 Good morning and welcome to our subspecialty round service. I want to congratulate all of you for planning for the weather. I also want to introduce a guest. This is a return international observer, Dr. Ikwesi Ahmed from CAATH in Ghana. Dr. Ahmed has finished a five month Retina Fellowship at Tilganga in Nepal. He will now be with us for one month and then he'll be working for one full year doing a Retina Fellowship with our partners at Erevent. And then he'll return to be the Retina Specialist for CAATH. So welcome. Would you like to say anything? You don't have to. All right, very good. We'll get you at the very end. With that, I'll turn the time over to Dr. Emmy Hartnett for our Retina subspecialty round. Thank you all for coming. I think it's an exciting time in Retina and genetics. And so we have a theme in this grand rounds where we'll have our experts present cases and then hear about some of the genetics from our genetic counselor, Emily Spoth, who I hope you all continue to use her expertise. So first, we're going to have Chris Kamansky, who's one of our first year fellows. And he's going to present a case of melanomelitic glaucoma and discussion of UVL melanoma genetics. Chris. All right, so this is an interesting case that I was able to see with Dr. Jacoby. And the history is that the patient came in complaining of floaters. He's a 69-year-old gentleman with a past medical history of diabetes, kidney stones, chronic kidney disease, stage three, who presented and complained of these new onset floaters in his right eye and denied any pain. He had a history of moderate myopia. He had a multifocal lens in his right eye that was positioned in the sulcus due to vitreous loss during surgery. His past medical history, as we talked about, CKD stage three, when I was looking at the chart initially thinking that was from diabetes, is actually due to severe and chronic nephrolithiasis. His diabetes was well-controlled with diet and physical activity. His hypothyroidism, hypertension, and hyperlipidemia had no family history of cancer. Married Liz at home with his wife. Medications were simple as the synthroids and the statin aspirin. And he was allergic to linoglyptin. His eye exam, his visual acuity, his hand motion in the right eye, 2020 in the left eye. His last refraction was actually done before he had cataract surgery in his right eye. And this is his refraction and vision. Pupils were normal, pressure normal, were unable to obtain visual fields in the right eye but normal in the left eye. On slip-like exam, he had a large caliber vessel temporally in his conjunctiva. He also had, in his anterior chamber, two millimeters of a layered hyphaema with three plus-pigmented cell. Again, he had the multifocal sulcus lens. On dilated fundus exam, in the right eye he had a dense vitreous hemorrhage. He had no view posteriorly in that eye. The other eye was normal. So at this point, do we have any of the residents here? We have lots of them. Lots of them. Theresa, what's your differential for a diabetic with a vitreous hemorrhage? Perfect. Since he doesn't have diabetic retinopathy in these other eye, what other things would you think about? Yeah. So things that cause neobascularization, like ocular scumic syndrome. But what's probably most common in someone without diabetic retinopathy? So like retinal tear, hemorrhagic PVD, 69, retinal detachment. Because he didn't have diabetic retinopathy, and this is just kind of the complete differential on vitreous hemorrhage, we won't belabor it too much. But the general categories of the vitreo-retinal interface, which is most common at the top, then there's neobascularization due to retinal vascular disease, which you see the list there. You can have a RAM. Coroidal is interesting, because you can actually get vitreous hemorrhage from Coroidal neobascular membranes, but also Coroidal tumors. And then trauma, which he doesn't have a history of, blood disorders, and then some less common things than masquerades at the bottom. So additional testing, we did an ultrasound of the right eye, and the B-scan revealed this Coroidal mass, measuring 11 and 1 half millimeters with a thickness of a little over 11 millimeters. And the notes was medium reflectivity, 1 plus irregularity, and 3 plus vascularity. And this is a representative B diagnostic A-scan. So at this point, we have a patient we're diagnosing with Coroidal melanoma, with the right eye, and wanted to recommend an evaluation for brachytherapy with a radioactive plaque. And we wanted to perform genetics to give him a prognosis of this tumor, and then also get liver enzymes, chest and abdominal imaging. At this point, he elected to be referred to Philadelphia, where Dr. Shields performed his plaque treatment. This was this highlighting a classic case of Coroidal melanoma, and then we were just going to go through a discussion of Coroidal melanoma, and then of the genetics associated with it. So it's the most common primary malignancy of the globe. And the annual incidence is 1 per 200,000 people. You can have amelanotic melanoma, like you see here, or a classic ciliary body melanoma, extending underneath the retina and breaking through poox membrane, causing a vitreous hemorrhage and some pigment dispersion, or a super-tempo, this large, Coroidal melanoma. The demographics is pretty equal amongst men and women. Now, it's typical a disease of older people. However, it's arranged in this series with anyone from six years old to 100 years old. It's also a disease primarily of Caucasian people, with about 98% of these in the US being diagnosed in Caucasians. Interestingly, there's an elevated incidence of prior malignancy at 11%, but most of these people do not have a history of prior malignancy. In terms of tumor location, the majority of these are confined to the Coroid. And in this series of over 1,000 Coroidal melanoma, or UVL melanoma, is 65%. We're in the Coroid. 15%. We're in the ciliary body, or iris. And then the remainder were undetermined or not listed. So the treatment options for Coroidal melanoma, historically and still sometimes requires surgical resection, which is a nucleation. However, many of these eyes can be saved by the use of radiation therapy, most commonly brachytherapy, but also protein beam irradiation at some centers. And so quite brachytherapy, this is just a cartoon showing generally what is done. Pertimia is made. These radioactive seeds are placed by radiation oncology in this metallic plate, which is then sutured to the sclera and left there for about four days, then removed. And then the pertimia is repaired. So this is what it looks like when a plaque has been sent on to the sclera. As you can see from the trends in how UVL melanoma has been treated in the 70s, almost everyone was being eneupliated if this was diagnosed. However, through a lot of hard work and then the results of the comms study, it was shown that radiation treatment is actually very effective for Coroidal melanoma, and now it's become much more common. So the case continued. So the patient got his plaque and was doing very well under the care, co-managed between Dr. Shields and Dr. Jacoby. But 12 months after the plaque, he presented to the triage clinic at Moran, complaining of pain, photophobia, anterior, he was found to have an anterior chamber cell, vitreous cell, an ocular hypertension, his right eye was 26, left eye was 10. Dr. Harry was able to perform a B scan that day, and that revealed excellent tumor regression, so similar basal size as expected, but the thickness was previously 11.2 millimeters and now it's 5.3 millimeters, and we have a photo from around this time. And we can see this temporal mass with a little bit of overlying vitreous hemorrhage, and it's a little bit hard to see, but in the inferior vitreous, there's some vitreous pigment that you can see through the eyelashes. Those scars around the tumor actually laser that was performed by Dr. Shields to some non-perfuse retina in the hope of preventing neovascular glaucoma. What was interesting is then we expected this to probably be neovascular glaucoma and expected to treat with anti-vegeta therapy. However, on gonioscopy, there was no neovascularization. There was dense pigment within the angle, as you see in this excellent goniofoto. And this raised some concerns for us. Is this tumor actually seeding the vitreous and now we're getting infiltration of the angle? Or could this be something else? So we sent these images to Dr. Shields and she decided she wanted to see the patient, saw the patient three days later. We started the patient on Prid Forte and Timo on the meantime. By the time the patient followed up with Dr. Shields, the pressure had normalized. The eye was feeling comfortable to the patient and he was feeling back to baseline. She assessed it and determined that this was likely just from tumor necrosis and that this is pigment being dispersed into the vitreous and then being ending up into the angle of the trabecular mesh work. But this is something we're gonna be watching very carefully over the next few months. Does the patient have translimination defects? In the eyes? Because I think there's only really one kind of multifocal you can say, but the rest are all gonna be single piece and that could be complicating the issue with. Absolutely, I think that's a great point. The patient was dilated when I saw him and I did not notice translimination defects, but it's something I might wanna go back and look. Look and see if it's a single piece or a three piece. If it's a single piece then. Then that could be a, yeah. Absolutely. Thank you for that. And what we're most concerned with is that. This shows the issue sometimes in the front of the eye forgets there's a back of the eye, the back of the eye be able to find out. Absolutely. It's just a clear window, right? So, we really wanna focus on that in cordial melanoma we're treating more than just the eye and we're treating the patient and that's because this is a disease with significant mortality. Despite advancements in the treatment of cordial melanoma, this mortality has been about 20% over five years and that hasn't changed over the last 40 years. And as you talked about there's the comm study which showed that radioactive therapy was safe and effective and this is the main result from that which this is death for many cause of the brachytherapy group versus the nucleation group in medium size tumors. You can see through 12 years there's no difference in survival. This is also true if you look at the results looking at only metastasis free survival. But there's also a lot of interesting data that was gained in the study. There are things that will put patients at risk for mortality and metastasis. And two of the biggest things I identified in this study was age. So if patients were over the age of 60 they were more likely to die from any cause but they're also more likely to develop metastasis. And if the tumor had a greater mean basal diameter of 11 millimeters. So after the completion of comms there's a number of people who looked at a lot of these risk factors to come up with predictors of metastatic disease. So hopefully we can identify these high risk patients and start learning of ways to help hopefully treat them. And this was mostly done looking at a nucleated eyes and they would calculate the largest basal tumor diameter the presence of different histologic results like closed loops, epithelial and cellularity, the metotic rate and then whether or not there was metonic spread. And this could be put into essentially a risk calculator that would hopefully predict how likely metastasis would be to happen. But what became clear to the oncologist is that this wasn't very good at doing that. And so the next step in trying to figure out uveal melanoma metastatic risk it was really to focus on genetics and how genetics could help us figure this out. There are two real main schools of thought and that was chromosomal analysis, DNA analysis which is led in Philadelphia and then gene expression profiling which is mRNA analysis which has really been at the forefront or been led by a big group down in Miami. And so we'll talk about each of these approaches. So there's some chromosomal changes that really have been linked to metastatic disease and melanoma and I'll talk about two of them. There really are three chromosomes involved. Chromosome three is probably one of the most important predictors of metastatic disease. And this is important to note this is the genetics of the tumor, this is not the patient, this is the tumor's genetics. And if you have a normal chromosome three you have relatively low incidence of metastasis three survival. However, if you lose one of your chromosomes three to an osomy of chromosome three there's high risk of metastatic disease. There's a similar story but somewhat flipped for chromosome eight Q in that if you gain chromosome eight Q you're having this increased risk of a metastatic disease. And what this study was looking at some of those basic characteristics of the tumor that you can get from ultrasound or from the biopsy and then looking at chromosomes three and chromosomes eight Q. And what I wanna show is that these the hazard ratios and what you can see is that the hazard ratios are elevated for some of these characteristics that have been shown in other studies to predict metastatic disease but when you look at the magnitude of the hazard ratio these chromosomal changes are much, much more important to predicting metastatic disease. And there's a really a similar story that's told when looking at gene expression profiles and metastatic risk. This is Dr. Harvey in South Florida. He had two major studies that looked at this concept of just breaking down tumors into either class one tumors, low risk tumors for metastatic disease and class two tumors which would be high risk for metastatic disease. And the initial study was only 26 patients and they actually identified 3,000 genes that were linked to risk of metastasis. And it's a busy slide but when you look in the molecular class which is not for right, you can see that class two tumors as determined by these 3,000 genes had a much higher incidence of metastatic disease and in the small sample size, a lot of the other things that were known to affect it weren't, they weren't able to determine that and then some of the things that shouldn't affect it like gender, there was no effect. This was then followed up eight years later a much more detailed study looking at 459 patients and to make this a more achievable test they truncated it from 3,000 genes to 12 genes and looked at the gene expression of those and they confirmed some of the things we know that age has an increased risk of metastatic disease, thecillary body's involved, it's an increased risk, a bigger tumor has an increased risk but when you get down to the bottom two graphs you really see that if you have minus only three, absolutely that increases your risk of metastatic disease but even more so than that they would argue this class two tumor as determined by these 12 genes has an increased risk of metastatic disease. Just to talk about one of the more recent findings that a lot of people are talking about is this BAP-1 mutation. We've already talked a lot about chromosome three, well on chromosome three is this BAP-1 gene and what it's been found is that this is very often in almost all metastatic melanominal or UVL melanoma cases that there is loss of expression of this and so whether that's because you have a chromosomal deletion or you get somatic mutations if you are not expressing BAP-1 you have a very high likelihood of developing metastatic disease so thought it's maybe we should assess directly for BAP-1 but that's still being debated. So our patient was in Philadelphia so they got the chromosomal studies and this is essentially the breakdown of the main findings of those chromosomal studies so two of the chromosomal changes in this patient gave them elevated risk. Dr. Shields published just a few years ago essentially a giant table that you can go through the matrix and find where your patient is based on all these chromosomal changes and what they found is that or you can look up is this patient has a five year risk of the test disease of about 33% which is very high and now we have to consider if we wanna refer him to some of the clinical trials that are looking at prophylactic therapy to try to prevent metastatic disease. Look at the huge odds ratio on that though. Yep. You gotta be very careful of telling people I mean the spread on that or your standard deviation we wanna call it is huge. Is massive. The reason is that out of the 1059 patients with UVL melanoma that they did this study with only six had this specific break. Precisely. And so how predicted is that? Well single patient who's dramatically different is gonna dramatically change that and that's what that's why we often look at these average ratios and we get the one the spread is huge let's be a little bit cautious about acting with patients like this is deterministic. And I completely agree. And especially since the treatments that are being looked at as prophylactic therapy are not benign. There are certainly risk associated with it. So we have this really interesting patient with melanoma-elitic glaucoma which we'll be following and hopefully we'll do well with topical therapy. And I think it was one interesting case we got to learn about melanoma-elitic glaucoma that hopefully this is either chafing an OGG syndrome or this is this pigment being dispersed from the tumor or and hopefully he remains metastasize-free. Here are my references and this one I'd like to open it up for further discussion about the genetics. And yeah, so I'd like to introduce Emily Spolt who's our genetic counselor. She can talk a little bit about her service. I have a terrific presentation. Thank you. And my role today is to be the official genetic peanut gallery for these cases. But in general what I do here is I see folks with either suspicion of or confirmed genetic condition view that an inherited retinal dystrophy kind of runs the gamut. That's mostly what I do. For this case, if you noticed on the BAP1 slide there is a subsection of folks that have an identified germline BAP1 mutation. So this is always interesting. BAP1 is one, so this is essentially a hereditary predisposition to uveoloma melanoma as well as molybdenum mesothelioma, clear cell renal cancer, utaneous melanoma. So worthwhile, I think, if you have a uveoloma patient to just ask about family history. Because this is one of these dominant tumor suppressor to hit hypothesis predisposition. So I'll be quick, that's all. Well, and please, Emily does a lot of different helps with a lot of diagnoses as well as management of patients so you can consult her. Okay, thank you.