HPV testing, Dr. Huang says, next door to the cytology laboratory. “So our samples were still coming to one place.”
“We’re very fortunate,” he adds.
The laboratory completed its implementation in 2019. The American Cancer Society released in 2020 its guidelines recommending HPV as the preferred primary screening test. “We were ahead of the curve,” says Dr. Huang, a member of the CAP Cytopathology Committee.
For many laboratories, though, things aren’t so simple. It’s a frustrating reality for primary HPV champions like Mark Stoler, MD, professor emeritus of pathology, cytology, and gynecology at the University of Virginia Health System, Charlottesville. “We already know, based on Australia, Scandinavia, England, Canada, from large-scale clinical trials, that its safety and efficacy are unparalleled,” Dr. Stoler says. “And it just becomes more and more important as the prevalence [of cervical precancer] drops with vaccination.”
Chief among the barriers to adoption is instrumentation, but the logistical headaches that come with switching to a primary screening algorithm are significant too. Not to be discounted either is the attachment some physicians feel for cotesting, which improves the sensitivity of the Pap test and is why it was promoted originally, Dr. Stoler says. “Any time you add two tests—especially one that’s much more sensitive—you’re going to have better performance,” he says. The task at hand now is to prove that it’s safe to drop the less sensitive test. “The tiny fraction of a percent gain in sensitivity doesn’t offset doing two tests for no reason on the entire population of screening patients,” he says. “HPV testing is so sensitive it does the job by itself.”
On the diagnostics side, obtaining primary screening approval from the FDA is still something of a feat.
The parameters are stringent, Dr. Stoler says. “It’s a well-defined sweet spot that takes a lot of patients and a very detailed clinical assessment, more so than is usually done in clinical practice, to know what truth is in this space,” he says. Roche initially failed before becoming the first company in the U.S. to receive primary screening approval. Hologic’s Aptima HPV assay—which Dr. Stoler and Dr. Huang estimate is used by half or more of U.S. laboratories—does not have a primary screening indication in the U.S. “The concept for which, and then the criteria for which, came forward after the Aptima trial was done,” he notes. For many laboratories, transitioning to primary screening will mean a change of platforms.
“It’s a huge deal,” Dr. Stoler says of the potential need to change instrumentation.
When Dr. Huang and his colleagues at UW Medicine decided to offer primary HPV screening, the laboratory already used the Roche Cobas instrument. (Even so, the transition took about nine to 10 months.) For laboratories less well positioned, “that’s a lot of initial cost the hospital has to come up with,” he says.
Lynnette Pineault, MBA, SCT (ASCP), manager of laboratory operations and genetic counseling services at Regions Hospital in St. Paul, Minn., wouldn’t be surprised if the required financial investment tempts some laboratories to undertake a clinical validation of their existing non-FDA-approved platform, though the FDA’s proposed regulation of laboratory-developed tests adds a barrier. “The FDA regulation of laboratory-developed tests remains uncertain,” she says. “Rigorous oversight will have a considerable impact on folks who are using HPV tests that are not FDA approved for primary screening.”
Pineault was a member of the American Cancer Society Primary HPV Screening Initiative, an expert-led group active from 2021 to 2023 whose goal was to support the transition to primary HPV screening in the U.S. She chaired a subgroup on laboratory workflow. (Dr. Stoler was an ad hoc member of this subgroup.) “Our original charge was to look at all aspects that laboratories need to review, address, and implement when going from cotesting to primary HPV testing—instrumentation, ordering, collection devices, triaging samples, and the differences and changes in testing workload,” she says. “What we determined is the instrumentation you’re using is going to have a trickle-down effect for a lot of the other things that will need to be built.”
To help laboratories explore their options for method selection, Pineault and her colleagues developed a series of flowcharts that map out the workflows for the Roche Cobas and the other two FDA-approved primary HPV testing platforms: the BD Onclarity HPV assay and Abbott Alinity m HR HPV assay. Branches in the flowchart help laboratories determine which FDA-approved tests are available for their collection method and illustrate the reflex testing options available for positive HPV results based on the testing platform. “All of this is based on the current ACS guidelines,” she says. (The flowcharts can be viewed at https://bit.ly/4gPXc3m.)
The three FDA-approved methods have been engineered to meet certain criteria and therefore all perform similarly in terms of clinical validity, Dr. Stoler says. All are approved for both ThinPrep and SurePath sampling methods. But there are other decision points. “Do you like the dual stain approach as opposed to the extended genotyping approach for triage of the screen positives?” he asks. “If you have ThinPrep and you choose a Roche platform, you can’t get extended genotyping, but you can get the same performance with dual stain.” With the BD Onclarity or Abbott Alinity assays, “you have extended genotyping” for risk stratification, he says, “so there’s some savings there” in not having to implement the dual stain assay. Some laboratories may “mix the two.”
The other considerations are familiar ones, Dr. Stoler says, namely space and volume. “If you’re a 500,000-a-year screening lab, then you need a platform that has a very high throughput, like the Roche 8800. If you’re a 20,000-a-year screening lab, an 8800 might be overkill, and the Abbott or BD platform might be better sized.”
Many laboratories will require institutional support to acquire an approved platform, Dr. Stoler notes. How to convince hospital leadership to make the investment? Dr. Huang says it’s best to lean on the guidelines.
“The first thing to convince leadership is that this is what the American Cancer Society is recommending, and this is what cervical cancer screening is moving toward,” Dr. Huang says. “If we don’t make this transition now, we may fall behind.” Cotesting is still an acceptable option according to the guidelines. But as Dr. Huang says to those who are weighing the decision, “Whether you switch now or later, it’s going to happen one day, so you have to be prepared, even if you’re still running your old platform.”
“The ship has sailed,” he says.
Dr. Stoler agrees: “The guidelines are the strongest argument we have.” Physicians should be measured on whether they can provide what is considered best practice, he says. If that’s primary screening—and it is, according to the studies and the standard-setting organizations—the institution should invest in it. But “clinicians aren’t beating our doors down for primary screening.” And then there are the insurers that won’t pay until there is demand. “This is where the dual stain argument is,” Dr. Stoler says. “Well, nobody’s demanding it because nobody will pay for it.”
It’s history repeating itself, he says. “We had the same thing with conversion to liquid-based cytology in the mid ’90s, and then paying for HPV triage.” Ultimately, the science does drive the medicine. “But in the U.S., it can take 10, 20, 30 years for the medicine to catch up because of these complexities.”
“The fundamental argument,” he continues, “is that the guidelines now say more strongly, or will say more strongly than ever, that primary screening, like they do everywhere else in the world, is the way to go.” He adds, “They’re all we have, because there is no organized health care system demanding otherwise.”
Ease is another argument, Pineault says. “The easiest thing to do when it comes to regulatory oversight is to have a platform that is FDA approved and that meets the guidelines.” Then, too, Pap tests in some states are not well reimbursed, she says, “while molecular testing tends to have better reimbursement.” And HPV tests are being done already for cotesting; “you’re essentially getting rid of half the cost of screening when moving from cotesting to primary HPV testing,” she says. “Part of the ROI could be what you’re saving in test kits, consumables, all of the things you’re not going to have to buy for Pap testing.”
On the other hand, return on investment from the reduction in Pap testing won’t be an easy pill to swallow for cytology, Dr. Stoler says. “You recoup that cost, but that also might be a profit center. Ergo—conflict of interest.” The real return on investment, he says, is at the system level, through better patient management. Whether the laboratory sees that return depends on the system’s structure. “If the University of Virginia Health System saves x million dollars by going to primary screening, does the money filter down to pathology? That remains to be seen.”
When the UW laboratory went live with primary HPV screening, “there wasn’t much uptake because cotesting was still the recommendation,” Dr. Huang says.
Orders began to rise when the American Cancer Society recommendation was released in 2020 and rose further when the hospital made primary HPV screening the default option for cervical cancer screening in its Epic electronic health record system. “Our Pap volume was hovering at around 1,800 to 2,000 a month,” he says. “After primary HPV became the default, it went down to about 1,000 a month—almost a 50 percent drop.” Total primary HPV volume, he says, is now at about 900 orders per month.
The other options—cotesting, Pap only, HPV only, or Pap with reflex HPV—can still be ordered. “But when you go in, the default will be primary HPV with reflex Pap,” he says. To prepare their colleagues for the change, UW Medicine sent out an Epic email announcement that included a screenshot of the new order form. “Also in that Epic message, they highlighted that primary HPV is now the preferred method for cervical cancer screening.” Many clinicians intend to order cotesting but unknowingly, because of the default, order primary HPV and then call to ask why there’s no Pap result.
Most important for other labs to know, Dr. Huang says, is that the transition process takes time. “We’re already doing HPV testing; we’re already doing Pap testing. Why, then, is it so hard to start with HPV only? It sounds very simple. But once you start working on it, it’s not as simple as flipping a switch.”
Logistically, Pineault says, the process will be less complex for laboratories that perform HPV testing in the cytology laboratory, or, as is the case at UW Medicine, near the cytology laboratory. But when HPV testing is performed in the microbiology or molecular laboratory, the sample will have to go to that laboratory before cytology, “and then you’re going to have an add-on process or a reflex process depending on the results,” she says. “That’s one of the big challenges, that the routing of the samples is flipped.”
Working through the change with personnel from both laboratories will help, Dr. Huang says. “Most of it is logistics, trying to figure out what gets processed first and what gets processed second. And of course, you still have cotesting, you still have orders for Pap with reflex HPV, and it’s important for our people to know there are these different options, so that when they get a sample, they make sure they’re doing the right test first.” As for the laboratory directors, he says, “you want the two to work together.” In his case: “I run both labs, so I was able to make those decisions.”
With the flipped process, “there’s been concern about the quality of the Pap test,” Pineault says. “What I would say is, if you’re following the instructions for use for the current instrumentation, you should be pulling the HPV off the top of the vial before you’re doing the Pap anyway, for cotesting.” And the primary HPV screening workflow might be of help in reducing the need for recollection. “Let’s say Paps are behind because you don’t have enough cytologists and so you’re struggling with turnaround time. Depending on the stability of the Pap media, you may have to refrigerate to hold for the HPV [reflex testing]. This gets rid of all that,” she says. “You’re not going to have to hold those Paps for as long if you’re in that situation where you’re holding for add-ons.”
Behind the various workflows is IT. “Some laboratory information systems may have packing and tracking and billing that would be attached based on the routing,” Pineault says. “Even before it gets to the instrument, you may have routing rules that are going to impact how things are resulted and billed.”
A successful transition will require collaboration at every level. On that note, don’t assume hospital IT can do it alone, Dr. Huang cautions. “Hospital IT works mostly with overall Epic ordering, from the clinical side,” he says. “You have to have your pathology IT work with them.” Things can get sticky if the microbiology and cytology laboratories use different laboratory information systems, he says.
At UW Medicine, physicians prefer to receive both test results in one report. “When we cotest, we report them together,” Dr. Huang says. The same is true of a Pap with reflex to HPV. “If the Pap is ASC-US, then they’ll get a reflex HPV, and we wouldn’t report it until the HPV becomes available. Now, with primary HPV, if the HPV is negative, we’ll report that. But if the HPV is positive, where you need a reflex Pap, then we won’t report the HPV until the Pap result becomes available, and then they’ll get released together.” With a positive HPV result, Beaker knows a Pap test is being reflexed and won’t release the HPV result until the Pap result becomes available.
The need for change management tends to be underestimated, Pineault says, not just for physicians and IT but also for laboratory staff and pathologists.
Like the old joke about voting, communication should happen early and often. “That is going to be important to ensure you have a smooth transition and a solid culture moving forward,” she says.
She’s aware of the consternation among cytologists. “I’m a cytologist by training too, and our bread and butter has been the billing and reimbursement for this large bolus of work that has been the Pap test,” she says. A critical message for cytologists, and one that she and her colleagues in the Primary HPV Screening Initiative attempted to broadcast, is that primary HPV testing is intended for the asymp-tomatic low-risk population. “So there’s still a role for cotesting or reflex testing, depending on what the case may be,” she says.
It may also be time for a broad re-imagining of the role. “How are we advocating for those things that cytologists are great at, like morphology and locator skills, and reassigning that?” More rapid onsite evaluation is one answer, “especially with the changes in precision medicine and molecular testing.” Still, the concern is valid. “There’s not necessarily going to be that billing component to justify their roles,” she concedes.
For some laboratories that make the transition to primary screening, the workforce shortage plays a role in the decision. “I’ve seen laboratories go this route because of staffing,” Pineault says. “They haven’t been able to find the cytologists to continue with cotesting, which is sad. But it’s a reality.”
At UW Medicine, Dr. Huang says, the laboratory’s nongynecologic volume has increased, and yet they haven’t had to hire thanks to the decline in Pap volume. “If you’re having a hard time hiring cytologists, primary screening could be a solution,” he says.
Along with change management, physician decision support is another nonnegotiable. “Some may not appreciate how much primary care is ordering,” Pineault says. “They’re the physicians who may not have as deep an understanding and knowledge as their Ob-gyn counterparts.” Her biggest tip: Work with IT to build order sets that help busy physicians make the correct choice. “Some EMRs will allow you to generate an order or order set based on inputs,” she says. “So maybe you have a patient age, and if the patient is 30, it’s going to primary, but if the patient is 29, it’s routing to the cotest. Things like that, which eliminate the need for the clinician to make the right decision.”
The science behind it all is often a persuasive argument for physicians who have to buy in. “Moving to primary screening makes a lot more sense when you understand that the prevalence [of precancer] is changing due to vaccination,” Pineault says. “Once people understand that the things we used to see may be changing because of vaccination—because vaccination didn’t exist 20 years ago—that may help.”
Physicians can be reassured that the FDA-approved platforms have the sensitivity to refer patients who require further testing and the specificity to avoid over-referral, Dr. Stoler says. The HPV positives, he notes, are a relatively small segment of the population. “Those downstream decision points of the positives are not the same as the initial screening decision,” he says. “You’re talking about 10, 12 percent of the population for those decision points, as opposed to 90 percent of the population.” On top of that, dual stain and extended genotyping are superior to cytology for triage.
Ultimately, though, getting buy-in may involve flexibility. Dr. Huang is quick to reiterate that the laboratory still offers cotesting, Pap with reflex to HPV, and everything in-between.
“There’s still a lot of value in the Pap,” he says. “That’s why I let the clinicians decide which one they prefer.”
Charna Albert is CAP TODAY associate contributing editor.