“Don’t assume it's just a hemorrhoid,” says infectious disease specialist Cristina Brickman, MD, MSCE, in her talk on protecting high-risk patients from anal and perianal cancer. Clarifying which populations should be screened, she describes the use of high-resolution anoscopy (HRA) as well as other options when HRA isn’t available. She discusses new guidelines on precursor tissue abnormalities, offering evidence for the value of treating high-grade squamous intraepithelial lesions as well as images to help providers recognize both early signs and late-stage cancer.
Hi, everyone. Um, as you were all, um, hopping on, we were trying to figure out the lighting here, so I apologize that it's a little bit dark, um, but this is an old office, um, but I'm super excited to be here, um, I gave a similar talk um about 4 years ago, so I'm not totally sure if anyone was present for that. But actually, there's been a lot of really exciting developments in my field since then, so there's a lot of new information um to go through. Um, so I am a physician. I am trained in infectious diseases, and I, uh Work at the anal neoplasia clinic um Research and Education Center where we provide um high-resolution endoscopy to prevent anal cancer. And so that's really what I am going um to go over today with, um, a lens towards primary care and what I think are important concepts for the pri uh primary care provider, um, to know. I don't have any disclosures. And so, what I'm hoping to um accomplish today is identify um who it is that might benefit from anal cancer screening. Um, and I'm gonna go over what the options are um for screening. And then And I do think it's important to know what some of the presentations might be for anal cancer so that um everybody's aware. Um, in the interest of time, I'm not gonna talk about vaccines, which are arguably like a really important tool for prevention, but I'm happy to take questions about those um uh afterwards if that comes up. So, I'm gonna start with the first case, which is a 38 year old man who's living with HIV who comes in for follow-up. He's diagnosed with HIV at age 32, had a C4-NR of 400, no history of opportunistic Infections and is doing well on antiretroviral therapy. He's sexually active with men, and he doesn't have a history of prior squamous intrapithelial lesions. He also has no anal pain, bleeding, or discharge. And so the question is which of the following is appropriate for anal cancer prevention in this patient. Um, and we don't have to answer this right now, but I want you to just kind of look through the options. Think about what you might do or how you might counsel, uh, counsel a patient who is interested, um, in this, and then we'll come back to this, um, once I've gone over a little bit of information. So, what is anal cancer? So anal cancer is a malignancy that arises from the most distal portion of the digestive tract. So over here on the right is my little schematic of how I think about the anal canal. And basically for me, the, the anal canal starts um when the columnar epithelium of the rectum turns into squamous epithelium of the anal canal. We divide the anal canal into a proximal and distal portions, and these are separated by the dentate line. And, and the, the interesting thing is that, um, 90% of anal cancers are now known to be due to, um, infection with human papillomavirus. Um, and these are generally squamous cell carcinomas, and they're primarily caused by HPV 16. Um, so HPV 16 is the most carcinogenic, um, HPV type. Um, it's associated with maybe 50% of cervical cancers, which, as we know, is another HPV, um, associated malignancy, but in the anal canal, it's probably closer to like 80-90%. And then perianal cancers are basically cancers that are on the outside, um, and they're also HPV associated, and they are treated very similarly to anal cancers. So when you hear me talk about anal cancer, I'm really referring to both anal canal and perianal cancers. One quick thing before I, um, before I keep going about um kind of nomenclature and terminology, um, here at, um, UCSF, you know, there's, there's sort of been over time, um, more of an aim to be inclusive with regards to gender. And one of the ways to do that is to really separate, you know, gender from an structure and um try to do that when able. However, um, you know, the literature has not necessarily cut up to this yet. And so, some of the things that I'm showing do probably have what's a little bit of outdated terminology. And so I've chosen to show it because I think it's important in how we think about who's at risk, um, but wanted to acknowledge this limitation as well. Um, so this is a meta-analysis by uh Doctor Gary Clifford. And basically, what um, Him and his group did is they collected data on the risk for anal cancer amongst different groups of people. And then they created a chart um to um sort of stratify this and see who is at highest risk. Um, and this has become the basis for screening programs for deciding like who really uh might benefit the most from anal cancer prevention. And so basically, over here on the Y, everyone, I'm assuming people can see the pointer, but over here on the Y axis, you have incidence of anal cancer. So the higher it goes, the higher the risk. And then on the X axis, we have our different um groups of individuals. And so what you can see is Is that men who are sexually active with men who are living with HIV are by far the highest risk. And this risk really, really, really increases um with age. So, um, the incidence there is like 100 per 100,000 person years. And just to put that in context, in the general population, the Risk is probably is like 1.7. So this is like a 100 fold increase in risk. But you also see other groups that are, are pretty um high risk, um, such as, for example, um, women with a history of either gynecological pre-cancer or cancer, specifically women with uh vular cancer. And then patients who are solid organ transplant recipients after about 10 years, are also very high risk. So this is a way to really think about who is at risk, um, and who might benefit from anal cancer prevention. And so, similarities exist between cervical and anal cancer. Um, both are caused by persistent infection with human papillomavirus, and both have the same precursor lesion, which is high grade squamous intraepithelial lesions or H cell. We know that detection and treatment of cervical H cell led to dramatic reductions in the incidence of cervical cancer in countries where screening programs exist. So the idea was, can we apply the same concept to anal cancer prevention? And so, that is the idea behind what we do in our clinic. So, in the cervix, you know, um, um, women will get uh screened with some sort of cervical cytology or test. And if that is positive, um, then they are sent for cervical colposcopy, which is a dedicated exam of the cervix, aiming to identify these pre-cancerous lesions. High-resolution endoscopy is very similar in concept. Perhaps the practice of it is, is very different. Um, and so, um, you know, patients will screen in with some sort of test or have, will have some sort of indication, and then they will come to our clinic for a dedicated exam. And there's actually a definition of what high resolution endoscopy is, which is the examination of the anal canal and perianus using a colposcope for lighting and magnification after application of 5% acetic acid and glucose iodine to identify lesions. And so I just wanted to show you what our, what our rooms look like. You know, you see um the the microscope, which is a pulpo scope. Um, we have our exam table, and then on the right, we have the tray where we'll put our equipment. Um, this is an example of our equipment, and then we use the anoscope to look at the anal canal. And the vinegar, the acetic acid, will help us identify lesions. And so this is what we see when we do our exams. You can see um the area where the uh rectum and the anus meet, which is the squamalcolumnar junction. And a lot of precancerous lesions, high grade squamous and trippithelial lesions, arise from here. So we spend a lot of time going around and examining this area carefully. And then we also apply iodine, and iodine also helps us see um lesions, and so when it stains nice and dark brown, like over here on the right, that means it's normal. So basically, I'm showing you normal epithelium at this point. This is an example of a high-grade squamous intrapithelial lesion. And so, um, you, you know, we as people who do this are trained to recognize these. And so there are certain characteristics like these lacy borders, there's, you know, these sort of clustered epithelium, there's little vascular changes, um, that to us, uh, you know, makes us think that this is a precancerous lesion. And then we apply iodine. And it doesn't stain brown, it stains yellow. So this is something that we would biopsy because we think it's precancerous. Um, you can't do this with simple endoscopy. You really need the vinegar and you really need the colposcope to be able to identify these lesions reliably. And so once we've identified them, we come up with a treatment plan. Um, and so there's a lot of different types of treatments that can be done, and, you know, often you wanna individualize that towards the patient. Um, but a lot of what we do is electrocautery. So, we use this little machine that I'm showing you with a little wand on the um uh below. And we burn the areas off. Um, and so, you know, you can see here on the left is a lesion, and this is after I've burned it off, and then we let it heal. And this is a perianal lesion. So here we have, you know, with the vinegar, you can see this very clear acetyl white lesion, and on the right, we've burned it off. And, and I go through these because I think it's helpful, you know, if this topic comes up with patients to kind of give them an idea of what, of what we are doing in the clinic. But we obviously discussed this with the patients as well before, before we go ahead. So It would make sense that this treatment would work, right? They are known pre-cancerous changes, um, you know, we should treat them, we should get rid of them. But, you know, up until recently, we really didn't know that these treatments were, um, effective. And so why might treatment not work? Um, so one, maybe it's just not good enough, you know, it, it is, it can be hard to get rid of the anal H cell. And sometimes lesions are really big, or you might miss some, you know, um, these procedures require a fair amount of skill and experience, so if you're not very experienced, you might not see it. Um, and then patients can develop metachronous lesions, so they can develop new lesions at different sites at different points in time. Um, on the flip side, it also might not work because maybe you don't need to treat people, you know, like, not all anal, um, H cell are gonna turn into cancer, and so maybe you're overtreating. Um, so, so we didn't really know up until pretty recently. And this is why the Anchor study came about. Um, and so this is not to be confused with the clinic where I work, which is also called ANCE, but it's ANCRE. Um this is the anal Cancer HLL Outcomes Research study. Um and Doctor Joel Pulevski was the uh protocol chair for this. Um, and I've spent perhaps a lot of the last 8 or 9 years on, on this study, but it is just as winding down. Um, but just to be very quick about it, um, this was a very large randomized control study, um, where the point was to determine determine whether treating HI actually would reduce the incidence of anal cancer in people living with HIV. Um, and so people who were living with HIV who were at least 35 years old, were um screened, and if they had anal or perianal H cell, um, they were randomized to either treatment or active monitoring. And then HRA high resolution endoscopy, was used to diagnose, um, and do the treatment and look for recurrences. And primarily the patients were treated with electrocautery. And so this study um did find a 57% reduction in anal cancer incidence in the treatment are compared with active monitoring. Um, and we published this two years ago in the New England Journal of Medicine. Um. So this was very compelling um data to show that in people living with HIV, um, anal cancer can be prevented. So, what do we know so far in our case? Um, one, we know that the patient is at increased risk for anal cancer, um, you know, given HIV, um, given, uh, the sexual history and given age, and we know that HRA can be used to identify and treat anal H cell, um, and decrease the risk of anal cancer in people living with HIV who are at least 35 years old. So what does the primary care provider need to do with that? Um, and so I think the first thing, the first kind of break point that I would like to emphasize is, is the patient symptomatic? Because if your patient is having bleeding, discharge, pain, then it's no longer really screening, right? Then they're kind of gonna go down this. Route, and we can talk a little bit about what this means afterwards. But if they're not having symptoms like the patient in the case, your next question, am I able to refer the patient for high resolution endoscopy? Because if you're not, and this, you know, it depends on where you are geographically, but if there's no one around to do high resolution anoscopy, then you probably don't wanna do a test to look for H cell because you're not gonna be able to do anything with that when it comes back abnormal. Um, and so in these cases, we usually recommend, um, digital anal rectal exam or DARE only with the idea that that can pick up, uh, very early cancers. If you do have capacity for high-resolution endoscopy, then you're gonna recommend a dare, which I know you can't do, um, um, virtually, but you know, the patient would get done at the point where they go in for an HI detection test. And that's what usually is meant by screaming. So, big difference from the last time that I spoke is there are now guidelines for this. And so the International Anal Neoplasia Society, this year has published consensus guidelines for anal cancer screening. So, if this comes up, this is like a great reference um to look up. Um, these guidelines are for both people with and without HIV. Um, further guidance is expected from the CDC for people living with HIV specifically, and hopefully those are gonna be published soon as well. And so, what do these guidelines say? And so, um, they actually used um this chart as their basis, and they selected a cut-off, a cutoff, um, above which they thought it was worth, um, screening people. And, you know, the Choice of a cutoff is often um arbitrary, you know, it kind of depends on what the resources are, um, what's done for other cancers, but what they landed on was 10fold above risk above the general population. So if you remember I said the risk in the general population is above 1.7 per 100,000 person years. So basically, if you are above that, Screening is recommended. Um, if you are kind of a high risk but not above that cutoff, then it's shared decision making. So all of these groups over here, Are recommended for screening per the ENS guidelines. Um, and this is just the actual guidelines. You don't really need um to remember this at all. I just want you to know they're there. The one thing I will point out is that, um, um, MSM and trans women with HIV, um, start at age 35, which is what the Anchor study did, whereas all the other groups start later, and that's, that's partially because the risk for those groups doesn't really start going up until a little bit later. And then how to screen. Um, so the study, you know, I get a lot of these questions, uh, both from patients but also from primary care providers. It's like, what tests should we? And the guidelines also looked at this, and they did a meta-analysis of available studies on test characteristics. And so they had a total of 39 articles, most of them were amongst people living with HIV, um, and then, um, 17 of, of those 39 were MSM with HIV. Um, and basically, they looked at cytology and high-risk HPV testing. So now, when you are thinking about tests, You want them to have as much sensitivity as possible, cause it means it's gonna detect the most, um, but you also want them to have like decent specificity, because you don't wanna be sending everyone in, and especially you don't really wanna be sending on everyone in for something like high resolution endoscopy, which is an invasive exam. Um, so if you look at cytology, um, you'll see it actually has decent sensitivity, um, and specificity, um, but you are gonna get like a lot of false positives from this, and it's worth telling patients that if they get screened, chances are, you know, they're gonna have an abnormal test. They also looked at high risk HPV and high risk HPV has really good sensitivity, but it's not very specific. And I think the reason for that is like a lot of people have high risk HPV, but not everybody has H cell. Um, so, basically, you know, after they reviewed the data, it was a little bit like colorectal cancer screening in the sense that like, you need to, you should do it, or their recommendation is to do it, but they couldn't really say that, like, one test was necessarily better than another test. And so they recommended several options, and so these include cytology, high-risk HPV testing with or without genotyping, um, and then you can also do a code test. So you can do cytology, uh, with high-risk HPV codet, and the guidelines kind of go through the different algorithms for that. Um, personally, I think Any of these are acceptable. Um, I will say the patients that I really worry about are the ones that have HPV 16, and so if I was trying to prioritize, um, you know, those are the patients I would want to see, that's probably the test I would want if the amount that I can refer is limited. But again, the guidelines do not come down like one testing better than the other one you like. So, back to our question, um, you know, which is appropriate for anal cancer prevention? And so all of the options, um, The most, the one that goes within the guidelines is anal cytology now. Um, high-risk HPV testing at age 45 is not appropriate, uh, for the patient because, um, he's MSM living with HIV and so the age of initiation is 35. Um, prior history of squamous intrepithelial lesion is not a factor. Simple endoscopy, um, we discussed will not visualize H cell. Um, and then high risk HPV testing at age 40, that's not the right age, but if it had said age 35, that would be correct. So the patient gets an anal cytology, and it shows low-grade squamous intrapithelial lesions, and they are referred for high resolution anoscopy. And so they come to the clinic, and this is what we see on exam. And so this over here is a wart. It looks like it's, it's a wart in the anal canal, which is a form of low-grade squamous intraepithelial lesion. And so the lesion appearance is consistent with condyloma acuminatum acuminatum, and the biopsy confirms also. What is the best management option? So, A, you want to prevent, you want to treat it to prevent the L cell from progressing to H cell. B. You want no treatment since L cell is not precancerous, and C, you treat um if per patient preference. D. No treatment, treatment is not effective, or E, no treatment, additional biopsies are needed to exclude cancer before considering therapy. I'm gonna give you the answer in a second, but I'll let you read through those for a moment. All right. So, the answer is treat if per patient preference. So this is another point that I want to make. When we think about HPV causing disease, we think about either high grade or low grade lesions. We think of low grade as being benign. We don't think of it as being a long a continuum. We don't think it's gonna turn into H cell. It's there, and you really don't have to treat it because it's not considered precancerous. Now, there is one exception, and that exception is warts. So warts are just bunched up low grade. Um, but we treat warts because patients don't like having them. You know, there's nothing about a wart that's dangerous. So, so it really is up to the patient in, in that case, you know, sometimes patients are like, it's not bothering me. I never knew it was there. It's totally fine, um, to leave it. Um, our treatments do work. Um, I'm just looking through the other options. And then, um, it would be true if you were worried that it looks like cancer, but, you know, um, we're mostly able to look at warts and, and decide that it looks like a wart and, and, and we can treat it if the patient wants to. So, those are my uh clinical pearls for this case. Um, you know, things to remember, especially if patients counsel you, uh, ask you, you know, um, what the best next steps are, um, is that anal H cell is an anal cancer precursor. There are certain groups that are at high risk, and there are now guidelines, um, that recommend screening for certain groups, um, and then that low grade are typically benign, um, and include genital warts, and you treat that if the patient wants those. Treated. This next case is pretty quick, um, and I just wanna make like a quick point, um, related, um, uh, around it. Um, so this is a 65 year old woman who has a history of lupus, um, and stage renal disease, and for that, she received a kidney transplant in 2019. So, 6 months prior, she felt a perianal bump that was presumed a hemorrhoid, um, and this gradually enlarged and started bleeding. Two months prior, um, she underwent a colonoscopy where they found an anal mass, and a biopsy showed H cell. And then she was seen at our clinic. And unfortunately, you know, this is not that uncommon for us. Um, it's actually taken 6 months for the patient to make it to us. Um, and then, um, you know, As I was reading this referral, like, in my mind, I was like, oh my goodness, this patient has cancer, because when there's a mass, you know, it's, it's cancer until proven otherwise. And even if the biopsy only shows H cell, that doesn't mean that there's no cancer, it just means you probably haven't biopsied the right area. Um, so, this was The initial exam, um, and this is a perianus. This is not a perianal cancer. This is a mass that's extruding, so it's actually starting on the inside. And then this is the inside of the anal canal, and you can see this friable ulceration um showing up here. And so, you know, we did biopsies, um, they confirmed invasive squamous cell carcinoma, um, and she, unfortunately had liver mets upon presentation, so it's not a curable cancer at that point. So, why do I bring this up? Um, because I think it's really important when patients have symptoms, um, to pay attention. Um, and, you know, uh, uh, I have it in a slide afterwards, but a hemorrhoid is not always a hemorrhoid. Um, and so if y if patients have Symptoms, then they really do need to be referred for digital anal rectal exam, perianal exam, and then if appropriate or at risk, you know, they need STI testing as well as simple endoscopy to try and see um what's going on and risk stratified so that like things can be detected a little bit sooner. Um, and I just have some more pictures of anal cancer, um, because I think it's useful, uh, to see what it can look like. It's it's very friable tissue. It's not necessarily like a ball. It's like kind of like eroding in. Um, so this is all anal canal. And then this is the, the perianus with this like heaped up border um there. And so that's my clinical pearl, you know, um, I, I do think it's reasonable, you know, especially you're seeing patients virtually, um, to Make your best guess, you know, if you do think it's a hemorrhoid, like, tell them like basic things, but also tell the patient, this should get better, right? If it doesn't get better, then it really does need to be, uh, worked up. And so, um, I think it's reasonable, you know, you can do. Your first guess, but they do need to be followed up, um, because we do, unfortunately, um, not necessarily from one medical, of course, but, but we do see these cases where just like getting to the diagnosis can take months, um, because nobody wants to look. Um, so that is where I'm gonna wrap things up. I think I explained my main points, which is analatal precancerous, we can treat it, and there are guidelines. Um, and now I'd like to just open it up, um, for questions.
