 My name is Kirk Wynward and I'm in a retina group here in town. We used to get up here pretty regularly for various conferences and grand rounds and as life has got busier, it's just harder and harder to do that. Just by way of introduction, I'm from Utah, I went to medical school here. At that time, Moran just said, well, it wasn't Moran. We were over at the main hospital and we just had two residents a year. We had the internship and I matched as an intern here and then went back to Miami to do my residency in fellowship and came back here and joined up with a person and then we've hired some people over the year and right now we've got seven people in a retina practice here in town. One of the things that I end up doing is treating some of the melanomas and so that's what we're going to talk about here today. We'll go back in the history just a little bit. Prior to 1960, melanomas were, well, even now they were kind of a feared condition because there's, especially if they're metastatic, there's just really nothing you can do to treat them. But basically the dogma that we went by back then was when in doubt, take it out and lots and lots of eyes were nucleated for things that we would never think of doing it now. We tolerated about a 20% misdiagnosis when those things went to path and as things evolved a little bit, people started to take a little more conservative approach and we started to get better examination techniques, ultrasound, at some point there became developed, we became better at diagnosing them but we still had a fairly high misdiagnosis rate. There was also Zimmerman proposed a hypothesis where he noticed that about two years after a nucleation there was kind of a bump in the death rate from melanoma patients. And so he proposed, well, what happens is during a nucleation you disseminate a few little cells that then end up about two years from then killing the patient. So it made people rethink, you know, are we doing a favor, you know, being quite aggressive with a nucleation. So people started to observe them, at least the questionable ones a little bit and we recognized that not all of them grew. And in the mid-1980s, kind of the landmark study was started, the COM study or collaborative ocular melanoma study. I was part of that study in my training and that was really the landmark study that changed the way we treat these and of course there's been lots of other information that has come since then. But right now and even then is one of the results of the COM studies was that we recognized that we could get this right diagnosis wise almost all the time. In the COM study, when those eyes that went to a nucleation, there was less than a one percent misdiagnosis rate. So we feel, unlike probably any other tumor in the body, which if you have a question, well, even if you just make the diagnosis, you almost always biopsy that to confirm the diagnosis. And in the eye, well, we sometimes do needle biopsies now, but at least at this time we weren't doing that and we made the diagnosis purely clinically, which is a very different way of approaching it, but we are highly accurate. One of the reasons is because unlike anywhere else, we can really see and measure these tumors in important ways. So just a few little facts, it's by far and away the number one ocular malignancy and they generally tend to be older patients. The incidence is about 6 per million per year in the U.S. or in countries that have predominant Caucasian races. Certainly Caucasians have a much higher incidence than do pigmented races. That turns out to be about 1500 new cases per year in the U.S. and by and large it's felt to be a random tumor, at least as of right now. We don't associate it with sunlight exposure or a lot of the other things that other cancers have defined risk factors. It seems more to be bad luck or random than anything else. Other than as you might expect, conditions that give you more melanocytes can raise your risk of that a little bit. The symptoms, the number one symptom is none. The majority of these are just diagnosed on a routine exam for which the patient went in to update their glasses or something. If they do have symptoms, probably the thing that I see more than anything else are just kind of ill-defined photopsias. Just a lot of these tumors will leak a little fluid and it just seems like fluid under the retina tickles the photoreceptors and your brain interprets that as photopsias. Other ones or ones that get associated with some exudative detachment then can involve your vision or visual field defects would give you distortion. Occasionally somebody lets one go and doesn't show up until they kind of present with neovascular glaucoma or at least marked inflammation and pain. Obviously, we don't see that too often in today's world. On exam, important findings are sometimes you'll see sentinel vessels. Vessels are dilated. Episclerol, conjugal episclerol vessels over the side of the tumor. As these tumors start to grow, they need to have a blood supply and they can recruit that from the coroid and some of them even from the surface of the eye. Occasionally there's a mild arthritis, but I would say that's a little uncommon. Occasionally there's high pressure. Again, that would be more advanced ones that are shedding some pigment clogging in the trabecular mesh work. You might see some pigmented cells in the AC and victorious, but most of the time you don't see that either. About three-quarters of them are pigmented, a quarter of them are amelanotic. Most are kind of dome-shaped and like so many things in ophthalmology, it's pattern recognition and that's one of the things I'm, we're just going to go through and see some pictures of a number of them because once you've seen a half a dozen or a dozen or something then it's a lot more easily recognized. A few of them do tend to be kind of a diffuse infiltrative tumor or ring-shaped right around the ciliary body, again those are fairly uncommon. One of the things that you always want to take home from lecturers like this or what are they likely to ask you on the boards? This is often a board question here, a collar button lesion. That is nearly pathinomonic for melanoma, almost pathinomonic. And the reason for that is, is these tumors, you know they grow under Brooks membrane and Brooks membrane is reasonably tough and it takes kind of a tough tumor or whatever to rupture it. So metastatic lesions or others, they usually don't, Brooks membrane kind of traps them and they kind of pushes them down and they just spread out more diffuse and flat. But for melanomas they have a little more solidity to them or a little more form and they will sometimes rupture Brooks membrane and then it kind of becomes like a little tube of toothpaste where some of the tumor kind of squirts up through that little rupture and forms this little mushroom type or collar button lesion. A collar button lesion on the boards, Mark, melanoma and you'll be right. I remember one of them that I treated not too long ago, a patient from the VA, they came up and we treated him with a plaque and I saw him like a month or so afterwards and they look great and then I got a call from their ophthalmologist down there that said, this tumor is just really growing. We got to send him back up and as we'll get to in a minute, that's really rather unusual. We have exceptionally good success rates with treating these tumors these days. So I was a little suspicious of that and when the patient came up, sure enough that tumor that had been just a dome shaped it now had this big collar button shape which made it quite a bit taller to look at. But I looked at it, it also looked to me like the sides were somewhat flatter. So when we had Roger Harry do his ultrasound, sure enough he measured it probably twice as thick but the overall volume of it looked the same or smaller and so we opted, what I thought would happen is it just a ruptured Brooks membrane and just squeezed up through and so rather than rush that eye to a nucleation we just watched it and it just continued to shrink and that's exactly what happened. We have a dead tumor but one that just ruptured through Brooks membrane. Here's another thing that you may well see on the boards. There are shields 5 factors, there are shields from Philadelphia. One of the concerns has been that if we can diagnose this tumor earlier since if it once gets out of the eye, it's basically a fatal tumor. We just do not have a treatment for it once it's out of the eye and so he's looked at how can we treat these earlier and yet not a nucleator or irradiate too many eyes and initially came up with these 3-5 factors that if it's greater than 2 millimeters thick, if there is subretinal fluid, if there are symptoms, if there's this orange lipofusin spotal or speckled pigment on the surface and if the margin is within a few millimeters of the disc then that makes it more likely to eventually turn into a melanoma. In fact, he said, I always hit the wrong button, he said that if you have 3 or more of those and that will predict about a 50% growth. You still want to be a little bit careful about, I mean you don't want to have a 50% misdiagnosis rate so we still tend to often watch those but he subsequently added a couple of other factors to that and so now it's become this little mnemonic to find small ocular melanoma using helpful hints daily and again here's what we have. The tube or the T for the thickness, fluid, symptoms, orange pigment, margin within 3 millimeters of the disc, ultrasonographic hollowness and the absence of halo, kind of a depigmented ring around the tumor or drusen and that's, actually we'll come back and look at a couple of these a little bit later why the absence of that might be predictable. So in other words that often ends up being another board of questions, that little mnemonic there. So we're just going to go through and look at a few tumors. Here's one that has this little clumped orange lipofusin pigment. We think that that probably represents breakdown of more rapidly growing tumors compared to anivis. Anivis you'll often have drusen or you'll have chronic changes. If anivis has been there for a long time and hasn't been changing then you'll see what we think of as chronic changes like drusen, yellow drusen or black pigment, just a pigment metaplasia. But if you have a more metabolically active lesion then some of those breakdown cells as they're turning over end up being some of this lipofusin pigment. Here's one that you might consider that a little color but I have some better examples of that. Again just a dome shaped lesion, pigmented or amelonotic. Here's one. I find this kind of an interesting one here. You can see the orange pigment here and you can see some drusen here. In my mind what this was is this was probably anivis right here and it has some of these chronic findings like that. And can you see how this side is bigger? It's like wider there. I think this was probably anivis and somewhere right in here of it some cells underwent malignant degeneration and then those cells started to grow and they end up having some more typical features there. I actually think this same patient shows up a little bit later here. Again just another lesion, another lesion there. We'll just toggle through a bunch of these here quickly. Here's one that has a bit of a collar button there. This kind of pigment is the kind of pigment that makes you think chronic. That makes you think melanoma. Here's another collar button. This one is I think a really good example of probably some toothpaste squeezing up there. Sometimes you'll see a little hemorrhage associated with it. You usually don't see a lot of hemorrhage although I am going to show you one that we did. Again here's another collar button lesion. And often in these amelonotic ones you can see the tumor vessels, the retinal vessels that come over the top and then the larger tumor vessels that are down inside the lesion. And these are some of the things that you'll look for on angiography. Again one more. Here's a smaller one with just a little fleck of hemorrhage there. And this one ended up being kind of a challenging one to treat because it was an amelonotic tumor here. I'll show you in a minute how we actually go through the surgery and one of the things we do is we trans-aluminate the eye to kind of localize the tumor so we can get the plaque in the right place. Well amelonotic tumors don't trans-aluminate very well or don't block trans-alumination. But blood sure does. So when we got in there and started trans-aluminating this eye all we were finding is where the tumor wasn't actually in there. So that can sometimes be a little complicating factor is treatment. I think we're just about done with these. Okay so a differential diagnosis. By far and away a nevus is the, most of it boils down to is this a nevus or is this a melanoma. Sometimes a discoform I'll get patients sent in with a discoform scar wondering if it's a melanoma. More often this is probably the one that gets confused more often than others is kind of a peripheral CNV lesion that created a hemorrhagic PED out in the periphery. Ultrasound can usually sort those out. Ultrasound and angiography you don't see. You see blockage by the blood rather than tumor tissue and Rodger can almost always distinguish between blood and cells. And so those are usually fairly easy to sort out. Melanocytomas another lesion of melanocyte origin. It tends to be more jet black usually around the optic nerve often with kind of a feathery appearance. Congenital hypertrophy of the retinal pigment epithelium that's often fairly readily distinguished but when you get out in practice if you're in any kind of referral center anything that looks weird often will get sent in to you. Hemangiomas they can be sometimes difficult to sort out from an amelanotic lesion. They tend to be more orange rather than white so they're not really amelanotic. Usually an angiogram will sort that out. You'll see the vascular pattern in it. Reactive RP, metaplasia that's usually fairly straightforward to sort out. And metastatic lesions can sometimes be a little confusing but often you'll have a history of primary tumor somewhere always. They tend to, they're more likely to be multifocal. I mean if you think about it, if they make it to the eye they're usually spread hematogenously. They end up in the posterior pole where most of the blood flow goes first and it's not surprising that you would have kind of two or three nodules sometimes merging together. They also have a little bit of a different ultrasound appearance. Okay so some findings that suggest that the lesion is benign as we've talked about. These are all things that suggest chronicity. If there's drusen, we talked about that. Chronally ovascularization, usually you see that far more often with the nevus than you do with the melanoma. It just seems like it needs to be there long enough and irritating the pigment epithelium long enough to finally cause a little weakness in Brooke's membrane where some vessels can finally pop through. I had a neurosurgeon recently send in with what they were all worried was a melanoma and it had a classic CNV lesion right associated with it. It had given him symptoms. It was just temporal to his macula and of course he was a young guy. I've only been out in practice maybe four or five years and this is a potentially career threatening thing but we just gave him a little of Aston and CNV shrunk away and we've watched him now for a number of years and nothing has grown. That's all that was. A hypopigmented margin. This is the absence of halo and Bruce Shields mnemonic. Again, if the nevus has been there for a long time sometimes there's just a little chronic irritation around the edge of it causing the pigment epithelium to depigment and so if you see a lesion with a white ring around it it's far more likely to be a nevus and those dark or black like RPE changes over the surface. Again a sign of chronicity. Here's just a few of them. Some typical Jews obviously that was not a very big one either but that on top of it is a very positive sign. A very thin one under the macula. Obviously thin I guess is another one that a neviar can be very thick but more often are much thinner. Here's some RP metaplasia perhaps trauma or something in the periphery. On the work up you basically just do a good eye exam. You get an ultrasound and you look for low to medium reflectivity as opposed to a nevus that is usually more highly reflective and you look for vessels in them. They tend to be more vascular than neviar. They're more metabolically active tissue. They have to recruit and grow more blood vessels to make them survive. You'll do almost always do a fluorescein angiogram. There are no specific findings on angiography that really help you to make the diagnosis. I mean we look for some little punctate leakage in a tumor vascular pattern but more than anything that's probably to just kind of rule out some other things. Make sure you're not misdiagnosing a hemangioma or something. The definitive thing or if you are still wondering about it is you watch them for growth. Nevi can grow but they tend to grow very little over many years and melanomas are definitely quicker than that. And then we certainly can do needle biopsies. We'll probably talk a little bit more about that in a minute here. Here's just an angiogram. We often get these little punctate hot spots. They're like new vessels in most places in the body. They tend to be incompetent and tend to leak. And if you have metabolically active mass with a lot of vessels in it, you get lots of these little hot spots that just kind of give you that diffuse leakage late in the angiogram. Before we treat these, we always get a metastatic workup. I often leave some of the details of that up to their primary care physician. But basically a physical exam just to make sure you don't see signs of metastatic lesion elsewhere. That's pretty rare to see other than late in the disease. Just a routine CBC, LFTs to see. This tumor primarily goes to the liver. If it's metastatic, it often ends up everywhere. But the liver is where that gets diagnosed, 90% of the time. We get a chest x-ray. Again, it's kind of rare to find it in the lungs until late. And so this is probably the most important one. There's some kind of an imaging test of the abdomen or liver. In the ones that we treat, I mean, rarely does somebody come in with a big tumor. Almost always this is negative. An important thing that I always spend quite a bit of time with a patient is emphasizing does not mean the tumor is not already out of the eye. It just means it's too small for us to find. Creutal melanomas are very different than cutaneous melanomas. They spread hematogenously. They like to seed the liver. And it seems like it likes to be dormant there for some time and then subsequently reactivate. So that's where you're going to put your money. But when we're treating these, at the time we're treating these, I think in all the years I've been doing this, I think there's just one I've found where we thought it was metastatic before we treated it. An important thing is, in the comm study, average survival was less than six months. It's a bad tumor if it once gets out of the eye. So we want to go through the comm study since it was a landmark study. So collaborative ocular melanoma study started in 1986. They somewhat, I was going to say arbitrarily, I mean this was based on their best thought process at that time as the investigators sat in a room and hammered out how we were going to do it. But obviously, they divide the tumors into three categories and so they had to decide on a size to do that. They divided them into small, medium and large. And they defined these were small, was less than two and a half millimeters thick. Actually initially it was three millimeters, and part way through the study we thought we got good enough that we dropped it down to two and a half millimeters. Large were greater than eight millimeters thick or a base greater than 16. The way this came about was most of the investigators thought that if you're going to irradiate a tumor that big since you treat to the apex of the tumor, that's where you calculate how much radiation you give them. So a thicker tumor gets an overall higher dose of radiation so the apex gets usually around 85 gray is what we target. That's enough radiation that you can kind of expect that that eye is not going to do very well. And ones that are bigger than 16 millimeters, we like to have a two millimeter margin around the edge of the lesion. So if we have a 16 millimeter tumor, we've got to put a 20 millimeter plaque around that and beyond 20 millimeters is just technically difficult to get a plaque bigger than that and fit it in the eye and not have to remove so many muscles and other things that you end up with a bad result anyway. But the purpose of the study was kind of two-fold. One is to decide whether plaque one could treat the tumor well but probably more importantly is what does it do to the death rate because that was the big concern. People had started to treat these with plaques before this but the argument was well yeah you save a few eyes but you send more people to the grave is that worth it and so that's kind of the main indicator right there is what was the death rate and then on these larger ones it was kind of the Zimmerman hypothesis if we irradiate them before we nucleate them and kill those cells so if we cause some dissemination of cells or dead cells does that change the death rate and the results were that pre-radiation had no benefit it added complications and expense did not change the death rate kind of put the Zimmerman hypothesis to rest. The plaque treatment there was no increased death rate in fact technically there was a slight trend towards longer survivability with the plaque interestingly we're kind of left to speculate why that would be again that was not statistically significant we say that there was no difference but it actually favored the plaque slightly and one of the things that we might after the fact attribute to that is you know maybe these tumors are causing a little bit of an immune response that if you remove the tumor your immune response goes down and if there is a hidden cell somewhere you don't have that low grade immune response still working whereas if you have some dead tumor cells still there in the eye it might kind of keep that going it might kind of work on those other ones again speculation but a possible explanation and we also kind of another thing was is we saw that the small tumors could in fact be observed with little change with no measurably different change in the death rate so it made us more comfortable in watching the suspicious ones or the inconclusive ones so the conclusions that kind of came out of this if they're small most of the time we just observe those to see if they grow before we're going to treat them we consider Schild's risk factors and the health of the eye and the age of the patient and all those things but most of the time we end up watching those for a while and if they do grow it's often not a few months it's often a few years before you pick that out there a small volume of tumor we think they have once they are a quote melanoma they probably have a fairly steady doubling rate but if you have a small tumor doubling it just doesn't seem like it's growing as much as a big tumor doubling so we figure Roger is probably accurate to with Roger Harry is probably accurate to within about a tenth of a millimeter I mean his air of reproducibility so if it grows a couple of millimeter I'm sorry not a millimeter a tenth of a millimeter if it grows a couple of tenths of a millimeter boy that's not very much but that still often takes a year or two or three in my experience if they're a medium-sized tumor or a large tumor if you look at the clinical and angiographic appearance consider that excuse me how typical that is for melanoma you look at the ultrasound you know do they have low to medium internal reflectivity and high vascularity and growth those are kind of we kind of categorize things into those three if you have two of the three I'm usually ready to treat right off the bat and if there's something that you know if the appearance is atypical or the ultrasound there's something atypical then we'll watch those for a little bit before we treat them but most of these that come in into this size range we usually figure we know the diagnosis and move forward with treatment of some type and in the large ones we just usually send those to a nucleation other than I just got one from you guys the other day a patient that has a permanent carotoprocesis in one eye and lousy vision and now has a sub-phovial melanoma in another eye that's a challenging situation there anyway if they're small we either observe them for growth and then when they grow we do some kind of a vision sparing treatment a medium we recommend vision sparing treatment in the large we generally will enucleate we ought to look at the various other options I mean most of these end up in the US getting plaque or breaking therapy but there's I have one patient that I know she has a melanoma and I'm just watching it and I've been watching it for over 20 years now she is now 90 some years old it took about 10 years and it grew and so that told me that this is probably a spindle A or a very inactive spindle B oh actually we didn't mention that so you're nodding your head so Nick has told you about these I guess we kind of categorize them into pathologically spindle A, spindle B mixed in epithelioid and their kind of aggressiveness follows in that same order so I know hers is a low grade melanoma it's in the periphery she has great vision and we've just been watching it I see her twice a year it's now still only about three and a half millimeters thick so it's still a fairly small one but interestingly she had a sister who died from a cradle melanoma so we've had a few discussions about what that means over the year but every year I tell her we can treat this if you want we can probably treat it without causing any visual loss but you're going to die of something else and if it were me and I were 90 three and a half millimeter melanoma I'd be watching it nucleation for big ones occasionally you get somebody who's just so nervous they can't stand to have cancer in their eye even though you recommend otherwise they want it out plaque radiotherapy is the main way we treat that and we'll walk you through how exactly we do that in a minute proton beam radiotherapy it seems to be as good as plaque therapy it's just another way of giving a localized dose of radiation we don't treat these with external beam radiation it gives you radiation all through the beam course whereas a proton beam has a magic way of just making the radiation unload at a given at a given point and there's just a handful of places around the country that have a proton beam accelerator they tend to be somewhat more expensive but if you have one you use it so you pay for it I guess and everywhere else we do plaques trans people trans people thermal therapy it had a still occasionally do it but not very often there was a short window of time when that looked promising that's kind of a heat induced laser that kind of burns them it's different than like your argon laser that coagulates them it just heats the tissue but kills it but it ends up leaving a scar very similar to what an argon laser would it and so it can't penetrate very deep that's the next thing up here is laser and cryo you just can't treat very thick with a laser especially if it's a pigmented lesion it will absorb the power if it's a melanotic one then it's really difficult to laser but if it's a pigmented one you can burn a little ways into the tumor and kill the cells it's just you can't burn very deep so you end up having to treat again and again and that only works for relatively thin tumors in isolated places and it's kind of the same thing with TTT TTT has a propensity to cause a vein occlusion if you treat over a vein so that also eliminates some other ones but I'll show you an example of one we did end up treating like that local resection again not done a lot but basically you create a trap door in the sclera and shell out the tumor and hope you get it all so metastasis you can look at risk factors older patients increased size of the tumor scillary body location definitely has a little higher risk epithelioid cell type more aggressive tumors more likely to spread there's extra ocular extension that's really rare we always send it up here to Nick to look at it's really uncommon that you see it spreads hematogenously and then there are genetic markers and we're going to talk about that the incidence of metastasis any article you read will usually say up to half of patients die from metastatic disease I think that half percent number comes from I mean it comes from papers in the literature but it comes from papers that look that larger you know if your set of patients has more of them that started out as a larger tumor you're more likely to see that in the comm study it was less than 20 percent that died from metastatic disease so it's somewhere in there 50 percent often is the number that's thrown around when people are talking about it but it certainly seems less in my experience I have much less than 50 percent of my patients die from it again there's still there's always an experimental protocol somewhere where somebody has figured out some new combination of therapeutic agents to test these patients with so far there's nothing that's been shown to be effective this is one of the things that gets talked about most right now and I would think there's a fairly high chance that you'd see something of this on the boards the genetic analysis or the expression of this tumor we said that it was just kind of a random tumor or it's just popped up randomly just kind of bad luck to get it but it seems to be at least a large number of them it's due to a random mutation not the mutation that you inherited it's very rare to see this run in families but just one of those random mutations that triggers melanoma cells to go so initially when this information first came out a monosomy 3 seemed to be the big risk factor with a much higher incidence of metastasis if the tumor had that than if it didn't but there were you know it wasn't always that there was a number of other things that were looked at and so people started to look at various combinations of these things and then the thing that has come out recently well recently in the last maybe four years or so gene expression profiling or GEP and what that looks at it's a PCR assay of 15 different gene products and it's commercially available now that's what kind of really turned the corner on us being able to do it it was not just an expensive research test that could be done in one place in the world but it's commercially available and then it will categorize the tumor in either a class 1 or a class 2 and class 1 has a much much lower risk of metastasis and class 2 has a high risk of metastasis and this type of information makes a lot of us think that you know your prognosis depends on what the genetic makeup is of that tumor because if you have the bad genes that tumor probably disseminates very early on and you're probably dead before you realize it no matter what we do and because even sometimes when we treat these little small melanomas patients still die down the road and on the other hand if you have a class 1 set of markers then you know this patient I just talked to you about that has the carotoprocesis I'm hoping she has this because if she does she can let that tumor grow in her macular for a long time and still have she'll probably keep really good vision in that eye for years as long as we don't do something to make it bad and she would have a low risk of death but again no test is 100% and so if you're class 1 you can't sleep easily because it doesn't always so and if you're class 2 you don't have to you know go do your bucket list immediately because not all of those do do die but the rates are very different between those two I'll often get a what actually comes back to me when we send that in is something that says this is a you know this is a class they actually split the class into one A and one B and they say you know this patient has a 98% chance of being metastasis free at 5 years and a 92% chance at 10 years those are fairly nice numbers and if it comes back class 2 then it's you know you have a 60% chance of 5 years having had metastatic disease and so it's helpful and it's helpful in counseling the patients but it's not 100% accurate the other challenge that we have with that and it's a challenge that I struggle with is that even though we can get this information it doesn't really change what we do as far as I mean if it since we don't have a treatment for it you have to ask yourself is how important is it to have this information because what are you going to do you're still usually going to treat those eyes unless there's some extenuating circumstances like the one patient I mentioned and then you're going to have to follow them postoperatively to look for metastatic disease and the question is how much money do you spend and how much risk do you give that patient with CT's scanning their abdomen every 6 months or something if for a disease that you can't treat because the you could argue that you don't even need to do postoperative screening unless the patient just wants some advanced notice and it doesn't really change what you're going to do the other thing is it's not entirely benign to do a needle biopsy I mean most people will say that risk is low but there have been at least 4 cases where you had seeding of the tumor along the needle track those were eyes that didn't have to have a metastatic disease in my mind and if you can't treat them I wonder if we help those patients at all and then you also have the risk of you know false biopsy especially in thin tumors like this keroprocesis patient I'm not going to put a needle in that one you know it's just 2.5mm thick I mean the bevel of your needle is not much less than that and to make sure you're in the tumor get a good sample and you're not sampling coroid or retina that's a little tough to do and then you know we could seed the tumor along the track we might give her a subretinal hemorrhage intermecular we might give her retinal detachment all of those things in my mind are things that they don't change the eventual outcome other than maybe give you some prognostic factors and I tend to be one that does very few needle biopsies other than in eyes that I nucleate once the eye is out of the head then I always take a sample and send it for the gene expression profile alright well here's how we actually go through what we do for most of these patients so we have a custom plaque it's designed specifically just for that patient we use iodine 125 seeds you'll see a picture of them that look like little fragments of pencil lead a key thing is is to place it directly over the tumor with no intervening tissue you want to make sure you have tenons out, muscles out no reason to irradiate a muscle all that does is hold the plaque a little farther away from the eye and reduce your dose these little seeds are kind of magic in that they give a real high dose of radiation right next to the source and almost none even on the other side of the eye so unless the tumor is real close to the optic nerve or the macula we usually have great vision in these we treat them in comms, we treat them with 85 gray to the tumor apex and people will sometimes worry that just a little bit and what that means for most patients it means that we put the plaque on and we leave it there for about four days and then we take it off we get a little print out that gives us a million members there that don't mean too much to me other than what time I'm supposed to take that plaque off here's how we go through the actual surgery you've got to expose the quadrant so you take down conjunctiva like you were doing a sclerobuckle or something you isolate the muscles there's a couple of muscles on traction sutures you expose the quadrant you're after then you transilluminate the eye and you'll see the tumor right here and you can see a dark line right there that's actually I've already marked that one with a marking pen you just transilluminate the eye and just draw a circle around it now you've got it marked I always double check that with a little scleral depressor here very carefully especially if you have a more columnar shaped tumor depending on your angle of where your transillumination source is you can sometimes cast a shadow a little bit differently so I just double check it this way to make sure that where I've marked is in fact the base and the edge of the tumor and not just a little bit off the surgery work is you've got to get the plaque in the right place and this is what it looks like we have a dummy plaque that we work with until we're ready to get the live plaque out of the little lead can this is what the live plaque looks like the outside of it they're gold and then the inside it has a little rubber matrix and all these little fragments of the I-125 and this is probably a 16 millimeter plaque and 13 seeds and so now that we have the tumor exposed and we take the dummy plaque and we hook it on there and we secure it with 3 little 5-0 nylon sutures until we get it just right making sure we have a 2 millimeter margin around the tumor and again I check that both externally you can kind of see my little mark underneath there that's my pen marking there and internally just a little scleral indentation make sure we're perfectly centered on the tumor and once everything is good then we just unhook the close up of it again and we just untie those sutures and and thread them through the corresponding eyelets on the live plaque and put the live plaque on and then we just close tissue over top of that and the patient goes home for 4 days and then they come back and we just it's usually pretty easy to snip those sutures and pull that out and they're good to go the challenges we run into sometimes with the big ones well even with the others with 6 muscles inserting in the eye there's probably at least half the time there's one muscle insertion that's in the way and so we'll have to take down a muscle and then hook it back up at the end on the big ones sometimes there's 2 and 3 and you guys know what could happen you start taking off several muscles not only to increase your risk of dyplopia but you can get an ischemic syndrome from having too many I've never had an ischemic syndrome but even if you don't have to take down a muscle double vision you still get a low percentage of that wherever you radiate makes that area real sticky and any muscle that has to pull across that very often you'll get a little adhesion in that area and it doesn't pull I shouldn't say very often but occasionally it doesn't pull the same way and you end up having to deal with some double vision afterwards again almost everybody's double while the plaque's in place because they just can't move their ivory much and then they're often double for a few weeks afterwards as the muscles are soaring or healing but most are not dyplopic long term but a few are you just put a patch on them and send them on their way home alright so here's just one result you can see this a melanotic tumor right here treated with a plaque poor vision because there was fluid in the macula 5.2 millimeters thick and 7 months later vision improved to 2040 and now about a 2 millimeter tumor they're not always this dramatic but they often are as I said we have nearly we just reviewed our we reviewed over a little over 100 cases of these I've had in all the 20 some years I've been doing this I've only had one tumor recur and that was in a patient that I told her the plaque wouldn't work that her tumor was just too big it was kind of curving around the optic nerve that's the other place where you run into a little problem is the nerve on the outside of the eye has a myelin sheath around it so it's a little bigger than the nerve on the inside of the eye and if the tumor butts the nerve and especially if it kind of curves around the nerve a little bit you can't get around plaque outside of the eye to cover it all so we use a notched plaque in those situations and we still get very good results but her tumor was just so big I said I recommended a nucleation she just absolutely refused so we treated it with a plaque and it she did well for you know three four maybe in five years and she got a little recurrence along one margin and and we ended up removing her eye at that point that's the only one we haven't had knock on wood because I'm sure at some point we'll get others but right now we're running almost a hundred percent local tumor control about two thirds of successfully treated one shrink they don't have to shrink as long as they don't shrink I mean as long as they don't grow they're equally dead in my mind and some other people we think that the ones that are likely to shrink a lot are probably the more epithelioid that is actually maybe a bad sign patients are usually really happy if they come in oh my tumor is a lot smaller and in my mind I usually don't say anything but I think that was maybe a bad tumor you maybe have a little greater risk of metastasis whereas like a spindle a you know it's a more solid tumor dead spindle a cell may not shrink hardly at all again you know anywhere from some studies as low as five percent it kind of depends on how big the tumors were in your study and how long you followed it if you have a ten year study you show more die than if you have a five year study and if you have more big tumors you have more die here's one patient that we did treat with trans people with thermal therapy it has to be a fairly thin tumor and you usually don't like it under a major artery but it gives you this really dense scar you don't get surrounding collateral radiation damage but with the plaque she often don't get too much but you do get a very dense scar right there and this is a very happy patient because she has another good eye and she was terrified of her tumor but she's she's been 2200 and 2400 ever since we treated it where she was pretty close to 2020 when she came in and but anyway that's life with your tumor you kind of have to live with where it grew here's just a couple of cases and then we'll finish thing up and a couple of these these were from again I was in Miami at the time the comms was getting under way and so before that time we had different of our doctors there managing things a little differently and some of them were a little more conservative than the other so these are a couple of pictures that I can show you now that I don't think I could generate again because we wouldn't have watched these so this is a 75 year old man good vision but he had noticed a little decline and the ultrasound showed 2.9 millimeter thick tumor so not too thick kind of a more nevis like echo pattern internal reflectivity pattern the other thing I'll mention is that you also have to take the internal reflectivity with a little grain of salt in thin lesions because there's just not as much tissue there for Roger to measure you get a thicker tumor then there's a lot of tissue and he can give you a better pattern and if you have a you know 2.5 millimeter lesion there's just not as much for him to try to recognize a pattern within that anyway so you just watch kind of watch these blood vessels here and I'll show you so 2 years later here's what the tumor look like this is that same picture I just showed you and if you look at it you can see that that looks bigger in fact when we did the ultrasound it had gone from 2.9 to 3.6 there's that same picture again that we just showed you and it was so in my mind we would have treated it even before here today I mean that's a 0.7 millimeter growth but this one was watched for a little over a year and grew to 4.2 I mean if you kind of you see this blood vessel right there that's this one right here this one that it was right there that bifurcation there you see it's gone past a little bit and very clearly that's a growing tumor and then at that point it was recommended to treatment and that patient chose a nucleation it was a mixed cell tumor here's another one a 66 year old woman she had been told in the past some time ago she's had this little spot in her eye that they had been watching but now her vision was a little blurred to her that's a clue there but it was just 2.5 millimeters thick but otherwise typical for melanoma with a low to medium reflectivity and some internal vascularity that was kind of at the lower limits of a medium category and so she entered the COM study and was randomized to a nucleation and it was a spindle cell with a little intrasclerol extension here's one that one of my classmates sent me 63 year old woman she was asymptomatic, 20-40 he's a good doctor he had done multiple previous exams on her when he took her cataract out the next day he noticed this in her eye and so that was really concerning because he had never seen it before and there's just a center dial we got her ultrasound 2.4 low to medium there's no other worrisome category but no vascularity and it kind of has these little almost drusen like things on the surface and so we opted just to watch her and she's about 10 years out now looks exactly like that never grew here's her ultrasound here and again it's hyper fluorescent but it's not really leakage there that doesn't really seem like there's incompetent vessels there in that and I think this is that same one I showed you earlier that kind of looks like this part became malignant and this part was probably a nevus this is how it kind of evolved 65 year old man routine exam asymptomatic 2.9 millimeter stick low to medium internal reflectivity with a questionable vascularity and so it was watched at that time and again you can kind of see that that is the part that really grew there a year later it went from 2.9 to 3.3 so it's definitely growing there and again this is one that was watched there I wouldn't have watched it beyond that one there it was still watched another six months and grew just a little bit and then it was treated it got randomized to nucleation it was a spindle B tumor this might be the last one close to it 59 year old asymptomatic there was a little spot that we noted many years before by some ophthalmologist that had seen her so it was had been followed every six months and hadn't been growing and was she had this other history of a lot of other tumors that was maybe raised the question of could it be a metastatic disease but not really with that history metastasis would have changed in that time anyway so the doc who sat there had an ultrasound low reflective that's a little worrisome on the ultrasound but with that history of having been followed for seven years without noted growth although probably not with really good baseline studies I said that's probably need us to do the same thing again come back in six months and that's what it looked like in six months so now at 6.4 there's an inferior exudative RD and you can just anticipate that that's going to be a little worse cell class of tumor to grow in that month that's a very significant growth in six months there well there's one last one here just a 45 year old woman 2050 vision you kind of see this as kind of a multi-lobulated tumor there here's what she looked like a few months later and there's just another picture of it even a few months after after some chemotherapy for her breast cancer just a reminder that not all dome-shaped tumors are melanomas in the eye and one of the clues of course is kind of this multi-lobby of their nature this probably started as a couple of different foci metastasis that kind of merged into one so take home point if you're not going to treat tumors when you see something even if it's not too suspicious I encourage you to get good baseline studies those are invaluable and we see these patients by baseline studies I mean get a good color photograph and get a baseline ultrasound ultrasound is very good for measuring thickness in particular and color photographs are very good for documenting margins and those are very very helpful if most patients come in without those and those that do are just I mean I get down on my knees and thank that ophthalmologist who did that just makes us be able to make the diagnosis sooner with a lot higher accuracy alright any questions then do you send eyes after a nucleation up to neck always send them to neck we don't do that many nucleations because in today's world we tend to catch them when they're smaller I mean I do a handful of maybe one or two nucleations a year it seems maybe one there's not very many well I mean it's a fairly rare tumor I think it seems like we see probably between I think the most we've ever seen in a year is close to 20 and it's more often around 10 we get them sent in from all the intermountain states here there's none of the as far as I know none of the doctors in Idaho or Wyoming or Montana they still keep sending them down here to us any other questions yeah so so have you seen her so her object in this is that she also has a 99 year old mother for whom she's the sole caregiver and she has no family of her own other than like nieces and nephews or something so her thought is I've got to die of something I might as well live with good vision for as long as I can I'm trying to get some old pictures Dave Faber apparently took some pictures of her four years ago they've been archived so their offices digging those out of the archive to send to me I'm fairly convinced that's a melanoma and when Paul Bernstein told me that he saw her four years ago and wasn't worried and he saw her didn't get pictures of it somehow that didn't happen but when he saw her this time he said this is definitely bigger I mean I believe him I think that's a melanoma I think I'm going to encourage her to have some treatment because dying from melanoma is not a good way to go but that's right under her macula no matter what you do with that I mean you could do TTT or laser and have instant visual loss but localized or you could do a plaque or proton beam and you could probably have good vision for a few years but you would for sure get some radiation maculopathy I'm going to try to encourage her to go see Devin Char in California I just for a second opinion he's he's he's likely to want to do proton beam on that or or laser he's ones that there's not no way to have a good outcome and I'm very happy to share those with somebody else I feel really really bad for her I mean some patients their insurance won't cover them to go there they just don't have the ways to do it but you know some of those back around the small tumors back near the optic nerve a little bit hard to get to you can get to them and we've certainly plaqueed a number of those you know some of them you get surprisingly good results and sometimes you also get worse visual results somewhat you expected but technically that's a little hard to get to the small I mean if you have a big plaque you're still so on the front edge of that plaque up where you can reach it but hers is a fairly small one so you've got to get way back there to sew it on and technically that's a little bit more challenging I think that's a good spot for proton beam just just because it doesn't require you to do that a little bit and California has the closest proton beam accelerator around that's I think what I just ask her to think about that for the next week or two while I'm waiting to get these pictures and confirm that it's growing and then we'll talk some more but right now she's not anxious for treatment she's that's why I said I'm really hoping she's a class one because if she is she'll probably do well for a long time but I don't know what's her vision right now what's her vision right now it's good it's like 2025 or something like that she just has a little cataract everything else is normal I think she's got a little cataract she has good vision and she has 2200 out of her carotoprosthesis eye but it's a pretty lousy 2200 I mean Dr.ombadi did a great job to get that eye but I think that would be hard for her to live with just that as her only C&I so we would probably still do better her eye with the melanoma would probably still see better than her than her other eye would and unless we had radiation retinopathy I'm not radiation optic neuropathy so if you get the optic nerve you can sometimes lose a lot of vision but if you just you usually get fairly localized radiation damage just right around the plaque and not too much elsewhere and hers is small so she's not going to get a very very big dose she'll have a much lower dose of radiation if you treat it when it's small if you wait and let it grow until it's 4 or 5 millimeters thick and then she should start losing vision from the tumor at some point there then of course their dose of radiation goes up and risk of side effects go up alright well