 Good morning everybody. It's my pleasure to introduce our speaker for today. This is Dr. Joel Welch. So Dr. Welch did his undergraduate in biomedical engineering here at the University of Utah, graduated in 2007. And then he attended medical school here, graduated in 2012 where he and he was a student body president from 2011 to 2012. He then attended residency at Troulson Eye Center at the University of Nebraska. And currently he is a clinical oncology fellow at Will's Eye with Carol and Jerry Shields. On a spare time he likes to cycle and during his time here as an undergraduate and medical student he founded Eye Canyons. I think Eye Canyons sets an annual 110-mile bike race that has raced over $15,000 to benefit a four-street clinic. With that said, I'd like to introduce Dr. Joel Welch and his talk today is an ocular oncologist's cookbook. Yes, thank you very much. It's exciting to be here, good to be back in my hometown. And, you know, hope everybody had a nice Valentine's Day last night. My wife and I went and saw the movie La La Land. So forgive me or perhaps join me if I break out into random song or dance. But it truly is a pleasure to be here. And Valentine's Day is interesting for me. On Valentine's Day, February 14th, the year 2000, I was messing around up in the mountains with some buddies and suffered an orbital blowout fracture, floor fracture on my right side, and which ended up needing repair by oculoplastics. And so that was 17 years ago and in many ways that started this love affair with ophthalmology. I also have an uncle who's a comprehensive ophthalmologist up in northern Wyoming. He was a mentor along the way. And so I started medical school with ophthalmology on the mind, on the brain, and then was distracted by tumors for a second, third year. And as an early fourth year, I was deciding between oncology, medical oncology, perhaps radiation oncology or even surgical oncology versus ophthalmology. And eventually went with ophthalmology, glad I did. I was lucky enough to match in Nebraska, had great mentors there, and then fell in love with retina, loved seeing interesting things in the back of the eye. And when the opportunity arose to join the shields at the Will's Eye Hospital, I pounced on that. And it's been a wonderful journey. Moving forward, I want to be an academic medicine and ocular oncology with some retina on the side as well. So I was a little bit nervous. I was a long intro, but I was a little bit nervous speaking in front of the hometown crowd. But a headline in a Philadelphia newspaper just about a month ago, as I was preparing, set me at ease. It was this headline here. I read this and I said, okay, my timid little heart was calmed and I was encouraged and boldened. But unfortunately, that's Joel Embiid, the young 76ers talent. Unfortunately, I don't have his finances to disclose. But today, this is just kind of a list of what we'll be talking about. A mystery case. Diagnosis won't be so much of a mystery, but maybe the treatment can get a little bit tricky. Then we'll run through some retinoblastoma quick before and after cases. Talk a little bit about my clinical research on small retinoblastoma tumors. We'll do an adult tumor case after that. Then we'll talk about some bread and butter, oculoncology, nevus risk factors, a little bit about some pseudomelanomas, and then we'll close with a little bit of research I've done on a unique pseudomelanoma. Very well. So let's get started. This is our 15-month-old girl who presented or was discovered to have leukocoria on the left side at her well child exam, referred to pediatric ophthalmology, and then referred to the Wills Eye Hospital, oculoncology service. No family history of eye disease. So when we see a child like this, the first thing that runs through our mind is this broad and vast differential for leukocoria, maybe even some strabismus. This is from Munier in Switzerland. Leukocoria could be anything from retinoblastoma on the top left, vitreous hemorrhage on the bottom right. It's a wide and diverse differential. But you may know what I'm going to be speaking about today, and let's go back to this child. Fix and follow vision, no pupillary pressure defect, a little bit of strabismus. I enter your segment as normal, but when we look back or look into the back of that left eye, what do we see? This large. I hope this is projecting okay. This is probably the worst picture of the presentation, so just bear with me. On the first visit, Dr. Shields gets the reticam pictures in clinic without anesthesia, so the quality is not the best. But we see this large white retinal mass, a small cuff of subretinal fluid surrounding the mass, and you can see just the normal luteal pigment of the macula, which is prominent against the white backdrop of this lesion. If we scan the periphery, we'll find really tough to see, but another small white lesion in the peripheral retina there. If we look at the thickness of this lesion on ultrasound, we see that it's about 3.6 millimeters thick. There's some acoustically dense bits to it. Every patient at the Will's Eye oncology service gets a large drawing, adult or small, and it's been a pleasure for me. We didn't really do too much drawing as residents, but I really think it's a good way to document what's happening in the back of the eye. We can see our 10 by 10 by approximately 4 millimeter retinal lesion and the smaller supranasal tumor. Just for those, I had to learn this, but on a drawing, this represents the equator, this line here, this line represents the aura serata, and this line represents the transition from the pars plana to the pars placata or some of the older or more seasoned experience ophthalmologists in the crowd. That's old news, but it was something interesting for me to learn. So let's go back to this case. We've got it figured out. We know why there's leukocoria in the left eye, so let's figure out treatment. But first, let's look in the right eye, of course, and there's an even larger retinal mass on that eye with dilated feeding and draining vein there. And if we look elsewhere, we'll see some small white lesions that appear to be subretinal, and these are classic subretinal seeds. And if we look at ultrasound, this tumor is 5.6 millimeters thick, and the drawing would appear as such, blue representing subretinal fluid, the other yellow bits, subretinal seed, and there's another tumor out nasally as well. So a 12 by 12 by approximately 6 millimeter tumor. And just another note on measuring intraocular lesions. It's nice to use the optic disc as a scale, right? One and a half, two millimeters. But that can be difficult when you're measuring large lesions out in the periphery. So a good hint is with your 20 adapter lens, if you're looking at a lesion and it's filling your lens, that's 12 millimeter intraocular lesion. Half that would be 6, and it's a good way to estimate the size of intraocular lesion. So what do we have here? We've got our 15-month-old girl with bilateral, this is retinoblastoma, right? So what are our treatment options moving forward? Well, that's when we pull out the ocular oncology cookbook written by doctors Jerry and Carol Shields. And that's really been the best part of the fellowship is having access to this cookbook from these great mentors who are certainly pioneers in the field. Well, the bottom line, if you could give a summary of the cookbook in just one slide, this would be it. This is what we're trying to do with ocular oncology. We're saving lives first. And then once that's taken care of, try and save the globe. Try and save the eyes, one or both. And then last priority is saving vision, okay? And that's a little bit maybe backwards from how a lot of ophthalmologists think and that's okay. But this is really what our focus is in ocular oncology. Well, what do I mean by saving lives? What are we talking about here? Well, 150 years ago retinoblastoma was almost a universally fatal disease. It's just a, you know, a bleak dismal survival rate of 5%. The only treatment at that time was really a nucleation. And if you could catch it early enough, that would be a good treatment. But a lot of doctors weren't, you know, willing to enucleate eyes, especially that early. Then around the early 1900s, external beam came about, which was a good treatment. But the side effect profile wasn't too positive, as we'll see. So survival rate has been increasing. And nowadays this is a paper from Dr. Covella in Finland, who it's a busy slide, I know, but if you zero in here, this is the mortality rate for retinoblastoma in developed countries like Japan, Europe, North America, mortality rate from 3% to 5%. So that's a survival of, you know, 95 to 97%. And there's still a lot of work to be done around the world. As you'll notice, other developing areas, mortality rate as high as 70%. So there's a lot of global work that needs to be done with retinoblastoma. But we've come a long way. So I'm confident that we can save this 15 month old's life. But what about our eyes? Well, globe salvage, this Reese Ellsworth classification came out in 1969. And this was really the external beam era of retinoblastoma care. And it's just a way to classify the eyes and determine a prognosis for globe salvage moving forward. And what goes into it is essentially tumor size and tumor seeding. And it ranges from very favorable prognosis for globe salvage to very unfavorable. So if we were to use this Reese Ellsworth classification for our 15 month old patient, we would get a Class III in the right eye, Class II in the left eye, which would equate to doubtful prognosis to save this globe on the right side and favorable on the left. But I think we can do better than doubtful. And remember this Reese Ellsworth was in the external beam era. And we've since moved away from that gladly. Because the side effect profile is just really difficult with external beam. This is a great picture published by the Shields group just last month in JAMA showing retinoblastoma then and now. This is germline retinoblastoma. Both of these patients, this is mother and daughter, both of them have bilateral retinoblastoma. But you can see how far we've come in treating this disease. The mother had one eye nucleated and had this severe facial disfigurement from the external beam radiotherapy. The daughter has bilateral disease but has had systemic chemotherapy and some arterial chemotherapy. Both of these patients have have stable regressed retinoblastoma, but the treatment is so much different. So if we're not using Reese Ellsworth, what are we using now? We're using this international classification for retinoblastoma. And this came about in the mid-2000s and this is really the chemotherapy era classification. And it's from A to E depending on tumor size and seeding. And there are some hints to remembering this. What I like to remember most of all is just group C. That's when the seeds come about. And they're contained seeds close to the tumor. D is when the seeds become more diffuse. And there's other little hints to remember that. But now using our new international classification, what are we going to classify these as? Well, we're group D in the right side because of that subretinal seeding just further than three millimeters away from the tumor. No seeding in the left eye, macular tumor. That's still group B. So, all right. What are we going to do now? We've got our classifications. We're ready to treat. That's when we open up the cookbook and look at all of our options. Well, a nucleation is probably our oldest treatment for retinoblastoma. And it's still being used. It's still a good treatment in certain situations. External beam, we're not using too much anymore. Radiation therapy otherwise with local plaque brachytherapy, we use it from time to time in retinoblastoma. And just as a little aside and interesting aside, the doctor who really pioneered plaque brachytherapy, Dr. Henry Stollard, was a British ophthalmologist who before he became an ophthalmologist was a member of the 1924 Paris Olympic team, you know, from Great Britain, from England. And he was on the team that is the basis for the movie Chariots of Fire. Now, of course, he wasn't Eric Liddell or Eric Little, but an actor did play him in the movie and he did win a bronze medal in those Olympic games. He later became an ophthalmologist and pioneered plaque brachytherapy. So, other treatments that we have, laser, we still use laser, transpupillary, thermotherapy. Dr. Linkoff introduced cryotherapy in the 1960s. We'll use that for peripheral tumors all the time. Systemic chemotherapy, had these different waves of introduction and effectivity over the years. Periocular chemotherapy, subconjunctile subtenance dose of chemotherapy, we don't really do that too much anymore. And then, eight and nine here, intra arterial chemotherapy and intravitral chemotherapy have really revolutionized retinoblastoma care over the last 10 to 15 years. Well, when do a nucleate? If it's a massive tumor and there's any suspicion of extraocular extension, then that's probably the time for a nucleation. And maybe some eyes with advanced group D. And just depending on, you know, it's a decision for the parents and the doctor to make together, the first a nucleation or recommendation for a nucleation came from Dr. Wardrup in 1809, but still not a bad treatment for retinoblastoma. Well, when do we use intravenous chemotherapy, otherwise known as VEC for vincristine, utopicide, carboplatin, chemo reduction, or you know, IVC, intravenous chemotherapy, systemic chemotherapy. This is germline retinoblastoma, bilateral retinoblastoma, younger age, less than four months, or you're suspicious for early optic nerve or crudal invasion. And there's debate here. Some people don't even use systemic chemotherapy in treating retinoblastoma. That's a hot topic in retinoblastoma care. Well, when do we use this intra arterial chemotherapy? Well, this is unilateral disease, age greater than four months. If they failed prior therapies, if they have recurrent or resistant seeding, sub-retinal seeds or vitreous seeding, also known as ophthalmic artery chemotherapy. And as I mentioned, there's debate. Some people will use bilateral intra arterial chemotherapy, but Dr. Shields doesn't necessarily subscribe to that yet. Well, when do we use intra vitriol chemotherapy? Actually injecting melphalan, topotican, into the eye. Well, this is for vitreous seeds that aren't responsive to other therapies. And we'll call that IVETC from time to time. We do this in the operating room under general anesthesia, sterile technique, and oftentimes we'll even inject and direct the flow of our medicine towards the seeds. And we'll do that under indirect ophthalmoscopy. And we'll use cryotherapy as we remove the needle, but otherwise, you know, standard intra vitriol injection protocol. So now with all these therapies, how are we doing? Okay, we're talking about globe salvage here. And we have our rice, sorry, we have our international classification across the bottom here. And how are we doing at saving these eyes? Well, if we just use chemotherapy alone, we do pretty good with groups A, B, and C. And we can save about half of group D eyes. Well, once IAC came along, we could save a lot more group D eyes, and even some group E eyes, eyes that had previously always been enucleated. And now with adding intra vitriol therapy to the mix, we can save most of A through D and a fair amount of group E eyes. So these developments over the past 10 to 15 years have really been revolutionary. So back to our case, what are we going to do? We have got group D and group B. Well, if we just open up the cookbook, it tells us we're going to use systemic chemotherapy for this child, at least in Philadelphia. So after just one dose of systemic chemotherapy, which is administered by pediatric oncology, pediatric hematology oncology. So it's certainly a team effort. It takes a village to take care of these kiddos. But we can see good tumor regression in the right side, calcified bits to the tumor, some maybe sub retinal exudation, some surrounding RPE changes. But that's, you know, good regression. The left eye is similar. Regressed tumor with, you know, calcified part there inferiorly. If we did fluorescent angiography, you could see some, you know, lingering hyper fluorescence to these tumors in the right and left eye. You can see before and after how much just one dose of chemotherapy really zaps these tumors right and left eye. So she received per standard protocol six monthly doses of this chemotherapy cocktail. And in that right eye, because it was a non macular tumor, we did some lasering to it just to make sure it was fully consolidated, fully treated in that left eye, that small peripheral tumor we treated with cryotherapy. But we didn't laser the macula in the left eye. We don't like to laser the macula. And it's too far posterior for cryotherapy really. So we're really just relying on the chemotherapy for the macula in that left eye. And this patient did well. You know, this is after all of that chemotherapy and those treatments, you can see tumors well regressed with some RPE changes, RPE hyperplasia surrounding the tumor. The left eye similarly looks great. So it looks like we're out of the woods. Here's our cryotherapy scar in the periphery of the left eye. So how have we done? We've saved a life. We've saved both eyes. And have we saved any vision? I think so. Tough to tell with, you know, 15, now 21 month old, but the OCT on the right eye looks great. She'll probably see pretty well out of this. I'm moving forward. And you know, just given the location, bad luck in the left eye for location of the tumor, but peripheral vision should be intact in this eye. So we've done well. Time to stretch out our follow up and watch for recurrence. Now, if you had to guess which of these tumors, I'll tell you that one of them will recur, which of those tumors in the right and the left eye will recur. Well, we'll find out. Three months later, the right eye looks nice and stable. That's great. That's what we like to see. But this left eye looks like we've got a recurrent tumor here superiorly. You can see that white mask comparing before and after. Not too hard to see that there's something going here. It looks like the non-calcified portion of that tumor has recurred under fluorescein. Nice hypo fluorescence of a regressed retinoblastoma tumor in this right eye and some, you know, blocking defect from the RPE changes. But this left eye, we've got this persisting hypo fluorescence. Significant for active tumor. If we were to draw these, the right eye would look like this. And whenever Dr. Shields calls for the orange pencil during an exam under anesthesia, you know the intensity level is about to increase because there's tumor recurrence here. So now we've got a recurrence. Well, what does the cookbook tell us? What can we use next? We could enucleate, but I don't necessarily think we need to jump to that. Could we give more chemotherapy, perhaps, external beam? It's always an option, but that side effect profile is just so terrible. We could slap a plaque on there. It's a little bit too far posterior for cryotherapy. We don't like to do laser to the macula. Could we use intervitual chemotherapy? Well, there's no seeding, so no real indication for that. How about interarterial chemotherapy? When do we use this? Just rehash this recurrent retinoblastoma following previous chemotherapy. That's exactly what we're doing here. Do we have data to do this? Yeah, we certainly do. Secondary IAC. IAC is a salvage method after failed chemotherapy. These arrows indicate the group that we're talking about, 15 tumors specifically. And IAC controlled the tumor in 14 out of 15, 93% of these tumors. So it seems like a good option. Let's move forward with that. We're going to use melphalan. Sometimes you can use melphalan and topotekan if there's some seeding there. You can even use carboplatin here if you're doing bilateral tandem IAC, but we don't necessarily do too much of that. So I just want to show a video here. Let me get this to pull up. So we don't do this as acryloncologist, as ophthalmologist. Instead, as I mentioned, it takes a village. We rely on the expertise of interventional neuroradiologists or neurosurgeons in Philadelphia at Jefferson. There's a great neurosurgeon who does all of the IAC for Dr. Shields. So what you'll do is you'll thread a catheter from the femoral artery up through the abdominal aorta, thoracic aorta, get into the internal carotid, eventually up to the ophthalmic artery, and you'll provide a very local dose of chemotherapy. The whole goal of this is to provide a powerful local dose and limit the side effect systemic profile. So I'll just show here. This is just one of these doctors threading this catheter. I think they're in thoracic aorta just above the heart here, and they'll eventually make their way up into the carotid. You can see the moving lungs, the beating heart. Pretty amazing work that these guys do. Good. So now maybe we're in position. So now we're at the osteum of the ophthalmic artery and time to infuse some chemotherapy. Well, really, this is just contrast, but it's showing the path. Nice carotid flush. You can see the ophthalmic artery and its branches. This is contrast here, but chemotherapy would follow the same distribution, of course. And that's our local dose of chemotherapy to the tumor. Really pioneered by doctors in Japan, and then later doctors here in America, doctors Abramson in New York, Dr. Shield in Philadelphia. Okay, I think we're back here to our presentation. Click this. So after IAC, how is this done? Well, we didn't need to treat the right eye. That's been stable all the while. That's great. Well, this left eye, you can see tumor regression. That's what we like to see before and after. This is after three doses of IAC. We do those monthly. So Melphalan 5 milligrams times three, over three months, and we see good tumor regression here. Hypofluorescence or at least isofluorescence of this regress retinoblastoma tumor. So let's watch or see if she does well. Right eye, three months later, looks great. Just what we want to see, but oh my goodness, there's this recurrence in the left eye. What a resistant tumor to our treatments. We've thrown some of our best ammunition at this tumor, systemic chemotherapy, inter arterial chemotherapy. I've got hyperfluorescence of an active retinoblastoma tumor. So this is our second recurrence in this eye. What are our options now? More chemotherapy? Well, we could. Jump to external beam. No, we don't like to do that anymore. Cryotherapy laser is not going to work. Intritorial, still no seeds. Well, let's put a plaque on there. Plac works pretty well in these situations. I don't have good data for plaque after systemic and IAC, but I've got good data for plaque after systemic chemotherapy has failed. In 84 tumors, we have tumor recurrence in just 5% of these tumors. So 95% success rate to 5, 10, 15 year. You can't have some radiation complications in the eye from the plaque bracket therapy. But as far as tumor control, that's what we're doing here. We've got to save the life first. We've got to save the eye, then save vision. We've got to control this tumor, save this child's life. Well, let's put a plaque on this resistant retinoblastoma tumor. That's exactly what we did. An interesting surgery. There's just not this eye specifically, but that's more or less what it looks like with this gold concave disc that we use in these iodine I-125 seeds glued to the disc. There's a radiation oncology team that prepares all of this for us. We give them tumor dimension, tumor specifics. They prepare the plaque and the distribution of the seeds there. And they're in the room when we put it on. So two months after plaque, right eye still looking great. Haven't needed to treat that. This left eye shows now regression of our retinoblastoma tumor with these calcified bits superiorly and inferiorly. It's surrounding retinoblastoma changes, or sorry, RPE changes, and at least it looks like we've got hypoforacin, or at least isophoracin tumor in this eye. So we've brought you up to speed. That was just a couple months ago that we placed that plaque. But I think we've done a good job with this patient. I think we've saved her life. That's certainly the most important part. I think we've saved, sorry, I think we've saved both for eyes. And I think we've saved some vision as well. I didn't expect to get emotional here. But good vision on the right side moving forward. That's great. She's going to use that eye. She's going to see great throughout life, some before and after. Now we'll just talk about a few quick cases. Retinoblastoma, a 17-month-old here, unilateral. Tough to see which eye has the disease here. But if we look and see, we see a large tumor in the left eye. And this is treated well. Here's just a different view showing the vitreous seeding here next to the tumor. This is still group D, though. There was more distant seeding. So if we can give intrarterial chemotherapy to this side, I think it would work out really well. And you can see how it just blasts these tumors away. Good macula, good vision. He'll do well moving forward. We have got a five-year-old with a rather large tumor superiorly. And you could see how these tumors could get out of control. And how 150 years ago they would grow, overtake the globe, overtake the orbit, cause metastasis, cause death. But luckily, we've come a long way. We give some intrarterial chemotherapy. And this is probably the most impressive before and after that we have. Just completely blast this tumor away. And just this little calcified remnant, some surrounding subretinal exudation. But this patient has done fantastic. Well, what about subretinal seeding? This patient is a young patient, unilateral disease, had systemic chemotherapy, was under good control, but lost a follow-up. They lived a few states away. And there were economic reasons why they couldn't get into CS, but so it couldn't get into CS at one, two, or three months, five months past. And you can't let that happen with retinoblastoma. Look at these subretinal seeds. Again, not hard to imagine how this could grow quickly to overtake the eye. But IAC is very effective at treating these subretinal seeds. Just one dose of IAC, we can see how well they're treated with just the calcified remnants of those tumors. Now, three-year-old with unilateral disease, big tumor with extensive vitreous seeding. Now, this is true vitreous seeding here. This is the real deal. And just 20 years ago, 10 years ago, before really IAC came along, this was a very difficult aspect of the disease to treat. But now we can treat it well. This is just IAC. IAC does a fairly good job of treating seeds. But if you can augment that therapy with some intravascular chemotherapy, then you can get good result like this here. That child's done well. Now, this is an interesting case. It came to us from Brazil. Four-year-old, unilateral disease has had systemic chemotherapy, has had interarterial chemotherapy, stable posterior exam. Everything looks great in the back of the eye. But then these anterior chamber seeds popped up. Well, how are we going to treat these? Chemotherapy is not necessarily going to get those. So this is another good indication for plaque bracket therapy. Put a plaque over the anterior segment. There may be some you know, radiation effects to the cornea and lens moving forward. But remember, we got to save life. We got to save glow. And it just blasted these seeds away. And there's just nothing but some peripheral anterior synechii left as scarring. So we've talked about these treatment options for retinoblastoma. They're all in the cookbook. And I'm thankful that others have gone before and really written out this cookbook for us. But we've got good treatment for retinoblastoma nowadays. Just a reminder that we can save most eyes currently and certainly save most lives. Some say that the survival rate here in the States now is up to 97.99% for retinoblastoma. So we're doing a good job with our priorities at the first page of the cookbook, right? Okay. Well, let's change gears here. All right, we're going to talk a little bit about some of my clinical research in small retinoblastoma tumors. And let me just look at it. We're doing good. So the retinoblastoma cure rate, as mentioned, has, we've made a lot of progress here. Retinoblastoma has been the vehicle for many understandings in cancer genetics, including Alfred Knudsen or Knudsen's two hit hypothesis. That was a statistical analysis for retinoblastoma that he came up with that hypothesis, hypothesis, which proved to be true. Retinoblastoma was the first tumor suppressor gene to be mapped. That was Dr. Dryjub in Boston back in the 80s. So retinoblastoma has been the vehicle and we've referred for so many important discoveries and we've made so much progress, but there are still some fundamental and debated questions in retinoblastoma like, what is the retinoblastoma cell of origin? We've got our two, we've got our mutations, our homozygous mutations for retinoblastoma, no protein product. And why and what cell does it affect and which cell is the cell that proliferates? Something that it's one of these retinal progenitor cells, the mother cell to the six retinal neurons and the muller glia. Something that's that cell others think it's a more different or the differentiated daughter of that cell. Either way, okay, the debate rages on, but either way, it's a cell that has either remained in the cell cycle and it's still proliferating, still undergoing mitosis or if it was a differentiated cell, it's now re-entered, de-differentiated and re-entered the cell cycle. So over the past 20 years, this is what people are thinking. Some, you know, this group up above think it's just retinal progenitor cell alone. Others think it's RPC and maybe a cone precursor. The most recent work seems to implicate the cone precursor that then de-differentiates, enters the cell cycle, proliferates and that's what causes retinoblastoma. But others have mentioned an implicated horizontal cells, other cells in the inner nuclear layer and even the muller cell. So there's a debate there and there's been limited histopathology of small retinoblastoma tumors just because usually a nucleation comes after the tumor is a little bit larger, more, I should say less differentiated, less difficult to see what kind of cell type they're dealing with. Dates back even to, you know, the late 19th century, Dr. Flexner states this drawing that he did, this tumor started in the outer nuclear layer, he claimed. But just a few years later, Dr. Wintersteiner claimed that this tumor started as a widening of the inner nuclear layer. That's a great drawing there. And then an interesting paper from 1993 shows these microspherials, these tiny neoplasms in both the outer nuclear on our left and the inner nuclear layer on our right. So it's seemingly, this layer debate seems to follow the cell of origin debate. Is it inner outer nuclear layer? Is it an RPC? Is it a cone precursor? And some further histopathology of, you know, smaller tumors. This seems to be an expansion of the inner nuclear layer but the tumor certainly grows to include all of the layers. Dr. Galley, great retinoblastoma doctor in Canada. This picture on our left seems to show that it's originating in the ONL, the outer nuclear layer. But when they zoom in, she claims that those cells have morphology more similar to inner nuclear layers. So she thinks it's an inner nuclear origin. And this is a mouse model showing clear inner nuclear layer origin, but it's a mouse model. How well does it reflect true human retinoblastoma? Here's mouse model with OCT correlation showing inner nuclear layer. Drs. Rootman and Galley et al showed some small retinoblastoma tumors in 2012 and they claim that these tumors originated in the inner nuclear layer. But in 2016 the group down in LA showed a tumor, if we look at the bottom here, tumor originating here in the outer nuclear layer and growing. Well, we, and then lastly here, we've just got, this is a mouse model, but good OCT, histopathology correlation demonstrating inner nuclear layer origin. But again, that's a mouse model. So we wanted to contribute, if we could, to this body of literature. Just the OCT features of 20 retinoblastoma tumors smaller than one millimeter in thickness. Okay, so these are tiny, tiny tumors that we're looking at. Forgive these tables here, but we're dealing with young patients with mostly bilateral disease. Average age is four months. All patients were less than a year. And mostly group BIs here. And just given the nature of how Dr. Shields runs her clinic, she likes to get these patients treated. And so most of these patients had treatment by the time we're able to get them into EUA. And so she does her initial exam in the office without anesthesia, decides treatment at that point. And later we take them for EUA after their first treatment and do all of our diagnostic imaging, including OCT at that point. So they've had some treatment, which may alter the morphology of the tumor somewhat, but I think it's still a good study. So some of our results mean tumor width, 2.2 millimeters, tumor height, about half a millimeter. And we claim that tumor origin, internuclear layer, and just over half, outer nuclear and just under half. So, you know, the debate rages on, I think. Big table here, forgive me for this, but just goes to show that inner retina, mostly normal, 75 percent. Outer retina, arpein, coroid, mostly normal. It's just these retinal layers that are infected, outer nuclear layer, irregular, and 100 percent of these tumor, inner nuclear layer, irregular, and 65 percent. And, you know, I'm not sure if this was the best way to break these up, normal, irregular, not visible, not distinct, but that's how we did it. So here's some pictures from our study. This is our smallest tumor, and these are all representing inner nuclear layer origin in our minds, in our opinion. And this is the smallest tumor in our study. Here you can barely see it on exam, barely see it on photography, but you can appreciate that it seems to be an expansion, a widening of the inner nuclear layer. These are what we think are outer nuclear layer origin tumors. Again, this had been published prior, this tumor has an invisible retinoblastoma. You can hardly see it, if at all, on the photography, but you can appreciate this outer plexiform layer, this hyperreflective layer here, draped over this small tumor here, seemingly indicating outer nuclear layer origin. Another interesting sign that we saw was this, what we call the outer nuclear wave, this hyperreflective wave that seems to envelop the edge of many of these retinoblastoma tumors. We saw this in 13 out of the 20 tumors. And, you know, we're not sure exactly what this represents. Could this mean that it's starting in the outer nuclear layer, because all the edge is right there in the middle of the outer nuclear layer? Or could it be an expansion of the inner nuclear layer, and we're now invading the outer nuclear layer? Or, because most of these tumors had had some sort of treatment at this point, is it some sort of retraction cleft from tumor shrinkage or tumor evolution? Tough to say, but we saw it in several of the tumors. And so, we, you know, agree that it could be in both the inner nuclear and outer nuclear layer, and we have, you know, perhaps a decent explanation for this, maybe dealing with the altered intraconetic nuclear migration of these RPC cells, as they're dividing in that early neuroblastic layer in the retina. And just depending on when and where that OPL or plexiform maturation occurs, might trap the tumor in the inner outer nuclear layer. It's just a theory, needs some, just out of time, I won't go through this, but essentially what I was saying. So, still needs peer review, but hopefully it makes it into the literature of this paper. Changing gears again, let's move to adult tumors. Now, leaving retinal blastoma pediatrics behind. Mystery case, okay, it's a 39-year-old, he's a Caucasian man, history of cordal nevus in one eye, and presents now with one week of visual field disturbance, and even had some flashing lights. Shows up to the Wills IER, then he's promptly referred up to the oncology service. History of this cordal nevus that some other doctors have been watching, and a young guy to have two pneumothoracies, but he's had them, and also family history of renal cancer. External, sorry, exam, pretty much normal, except for this field defect. External exam notable for these cutaneous amelanotic papules on the face, neck, and upper chest. Slit-lamp exam of the right eyes, normal slit-lamp exam of the left eyes, notable for this sector iris melanocytosis. You can see it better here, comparing both eyes. Fundus exam of the right eyes, normal apart from these white dots in the periphery, overlying patchy, caroidal pigmentation. So, go zoom in here, got some arrows. All right, now left eye, fundus exam, see this patchy, caroidal pigmentation here. Similar white dots overlying patchy, caroidal pigmentation. And then there's our tumor, large, caroidal melanoma in the infronasal equatorial region, measuring 14 millimeters in base, thickness of about 7 millimeters. You can see that it's acoustically hollow here. I've got some dependent subretinal fluid. And with an eye of faith, you can maybe appreciate that it's arising from a bed of sectoral, caroidal, patchy pigmentation, and a similar distribution as the iris melanocytosis. But what about these white dots? We'll get back to the tumor. Just interesting. Fluorescine angiography that demonstrated pinpoint hyperfluorescence. But OCT showed them to be these tiny, pedunculated detachment of the pigment epithelium. Interesting. Here's a few other ones. Seemingly have this hollow core. Are they just drusen? I don't know. Are they associated with something else? That's what we'll talk about. So we have this 39-year-old. He's got caroidal melanoma. That's not a hard diagnosis to make when you see a pigmented mass like that in the fundus. He's got these pigment epithelial attachments. He's got the sector melanocytosis. He's got skin findings. He's got history of pneumothorax twice, family history of renal cell cancer. So is there anything linking all this together? Well, perhaps. The link between melanoma and oculodermal melanocytosis is well known with 1 in 400 chance in Caucasian individuals of developing melanoma if you have some sort of oculodermal melanocytosis. But what about the skin, the lung, and the renal findings? Well, what's going on here? He had known history of this disorder. This is Burt, Hog, Dube syndrome, a rare autosomal dominant cancer disorder, inherited cancer syndrome with cutaneous findings, pulmonary cysts, and the cancers are multifocal renal tumors. Chromosome 17, the gene is folliculine. The protein is folliculine. The function of that protein is largely unknown, but it has been linked to tumor suppression pathways and the end-door pathway. So are there links between this Burt, Hog, Dube syndrome and caroidal melanoma? Well, there's been one prior report by Pulido and Fondcuberta at the Mayo Clinic. They showed a 63-year-old gentleman with these lid fibrophiliculomas and a large intraocular caroidal mass with this small focus of extraocular extension that they saw at the time of plaque. That's okay. You can still treat it with plaque. Well, are there links between these RPE changes and Burt, Hog, Dube? Well, there's been one prior report of flectocoryl retinopathy, which is certainly more significant than what we are seeing in our case, but the cutaneous findings were similar. Very well. Well, back to that tumor. How are we going to treat it? I'm not going to go through all the cookbook options, but we open up the cookbook. Well, we got to save this guy's life. We're going to save his eye. We're going to save some vision, hopefully. So what we can do, our workhorse for caroidal melanoma really is the plaque, radioactive plaque here with our iodine. Iodine 125 is what we use most commonly. So this patient did well, tumor regression. Plac works in 98% of cases to kill tumors, cause tumor regression, so we like using it. We do these surgeries on Thursdays. We put the plaque on and then they stay around usually four nights, sometimes longer, just depending on how much radiation they need. They come back on Monday, we remove the plaque and they go home. They stay in a hotel nearby or if they live locally, they can go home. But they'll have this plaque on for usually four nights, five days. Well, that was a melanoma and a rare cancer syndrome. I'll give you that, but what about when it's not so easy to diagnose melanoma? When we're looking at tricky nevi, tricky nevis. Well, this pneumonic is helpful to find small ocular melanoma using helpful, hence daily. This will tell us how likely a nevis is to transform into melanoma. And we're talking about thickness, fluids, symptoms, presence of organ pigment, how close it is to the disc. If it's hollow on ultrasound, if there's halo or not. So depigmented halo around a nevis is a good sign. So if there's no halo, that's the risk factor. Druzen is a good sign. If there's no druzen, that's the risk factor. So if you've got one or two risk factors, then you could just probably watch this initially every four to six months, but if they've shown stability, you can stretch that out longer. If there's three or more, maybe get the patient in to see somebody who looks at these a lot for possible treatment. So, you know, we run this every day in clinic. We have to write in the chart TFSOM, U-H-H-A-D-A, positive, negative. Next. So this is bread and butter ocular oncology. And so looking at this tumor, what do you think? A little bit difficult to tell thickness, but it doesn't look too thick. There's no fluid here. This patient was asymptomatic. I don't see any orange pigment. In fact, I see some RPE kind of atrophy, some hyperplasia, maybe some druzen down here. It's not close to the desk. We'll see on ultrasound if it's hollow or not. I don't see a halo. I maybe see a little bit of druzen. So we use fundosodal fluorescence for the orange pigment. This really helps us determine orange pigment is really just lipofusion accumulation. Fundosodal fluorescence is fantastic at showing us the health of the RPE. This isn't projecting too well, but you can see that I don't see any hyperautofluorescence here. In fact, I see hypoautofluorescence signifying that the RPE is either completely atrophy to here or there's some RPE. Well, yeah, mostly RPE loss is what we're looking at there. Now, OCT over the lesion shows no subretinal fluid. That's good to see. A little bit hollow on ultrasound. Thickness, greater than 2 millimeters. A little bit hollow there. So running our risk factors, we've got thickness. I don't see fluid symptoms. No orange margin. Plus minus here, but we'll call it plus. Halo absent. Yeah, there's no halo. I see a little bit of druzen. So this is three out of eight risk factors. I think we can just watch this one. Just given the chronic appearance of the RPE here, it doesn't look like an active tumor. And sure enough, over 10 years, this has been stable with just some RPE changes. We look at our landmarks. It's similar as far as growth, maybe a little bit of growth, but that can be okay with NEVS. What about this lesion? It doesn't look too alarming, does it? But let's run through the risk factors, see if they help us out. Well, okay, we'll go through these. It doesn't look too thick. Fluid, I don't really see any here. OCT will help out with that. This patient was symptomatic. However, visual field loss and flashes. Is there orange pigment? Tough to say. We'll really lean on fundosodal fluorescence, but maybe there is some orange pigment here underneath this infrotemporal arcade. It's pretty close to the disc, right on the disc, really. Is it hollow? We'll see. I don't see a halo. Maybe see a few druzen. Fundosodal fluorescence shows a lot of lipofusion accumulation. This is the orange pigment. We call this orange positive, okay? OCT, I see a little bit. It's just a little bit, but that's sub-retinal fluid. So there's fluid there. That might indicate that there's something active here. And this looks really quite hollow on ultrasound, doesn't it? Thickness of around three millimeters. And A-scan shows how hollow it is. So while looking at this, it didn't look like it, but man, that's seven out of eight risk factors. So I think we need to treat this. The earlier we can treat melanoma, the better, okay? You don't want to let it grow. You don't want to let it get out of control. You don't want to let it metastasize. So we'll put a notched plaque on here. The patient did well. Well, what about when it's not melanoma? Over 25 years, 12,000 referrals to the Shields Clinic, and about 2,000 of those weren't melanoma. So we call these our pseudomelanomas. The number one pseudomelanoma, of course, is carotonevis. Followed distantly by PEHCR, an interesting lesion. Fun to diagnose. It's always nice to give the pseudomelanoma news to patients because it's not cancer. They know they're coming into a cancer clinic, so when you can tell them that they don't have cancer, it's always a good time. And there are some other pseudomelanomas here. I've taken a special interest in amelanotic pseudomelanomas, amelanotic fundus lesions, including this one. Unique lesion, very rare. We don't see it too often. But what is this lesion? Well, I think the cookbook will tell us. It tells us everything, right? So let's open up the cookbook and see what we can see. And there are real cookbooks. The Shields have these atlases, which are fantastic books, and I'm so glad that they've been written. This is pictures from their atlas, looking at amelanotic fundus lesions. And let's see, what ours looks like, maybe, I guess it kind of looks like A, maybe it kind of looks like B, maybe it kind of looks like K down here, maybe J, but what are we looking at here? I think we have nevus, nevus. This is a fund diagnosis, sclerochoroidal calcification. We're seeing that again down here. This is a melanoma. We're looking at metastasis here, all different sorts of metastasis. But this focal choroditis, so what does our lesion look like? Well, it looks like maybe one of those amelanotic nevi versus maybe a focal choroditis, perhaps. Maybe something else. Well, let's take a closer look. Fundus autofluorescence shows hyper autofluorescence, but not in that typical lipofusion accumulation pattern. It's pretty dense on B-scan. OCT is what is most revealing about this lesion. You can see the dome shaped elevation here. But if you look, it's not really a choroidal lesion at all. These choroidal vessels are all being compressed. Seems to be coming from something more exterior to the choroid, maybe the sclera. Interesting. So it's not a choroditis really, but this lesion has been called choroditis over the years. Unifocal helioid, because it looks like the sun helioscreek origin, looks like the sun choroditis. Solitary idiopathic choroditis, this is the largest write-up. These are patients who have this seemingly focal choroidal granuloma with negative syphilis, negative bartonella, negative sarcoid, negative Lyme, negative workup. So it's this idiopathic choroditis or so we thought. Then we really started to learn about this with the advent of Enhancedept Imaging OCT, which showed us that these tumors really aren't in the choroid. They're not necessarily tumors. These lesions aren't in the choroid really at all. This is a great paper from the Shields Group and Dr. Fung from Australia in 2013. Well, here's another one of these lesions. You can see its appearance there. Hyper auto fluorescence. This isn't from lipofusion accumulation. Instead, this is just unmasking of the natural auto fluorescence of the sclera. There's just a really thinned out RPE here, and we're just seeing hyper auto fluorescence of the sclera. OCT here is telling compression of the choroidal vessels and something seemingly arising out in the sclera. Here's another macrolesion compressing choroidal vessels. It's not in the choroid. It seems to be exterior to that. Here's another lesion. So we're going to contribute 26 of our cases that we have good OCT for. There's been this collaborative effort around the country. Here's just some characteristics, but we're going to contribute our 26 cases. I map them out, and they have this distribution. So if you see, this is all 26 of our tumors that we're contributing to this collaborative study. They have this distribution kind of around the nerve in the posterior pole with maybe a slight preference inferiorly, and we're working with Bailey Freund in New York, Dr. Jan Paul in Chicago, Dr. Seraf in California to rename SIC because it's not a choroiditis. It seems to be some sort of focal scleral nodule, but that's essentially what I came to talk about today. It's a little bit scatterbrained, a couple of different topics, but it's been a good time. I'll leave you with this. This is a word cloud of ophthalmology. This is, I guess, the ophthalmology cookbook. What I did is I took all the titles from the 2016 Blue Journal, AAO ophthalmology, the Blue Journal. I took all the titles and I plugged them into this word cloud generator. And the words that appear most frequently in 2016 are the larger words on this word cloud. So you got to hand it to the retina guys. Age-related macular degeneration seems to be getting the bulk of it. But hey, glaucoma, they're not too far behind. They're hanging in there. Optic atrophy, some neuro-ophthalmology, cataract surgery down here. It's interesting. I think this is reflective of what's happening in our field perhaps. I did this as well for 1991, 25 years ago, and for 1966 as well. I was surprised to see that the 1991 didn't look too different than this. Age-related macular degeneration wasn't much of a term, but it looked fairly similar. And then the 1966 one was just way off. But anyway, thank you for letting me talk about the small corner of our field, melanoma, retinoblastoma, oncology here. It's part of the pie, although it's a small part, but happy to provide any references upon request. There's my email if you have any other questions, and thank you for your time. You know, very fascinating lecture. Those of us who lived back in the time when external beam and a nucleation were the standard of care, it's just amazing. I can see Roger over there as well, how this field has evolved. I mean, I remember seeing these patients come in with bilateral nucleations or bilateral severe and the atrophy and the change and the rest. And to change that, you know, we don't think about that. I mean, we're saving people, but the saving from that awful disfigurement is just, I think, just an incredible blessing that's happened over time. I think so. And I'm really just hopping in on the tail end of this. And I'm very appreciative for the docs that have gone before and have been brave enough to do all those treatments. And, you know, it's fun to chat with Dr. Jerry and Dr. Carroll about the progress that's happened over these years. You know, for me, it's normal to see that reaction after I see it. But, you know, for them, it really is a thanks to America. Yeah, they've lived it, they've lived it in their career. Excuse me, in the case of arterial occlusion, was your cartilage in that area? Yeah, that is one of the more devastating side effects is ophthalmic artery inclusion. Devastating because it may prevent further therapy when you forward the chemotherapy. And also devastating because you'll have almost total cordial infarction. And you've lost the vision valve at that point. And you may even lose the eye moving forward. And so some estimates say that's down around, you know, less than 10 percent. Some say less than 5 percent. Those that are really bold say it's even less than 1 percent. But it's probably getting there from 0 to 5 percent that gets some arterial occlusion with IAC. That's where this debate is at, you know, I was at AAO two years ago and it was a heated debate between, you know, there's a New York group, there's a Memphis group, there's a Toronto group, and it gets pretty heated. And I'm glad that Dr. Shields, Dr. Carroll Shields is somewhere in the middle. So we're not too far on the extreme on either side. So I think I'm going to get to benefit from that. But yeah, a lot of people don't like IAC. And I still want to stick with systemic chemotherapy or even an inundation over IAC. So it's that a big rage is on them. So it's still that very smallest mental blast. Yeah, most of those kids were bilateral disease and family history. And so I got to say that I've been in EUA's where we discover them incidentally on OCT. And we call those invisible retinal blastomas. Dr. Shields has published on that. But on exam, the stereoscopic view with indirect is better than these pictures. So you can see, you know, these small white tufts in the retina. But yeah, you really got to, you really got to look tough to see this. Great talk. I've been involved in retinal blastoma care here since the days we did the creation of the X-ray radiation. And the thing I urge you to stay active and train people internationally. I wish this would survive in each last week. They now have two survivors of retinal blastoma in their oncology service here. Almost 100% of their kids show up with extracurricular spread. Yeah. And the debate, the first patient they showed me the first day I was there in the resident report was a patient where the discussion was, do we enubilate or do we do an evisceration? Yeah. And evisceration is the most common procedure done there for retinal blastoma. And my colleague who does eye care oncology there has a whole ward full of kids who are getting palliative care while they're dying from retinal blastoma. Yeah. So there's a huge amount of work. Anybody who's interested in doing eye care oncology and the developing world may hear the survival rates are high. But there now, Dell Futures got two patients who have a two-year survivor who the restaurant did. Yeah. It's tough. It is really tough internationally. And that paper by Covella, he actually claims that retinal blastoma is the most common intracurricular primary tumor worldwide, even more than you'll know. And he might be right. But yeah, up to 70% and maybe even higher mortality in these developing countries. So there certainly is a lot of work to do. And just getting the news out so they get the kids in a timely fashion and to educate parents so they don't, when they get the news, when they could be treated, they'll disappear. Yeah. And they come back when they have a huge funky tumor coming out of the orbit. It's discouraging. Anyway, this is great stuff you're doing. Thanks. Yeah, certainly. Thank you.