DESCRIPT Journal Review in Colorectal Surgery Anal Dysplasia and Anal Squamous Cell Carcinoma enhanced

Hello, Behind the Knife listeners. We are very excited to be back with you for another Journal Club in Colon and Rectal Surgery. Today we're going to dive into two papers on anal dysplasia and anal squamous cell cancer with the Leahy colorectal surgery gene. Reminder, there is, yes, another awesome colorectal group coming to us out of Louisville.

We've recorded two episodes so far on ostomies and perineal wounds flaps. And we do have another very, very special guest who is joining us today and I'm going to introduce them shortly. So welcome again, team, Dr. Peter West Marcello, Dr. Tess Hanna Allett. How's it going guys? Oh, it's awesome. It's great to be back together.

We're getting into the holiday season. And so. We just had Thanksgiving. There's a lot to be thankful for. We did tremendous in our match for our residency, and we're very excited about that. Last night, we just had our holiday party, so it was a time to get

everybody together and enjoy. And as we get to Christmas coming, Santa was very nice to us, and I think I'm very proud of the number of presentations we have at the podium, his posters, and video for the national meeting.

So, a lot to be thankful for. I want to wish All I'll be having tonight, listeners, a happy and healthy holiday season. Tess? Man, I can't really follow that. That was a great update on that. Things are good. Things are good. Yeah. That's it? I mean, I guess I'm pregnant. I'm expecting. Yes! Yeah, so I'm doing my best to stay hydrated and eating fiber to avoid the hemorrhoids and fissure.

Okay, well, we'll TMI, but thank you for that anyway. Very nice. And this is number two. This is number two for tests, we have to say, so congratulations. Thank you. All right, let's introduce our very, very special guest who's joining us.

I'm honored to take a first crack at introducing Dr. Lisa Breen. So Dr.

Breen completed her medical school at Brown University. She then went on and did her general surgery training at Beth Israel Deaconess. And then she completed her colon and ritual surgery fellowship at, obviously, none other than the hospital medical center. But was, wasn't called Lady Hospital Medical Center then, right?

It was Lady Hitchcock, where we're in the, Yeah, I think I was the one Lady Hitchcock here. No, me too. We're both Lady Hitchcock. Okay. All right. All right. She then took a job at Brigham and Women's Medical Center, where she spent 20 years, and then we were lucky enough to have her rejoin the team at Leahy, and she actually served as our fellowship program director starting in 2017, so we're thrilled to have her join us today and share her expertise on the topic.

Thank you for coming. All right. Well, thanks for inviting me. I was saying earlier, I think my role here is the

history. So Peter and I were talking earlier before the recording started about this is a very different disease back when we were fellows, but I'm looking forward to hearing all the new stuff.

Well, I just want to give a shout out to Lisa because she really broke ground as the, as one of the first colorectal surgeons to be at Brigham and Women's, did a tremendous job there. And then also her, her role in education, I mean, she was a year behind me. But I've learned a lot from Lisa Breen in terms of education.

She was in charge of the Harvard clerkship for the medical students. And then we were lucky to have her here and take over our residency program. And we're really excited to have her with us and to be with us tonight. Go ahead, John. All right. Well, let's dive into the heart of this discussion of anal dysplasia.

And this is. It's a very, very confusing topic for all, and admittedly sometimes even for us colorectal surgeons. And a part of that is because the terminology, at least in regards to pathology, is actually quite variable.

And, and the literature is a bit limited. And so there's extraordinary variability in practice paths.

And so hopefully we, by the end of today, we'll be able to break down some of the barriers to understanding this topic. So we have two great articles to review. So Tess is going to start us off with an article from Diseases in Colon and Rectum. That was actually coming out of Spain, published in 2022. And then I'm going to share the results of the much anticipated ANCHOR trial that was published in the New England Journal of Medicine in 2022.

So, Tess, why don't you take it away and we'll go to the next slide. Again, a reminder for those of us who are, those of you who are watching on YouTube, you can follow along with us. Thanks, John. So, this study aimed to determine the incidence of anal squamous cell cancer and the efficacy of a screening program.

It took place in an HIV clinic in Spain from 2004 to 2017, and their primary outcome

was the incidence of anal squamous cell cancer, ultimately finding that participation in a screening program reduced the incidence of anal squamous cell cancer. Before I dive in too deep, I just wanted to clear up some of the terminology that you alluded to, which I think reviewing the literature can be very confusing because the terminology can be so variable and why discussing this topic can be challenging.

If you're following again on YouTube, check out this slide. I think this schematic is helpful in terms of understanding dysplasia and progression to anal cancer. Additionally, Anal cancer is mainly caused by the HPV virus type 16 and 18. This virus changes the cells and again can cause both L cell and H cell.

This terminology has been confusing because previously it was termed AIN 1, 2, and 3. And so

there can be a lot of variability when you're looking at They're either doing re studies or reviewing pathology or outside providers notes in terms of the pathology. Now we are recommending that everything get lumped into two categories.

Low grade or high grade, this L Cil or H Cil. So, we're going to try to be consistent tonight in using those terms. So And I'll just, I'll just jump in, sorry, I'll just jump in one second, Tessa, sometimes I remember a professor or a a surgeon who taught us in residency would be very, very, very, very particular about the words we used.

And I, I think as a trainee sometimes found that maybe a little annoying. But I do think when you're talking to talk, it is important actually. to really be able to speak the correct lingo. So it might seem like a, maybe a silly thing out there, but it actually is quite important. So I just want to emphasize that.

Completely agree. So HIV, as many of us know, is

associated with increased risk of anal squamous cell cancer. The study that they performed in Spain was conducted in an infectious disease clinic in Spain where patients living with HIV were routinely followed. So this is an existing population. Data was prospectively entered beginning in 20, 2004, and patients were basically included if they had at least one follow up visit.

Beginning in 2010, they instituted a specialized screening program treating anal neoplasia that was abbreviated SCAN. And this program was specifically for men who had sex with men within the clinic. This program included various efforts, including anal cytology, high resolution manoscopy, as well as some treatment, mainly thermocoagulation of high grade or H cell lesions.

I think this is a very important point in all of these studies on anal

condyloma or anal cancer, you know, what is the intervention? And so again, they did screening with cytology and high resolution anoscopy. And then performed, again, some thermocoagulation for the high grade lesions. The study was divided into two periods.

So the first period was in 2004 to 2010, before they instituted the scan program, and then afterwards from 2011 to 2017. They had a very fairly robust population with a total of 3, 800 patients participating in the study. 41 percent of these were men who had sex with men and 17 percent were women. So a majority of these were male patients.

In total, 897 participated in the scan program when it began in 2020. They also monitored CD4 counts as well as immune restoration in terms of HIV status.

During the study period, a total of 20 anal squamous cell cancers were diagnosed, worked out to about 1. 5 cases per year, 55 percent of these being diagnosed within the MSM population, and 4 of 20 were diagnosed in the SCAN group, who are being actively screened and potentially treated.

All of these cancers, the 4 out of 20, were early stage cancers, T1 or T2. Two of these were asymptomatic and were detected at routine visits, the other two had actually not attended the recommended or scheduled visits and were diagnosed due to symptoms later on. Whereas in the non screening group, the non scan group, only 25 percent of these cancers were diagnosed at early stage.

So more likely to be a later stage at the time of diagnosis. Which I think is an important point. The overall

incidence and rate of anal squamous cell cancer was 68 per 100, 000 person years in this cohort of HIV patients. And looking at the various time periods, they did note an increase in incidence throughout the study with the later time period having an increased incidence of anal squamous cell cancer.

You know, squamous cell cancer. The rates were dramatically higher in the MSM population. They did look at immune reconstitution and that was noted to be a protective factor. So if your HIV was under better control, highlighting the importance of heart therapy and HIV suppression in developing anal squamous cell cancer and the strongest impact that they found was.

The lack of immune restoration in terms of your rate of developing this. If you're less than 35 or over 50, you had high education or injection uses to transmission of HIV. This was protective for squamous cell

cancer again in their population. So when comparing. squamous cell for 2010 to 2017? In the scan group.

Compared to the follow up, there are significantly decreased rates of anal squamous cell in the scan group, the screening group. Based on this, They concluded that participation in this screening program, You Significantly reduced the incidence of anal squamous cell cancer in the MSM population. So I think this overall study had limited data in terms of adherence and compliance to the program.

While their initial numbers are really good, 3800, a smaller number that was actually enrolled in their screening program. And again, this applies to a limited population. This was a HIV. MSM population that was in the screening program. So thinking about how this is generalizable to the broader population that we may be seeing.

So it also, the other thing, we didn't get the specific details on maybe the treatment that they had received and what the

patients got.

Thanks, Tess. It's helpful to go through these papers and really try and hit on what are some of the key points. I guess I'm interested to hear, Lisa, your thoughts about the paper, I guess putting it into a little bit of the historical context about training, early part of your career. What was the, what were some of the thought processes about how do we screen these patients or some of the treatment options?

So what do you think? So I guess, first of all, I thought it was well presented, Tess, thank you for going through that. And I do think the value. particularly talking about who are the high risk people that really you need to be watching out for screening. But I think Peter and I were talking earlier, like, when we were fellows, right, this wasn't a disease, right?

Because no one had HPV really back then. Or if they did, they didn't have it long enough to be starting to have these problems. And when someone had anal squamous cell, it was a big deal. And when someone had anal dysplasia, it was really unusual. And so we would, take these people to the OR, do these

mapping biopsies about 10 centimeters out from their anus.

And a lot of times it would microscopically come back positive, even though we might have seen this little area of demarcation on the perianal skin or some frond like lesion within the anal canal that came back H cell and we would remove. And then we got really stuck with, what are we going to do about all this microscopic stuff?

And so then there were kind of two schools of thought. One school of thought was, we have to find a better way to identify H cell besides just looking at it. And then there was kind of the school of thought that said, well, it, it's going to have to go through a phase where you're going to see something to the naked eye before it goes into invasive cancer.

And so if we just survey people frequently enough that we catch anything, that And so I think for people of my generation, that's always been the trouble. It hasn't been, should we survey these people? It's been, how can we survey them frequently enough or effectively enough that we catch these lesions?

So we don't really know the timeline and we don't really know the best tools. And so this says, if you watch people

and see something you want to treat, it's probably a good idea. But I don't think you can say much more because they didn't say what, you know, the routine, what the policy was before, what it was after in terms of intervals, compliance.

et cetera, et cetera, where all these lesions only seen on HRA or some of them seen visibly. So it's tricky. Yeah. And I'll add to that just to say that I think it's a matter of also then figuring out your risk population, right? I mean, so we're talking about the patients who are at highest risk, you know, men have exactly men HIV positive population and how it relates to then to your general population.

And I think that makes it even more confusing, but I think the important message, there needs to be some screening done to help patients. Whether they're high, whether they're in the highest risk population or even a lower risk, especially if they have H cell versus L cell. And so, all I will say is, if you're L cell to begin with, you're probably not going to flip as often to H cell,

at least in our understanding of this.

And so, history can repeat itself. So, I worry less about somebody who doesn't have worrisome lesions. Well, where are some risk factors? Although it is really interesting because there are a lot of patients that I've seen in the transplant population, right? So they're immunocompromised because they're transplant and they had cervical or vulvar dysplasia, then it was perianal, then it went into the anal canal and so it kind of spreading that way.

So I feel almost like when someone, I do think the high risk populations that they've identified in Tess's paper are super important to pay attention to, but I think if anybody shows up with H cell, I can't seem to stop wanting to survey them. Yeah. Agreed. Agree. Agree. All right. Let's launch into the ANCHOR trial.

So this was also known as the treatment of anal high grade squamous intrapithelial lesions to prevent anal cancer. And so we actually had the, the benefit and luxury and full

disclosure to do a journal club within our Leahy program last week. And so we actually reviewed this article as well as the other article.

And so, you know, one of the interesting points I'll just bring up is like, all along there's always been this question of like, what do we do with HPB and HI. And the thought process was, well, let's just wait for anchor. Let's just wait for anchor. Then we'll know all the answers. So let's talk about the article and see if we have all the answers.

So the, the background or the, the impetus for the study. So we, we believe that anal cancer is preceded by by H cell. But data was really lacking from prospective studies about the treatment of H cell. and whether or not that can actually prevent anal cancer. So this was a phase 3 multi institutional randomized study that investigated whether treatment for H cell is effective and safe in reducing the risk of progression to anal cancer among persons living with HIV compared with active monitoring

of H cell without treatment.

The study was conducted at 25 U. S. sites. One of the things I learned is that one of our partners, Dr. Kunin, was at BMC when they were enrolling and was actually a part of, you know, helping enroll and, and take care of some of these patients. So patients with HIV who were 35 years or older with biopsy proven H cell were randomly assigned to either active monitoring or treatment of the H cell.

Okay, and so treatment, at least the way that they defined it in this study, is that this could be office based ablative procedures, ablation or excision under anesthesia, or the use of topical fluorouracil or imiquimod. So again, what I need to say is it's important to be clear what's the intervention.

Intervention in this study was ablation or excision of, or topical fluorouracil or imiquimod of Each cell. So the primary outcome was progression to anal cancer, and all participants underwent HRA every six months. So they had about 4, 400 patients who underwent randomization.

The median follow up was about 25 months.

There were 9 cases of anal cancer in the treatment group and 21 in the active surveillance group. And the rate of progression to anal cancer was lower in the treatment group by about 57%. so Kappemeier curves did demonstrate a decreased rate of progression to anal cancer in the treatment group. And so while the trial didn't necessarily look at the efficacy of different methods for treating each cell, most, in fact, were office.

based electrocautery. So overall the study demonstrates that the treatment for anal HDL does significantly reduce the progression to anal cancer among persons living with HIV 35 years or older. And there was a low incidence of serious adverse events. And so I think, I'll just say, I think it's a well conducted randomized controlled trial with good study design.

There, there's certainly limitations of the study, but I think I'm interested to hear again, start with Lisa.

So what are your thoughts about? Anchor trial and what this means for us going forward. I mean, I agree with you that it's good to finally have something that's, you know, this rigorous in terms of a trial out there to sort of give some guidance.

Like we were saying earlier, sure, if you know someone has H cell, you should definitely treat it. Right. The question is, where is it? And how do you know, like what the borders of it are? Right. Because this was great that it was biopsy proven H cell, but it wasn't like, Is it demarcated? Is it a field defect of the whole anal canal or the whole perianal skin?

And because they would treat it, a lot of times with things that didn't like non excision treatment, right? So you didn't know whether your margins were negative when you treated it, right? So it's great that the patients are being surveyed, maybe being surveyed by something that maybe is going to be more important at reducing the transmission.

I mean, the development of invasive square cell than just looking via

anoscopy, hard to say, but this is certainly one making you wonder about that. And then I think that the thing that historically has always been tough is that we would excise all this stuff. And there was a lot of morbidity with that.

And so this has shown you that you can probably do other forms of treatment, which I think we're going to talk a little bit more about, that you know, could be very effective and don't really harm the patients in terms of their continence or a lot of problems with pain and, and other, other things like that.

So I think it's all very positive and moving people towards paying attention to these patients and trying to figure out who's got H cell and. Where is it and is it a visible lesion or is it a field defect and, and, and what are your treatment options? Yeah. And for me, I'll just carry forward just the historical perspective.

When Lisa and I were in our trainings in our early years, all we had was excisional treatments. You know, we didn't think that just ablating, cerebral ablation would be adequate for these lesions. So the problem was the morbidity. Like you would excise and then we get a stricture and now

you're dilating the anus.

So again, also with vulvar lesions in a similar fashion that our only thought was, well, we better remove the tissue rather than try to treat the tissue. And when, so I think sometimes less is more and that I think our, our mode movement now is away from less major excisions and more about other options.

And so I think less is more, it can be helpful. Yeah, I think this anchor trial gives us really good data to say that treating H cell decreases the rate of anal cancer, specifically also in these high risk populations. It seems like we're all on the same page about that. If you have H cell, we have to treat it, right?

And this supports that. And it is a good study, prospectively well designed big study that helps to kind of solidify that thinking. I guess we've, Lisa, you kind of alluded to this, but what did they use? What treatment options? I think The question that I have is, you know, how are these

people being surveyed?

Do we have to do high resolution anoscopy for everybody or is office based anoscopy, digital exam? Okay. And so I, I kind of opened that up to the group to say, what are you guys doing now? And what should we be doing as a society? Because I know that there's still a lot of debate about how these people should be surveyed.

So I think that's a great question, Tess. I mean, I think, again, we used to call this the East Coast, West Coast debate. So everybody in the West Coast wanted to do HRA and everyone in the East Coast wanted to do anoscopy. And so I'm still not sure that these studies are granular enough to sort of say whether HRA is necessary to find the H cell or not.

It certainly doesn't seem like it hurts, particularly if, even if you're kind of not really sure where the margins of your H cell are the treatments aren't all that morbid. So It's okay to maybe overtreat

some areas or maybe undertreat and then catch them the next go around, you know, kind of thing.

But I don't think a digital exam is probably adequate because most of this stuff is soft and by the time it's firm it's probably already progressed. But I do think, you know, it, the very least a good anoscopy and maybe, and probably a lot of people are going to be comfortable with HRA once people get past what I think is a pretty tough learning curve for that.

Yeah. And I think part of it is the risk, the patient's risk. If you've got discrete lesion one, discrete lesion, you've removed and you haven't seen anything else. I'm not sure that person then, maybe they get HRA for a little bit and then they fall back out if nothing else is showing. And like, again, history repeats itself.

If you get somebody with multifocal H cell, then that person, and you keep finding it, then that person is going to keep getting high resolvus myoscopy. So part of matching a bit of what you're going to do to what you're concerned about for the patient. Yeah, not to

cross pollinate too much or be a self promoter too much, but I'll just throw a plug in there that our recent Gut Check podcast, which is our official podcast for ASCRS.

We talked about this and we talked about like all the different variations and practice and HRA and how you do screening and we sort of went around and talked about what our, how our offices are set up and who does it and there's just huge variability out there and I think. Yes, there was a concept I think that like, oh, we'll just wait for Anchor and that will tell us everything.

But like Anchor wasn't there to tell us how are you gonna do HRA the best? I think that, so I think that's where it's like really focusing on what is the goal of study and what's the takeaway And yeah. And I do think that there are, there's definitely room in the literature to kind. tHe next step in terms of hammering down, how are we implementing doing HRA and what are the like bigger prospective studies in terms of using that technique and

then specifically how often compliance adherence and some of the treatment that is being used, you know, along with HRA,

any other in terms of I know when I was at Leahy Dr. Breen, I believe that you were starting to do more in collaboration with I think maybe dermatology or ID in regards to some of the antiviral therapies. Are you still using any of these or what's been your experience with some of the topical treatments?

So I think, that's a great question. So I think again, how I approach visible lesions, something that's demarcated or raised. Or I feel like I know where the borders are and how I treat something that is just visibly completely normal and maybe some little pinch biopsies have shown H cell here and there, but I'm not really sure on the HRA how discreet these lesions are.

Those are kind of, kind of the

field defect lesions. So if it's small and definable. I'll usually excise it for PATH, and I like to know that there's negative margins. If it's a field defect, then I think cautery works well inside the anal canal. I think cautery of the perianal skin is rough. I think topical treatments of the perianal skin are a great choice.

But it's hard to get patients to put the topical treatments inside the anus all the way up to the dentate line. Yes. And it's kind of one of these things where, like, you try a little cautery, then you try a little Effudex. And then we started getting interested, like you said, based on collaboration with dermatology with an agent called Sidofavir, which is another one of these.

Broad spectrum DNA, against DNA viruses. And it's, I think it may end up being more helpful for L cell and condyloma because that's where a lot of the work has been done. And again, topical lesions, and so I've had a few patients that I've shared with dermatology who've had just confluent

condyloma of the whole perineum, and the topical sudophylia cream has been great.

But you have to fail ADARA. A couple times, then you have to really go at the negotiating with the insurance companies with all the letters, et cetera, et cetera, and follow up. I think when you were a fellow, we experimented for a little while with thinking about intralesional, it was called, sedoflavir.

And the idea here was, again, H cells keep showing up inside the anal canal. The patient can't put the topical cream up there. We've full graded it a few times. There's too, it's too diffuse to think about excision without causing stricture. So we were like, well, maybe we can just start injecting the IL interlesional sedophobia, which is something that has been done for like laryngeal condyloma.

But, you know, I think with people being more free with electrocautery and with the interlesional being, you know, I'm just not sure we've been feeling like there's a big need for it. And it, and it doesn't seem

as. diffusely applicable because you have to get under the mucosa and inject. So it's like, not like the cautery where you can kind of, you know, buzz all around.

Yeah. Just, I would say for me for treatment, it's hard for me to get patients to comply with topicals and therefore I'm more likely to be doing some intervention, whether it's excision or a seromal treatment. I've not had good experience in my population of the topicals long term. Of the perianal skin as well or just the anus?

Perianal skin. That's what I'm talking about. We have it on the outside. I just, sometimes I, I guess I'm more, I will cheat you and then we'll follow you. Whether than you're there, there's, you can control their disease. I find it harder.

Don? Well, I, yeah, I guess I would say like, and not to be too like off putting about it, but it's a little like you come to the barber and it's like, ah, and so I'm like, I'm more inclined to say let's cut some out on, so I guess I would say I'm not. I always like that for all

disease processes, but I feel like I'd be much more inclined to trust, like, going to the OR and trying to cut something out or ablate it, as opposed to saying, try this topical cream.

So that's, I think, my bias. I, you know, so far, early on, I don't have as much experience, but, you know, maybe patients where I'm a little hesitant to go to the OR or will try topical treatments where maybe they have some more comorbidities or frail. I've found even trying the topicals, they then often maybe will have trouble applying it and doing it like we've talked about.

So ultimately have still ended up having to go to the OR to ablate or excise. And so I agree with what everybody said. There's definitely a lot of, I think, limitations to the, the topical treatments. Well, I'll just say, I think this is a great discussion. I think our listeners will agree. Don't you guys agree?

Absolutely. Yeah. Well, thanks for joining us, Dr. Breen. So let's get to some of our takeaways. So,

Tess, why don't you kick us off? Yes. So, know your high risk populations and make sure when you're seeing patients that you're asking all the questions in order to identify and properly acknowledge what patients you should be following more closely.

And then depending on, you know, each patient, you're going to need to have an informed discussion about all the different options and kind of come to an agreement on, you know, what is going to be appropriate for that patient, whether you want them in a formal HRA program, whether you're going to do anoscopy in the office making sure you're following those patients and have a treatment plan, I think is key.

All right. I'll go ahead and give them ourselves must knows, but first treat H cell. Okay. I think we're all, all in agreement about that. Okay. History tends to repeat itself. If you've got somebody who's not growing a lot of lesions much, don't be as aggressive and sometimes I think less is more. I am doing more probably thermal treatments and less

aggressive resections to avoid complications.

Treatment can be worse than the disease. Right.

And I think I'm saying the same thing everyone else is saying here, which is treat any reliably identifiable H cell that you know of in any patient. And it can still be a little tricky what is reliably identifiable H cell, you know, like just saying plain anoscopy, high resolution anoscopy, how are we really going to find this stuff?

And then there are much less morbid treatment options available nowadays than just pure excision. And so I think that gives us a little latitude to be. a little more aggressive in treatment. Joanne, Abelson's, yeah, Abelson's approach. So I think it's, jury's still out a little bit about how we, what's the exact best way to do surveillance and treat.

And so I would just say, like, don't throw up your hands and not do anything. I would just say pick something that you feel comfortable with and follow your patients and watch closely. I think even that, hopefully, if there is going to be a cancer, you'll find it

early. All right. So with that, we're going to wrap up our eighth episode.

And again, if you like diving into the weeds, you consider joining us Sunday evenings for our colorectal surgery virtual education series. You can also check out some of our show notes for some details. And so we do hope we continue to have the privilege of creating awesome content for you in the future.

In May, we're going to present an interesting case about peristomal hernias, talk about a couple of interesting approaches. And I will say if you enjoyed the session, do take a minute or two out of your day, leave us a review. And so as behind the knife says, team, until the next time, validate the date and happy holidays from Leahy to the Beyond the Knife.

Listeners, happy holidays, everybody.

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