 So I want to welcome everybody bright and early this morning. We've got a very busy morning our Presentation we have from Dr. Welch. I'll talk about here in just a second, but right after that We have six visiting medical student presentation six and That means we've got to move pretty expeditiously And so we're going to make sure that we indeed get started by eight o'clock and We're going to try to make sure that those that are starting Don't get so much time that those who are going to talk later don't have any time which would not be fair So with that, it's my pleasure to introduce Dr. Joel Welch So I've known Joel for a long time went to medical school here And then at University of Nebraska where he was a real star and I had a chance to be visiting a professor there And hear about what a great job he had done at that institution So he already knew he wanted to be involved and wanted to be an ophthalmic oncologist And that's not a lot of people who take that as their primary desire moving forward And so He took the long road and did a full two-year fellowship with the shields group Wills and those who don't know the shields group. Well If you talk about, you know the world's center of Ophthalmic oncology and it has to be the shields group They handle a significant percentage of the entire united states Burden of ophthalmic oncology and at the same time they also handle An amazing amount of oncology in the world. So two years there And then a full two-year retinal vitriol fellowship So he's spending them as much time and is About the about the only one who's decided to take such a long road that I can see is our own brian stag He's smiling back here right now, but hey, he can beat you a little bit by all of this So, yes, this is a recruitment talk on our part The one area that miran has been lacking has been On oncologist. We briefly had one and then our husband and the lead we we love that opportunity And so we're very excited potentially to make this work out to where we can have that expertise So with that introduction and presentation Right now his his retinal vitriol training is at sacramento uc davis and he will be finishing up that In june of 2020. So with that I bring you dr. Wells. Joe Well, thank you. It's it's great to be here. Thanks for coming waking up so early I know it's early, but thanks dr. Olson and the department for having me here and And I'll never catch up to brian stag just I'll just give up right now But today I'll be talking about some eye tumors and some amendments. So to speak to the eye tumor constitution I have no financial disclosures, of course But if anybody has any questions this certainly can be interactive feel free to interrupt ask questions as we go along Okay So this document on our left was signed Over 200 years ago in this building on your right independence hall in philadelphia. This is of course the u.s constitution Signed there by delegates from 12 of the 13 colonies rhod island Didn't send any delegates to that convention But now if you fast forward over 200 years Up on the upper right is independence hall and if you follow that blue google maps trail It's just a few short footsteps away to get to will's eye hospital Passing through the square behind independence hall passing by washington square where over 2000 colonial soldiers are buried And then just a few few blocks more until you get to the will's eye hospital And that's where I came across the eye tumor constitution And spent a couple years studying that Constitution from some of the founding doctors Of ocular oncology. It was a tremendous experience. It's a place unlike any other the the pathology and That comes through those doors is really unparalleled and it was a wonderful experience But I won't be talking about The u.s constitution anymore will be talking about this eye tumor constitution and there are three central articles so to speak Of the eye tumor constitution three central tenants one This is different than most ophthalmology. Our first priority of course is to save life Followed by saving globes saving the eye And then we start to think about vision And this is more or less the credo of ocular oncology Of the eye tumor constitution and there have been several amendments written over the years, of course And I was lucky to be a part of just a few of them So today we'll talk about four of those amendments one regarding tiny retinoblastoma OCT of very very small retinoblastoma tumors. We'll discuss some uveal metastasis Amelonautic Coroidal lesions and then high-risk Coroidal nevus And you'll see these numbers in parentheses next to these amendment titles And those represent the number of patients in these series and I'm most grateful to these patients who have really written these Amendments and we're lucky enough to be part of their lives and to learn from them and learn how to help others from them So this is more or less our schedule. I'll talk about these amendments I'll bore you with those amendments, but hopefully excite you with some of these mystery cases And I was able to acquire yesterday some, uh, I think it's called swag. I'll put this right here Um, I've got some things If anybody can diagnose correctly Let's lie a little bit If anybody can diagnose these Mystery cases correctly just shout out the diagnosis as soon as you think it or know it And uh, we'll rely on the room to decide who was first, I guess, but uh, And then you get some of this University of Utah swag Propaganda Air funilia, whatever you want to call it. So let's jump into mystery case number one. It's a young woman 22 years old, right eyes great, sees well Left eye has this bizarre Legion invading the anterior chamber causing some iridodialis and even some lens subluxation there. Goneo shows this White lesion in front of the iris the striated red and white lesion behind the iris anterior segment OCT Shows this tumor Perhaps a tumor. Maybe I've said too much already this lens subluxation And that little island of iris sitting atop this lesion. Have you ever seen anything like that? How bizarre This is uvm. This is ultrasound. Maybe a little bit of a density there Great image here and a fluorescein angiography of the anterior segment wonderful image But maybe not too helpful from a diagnosis standpoint So we've got this young woman with this large red and white intraocular mass It's in seemingly involving the ciliary body and likely the retina maybe even the coroid Anteer chamber invasion. It's causing some iridodialysis and lens subluxation hypotony. Any guesses Medulla, I think that's a great guess. That's a good guess. That's certainly on the differential. I've withheld The complete names of everything on this list, but I think the med is down there I think that was made a lot to fill you almost so We'll keep going. I think that's a great thought and so what to do with this eye at this point I'll tell you what we did. They did a fine needle biopsy and the results Oh, of course, we're not going to give you the results just quite yet But we did treat the eye and we treated the eye with well, I can't tell you that either But one month after treatment the eye looked like this better, right? Lesion is shrieking the lens is coming back into place iris is starting to settle back into its place perhaps There's still something there Looking better on ubm and ultrasound six months. So after six months now After initiating treatment, there's cataract there But the lesion is significantly smaller by ubm And of course by ultrasound. Unfortunately, this young woman Was lost to follow up for two years So how did she look when she came back? Well, maybe not too much different, but if you look closer You'll see some white fluffiness in the anterior chamber a seed If you look underneath the eyelid, you'll see these sentinel vessels signifying something Lurking beneath the tumor has recurred and it looks just as bad as it initially did So what was this intraocular mass at the fine needle biopsy had shown that it was actually retinoblastoma And the treatment was systemic chemotherapy which caused an initial nice regression But it wasn't enough and unfortunately she was lost to follow up came back two years later. This I was then promptly enucleated and histopathology revealed massive uvial uvial invasion and More systemic chemotherapy was given So adult onset retinoblastoma is rare This is a survey from the indian journal ophthalmology and globe salvage is rare in these cases But we've recently published on treating Older patients not necessarily adults but patients older than five years Including some adults with intra arterial chemotherapy and found better globe salvage rates Albeit had shorter follow-up. This is an example of that a 23 year old gentleman that presented to the will's eye emergency room with this Legion diagnosis retinoblastoma and treated with intra arterial chemotherapy. All right. Well, I think Griffin Said at least the first diagnosis there, so we'll give him the Wasn't the correct diagnosis I don't know if it deserves an applause No, that's that's fine So instead of talking talking about large retinoblastoma adult onset retinoblastoma, which is Almost always a group D or group E. I let's talk about tiny Very small retinoblastoma. This is retinoblastoma. That's less than one millimeter thick As we see it clinically and this is ocp of that So just a little bit of introduction on retinoblastoma. We're doing quite well at least in the developed World these developed countries where our retinoblastoma cure rates are at an all-time high almost 100 Which is a far cry from over 150 years ago where 95 of these kiddos died But uh, that's how we're doing in The states here and other developed countries Highlighted here the red circle around the mortality rate just three percent But if we look at other areas of the world say, africa And asia not including japan, the japanese do a great job with retinoblastoma. This paper is from finland Ophthalmologist slash mathematician came up with these estimates But uh, you can see that there's a lot of need around the world further amendments to the eye tumor constitution The worldwide constitution need to be made This author also makes the case that we we think of the most common primary intraocular tumor Being uvial melanoma and that's certainly the case here in america, but worldwide it may not be He estimates that seven to eight thousand patients per year are diagnosed with retinoblastoma compared to a worldwide estimate of Six to seven thousand patients with uvial melanoma So, uh, he argues that retinoblastoma may be worldwide truly the most frequent primary eye cancer So like I said, there are worldwide amendments to be made to the eye tumor constitution and here at the moran, of course There's a very good reputation for worldwide ophthalmology and why not add Advances in retinoblastoma to the already illustrious reputation of the moran Despite knowing all these things about retinoblastoma, there's still a lot that we don't know Even though retinoblastoma was the first tumor suppressor gene to be mapped it was the Basis for Knudsen's two-hit hypothesis some fundamental oncology principles here. There's still a lot. We don't know even What is the true retinoblastoma cell of origin? And consequently the retinoblastoma retinal layer of origin. This has been a debate over the past Oh 50 years or so and recently Some authors think that it's the retinal progenitor cell the rpc which then sprouts and Colonially expands into these retinoblastoma tumors. Other think that it's the rpc and Differentiated cone cells others think it's a cone precursor Others think it's a horizontal cell which then localizes to the inner retinal layer others think it's Not nothing specific, but certainly the inner nuclear layer which might be Counterintuitive to what we think and feel because we hear about these rosettes and pseudo rosettes which are have at this Differentiated cone morphology on histopathology. So Maybe one would intuitively think that these would localize to the outer retinal layer And some even think that the Mueller cell is the source of retinoblastoma And it's difficult to nail this down because on histopathology. We rarely see small nascent tumors These eyes come to histopathologists looking like this group D group B large tumors that need to be enucleated So it's tough to analyze this histopathologically But some people have this paper from 96 showed Perhaps an expansion of the inner nuclear layer on histopathology galley, certainly an expert in retinoblastoma from toronto Shows this paper with a small retinoblastoma sandwiched in between the outer nuclear layer and the inner nuclear layer on histopathology So mouse models show expansion of the inner nuclear layer here a mouse model histopathology and oct correlate Not too easy to get but they show expansion of the inner nuclear layer even on oct But this is just a mouse model. Is this the same in humans? Here's another good mouse model This is from indiana and good oct images With histopathology correlation. You can even see the calcification there in these small tumors And they localize also to the inner nuclear layer Some oct studies have been done These authors and papers claim that the inner nuclear layer is the layer of origin And others claim that the outer nuclear layer a small nascent tumor You can see they're perhaps starting in the outer nuclear layer So it's there's some debate We decided to look at all the tumors we could find that were less than one millimeter thick and see what we could glean from the oct analysis So this there's no histopathology correlates here because these tumors are small and these eyes should not be enucleated and so we Retrospectively reviewed all these patients over five years and looked For all these tumors that were less than one millimeter thick that had oct imaging And then we did a layer by layer analysis looked at them these patients were on average four months old And most of them had bilateral disease inherited disease. That's not too surprising That's how you can catch them so young catch them so early usually through screening processes and most of these lesions were posterior to the equator And most of these lesions were in group b eyes. So this isn't The more advanced group d in group b retinoblastoma. These tumors were small about two millimeters in diameter About half a millimeter in thickness And we thought by analyzing looking at these images the three more senior authors on the paper Including myself thought that the majority of these tumors started in the inter nuclear layer and I'll talk about how we determine that But there was one tumor that we just couldn't decide if it was inter versus outer nuclear layer I'll show you a picture of that and we found these OCT features of retinoblastoma Of which I'll discuss fishtail shark fin and of course this tumor Calcification. Well, if you see a small retinoblastoma tumor It's no surprise that retinoblastoma can have calcification You can see a big chunk of it here causing that shadowing posteriorly And then you can also also see this micro calcification causing these Vertical shadow artifacts on our OCT Well, what about these kind of silly name shark fin and fishtail signs? Let's take a look at these Just go with me here with an eye of faith look at these pictures But if if you imagine drawing look at this area, but if you imagine drawing a line In between the inner nuclear layer and the inter plexiform layer And then another line around the lateral edge of the tumor and another line between the inner nuclear layer and the outer plexiform layer You might like I said with an eye of faith see what looks somewhat like a fishtail And you can maybe see evidence of that in these small tumors It's really just the expansion of that inner nuclear layer as it perhaps gives birth to these tumors And you can see small fishtails in these tumors OCT the shark fin I think is more obvious Where if you draw a line between the outer nuclear layer and the outer plexiform layer you get this shape looks like a wave or Maybe even a shark fin Like I say, it's just a silly name But I think these names might mean something you can see these waves or shark fins on several of these tumors Something that we just couldn't ignore and what do these mean? You can see maybe both of these signs on several of these tumors as well So does this help us determine a layer of origin? I think it might say you have this fishtail and it's not hard to imagine that that Could represent that the inner nuclear layer has expanded And given rise to this tumor And it begs the question. What on earth is this tumor doing in the inner nuclear layer? If we've always thought it was a cone or a cone precursor, but Uh What about the shark fin sign? What's it doing to the outer nuclear layer? Well, we hypothesize that as this tumor grows It invades and Sort of distorts or bends the contents of the outer nuclear layer around the tumor margin And that's what gives you that hypo reflective wave or that hypo reflective shark fin Maybe you can see that here where the inner nuclear layer expands on to this tumor And then the tumor kind of invades and displaces some of the contents of the Outer nuclear layer causing that wave or that shark fin and here's a couple other examples of that that May or may not be be evident but Back 20 years ago. Dr. Galley had mentioned something similar even with histopathology analysis Saying that it appears as though this tumor might be in the outer nuclear layer But on histopathology close inspection reveals that the nuclei have inl features And that the retinal blastoma has invaded and distorted the outer nuclear layer And even vintersteiner over a hundred years ago some histopathology drawings may have alluded to some Inner nuclear layer fishtail signs all that time ago So I think OCT is very useful in characterizing sub millimeter retinal blastoma not necessarily What we've talked about here, but even tracking its response to our treatments We think that retinal blastoma may originate in the inner nuclear layer These signs may or may not help us determine that and of course future work is needed Just some other reports on how OCT is useful. This was a very resistant retinal blastoma So after systemic chemotherapy the tumor looked like it had regressed well, but then The tumor recurred whenever you see these cysts Marked by these white arrows We have seen that from time to time in a chemo resistant retinal blastoma A chemo resistant because it's probably a very well differentiated tumor And there's not a lot of cell tumor turnover, but there is some And that's perhaps why it would be chemo and maybe even radio resistant So after intra arterial chemotherapy again, we thought we had good regression This is a vertical scan through the tumor. You can see some of the calcified scar there underneath the retinal tissue But the tumor recurred after a few months. And so What do we have left in our quiver after systemic chemotherapy and after intra arterial chemotherapy? Well, we would use a radioactive plaque in that setting And the tumor Finally regressed and was stable at at follow-up last that I checked in on this patient So OCT was somewhat helpful there. How about for retinal blastoma seeding? Here's a vitreous seed of retinal blastoma tumor cells sitting on top of the macula and We've started doing this precision intra vitro chemotherapy Well, you're actually inject under indirect ophthalmoscopy to localize the load of your of your chemotherapy and We can see that You know that vitreous seed was no longer visible by clinical tundoscopy and by OCT And then this cloud of vitreous seeding above a tumor scar that you can see on the lower images here Disappeared after But you do see some Melphalan retinopathy there In the lower left image with that kind of salt and pepper retina appearance Here's another Tumor that grew while being on systemic chemotherapy. These are two tumors actually b and c and then we treated them with Transpupillary thermotherapy Enhanced by actually ivy endocyanine green. It's kind of a poor man's PDT if you will And then this is an interesting case of a lesion where Intra arterial chemotherapy was given to the right eye, but we saw Not very small, but some response to Contralateral intra arterial chemotherapy in the fellow eye suggesting that there is some systemic absorption of that Supposedly local treatment. So we've talked about retinoblastoma bored you enough with that amendment to the itumor constitution Let's go back to a mystery case again. Yes Would that mean systemic absorption or just would that imply that it actually is circulating to the other eye? I think yes. Yes, and yes, so I think We give it to to say the right eye in that situation Some of the the melphalan gets of course out of that eye into the systemic circulation And then into the left eye through bloodstream So and then there have been reports of even the effects of Melphalan and these drugs we use for intra arterial chemotherapy affecting Other tissues that are undergoing, you know rapid proliferation or clonal proliferation like the gonads If you give too much melphalan Systemically certainly or even with IAC you can induce sterility. So you have to be quite careful Good mystery case number two. We've got a frisbee a kind of blow horn type thing and uh, what's this called a cup Cousy, thanks This guy there on top of it mystery case number two and this is kind of choose your adventure So I'll tell you that it's an older woman vision is down Uh, this is a throwback to my youth But I'm gonna let all of you be the heroes of this story What do I mean by that? Well, choose your what would you like to see on this patient? First we'll look at the right eye Go ahead anybody could you don't get a prize for shouting this out, but just shout something out Slit lamp let's do slit lamp. I like it So there's some prominent scleral and conge vessels the cornea is clear The iris has this diffuse lumpy appearance and there is significant cataract That's likely what's causing the vision loss, but you can see these dilated torturous vessels here So we've got our slit lamp exam gave us some good information. What's next? What do you want to do? Once the u.b.m. I like it. I like it. Let's look at this u.b.m. This is the right eye at 12 o'clock I think that that Celery body is thickened This it's not so obvious here and you can maybe see this iris pigment epithelium cyst right right behind the iris I called it out there. So that's 12 o'clock We didn't see too many vessels in that area Six o'clock. There's definite thickening of the ciliary body kind of this diffuse thickening of the ciliary body eight o'clock even thicker And then a 130 transverse you see that thick and ciliary body Flanking the iris here and then several of these large IPE or iris pigment epithelium cysts Bizarre u.b.m anything else B scan let's look at the B scan pretty normal in that in that right eye I won't belabor it too much, but you can see increased pigmentation in the angle and even this Kind of clear ish lesion invading the angle And maybe you can appreciate the lumpy appearance of this iris probably from all those cysts sitting underneath the iris Very well On dilated fundus exam. We see this pigmented lesion On autofluorescence. We see that pigmented lesion with some autofluorescence now OCT nothing too abnormal at the macula, but uh, there's some hyper reflectivity of that lesion and Kind of the surrounding coroid when we scan through that peripheral lesion not the best Quality study, but certainly something there. So that was the right eye Bizarre right wouldn't it be bizarre if we saw all the same things in the left eye? Well, we do lumpy iris increased angle pigmentation Thickening of the ciliary body with iris pigment epithelium cysts causing that lumpy iris appearance But here in this left eye we see scattered little spots of pigment And then in furrow temporally We see a larger area of elevation and pigmentation of the coroid and that does have some thickness And OCT there's maybe this focal area of thickening in that spot there Okay So uh past medical history. Ah, she has stage four endometrial cancer and uh Progression despite multiple therapies. So she's got active stage four uh genitourinary cancer So uh, we'll forego the joke and the trivia And just jump to our differential Our assessment differential diagnosis that we've talked and shown pictures of all these things This a melanotic angle mass in the right eye the vision's down thick ciliary body in both eyes multiple IPE cysts in both eyes cataracts in both eyes and irregular Coroidal pigment in both eyes So what's on our different? Could this be metastasis to both eyes in a very symmetric manner? Could this be melanoma could this be uvial fusion uvial lymphoma or could it be something perineoplastic? That's the big hint If you were to just look at this eye and describe it you might describe it as it's a bilateral process these lesions seem to be pigmented or Melanocytic it seems to be diffusely occurring through the eye And uh, we might get to a diagnosis here bilateral Diffuse uvial melanocytic proliferation a very odd presentation of a very odd Diagnosis so odd on top of odd. That's tough So originally described by machamer. There are these five cardinal signs by gas, but they don't necessarily have to occur As we saw in our case. So when do we see B dump? Well almost never but when we do see it It's in older people mostly women with urogenital cancers if it's in a man They'll probably have had or have a lung cancer in four 44 of cases the previous cancer Or sorry the underlying cancer was previously diagnosed These are just some histopathology images showing finding similar to our case with that thickening of the cellar body these ipesis ipesis here. This is an image from UCLA medical retina a dock and group down there Showing these ipesis and looks you know astoundingly similar to our case So I don't have any doubt that that's the diagnosis and that was anterior segment oct Who do I give it to on that one? What do you guys think? Nobody randy said slit lamp. So slit lamp this first. Yeah, that's right. Let's uh Oh gee Out on the ranch keeping uh, there you go keeping his diet coke nice and cool there There you go Very well good. So now let's go back to our amendments You can guys get a little bit of a nap in here for this early morning This paper was presented at asrs just a few Weeks ago a end of july and this is one of my favorite papers Regarding uveal metastasis and we wrote four papers from this series of over a thousand patients with uveal metastasis Papers regarding timing of primary cancer diagnosis patient sex patient age and then what the primary cancer diagnosis was And I was at the bookstore yesterday and there was this feeling of Freshness as the new semester was starting yesterday Down on lower campus and I thought well, it's no better time than now for a pop quiz For this new semester. So what percentage of patients with uveal metastasis present with undiagnosed primary cancer? What do you think we'll get to these answers If a man if a male presents with uveal metastasis and undiagnosed primary cancer Then the most likely primary site will be Oh, if a female that was easy, you guys are all over that if a female presents with uveal metastasis An undiagnosed primary cancer the most likely primary site is Oh, I like it Mean interval between primary cancer diagnosis and uveal metastasis is longest for which type of cancer We'll go over these answers five-year survival estimates are better If the primary cancer is diagnosed before uveal metastasis compared to if you see the metastasis and then send them for the workup to find Find the primary lesion. Well, this paper is really just a continuation of a paper that was published over 20 years ago This series had about 400 patients in it now 20 years later. There's over a thousand patients in The shields database with uveal metastasis. So we looked at all those patients looked at demographics clinical features Timing of primary cancer diagnosis whether that was before after or never in relation to uveal metastasis And overall survival based on timing of primary cancer diagnosis really just those questions I was asking over a thousand patients with all these lesions And we found that if the primary cancer was known That was about two-thirds of cases versus one-third had undiagnosed primary cancer A slight age difference between these groups. There's certainly a gender a sex difference between the two and A laterality difference. So primary cancer site If the primary cancer is known, it's most often women with breast cancer. I don't think that's any secret but if the primary site is undiagnosed and it's most often a lung cancer But quite often the Primary cancer is is never identified at least in this series So how is this helpful for us when we're examining a patient who doesn't have any cancer history? And we see something that looks like uveal metastasis in the eye We ask well, do you have cancer? They say no. So what's our job? It's to get on the phone with either a primary care doctor or a medical oncologist if they have it And say this patient needs a systemic workup and it's nice and you sound really smart if you can say, you know what? Start by looking at the Well, if it's a man just like everybody unanimously unanimously said If it's a man, you need to look at the lung eight out of ten of those patients will have a lung lesion but surprisingly Followed by a small amount with with gi surprisingly The majority of breast cancer and and uveal metastasis from breast cancer meds Is diagnosed the primary cancer is diagnosed 95 to 97 percent of the time That primary breast cancer is already diagnosed because we have such good screening for breast cancers We don't have as good a screening for these lung cancers So if somebody comes in with a uveal metabolism a woman comes in with uveal metastasis and they don't have a primary cancer diagnosis It's more likely to be lung even in those cases Which is interesting. This is probably my favorite Slide from all of fellowships something we put together But two-thirds of these patients will have known primary cancer the majority of those will still be breast cancer So the majority of uveal metastasis of course is still breast cancer But in those who we don't know the primary cancer diagnosis We may never learn it or if we do then more often than not it's lung cancer So on the phone you should say start just playing pure numbers both men and women You say start by looking at the lung and they'll say well, how do you know that and then you're just saying just trust me You know, you don't tell them that you have the data, but you just have a feeling So just the other day this happened this patient came in with this skull based lesion from ent At some tongue issues weakness on on the left side MRI showed this enhancing skull based lesion here MRI also showed The vision was 20 20 in this side, but MRI also showed that there's this enhancing ocular mass We had a call from ent They're saying Gentlemen has what's likely a primary eye tumor with a skull based metastasis We need you guys to take a look. What do you think and even over the phone that story just doesn't necessarily work A primary eye tumor that metastasis in the skull base. We never see that it's a 40 year old It might primary eye tumor. Is it a melanoma? Well that I've never seen that go to the skull base That usually goes to the liver, you know and and so it just doesn't sound right So everybody say yeah, sure. We'll see the patient you look inside the eye vision is good um, he does maybe endure some symptoms here and uh, but you can see this Large collection of sub-rentinal fluid this exudative choroidal lesion on b-scan. It looks like this. It's uh Kind of a diffusely thickened Homogenist and normal choroid Not necessarily hollow lesion on b-scan And this all looks like a metastasis So it's a 40 year old man and just playing numbers you would say get on the phone and say, you know I don't think this is an eye primary eye tumor In fact, I would I need the systemic work up and you start by looking at the lung and sure enough He has a lung lesion here on his pet scan So what percentage of patients with uveal metastasis present with undiagnosed primary cancer? 33 start by looking at the lung even in women look at the lung if the primary cancer is undiagnosed But you know a quarter of them also did have breast cancer. So The mean interval now is longest for which type of cancer? Well Mean interval is 5.2 years overall Somewhat longer for breast and really quite long for thyroid. This is an interesting Finding here why so long for thyroid? and then relatively short for lung And gi tumors and regarding the survival estimates Whether it's diagnosed before after the uveal metastasis turned out stage 4 disease is stage 4 disease No matter when we see the metastasis and the survival rates really aren't affected by when we look in the eye And so this isn't too surprising But there's no survival difference between these two groups on a five-year capillary estimate And what about if we never diagnosis? similarly the Never diagnosed group is a little bit underpowered here, but but there's also no difference in survival at least at five years There's some other survival data here that we won't go over So the take-home points today are really the answers to the questions that we've posed in our pop quiz Two-thirds of these patients have a known primary cancer diagnosis If it's not known start by looking at the lung and men and women The mean interval from primary cancer diagnosis to uveal metastasis was relatively short for lung and gi cancers Relatively long for breast and thyroid cancers. No difference in five-year survival Depending on the timing of when we diagnose these tumors in the eye Very well. So let's get back to a mystery case something for everybody here. Let's move to the anterior Segment maybe even the ocular surface or orbit. You tell me this is a young kiddo five years old Doesn't look too bad, but when you revert that eyelid you see this bizarre Padunculated lesion And you think this is kind of a odd looking What what do you guys think this is anybody Could this be we know it's not a conjunctivitis because I probably wouldn't be presenting on that but Uh, maybe I'd present on a papilloma. That's what we thought this is a bizarre papilloma And a kiddo but by the time we get to the operating room to remove this lesion it had grown significantly And I was scrubbing in with carol shield and she said That's that growth is much too rapid the diagnosis is this she said it and I said, oh, okay Histopathology comes back showing these findings Immunohistochemistry cytoplasmic Uptake here of desmin nuclear uptake of myo genin It's a ramp. It's a ramp. Hey, we we got to give that We got a he's going to get two things here. You guys got to catch up with this. This is boteroid Rhabdomyo sarcoma of the conjunctiva and a young boy Right behind you was dr. Petty Yeah, yeah, so he he was right there. He's are I'll let you guys fight over I don't want to Y'all at the residence That's right. You guys nailed that. That's a bizarre appearing rafdo of the conch And a young kiddo He's doing great Unfollowed. All right a quick paper on a melanotic carotid lesions. I know we're jumping all over the place But there's good learning in some of this. I think this paper is published in bjo Earlier this year it was presented at the international society of ocular oncology and la in march And it even won best paper of the day there. We were proud of that so you look at these lesions and These present to you in your clinic if you have some of the founding doctors some of the writers of the itumor constitution at your side Then diagnosing these lesions isn't difficult Uh, but say you don't have those doctors at your side at all times then these lesions can be somewhat perplexing And you can go read about all these a melanotic Coroidal lesions, but that would take quite a bit of time So wouldn't it be nice if there was a one-stop A melanotic shop where you could find all the info you need Maybe not all the info but a lot of the info you need on these lesions And it's important to get it right another question here because Two maybe three of these lesions may induce poor life prognosis For the patient anybody any guesses on which of those lesions which of these lesions could have poor life prognosis I would go with a a doesn't look good And then I would go with c c also doesn't look good. That's a metastasis And even f what on earth is f. Well, we'll talk about what f is Um, so methods we looked at all a melanotic Coroidal lesions over a 45 year time period the inclusion criteria was if this lesion looked More than 50 percent a melanotic we included it So it was very inclusive study And that's how we got up to 4 000 patients looked at demographics clinical features stratified by age sex and basal diameter And compared them to a melanotic melanoma. This is quite an undertaking especially In a clinic that is still clinging On to paper charts. So looking through paper charts for all of these lesions. That's what happened here and it Was quite the undertaking found all these patients and looked at mean age for all of these lesions So what are we talking about? We're talking about a melanotic melanomas nevi metastasis Coroidal homangiomas So a melanotic doesn't necessarily mean yellow. It could be like a red or an orange appearance. So we have PEHCR, which That's peripheral exudative hemorrhagic choral retinopathy, which more commonly presents kind of pigmented or red or kind of blood-like in its appearance, but Uh, it can be a melanotic duty exudative part sclerochroidal calcification That was the f that we saw in the picture before Choroidal osteoma granuloma lymphoma, then there are inflammatory lesions that make it into a tumor clinic Solitary idiopathic coriditis, which is a misnomer, but that's the diagnosis Some other lesions including Like a scleritis a posterior scleritis or a uveal effusion I think those were the types of lesions that were in that other group So mean age of melanoma is different from other other lesions and it's best seen here on this age Distribution graphic where melanoma presents at a mean age of 57 years at least a melanotic melanoma and that's Significantly older than these lesions and significantly younger than patients with these other lesions here We'll talk about this more, but what about patient sex? Well, a melanotic melanoma is kind of split Down the middle and then we compared these other ones to a melanotic melanoma and Nevis a melanotic nevis There were more females in that group In the metastasis group as well and the osteoma group as well. So that fits with kind of our understanding What about the size of these lesions? Well, the melanomas were significantly bigger than most everything else But from a basal diameter standpoint smaller than just one of these other lesions and that's kind of this diffusely infiltrating uveal lymphoma Which has a wider base, but certainly a smaller thickness compared to melanoma and that lesion can look like this This kind of diffuse oranges infiltration Of the uvea of the choroid in this in this picture. What about location in the eye melanoma was on average 3.5 millimeters from the disc lesions that were more posterior were metastasis hemangioma osteoma And lymphoma albeit that was quite diffused in its presentation usually lesions that were more in the periphery were Nevis and certainly this peripheral exudative hemorrhagic choral retinopathy And sclerochroidal calcification So I think this is the real strength of the paper if you're in a clinic and you see a lesion it's a melanotic You don't know what it is Well, if you know the age if you know The patient sex and if you can get an estimate on the size of the lesion you can come to this chart just in the paper and say Well, it might be this so if it's a younger male and it's a smaller lesion then Odds are that it might be a hemangioma You might be able to diagnose that without a paper like this But this at least gets some other things in your mind Versus if it's an older woman and it has a similar smaller appearances could be a nevus It could be that sclerochroidal calcification Or it could be pehcr But you can see that melanoma is really quite rare in that age group That's important to get it right because life prognosis may be poor for some of these diagnosis Melanoma the five-year survival estimate is 85% and even lower for metastasis So don't overlook your patients with metastasis because their survival is even lower than those with eye melanoma It seems that these more dangerous diagnoses are clustered around this age group 55 to 65 years old But don't overlook sclerochroidal calcification if this occurs in a patient with Hyperparathyroidism that can be fatal. It can be quite dangerous So if you see this lesion in the eye, which is Uh That calcification we saw kind of in the lower I guess second from the left on the bottom then you might want to be careful. There are limitations to our study I won't get into those but just like any other there are limitations So it's this paper is kind of a one-stop shop for amelanotic croital lesions Stratified by age sex and lesion size and it's really just a tool for helping us Making and making accurate lifesaving diagnostic and management decisions. Okay For more of the retina people in the crowd, let's go through this mystery case. We got a frisbee Here is our last prize It's a 63 year old woman in the right eye see this Yellowish appearing lesions It looks deep to the retina Deep to those vessels certainly in the left eye an autofluorescence. Wow, they're quite Uh Autofluorescent hyper autofluorescent there and they even seem to have this hypopion appearance almost like there's this life lipofucin hypopion in both eyes boat shaped Sub-retinal lipofucin deposits That are hypo fluorescent on fluorescent angiographies. They're blocking the underlying Choreoidal fluorescence here. That's what's happening OCT vertical scan you can see how that lipofucin is kind of gathered in this dependent fashion causing that hypopion appearance And this is the clearest image I was talking about with your photographer earlier. This is after treatment now Things are looking better OCT is looking better in both eyes as well Any thoughts on the diagnosis here? Is this a tumor or is this a perineoplastic ocular finding? Excellent. I love it Yes, uh exudative perineoplastic Retelliform maculopathy just like dr. Vita. I said this patient had cutaneous Melanoma so something about her melanoma is causing her eyes to do this So you treat the melanoma cutaneous melanoma now we can treat them with these checkpoint inhibitors She did quite well from that standpoint. Well, how do we treat the eye? This patient had several episodes of plasma freezes to get that regression that we saw in in the previous OCTs. That's great. All right I was worried I was going to have to take some of this stuff home, but I thought we were the dog. Good Excellent So you guys these mystery cases were no No problem for this group and that's not surprising. So let's finish here with some bread and butter Ocular oncology. This is high-risk carotonevis and we're hopefully most of us Are familiar with this pneumonic came out this version of it came out 10 years ago To find small ocular melanoma using helpful hints daily That's regarding you're looking at a pigmented lesion in the back of the eye and you're wondering When you see this patient is this Lesion going to grow do I need to be worried about this? So that's what this is assessing risk factors for growth nebis growth And if you have one or two of these features, it's probably safe to follow the lesion at least initially Then if you see growth certainly refer, but if you have three or more of these features Then you'd probably want to refer to somebody who looks at a lot of these That was essentially the gist of this paper from 2009. It was a continuation of work From before which just had the tfsom part of the pneumonic But this was in an era of More clinical exam and we're moving more and more into multimodal imaging And so these findings weren't based on our imaging the sub retinal fluid diagnosis was a clinical diagnosis not necessarily an oct diagnosis and The orange pigment was a clinical diagnosis and not necessarily the orange pigment equals life of fusion accumulation Which equals hyper auto fluorescence? So nowadays we kind of really lean on our auto fluorescence for our orange pigment So did we need to reassess these risk factors in the era of multimodal imaging? I don't know if we needed to do it, but certainly it was done and We looked at these features with multimodal imaging published a few papers And revised the pneumonic a little bit. There were some aspects of the old pneumonic which I and we others didn't necessarily love like that Margin close to the optic nerve. We didn't necessarily love that and this halo absent thing where You know this depigmented halo of anevis was actually a good sign But if it was gone was that a bad sign? Well, it's rare to begin with so maybe it didn't belong in the pneumonic But it came out on this multivariable analysis and so it was included in the paper So reassessing these things using multimodal imaging and some clinical features There's this new pneumonic which is gaining some strength. It's more or less the same But includes some other things now. It's still thickness has determined on ultrasound fluid now is determined by oct Symptoms that's just clinically of course this vision less than or equal to 2050 orange pigment mostly determined by auto fluorescence And of course, we still use our hollow ultrasound finding for melanoma or for high-risk nebis And now diameter if the diameter is greater than five millimeters on your clinical exam or on your fundus photography And this could have important implications Especially as we move forward and say artificial intelligence where we're using imaging to maybe screen Many many patients and we can examine clinically And the results here are great great and easy to remember So this five-year estimate for tumor for nevus growth zero factors There's very little chance that that thing's going to grow but if you have one factor, it's 11 Two factors. That's 22 three factors. It's just a little bit above 33. So isn't that nice? The four factors kind of gets thrown off But then we get back to our pattern with the five factors at 55 percent So that's real nice and easy to remember when you're looking at one of these lesions and in the eyes think Okay, this thing is this has a 22 percent chance of growing over the next five years And further than that we looked at every combination of all these Nevi and And then did a Kaplan-Meier analysis and determined based on all these different combinations Which are listed across the bottom of these signs or findings in the eye and what's the five-year estimate for growth And uh, let's do an example. This is a younger a woman It's not necessarily it's kind of right on the borderline. It's almost two millimeters thick, but we'll say it's under Fluid by OCT you can see on our top right symptoms Even though there was this little bit of sub-retinal fluid still seeing better than 2050 Definitely some orange pigment with that hyper auto fluorescence on auto fluorescence imaging And definitely hollow as we look at that b scan a scan would reveal it to be hollow as well, of course and the diameter is Larger than five millimeters as well. So when we look at this lesion Uh, we find it here and find that there's 40 for 7 47 percent Kaplan-Meier five-year estimate for growth And that fits because I think we said that there were four symptoms. So it's right around that 40 Or 51 whatever it was and so this is a little bit older woman. This is that halo This is the depigmented halo around an evis So that's that halo that was talked about in that original mnemonic Didn't necessarily make it into this mnemonic, but this isn't as thick As that other lesion certainly less than two millimeters. There's no fluid by OCT. There's no symptoms here There's no orange pigment Some of us might be fooled by that depigmented halo, but that's not true lipofusion. That's not true orange pigment That's just some Coroidal depigmentation there and it's not it's you know somewhat hyper auto fluorescent but not the Brilliant hyper auto fluorescence that you see with lipofusion or orange pigment accumulation It's maybe a little bit hollow on that b-scan and a-scan if you did it and then Diameter is larger than five millimeters. So we have two of these findings here and that those specific findings of hollowness and Diameter equate to a 28 percent chance For growth over the next five years. So I find this paper to be useful if you have you can Look at a lesion and determine how dangerous is this lesion? And you'll see that there are certain combinations of these findings that really are quite dangerous that have a hundred percent Estimate for growth over five years. So I think that's a nice and pretty valuable paper very well So we've talked about high-risk nevus here. That's bread and butter red and a bread and butter your oncology So thank you for dancing with me through these mystery cases and through these amendments. These are diagnoses that I Truly love and these these types of patients. I I also love and enjoy as well and Let's remember that it's the patients that are writing the amendments And we're lucky enough to be included in their lives and to be their doctors And I think that the next Amendments to the eye tumor constitution. There's no reason why those amendments shouldn't be Written by the patients of the inner mountain west Through the doctors here at the Moran eye center and adding to the worldwide eye tumor consultation As well. So thank you for your time