I'm Margaret Neal, and I'm pleased to be here tonight introducing Dr. Dianne Davey, who's going to give us an update on cervical cancer screening and management, what's new in the clinical guidelines. We welcome you all to this webinar, and wanted to let you know that there will be question and answer for the last 10 minutes. So you can add your questions in the chat. All right, I am going to introduce the Dr. Dianne Davis-Davey, MD, who is a professor of pathology and associate dean of graduate medical education at the University of Central for the College of Medicine in Orlando. She's also a pathologist at the Orlando VA Medical Center. Prior to late 2007, she was vice chair for education and cytopathology fellowship director at the University of Kentucky. She received her medical training at University of South Dakota and at Washington University in St. Louis, and trained in pathology at Indiana University and the University of Iowa. She then completed a hematopathology fellowship at the University of Iowa, and is board certified in anatomic and clinical pathology, hematology, and cytopathology. Dr. Davis-Davey has multiple leadership positions that she has served. These include the past president of the American Board of Pathology, past president of American Society of Cytopathology, and she is a current member and past chair of the Cytopathology Resource Committee for the College of American Pathologists. She's also a current board member of the Florida Society of Pathologists, and serves as a Florida delegate to the CAP House of Delegates. She continues to serve on several ASC committees as well. Dr. Davey is recipient of multiple awards. Some of these include the Papanicola Award from the American Society of Cytopathology in 2007, Lifetime Achievement Award from College of American Pathologists in 2011, Life Trustee of the American Board of Pathology, 2017, University of Iowa Department of Pathology Distinguished Achievement Award, 2007, and the American Society for Cytopath, for Colposcopy and Cervical Pathology Award of Merit. She has been an advisor to the FDA and the National Cancer Institute, and serves on editorial boards for three journals, and has over 100 peer-reviewed publications. We're lucky to have her here tonight to tell us about the current clinical guidelines, and I'll turn the program over to you, Dr. Davey. Thanks so much. And Erin, just so we would avoid any technical difficulties, I recorded it a few days ago, and we will show that recording, and then we'll be back live. And if there's any issues that come up with that, I will be back to switch to giving it. So, thank you. Hi, I'm Diane Davey, and I'm pleased to present this webinar for you, and I will now share my screen. Okay. We should be working now. I'm located at the University of Central Florida and the Orlando VA. And I'll give my presentation, and then there'll be time for questions. So the objectives are shown here. We're going to talk about screening guidelines for prevention of cervical cancer, including the HPV primary screening challenges. We're going to discuss revised consensus-based guidelines for follow-up and management of abnormal cervical cytology and screening results, and ways that you can work collaboratively with colleagues to optimize patient care. I don't have any financial conflict of interest. I have been involved with development of some of the guidelines, and I serve on some, have served on some committees for professional societies. So we've been quite successful with cervical cancer screening and prevention. Back in the 1950s, before the Pap test was adopted widely, cervical cancer was one of the most common killers of women in terms of cancer types. And it's decreased a lot in terms of a cause of cancer mortality in this country. However, there are some challenges with our opportunistic screening system in the United States. We're not as organized in calling back women for screening as in some countries. We find now that about half the women with cervical cancer in the United States have never been screened, and another 10% have not been screened at an appropriate interval. The screening guidelines vary somewhat by organization, and we're seeing some new guidelines being adopted. So I'm going to be talking about what we're seeing now. And I think that all organizations in the United States agree that you shouldn't screen very young women less than age 21. While HPV infections are relatively common in this age group, they're usually transient and don't progress to cancer at this age, young age. Similarly, young women ages 21 to 24 get a lot of HPV infections. So we want to avoid HPV screening, but we can do cytology alone every three years in this age group. The most common age group for screening is ages 25 to 65. And here we have a few different options. We can still do cytology alone every three years. That's an acceptable option. One of the favorite screening methods has been co-testing, or HPV and cytology together. And this has been used, I would think, in the majority of screening situations most recently in the United States. But we're now seeing a shift by some of the guidelines groups to move to HPV primary screening starting at age 25. In fact, this is a push from the American Cancer Society. And we'll get back to that in just a few minutes. Once a woman reaches age 65, she doesn't need to be screened any longer if she has had negative screening tests. So three negative cytology tests or two negative HPV tests in the last 10 years, with the most recent being in the last five years. If a woman has had her cervix excised, a complete hysterectomy with no cervix remaining, for benign reasons like a leiomyoma, she doesn't need to have screening any longer. But if there is a history of a high-grade precursor lesion or cancer, she should continue screening. There's no differences with HPV vaccination at this point. So women should get the same screening. Immunocompromised women have separate screening recommendations. This includes women who are HIV-positive, transplant recipients, and those who are immunosuppressed with rheumatologic diseases. And in these women, you may screen a little bit younger age, so within a year of onset of sexual activity, then annually for a few years, and then moving to less frequent co-testing. We're seeing a push for HPV primary screening. It will likely become more common among the professional societies. In fact, the American Cancer Society, when they published their 2020 guidelines, they signaled a move to HPV primary screening, and they implemented a cervical cancer screening initiative. The reason for this is HPV-based screening is considered more sensitive than cytology. With a higher negative predictive value, especially when you consider five-year follow-up. They're recommending starting screening at age 25, so you can just move right to HPV screening and not do a switch from cytology to HPV screening. Some of the caveats here are you need to use a platform, an FDA-approved, HPV platform approved for primary screening. And I'll get back to that in a minute. Anyone who has a positive HPV test, you're generally going to do a reflex cytology test. If the woman has genotyping done also, and you find that the HPV type is 16 or 18, the woman goes right to colposcopy. For other types of high-risk HPV, you do repeat cytology and HPV at one year. Any abnormal cytology result would be managed by the guidelines I'm going to be talking about once I finish discussing screening. The U.S. Preventive Service Task Force is now in the process of updating their cervical cancer screening guidelines. There was a public commentary period in the fall. Several major organizations and individuals submitted comments on their processes. The American Cancer Society Cervical Cancer Screening Initiative is a national consortium, and their goal is really to create a comprehensive implementation plan to transition to HPV primary screening away from cytology or co-testing. There are a number of workgroups, as well as a steering committee, that have been formed. And these workgroups include everything from insurance coverage to IT, electronic health records workgroups. And there's a laboratory infrastructure workgroup that is co-chaired by a few pathologists, Drs. Ritu Nayyar and Teri Daroff. I've been on some of the calls for just some of the information exchange, but I'm not currently a member of any of these workgroups. But we'll see more coming out from them in the future. What are some of the challenges, and what uptake are we seeing with HPV primary screening? Well, again, the HPV primary screening and doing surveillance of a woman without a cytology co-test requires the use of an FDA-approved HPV test, approved for primary screening. Right now, those are the Roche-Cobas tests and the BD-on-Clarity, BD-on-Clarity being used with SurePath Media. Many laboratories don't use HPV testing methods that are very good for adjunctive use and co-tests, things like Aptima and hybrid capture. But those are approved only for co-testing, adjunctive testing, and so forth. So if your laboratory is considering a move to primary screening, you should make sure you have an FDA-approved platform and make sure your clinicians are aware of that, too. One of the ways that we can work with our providers. Genotyping is also starting to be used more. So if you're not doing genotyping, you'd probably want to consider this. We're seeing it helpful mainly in two situations, and that is a push to do immediate colposcopy when the cytology is negative, but the woman is known to be HPV 16 or 18 positive. Also, we're seeing a push to do immediate treatment if the woman is known to be HPV 16 positive and bypassing colposcopy. Any one positive for HPV 16 or 18, we have to consider very high risk. We don't see a lot of laboratories getting requests in this area of the country and many other areas of the country for primary screening, to my knowledge. Be interested during the question session if you have heard otherwise. We're seeing it in some organized screening systems like Kaiser and some big metropolitan centers, but not that much in a lot of laboratories. What are some of the concerns we have? There are a number of professional societies that have submitted comments in the past. The CAP, the ASCP, the American Society of Cytopathology, those groups are all part of the Cytopathology Education and Technology Consortium, and I've been involved with that CETC, the consortium. We've submitted comments a number of times in the past, including the American Cancer Society Great Guidelines. Some of the major concerns are that there are HPV negative high-grade lesions in cancers. Many of the studies in our laboratory settings show up to 10% HPV negative high-grade lesions. We don't know if all of these are from testing issues or if they're truly not related to HPV in terms of their pathogenesis. Invasive cancers seem to have even higher false negative rates, especially 20% or so for adenocarcinomas. Studies will vary a little bit. The United States has opportunistic cancer screening. We don't really have organized screening. As I mentioned, many of the women who get invasive cancer have not been screened regularly or they lack appropriate follow-up. We see some disparities with underserved populations having less screening. So a lot of professional groups feel that if a woman's not being screened very regularly, she should get the co-test or be eligible to get co-testing, which may help allay fears about HPV negative cancers. We also have less than optimal HPV vaccine uptake compared to Australia and other countries that are adopting primary screening. A lot of the studies promoting HPV screening over co-testing have been done outside the United States or they're in organized systems like Kaiser Permanente in California, and some of them are modeling studies. There are quite a few studies showing some HPV negative high-grade lesions in cancers that are from actual laboratory data, and a lot of times it seems like the American Cancer Society and the U.S. Preventative Service Task Force do not look at retrospective data as much as some of the trials and modeling studies. A lot of clinicians and other groups, including patients, seem to have a preference for co-testing because of the added information and concerns about women not being screened often enough or coming back. Now let's move to talking about screening guidelines. We're going to be talking about the American Society for Colposcopy and Cervical Pathology Management Guidelines, and I provide one of the references at the bottom of the slide. These are risk-based now and personalized. The risk-based and personalized means that hopefully for high-risk patients they'll be safer and fewer unnecessary procedures for low-risk patients. There are a number of applications for this risk-based approach. I have one on my phone, and you can also do a web-based application as well. They term this process as enduring guidelines, and there are ongoing stakeholder and risk management groups. I was a alternate from the CAP to the consensus meeting that occurred in 2019, and now I represent the ASC in this enduring guidelines process. So the enduring guidelines means that they can provide additional new testing options and move them into the guidelines without having another conference. An example that we might see is use of the P16-KI67 dual stain as a triage for HPV results. So these guidelines were published, updated in 2019 and then published in 2020. I worked with Dr. Barb Crothers to write an article in CAP Today, and I have a chart shown on this slide, and it shows some of the major aspects of these guidelines. So the principle is really that a woman with equal risk will have equal management, even if the cytology results differ slightly. And the risk estimation is primarily based on the HPV testing results, but cytology does come in there, and we'll talk about some examples. I noted that we can have updates based on new testing methods. For example, we might see P16 dual stain, the balance of patient harm and benefit. Now, these guidelines are primarily based on women who are asymptomatic at the time that they enter the screening and to women that have a cervix. That's what they're primarily meant for, and also high-resource settings like the United States, not in lower-resource settings that we see in some countries of the world. The main aim is to prevent development of invasive cancer by detecting those high-grade lesions, CIN3 and adenocarcinoma in situ, or AIS. I mentioned the personalized risk-based approach with these technical aids, these apps, and so forth. So let's talk a little bit about the risk and how this influences the surveillance and management. So what you do initially is determine if the individual has an immediate CIN3 plus risk. That would be CIN3, adenocarcinoma in situ, or invasive cancer risk are greater than 4%. So that 4% gives you an idea of whether you'll go to colposcopy or treatment. If it's greater than 4%, you're in this green to reddish area here, and so that 4% to 24%, you know you're going to at least have colposcopy. If the risk goes up even higher, then you may elect to do immediate treatment. If the risk is less than 4% for that woman, then you're going to have some sort of either routine or expedited surveillance. So in this green to blue area, if you're less than 4%, but sort of in that intermediate area, you would come back in a year for surveillance. If it's even a lower risk, then you might come back in three years or in five years for follow-up. So we'll give some examples of that. While the HPV results are primary in this, we do use cytology as well, and that relies on the Bethesda system, and I should show just the categories. I think you're familiar with those. Our squamous abnormalities, atypical squamous cells, low and high grade cell cancers, and then we have the glandular abnormalities. So let's talk about use of this app, and again, I have it on my phone, and I pulled it up on the web, and I did some screenshots, and I know the screens, the, it's hard to enlarge it. I wanted to show you what the screens sort of look like and what you input, but then I'm going to give you in the larger print what the result is. So in the first screen you get, once you accept the conditions of the app, of course, then you're going to indicate the age range and the general indication. Is this for screening? Is it for management or treatment follow-up? You can add some special situations, like if the woman's symptomatic or if she's immunosuppressed and so forth, and then you put in the current HPV and cytology results and indicate whether you know a previous result. So you may be able to do that in your laboratory if you have the patient history, but this may require the clinician to do that. So let's start with some examples. So this is a 35-year-old woman with low-grade squamous intrapathy lesion and no previous cytology or HPV results. So this was HPV positive. You can see some of the classic ILSO criteria with nuclei in large, more than three times normal size. You can see some examples here with some hyperchromasia, coarse or smudgy chromatin, slightly regular nuclei, but no nuclei. Then you can see some HPV cytopathic changes. I'm showing by the arrow there with sharply defined clear perinuclear cavities and some peripheral dense cytoplasm. So about 75% of the time, low-grade lesions will test positive for high-risk HPV types. Some of the low-grade lesions are going to be test positive for low-risk types, and those are not likely to progress. So if there's no previous negative result, the CIN3 risk in this woman is going to be over 4%. It's 4.3% if you put it in the app and they give you a reference. So then the recommendation is colposcopy, and this is similar to what we saw in the past. So that's simple enough. But let's take another example of a woman with current ELSO. She's age 50 and also HPV positive. But now we know that her previous result was ASCUS HPV negative. Now, because her risk of CIN3 plus goes below 4%, it's 2.6% when you put it in the app, then she's going to have a one-year follow-up with HPV-based testing instead of going right to colposcopy. So that prior negative result is important, negative HPV result. So for ELSIL now, it matters what the history is. So if the HPV test is positive and there's no prior HPV testing result, you're generally going to have colposcopy recommended. This includes pregnant women, although you're going to, in pregnant women, the clinician will avoid use of endocervical carettings. If the HPV result is negative, remember some of the time ELSILs will be HPV negative, and I certainly see this in some of the VA patients, a one-year surveillance will be suggested. Also, if you know that the prior screening result was HPV negative, ASCUS or an HPV negative, cytology negative, one-year surveillance. Under women ages 21 to 24, a one-year repeat is going to generally be recommended. You don't use HPV testing as much in this age group, and you try to avoid colposcopy with sort of low-grade lesions on cytology. If you could do colposcopy and you don't see a high-grade lesion, so it's either CIN1 or negative biopsies, you're going to follow women generally with one-year surveillance and not treat them. Now let's move to a high-grade lesion. High-grade squamous intrapathy lesions are usually more immature cells, smaller in size than a low-grade lesion. The cells can be single or in clusters or aggregates. These cells have higher NC ratio with less cytoplasm, and you can see that in this photo. You see nuclear changes with hyperchromasia, coarse chromatin, and regular outlines. Nearly all of these are going to be HPV positive when you test them, but again, remember that studies in our actual testing situations in many of our laboratories that are published show up to 10% HPV negative results. So HPV is not always perfect in detecting these, and if you think you see a high-grade lesion, call it high-grade regardless of the HPV result. Some more examples here, the left and top, this is a 35-year-old woman, and she was tested positive for HPV, not 16 or 18 type. And if you put that in, she's got a 49% risk of a high-grade CIN3 plus lesion. The 23-year-old woman in the lower right, because of her age, her risk is going to be somewhat lower, but she's still going to need colposcopy. So management of high-grade lesions is still generally always going to be colposcopy, but there is an option for expedited treatment by loop excision unless you have some special populations, and I'll mention those in a minute. You cannot rely on repeat cytology or HPV triage alone because you're going to miss some cases. If you know that the HPV result is 16 positive, then you go up above 60% CIN3 risk. Your risk gets up even higher. And at that point, it's preferred that you go immediately to excision, but that's going to depend a little bit on physician and patient preferences. The treatment, if you first do colposcopy, can be either excision or ablation. I'll get to that in a minute. It is recommended in these guidelines that you qualify the histology as CIN2 or CIN3. More on that in a few minutes. And then after you treat someone, there's going to be very close surveillance, and I described that a little bit here. It depends a lot on HPV results, initially at six months and then annually and then moving to less frequently. But say if you have a woman treated for a high-grade lesion when she's 55, you're not going to stop screening at age 65. You're going to continue for 25 years because of the risk of recurrence. Now this shows some of the management. And I don't want to get into a lot of details because we're not clinicians here, but again, you can either do colposcopy, and you can do a diagnostic excision, or you can do a colposcopy alone, or in some women, you can go right to a diagnostic excision. Now you don't want to do ablation as treatment if you can't see the entire lesion, if it's recurrent high-grade lesion, or if you can't see the squamo-culmonary junction. So that's a reason that you really need to rely on excision. And then some of the follow-up is shown here that I already mentioned. Again, quite frequent follow-up initially, and then it's spaced out to less frequently if everything is negative. I mentioned the desire to divide biopsies into CIN2 versus 3. And this is predominantly for younger women and for those with treatment concerns, women that are planning on childbearing, and there's concerns about excising too much tissue in the cervix because of possible pregnancy complications. So in these women, if you know that it looks like CIN2, and that's what the biopsy says, you can observe these women, whereas once you decide that it's CIN3, then you still want to move to treatment because of the higher risk of progressing to invasive cancer. So there's somewhat of a complicated algorithm. Again, I think for the purposes of our lecture, just keep in mind that there are some women that would, you know, it's desirable to separate out CIN2 versus CIN3. CIN2 is a challenge, and you may not even agree if this is CIN2 or not. These could be, have problems with reproducibility between observers, and the cytology preceding them can also be a problem. Is it a low-grade lesion or is it a high-grade lesion and so forth? And sometimes we see reports of ASCH along with low-grade before these CIN2 biopsies. If you can't tell if it's a high-grade lesion or not, or if it's a very small fragment or not very well-oriented, a P16 stain can be helpful, and I refer you to some references on how to interpret the P16 stain. If you really cannot grade it, it's good to say that you can't exclude a high-grade process. I find that some clinicians don't seem to understand the concept of ungraded CIL, and they may assume it's a low-grade process. And we've seen a few patients at the VA that were not followed aggressively enough because the clinician did not understand what ungraded CIL meant. In special populations, there's a few differences. So very young women, again, that's one of the areas where there may be treatment concerns. Even if the woman doesn't voice that then, it's better to be, to try to follow lesions that are CIN2 more conservatively, whereas if you find CIN3, again, you're going to want to elect to do treatment. And so there's slightly different recommendations for very young women. And also pregnant women, you're going to, again, avoid using, doing a curetting during pregnancy, but you're going to still do colposcopy. And when possible, you're going to delay treatment of invasive cancers and high-grade lesions. Now let's move to atypical squamous cells. These are one of the most common cytology abnormalities reported in our laboratories. So we have two subcategories, undetermined significance and can exclude high-grade lesion. So undetermined significance is where we're concerned about a low-grade lesion, but there's not enough cells or they don't have sufficient criteria. Average reporting rate, again, it varies from patient population and so forth, but it's around 5% if you look at CAP checklists. About half the time, these test HPV positive for high-risk types. Then the remaining atypical squamous cells are can exclude high-grade lesion. This is where you're concerned about a high-grade lesion, but again, you don't have enough cells, they don't have enough criteria. This is much less frequent, and most of the time, these are HPV positive, a higher rate of HPV positivity than ASCUS. But the predictive value for a high-grade lesion is generally lower. It's going to be higher than it is for ASCUS alone, but not as high as if you called it an H cell to begin with. So ASCUS is more mature cells with some nuclear enlargement, but not as much as you see in low-grade lesion. ASCH tends to be atypical metaplastic cells. They can be single, they can be in clusters, and so forth. So they've got some nuclear enlargement, higher NC ratio, but not as many changes, not as many cells as a high-grade lesion. Now, there are cases that are difficult. We know to differentiate low-grade and high-grade. And you see some studies reporting those as low-grade can exclude high-grade. So LSILH is something you'll see in the literature and in reports. The Bethesda recommends that you call cases like this that have LSILH and then cells worrisome for high-grade to put both ASCH and low-grade on your report. And the ASCH is the most abnormal finding, and that would drive the management. So here's an example of a patient with ASCUS. She tested positive for high-risk HPV types, and she had both CIN1 and CIN2 on her biopsies. Some examples of atypical squamous cells can exclude high-grade lesion on ThinPREP. Both these patients had CIN3 on biopsy. You could argue whether you'd call these high-grade lesions. I think they're definitely atypical, higher NC ratio, some nuclear irregularities. It may depend on your threshold and how many abnormal groups you have. But certainly, if there's a lot of abnormal groups, think about calling it a high-grade lesion. ASCUS management, you're going to definitely want to have HPV testing on there unless the woman is very young. And if the HPV test is negative, remember that's about half the time, the woman should have a three-year surveillance because the risk is sufficiently low. She doesn't have to have colposcopy. If the HPV is positive, it depends on the history, sort of like what we saw with low-grade lesion. If you knew the previous HPV result in this patient was positive, her risk is above 4.4%, and also if there's no previous test. So both of those results are above 4%, and colposcopy is going to be done. If the HPV is positive and you knew that the patient was previously HPV negative, then the risk goes down below 4% so you can bring the woman back in a year. Older women, same management. We used to see some differences, but one thing I'd say is if you have a 64-year-old with HPV negative ASCUS, she can't exit screening. It's considered an abnormal result still, so she should have a repeat. Younger women, we don't use HPV testing as much. We're going to generally see surveillance at one year. And genotyping really doesn't impact on management of atypical squamous cells. We've been talking a little bit about the role of knowing the previous results. So this is an example of a table in one of the papers from the ASCCP guidelines. And in this example, all of the history was previous HPV negative. And you can see how, assuming that the current cytology result is either negative or L-cell or ASCUS, you're generally going to fall below 4% for your risk of CIN3+. So you're going to have somewhere between one year and five-year surveillance. Anything that's a higher-grade process, though, even if you do have an HPV negative prior result, you're going to see recommendations for colposcopy here. So again, but the prior negative, knowing prior negative, it generally means that colposcopy is not going to be indicated if the current cytology result is relatively low-grade or negative. So let's talk about ASCH. Generally, we're going to see colposcopy, and that was true in the past with the prior guideline, and it's true now. We do see in older women some HPV negative ASCH results, and some of those women have cancer, so you can't ignore it in an older woman. So here's some screenshots of a woman age 45 with ASCH. She tests positive for HPV16, and her risk of CIN3+, is about 28%. Let's talk about an example. You can see what you think. So here's a woman, 31-year-old, no previous cytology or HPV results. So what would you call this? Well, there's some inflammatory cells, but I think there's significant nuclear enlargement at least three times compared to this cell. So I think I'd be comfortable calling this ASCUS, and I'd want to see the HPV results. So the HPV test was positive for high-risk types. Colposcopy was then performed, because there was no prior information, and no high-grade lesion was seen. It was either, let's assume that they saw a little bit of CIN1 on the biopsy, one biopsy, and a negative in another biopsy. Then she comes back in a year, and her follow-up path is shown here. So I think we can say that this is abnormal again. We have nuclear enlargement, but a lot of cytoplasm. You might call this L-cell. You might call it ASCUS. So what do you want to do next? Well, again, in this case, the HPV test was positive again. So we're in this area. So she's still going to get one-year surveillance. So she's already had the one colposcopy, didn't show a high-grade lesion, and then at that point, one-year follow-up was recommended. So she has an abnormal result again, but it's a low-grade abnormal result. So you're going to allow her to have another one-year surveillance before colposcopy is done again. So one of the reasons you don't want to just do standard recommendations, HPV positive, ASCUS always goes to colposcopy, is that this woman already had colposcopy. So referring clinicians to the guidelines is really more helpful in this situation. Another case, 32-year-old woman, let's just, again, say this was HPV positive. I think these are very worrisome cells. They've got high NC ratio, hyperchromasia, regular nuclei. So I personally think if there's enough of these groups, I would call the high-grade lesion. So she had colposcopy. One biopsy showed CIN1. The other one showed cervicitis. So no high-grade lesion. So we see this in our labs, right? We see women that have low-grade biopsies preceded by a high-grade cytology. So these women need to get closer follow-up than a woman who had a low L-cell cytology and CIN1 on biopsy. So there's three choices. You can either elect to just go straight to excision. You can follow the patient very closely. That's what's shown on the left here. And I don't want to go through all the details because of time. But the clinician is told exactly how often to bring the patient back. And this may be a time where the clinician asks you to review everything. And hopefully, if you have both the cytology and the biopsy in your laboratory, you can go back and look at them. And if the cytology really looks like a high-grade lesion, they may then elect to do an excision instead of conservative management. So this is, again, where we can work with our clinicians a lot. Younger women, I've sort of touched on this. If the cytology result is negative or ASCUS or L-cell, we're going to generally see one-year follow-up and not colposcopy so much. However, with higher-grade cytology processes, we're going to still see colposcopy. So there are some different guidance for younger women. And we don't use HPV triage quite as often. Let's move to another category. Here is a 45-year-old woman, and she had a history of abnormal PAPs. So we see some very crowded groups and very crowded clusters, three-dimensional. Some of them look like they're lining up, maybe palisading, and they're very hyperchromatic. So this is an example of a woman who had adenocarcinoma in situ on cytology, strips and clusters of hyperchromatic cells with a columnar shape. So atypical, and now you may not always be able to call it AIS on cytology. You may call it atypical glandular cells. Atypical glandular cells then show some but not all features of adenocarcinoma in situ. And a lot of times, we can subclassify them as endocervical, favor endometrial, or favor neoplastic. But you can't always subclassify them. And sometimes, it can be misleading to try to classify them if you're not really sure because you want to have the patient have the best management possible. These are relatively uncommon but often poorly reproducible. A lot of times, we show these cases around in our laboratory, tend to see them more in older women because of endometrial pathology also coming in there. And there's a significant risk of both high-grade lesions and cancer. There are benign conditions that can cause atypical glandular cells. I list some of them here, polyps, hyperplasia, IUD changes. Generally, with these women, we're going to see colposcopy with endocervical sampling. And again, you don't want to rely on HPV triage or repeat cytology alone as you're going to miss some significant lesions. If the woman is age 35 or more, if she has a bleeding history or she's at high risk for endometrial pathology and ovulatory conditions, you're going to want to add endometrial sampling as well. If your laboratory subclassifies the case as atypical endometrial cells, then the clinician may elect to just the sampling without colposcopy. So that's why, if you're OK with that, that's OK. But if you think colposcopy should be done, maybe it's better not to subclassify it. Keep in mind that some of these patients will have high-grade squamous lesions on follow-up. It can be very hard to tell clumps of high-grade lesions from adenocarcinoma in situ. Here, we see a little bit more streaming of the cells, more of a horizontal configuration than the columnar configuration here. So I think I mentioned this. Generally, for most atypical glandular cells, we're going to get colposcopy with endocervical sampling. Some women will get endometrial sampling. If we call it endometrial sampling, atypical endometrial cells alone, we may omit the colposcopy initially. And then follow-up tends to be, again, very close, because sometimes colposcopy can miss a significant process. If you said that the cytology was adenocarcinoma in situ or favor neoplastic, even if they don't see anything on initial colposcopy, you're going to the clinician's going to want to definitely consider a diagnostic excision to avoid missing adenocarcinoma in situ, which can be very challenging to see on colposcopy. These patients also have close follow-up after treatment, similar to a high-grade lesion. Now, we also see glandular cells that are just endometrial. And in the Bethesda 2001, we don't need to report those in young women. But once a woman gets to be age 45 or more, we report them in the other category. A lot of times, we don't know the menstrual history. The women can be getting hormonal therapy. In younger women who are still cycling, it's very unusual to see endometrial pathology. But in older women, you may see only be able to report endometrial cells, and you won't be able to call them atypical. So if the clinician, if you report endometrial cells in an older woman or a woman with symptoms, they're going to, endometrial assessment is usually going to be suggested. But if the woman is still cycling, they don't need to do that, even if she's over age 45. Similarly, if you, sometimes you can see benign-looking glandular cells. They usually have an endocervical-type configuration in women after a hysterectomy. And as long as they look benign, nothing else is needed. So on this slide, I'm just showing you some examples of what combination of results can lead to different management. And this is not an all-inclusive list, but you can see times on the upper left when one-year-based HPV surveillance is generally indicated. And I gave you several examples of this. When three-year surveillance is done, and when you need to multiple colposcopy, again, that, meeting that 4% threshold. So this is not an inclusive list, but just some examples. So some take-home points, I'm just about done with my formal presentation, is just to emphasize that we're seeing an increasing push towards HPV primary screening. And we'll see what the U.S. Preventive Service Task Force guidelines come out, but we already have seen that from the American Cancer Society. We now want to make sure that if you're doing HPV primary screening in your laboratory, that you use a testing platform approved for that use. Again, COBAS, BDN, Clarity. Cytology is still used as a triage when the HPV is positive. And there are some concerns among a lot of professional societies about HPV negative results and the opportunistic screening system we have. The management guidelines, as I discussed, are now more personalized and risk-based. And the HPV test results really help drive the management. And I think one of our roles as pathologists can be to educate clinicians on the availability of the free ASCCP web-based app, and then the phone app is a very, very low charge. And you can suggest that they use that. So with that, I thank you for your attention. And I think we're now at the question time. I certainly want to thank you for that excellent presentation, Dr. Davey. You gave us a lot of really good examples and some beautiful cytology to look at. I encourage everybody to write in any questions you might want to ask. And in the interim, I would just like you to maybe to expand a little bit on the complexity of these guidelines have become increasingly difficult, I think, over the years to the point now that you really almost have to look up each patient with an app unless you have a straightforward case. And I know in the past, we've put in very specific comments for how we would suggest for follow-up, and that becomes increasingly difficult. Are there cases that you would recommend that we still find that appropriate? Well, you know, I think I agree with you, Meg, that for some of the negative and low grade, it really depends on the history. So you can have a double negative, a cytology, an HPV negative current case. But if the woman was treated for a high-grade lesion and had a leap a year ago, then you really can't be recommending five-year follow-up, for example. I mean, you don't really know where they are in that surveillance. And for the low-grade abnormalities, it's really, the history is really, really important. Now, I think given that with higher-grade abnormalities, which I would include high-grade lesions, most atypical, you know, atypical glandular cells and atypical squamous cells can't exclude high-grade, then it's still, we're going to, you're going to see colposcopy done a lot. So I think all of us have seen probably cases where the clinicians really didn't have a clue and they weren't doing appropriate follow-up. So in those cases, I think you can still recommend something, you know, something more aggressive. But for the low grades, and especially if it's a persistent abnormality or previous known, I think providing guidance on that app is probably going to be the best. So I look them up sometimes, and, you know, we, I will chat, you know, through Teams messaging with some of the clinicians at the VA, because we have a variety of providers. And, you know, I'll look it up for them sometimes, or we'll, you know, that kind of thing. If I have time, if we all have time, but it is challenging. And they have told me that they have hard time. I think it's easier on the phone also than the web-based one. But people may not be able to put it on their phone. It depends on what they're using. So. Well, thank you for that. Yeah, I think it is, I think it is difficult. And as you say, even for the clinicians who have to use it on a regular basis. We do have one question here. Can you clarify the 4%? Okay. Yeah. So the ASTCP decided that 4%, and they came up with that. And I think it was just a lot of experts coming together that 4% was really the threshold where they felt that something needed to be done more than just following with close surveillance. And that, I think it's partly just a philosophy that in this country, we're pretty risk-averse. And we wouldn't feel comfortable missing that percentage. So the idea is that 4% of them would have a high-grade lesion if you did colposcopy. And so certainly that 4% is an area where I think most clinicians would feel comfortable looking and not just doing repeat. Is that, the 4% basically just refers to the risk of a high-grade lesion. Okay. That sounds good. I see another question in there. Great. Do you want me to go ahead? Are we looking toward dropping the PAPs and training residents to read PAPs? I think this is a big concern. We certainly, the American Board of Pathology is decreasing the emphasis on PAPs. But I think it's something that people need to feel comfortable doing. Because if you have a positive HPV test, knowing, and say if it's HPV-16 positive, the clinician's really going to want to know, does it look like it's cytology negative? Or does it look like a high-grade lesion? Because that can really help them determine what to do. So, you know, one of my big concerns with moving to HPV primary screening, if you're sending out your HPV testing like we're doing currently at the Orlando VA, then, you know, we do the cytology and we send off an aliquot. But for a lot of laboratories, if you move to primary screening, I think maybe one of the risks is that everything is going to get sent off and you won't have that biopsy to look at and correlate, doing cytologic-histologic correlation. And you also are going to lose training opportunities in your residency program. We're seeing a decrease in PAP volumes already. And certainly, you know, I do agree with decreasing the numbers of questions on the boards. I used to put the cytopath exams together. And they're slowly dropping that. But I think it's still an important skill because you can see that abnormality level in the guideline drives management. There's also age 65. And that is just the screening stopping at 65. Remember, that's only if you have documented previous negatives. We do see women that are diagnosed with invasive cancer in their 60s. And those women are generally women who have, you know, because of opportunistic screening and perhaps disparities in healthcare, they're not getting screened. And maybe they were going to another doctor for blood pressure or so forth, but they're not getting cytology screening. So those women, if they haven't had prior negatives, they should be screened. But if you have some women that are, you know, getting PAPs regularly, that at age 65, it's just thought that it's very unlikely to develop a new high-grade lesion without some prior history. Again, a woman treated for a high-grade lesion when she's age 60 continues on. So it's only with the documented negatives that you stop. What about sampling of cervix by, yeah, HPV screening alone? One reason I think people are interested in HPV primary screening is that self-sampling will be easier to do. Certainly, the HPV testing is less likely, it's not as important where you get the sample exactly as if you're doing cytology. Sort of like what we're seeing with COVID now, where you're testing if you're doing PCR versus antigen testing, right? Okay, so if the woman self-samples and is close to the right area, and there's HPV there, probably it's going to show up. So one of the thoughts is that certain women who will not seek out regular screening may be more likely to do self-sampling with HPV. Certainly, we are not seeing as good of results with self-sampling of cytology. And I think if you do self-sampling, what you're going to see then is women who are then referred in to their doctor for additional evaluation. But that's not happening in this country at this point, except in studies, but we are seeing it elsewhere in the world. Okay, well, I think our time's about up and I don't see any other questions. Thank you so much. Okay, thanks so much for your attention and appreciated everyone being here. And I hope you got something out of it. So anyway. Just a reminder for everyone on the call to complete the evaluation and receive your one-hour CME. And you do have until January 23rd to get that finalized. Okay. Thanks and Happy New Year. All right.

cervical cancer screening

HPV primary screening

clinical guidelines

Dr. Dianne Davey

American Cancer Society

personalized risk-based management

FDA-approved HPV platforms

cytology

self-sampling

screening accessibility