Melanie Cole, MS (Host): Welcome to Better Edge, a Northwestern Medicine podcast for physicians. I'm your host, Melanie Cole. And today, we're discussing primary vitreoretinal lymphoma, PVRL, a rare and complex disease that poses unique challenges in both diagnosis and treatment. We have three experts today from Northwestern Medicine joining us to unravel the mysteries surrounding this condition and its management: Dr. Chris Bowen, an ocular oncologist; Dr. Karan Dixit, a neuro-oncologist. and Dr. Stephen Magill, a neurosurgeon. Welcome Drs. Bowen, Dixit and Magill.

Dr. Bowen, I'd like to start with you. As primary vitreoretinal lymphoma is a rare and challenging disease, please explain the key differences between PVRL and primary central nervous system lymphoma.

Dr. Chris Bowen: Sure. It is true. It's a very rare disease. And it's actually fairly simple in that between the two, if it starts in the eye, it's considered the primary vitreoretinal lymphoma. And if it starts in the brain, CNS, it's considered primary CNS lymphoma. Predominantly, a diffuse large B cell lymphoma commonly, can be T cell, but those are the most two common types. If it starts in the eye, vitreoretinal lymphoma, there's about a 70% chance that it's going to manifest also in the brain or in the CNS. And then if it starts in the CNS, about a 30% that it'll also manifest in the eye.

Melanie Cole, MS: Well, thank you for that. And Dr. Dixit, why is PVRL often misdiagnosed? What are some of the most significant hurdles in diagnosing it?

Dr. Karan Dixit: Yeah, the challenge with this disease is that the symptoms are often quite vague, and people can have primarily visual changes. So when it's PVRL, it's primarily kind of subtle vision changes that can, you know, manifest for months and months, and that can often go misdiagnosed because it can mimic other conditions, such as inflammatory processes of the eye. And oftentimes for those the people that get steroids, which can help the condition transiently, but also makes diagnosis very, very challenging. You know, so for rare conditions like this, if you don't think about it, because it's so rare, it's often missed. And that's kind of one of the challenges, is it can mimic other conditions and then kind of having someone who's an expert who's thinking about it and kind of knows how to get the fluid appropriately and testing it appropriately is really important to get a diagnosis as quickly as possible.

Melanie Cole, MS: This is such an interesting topic. And Dr. Bowen, after Dr. Magill answers, I'd like you to expand, but how do you collaborate as a multidisciplinary team? This is so important and you represent many specialties. Please tell us a little bit about your combined clinic and what are you finding are the largest benefits. Why is a multidisciplinary team so important for these patients?

Stephen Magill: Yeah, I think a multidisciplinary team is really important because it's a complex disease. As Dr. Dixit was talking about, it can be misdiagnosed for other things. And each of us come at this from a different standpoint. So me as a neurosurgeon, I'm often involved once the thought has been, "Hey, there's something going on. It's in the brain. We need to get some tissue." But figuring out how to be there, how to determine what is going on, how to have an idea of that, you need people who have different insights. So, Dr. Dixit comes at it from an oncology standpoint, Dr. Bowen from an ophthalmology standpoint.

And I think once you start seeing these things and it raises questions, then we can work together and we can talk together. And when we have a team, we can pick up the phone or walk across the hall to the other doctor and say, "Hey, I've got a patient. I'm not sure what's going on. Can you take a look at the scan? Can we just have you see them as well?" And so, working together, it helps us us all stay sharp at the tip of our game, learning what's going on. It gives you different perspectives of learning how other people see disease, how other people work it up. And then, it also allows us to expedite care so that when something needs to be biopsied or we say, "Hey, we need a better ophthalmology exam," we can facilitate that very quickly. It's not, "Wait two weeks, wait three weeks, then we'll get you an appointment a month from now when things are totally different or your condition has declined." We can just walk across the hall and say, "Hey, Dr. Dixit, can you come in and see this patient with me? I know they were scheduled to see me, but I think we need your expertise."

Dr. Chris Bowen: Yeah, I completely agree. And there's a case in point. We had a case a little while ago where the patient had primary vitreoretinal lymphoma, was receiving injections of methotrexate, but then had some changes and immediately was seen by Dr. Dixit, did an MRI, saw an enhancing lesion. And if I remember right, you just called Dr. Magill. And then within a week, he was in the operating room, had a biopsy, and had a result. And I think that's the power of these experts, you know, all of us working together on this common goal of preserving both life and vision.

Stephen Magill: You know, lymphoma is one of those diseases that, and I know Dr. Dixit can talk more about that, where we can initiate treatment upfront and be more aggressive and getting the right treatment. You talked earlier about steroids, you know, kind of masking it. Then, we do a biopsy. It's non-diagnostic because some of the cells have gone. And so, if we can get the right diagnosis upfront and initiate treatment quickly and effectively, we can provide the best outcome as a team for our patients.

Dr. Karan Dixit: Absolutely. And getting to the bottom of something quickly, I think we all put ourselves in the patient's and family's shoes. You know, if anyone were to have a medical issue, something serious, when this is even a possibility, getting to see someone who knows it quickly is important. And it's as easy as picking up a phone and sending a message. You know, with this case, Dr. Magill immediately, biopsy was scheduled at the next open OR date, got tissue that day, got a preliminary diagnosis from the OR. "Hey, this is lymphoma," and then we started treatment pretty much within a day or two. So within a week's time, we had a turnaround of a possibility of a diagnosis to treatment, especially with a disease like this, which is is eye only, which have relatively high risk of having brain involvement at some point. And then vice versa, which is brain involvement, we have to stay on top of the visual symptoms. So, it's very nice to have someone like Dr. Bowen to examine the eyes. I can't do that. I can see someone's strength, I can get an MRI, and that's where disease hides.

What's challenging with CNS lymphoma is that it comes back oftentimes. And, you know, one of the reasons that can happen is because the eye is often a reservoir for disease. And so, kind of finding that, staying on top of it is really important. And then having a close neurological surveillance between myself and Dr. Magill, I think are kind of really key points to ensuring really kind of high-level assessments for these patients, because you want to pivot quickly. The challenge with these diseases are they're hard to treat long term. I mean, you treat them and they come back. You know, when you treat them in the eye, like this specific patient we're discussing was diagnosed many years ago and the disease keeps coming back, keeps coming back. And then, ultimately it went to the brain. And then, that's when we had to pivot really quickly and change treatments. Now, the patient's doing really, really well. She's doing amazing actually. And then, kind of all of us working together has really helped this patient live kind of really the best life that she can have.

Melanie Cole, MS: Well, I love the way that you put that because there certainly is power in that multidisciplinary approach. It's so important. And Dr. Bowen, preserving both life and vision is a key goal in treatment. Could you please elaborate for us on the advanced systemic and ocular treatments you employ to achieve this objective and how the Northwestern Medicine's team of expertise and specialization in this field has influenced that outcome for patients? You just touched on it briefly, please expand for us.

Dr. Chris Bowen: Sure. And I think maybe going through, you know, when a patient comes in, might give a little bit of an example of how that works. But let's say someone comes in and they've got new floaters, flashing lights, and if they're seen by an ophthalmologist first, actually the most common thing would be like a retinal tear or detachment. We need to rule that out. The next thing is make sure it's not an infection. Make sure that it's not due to like a rheumatological or an autoimmune condition. And then, the less common thing would actually be the vitroretinal lymphoma.

And so at that point, when we're looking inside, and actually, fortunately, from an ophthalmology perspective, you know, we're able to use 48X magnification on our scope. So when I look inside, I actually see the large white blood cells floating around in the eye. And it actually looks different than when I see other cells that are inflammatory. They just behave differently. And so, that gives us our first kind of cue. And then when we look at the retina, these will oftentimes deposit or hide, you know, very neatly within the retinal, subretinal walls.

And the first thing we can do is a liquid biopsy. So, it's a very non-invasive, easy approach, just pull some fluid from the front of the eye. And then, we can send that off for diagnostic testing. That's usually MYD88 and IgH, IGKappa that we'll send off. And then if those are positive, then we'll go and do a vitrectomy, which is pulling out all of the cells from that jelly. And we'll have our expert ocular cytologists and hematopathologists look at that and provide a confirmatory diagnosis. And then, we're able to have Dr. Dixit. You know, usually I call him the same day and I'm like, "Hey, I've got a case." And he's like, "Great. We'll get the MRI, the lumbar puncture, body scans, labs," boom. And then, you know, very similar, like we talked about, if there's something in the brain, you know, we've got this nice cycle that together. And then, you know, depending on what we find, we may choose to either do intravitreal injections for local treatment, or we'll start systemic treatment and sometimes a combination of both. Because oftentimes, you know, vitreoretinal lymphoma doesn't just cause lymphoma in the eye, it also causes a lot of ocular inflammation, and so we have to treat it with local steroids.

And so, it's a teamwork approach. I mean, I think I probably email you more than most other physicians. You know, saying like, "Hey, so and so is doing well," you know, "We've got this, got a lot of inflammation." But because of this close collaboration, you know, we have very happy patients. Patients that not only are doing well, but I think really appreciate that we talk to each other a lot and are working toward this common goal of a better life.

Dr. Karan Dixit: Yeah. And since Dr. Bowen's been here, it's been really kind of quite helpful just to have like a direct connection. Because when there's eye involvement at the initial discovery, having brain involvement is about a 30-ish, maybe some studies up to 50% chance of brain involvement, which is why we need to kind of quickly assess their nervous system, which is brain imaging, spinal fluid imaging, and then really the body as well and so, kind of getting these things in very quickly so we can direct management.

You know, when it comes to systemic management, currently we employ, you know, a drug called methotrexate intravenously, high doses of it. You know, we use that often when there's a concern for brain involvement or spinal fluid involvement. But, you know, when there's only eye involvement, oftentimes we tend to favor local eye treatments, which kind of balances quality of life and maybe holding back on some of the more aggressive treatments that might be needed later. Because, unfortunately, even with aggressive treatment of the eye disease, within five years, a fairly high, as Dr. Bowen mentioned earlier, up to 70% involvement of the nervous system. And their treatments are also, you know, advancing as more and more drugs are being discovered for other diffuse large busy lymphoma, and a lot of it's extrapolating from that, monoclonal antibodies, more targeted agents, there's a class of drug called BTK inhibitors, Bruton's tyrosine kinase inhibitors. You know, and these are all showing in small studies that there is involvement of improvement in eye disease as well, especially because it keeps coming back.

And so, you know, we want to make sure we're always thinking about what's the latest greatest, you know, what all the research is, and kind of employing every possible technique we have. So, my hope is that in the future that, you know, when there's involvement of the eye, we kind of very quickly stage the the nervous system, stage the body. We start with eye treatment and then maybe in the background have something, kind of maybe not as aggressive as chemotherapy, but something less toxic, but to kind of maybe prevent relapse of the nervous system, you know, how can we prevent that. They're very difficult complication that can develop. Small molecule agents, the plasma blood-brain barrier is really important, the blood retinal barrier going to be important. So, there's a lot of, work that, you know, we think about that we're working together on, on how to, you know, improve local and systemic treatments.

Melanie Cole, MS: Dr. Magill, when is the involvement of neurosurgery warranted in the patient's treatment strategy? How do you and Dr. Bowen work together on the surgical resection of these tumors? Could you please, for us, elaborate on the surgical approach for resecting these tumors in the process we're determining that optimal approach?

Stephen Magill: Yeah. So, a lot of the neurosurgical involvement is when there's diagnostic questions. So, Dr. Bowen and I don't actually do the surgeries together, but he does any interventions in the eye, sampling in the eye. I don't go into the eyeball, that's his territory. But then, when tumor spreads to the brain or there's lesions seen in the brain, we don't know what it is, often these patients are at an age and they already have a cancer diagnosis where they could have a separate process going on. It's not assumed that it could be lymphoma. And lymphoma is called the great mimicker because on imaging, it looks a lot like a lot of other things. So, before you go and treat a patient for lymphoma, you want to make sure you're not missing a primary brain tumor like a glioblastoma or something like that.

So, in that case, that's when they get me involved, call me up, and I can do a brain biopsy for them. When I do a brain biopsy, it's interesting how that's evolved over time. But I'm now using a really minimally invasive approach where we use stereotactic guidance. And then, we only make a puncture incision in the skin, a single stitch with a very small hole through the skull. And then using image guidance with neuronavigation, we can then pass the needle directly into the lesion and take a sample. At that point, then we send that sample for frozen pathology, which is a quick look by the pathologist. And if we see lymphoma, that helps us quickly expedite inpatient transfer for a more aggressive treatment of the CNS disease. If it's something else, other inflammatory conditions, something that doesn't look like lymphoma or a brain tumor, totally different set of treatment, totally different set of management, different chemotherapies, so that's when they get me involved. And I think from the biopsy standpoint, you know, we've just been making the incision smaller and smaller and smaller to where now it's only just a stab incision with a single stitch. And so, that's helping patients recover quicker. And we incorporate a lot of the latest navigation technology in order to be able to do that safely.

Melanie Cole, MS: Dr. Dixit, next word to you, Northwestern Medicine is actively involved in the development of therapeutic clinical trials for vitreoretinal lymphoma. Can you please share some insights into the novel treatments being investigated and how they benefit patients? Additionally, how are you working to expedite the diagnosis of these challenging diseases?

Dr. Karan Dixit: I'll start with the second part of the question first, because I think the first thing is rapid diagnosis, just because it's such a tricky disease. You know, it mimics so many things. So, one thing is when Dr. Bowen came, you know, he enlightened me on some kind of novel fluid testing that we can do in the vitreous fluid in the eye and also for spinal fluid for these patients, because getting a diagnosis in the nervous system, if there's no brain lesion, it's very tricky. Even spinal fluid is a very, very challenging fluid to work with. If there's tumor cells in there, they'll lyse, they'll break apart within 30 minutes of collection. And so, this is kind of where we want to use more molecular testing. And so, we were starting to do that now when we see these patients, just to maximize the yield because it changes management upfront. And if there's any suspicion of nervous system involvement, then we would employ systemic treatments.

So, a lot of it is in working with new partners in the industry. Recently, I made a connection with another lab where they do a lot of really advanced spinal fluid testing and really form a connection with them. So, we'll be sending spinal fluid to them. So, part of it is just kind of knowing who in the field is doing what. It's kind of improving our molecular testing for these patients, in-house testing as well, you know, rapid with our hematologists. And then, when I think of a clinical trial or a drug that we want to use for CNS lymphoma, at least, we have to conceive eye involvement as well, I mean, just because there's such a high concordance of both of them. And so, part of it's kind of finding drug targets or drug options that have , blood-brain barrier penetration, and by some extension, bloo-retinal barrier penetration as well. And so, you know, we're working with partners all around the world, with kind of new compounds, small molecule inhibitors, so BTK inhibitors, immunomodulatory drugs like lenalidomide or pomalidomide. These drugs have been shown to be effective in CNS lymphoma and, by extension, also refractory vitreoretinal lymphoma, Bruton tyrosine kinase degraders. There's a lot of new compounds, immunotherapy. These are all being studied here and us and as a community, worldwide as well.

I mean, that's the other thing, is we work closely with experts at other centers with something so rare. You know, when there's a disease that's less than a hundred per year for a country, you know, we have to pool our resources as a community to kind of really drive a lot of the diagnostic techniques, management techniques. And so, kind of being plugged in with the community at large is also something that, you know, that we also do as a group.

Dr. Chris Bowen: And I would add our cytologists that are doing our ocular cytology, as well as the hematopathologists that do all the flow analysis, I mean, they are just amazing because when we get a sample from the eye, oftentimes it's a very small sample. And so, they're able to do the necessary immunocytological stainings as well as very specific flow analyses, you know, in order to help us get those answers. I think one thing that's been helpful too is when we do a vitrectomy, very similarly, everyone's going to the smaller and smaller gauges to try to make more minimally invasive incisions. And then when we have a vitrector, we put a very low cut rate and I think that's helping minimize the shearing and the cutting of the cells so that when we actually have the cells that we deliver to our cytologists, you know, they're not all cut up and they actually are able to make a helpful diagnosis.

Stephen Magill: I think I'd just chime in. I think part of having a multidisciplinary team, there's us, but it's also the lab, it's all of that. And then, one of the other benefits is that when we do that, we're involved in studies, you build the connections nationally, internationally, and all that together really helps keep us on the cutting edge, really providing the best care for the patients possible, whether it's surgical interventions, ocular interventions, oncology interventions. And when things come up, because what we're doing here, we're all plugged in and ready to connect our patients to get the best care they need.

Melanie Cole, MS: Well, I thank you all. This is so fascinating. And Dr. Bowen, since it is such a rare disease, many providers probably don't see a lot of these types of patients in their everyday practice. Would you like to talk through one of your recent difficult cases and how you managed it? Tell us a little bit about the case, the patient's clinical presentation and the patient's journey.

Dr. Chris Bowen: One of the more recent ones was a 50-year-old gal and she came in with floaters and some flashing lights. And she was initially seen by one of our retina specialists that noticed retinal tears, and of course, the more common reason to have these floaters. And they did a laser around the tears and it looked really good. But what was interesting is on follow up, they noticed actually worsening floaters and more floaters and then these vitreous veils that were starting to just occupy the entire inside of the eye, the vitreous cavity.

And so, they sent them promptly to me and when I looked in I could see these very large white blood cells that were floating within the vitreous. So, it was atypical, it wouldn't be the normal pigmented cells that you'd see with the retinal tear. And so then, we got the liquid biopsy from the front of the eye and that was positive for MYD88 and IGKappa as well as IGH. So then, we took her to surgery. We did a vitrectomy. We did the low cutter rate, very low, small gauge. We sent it to our cytologists as well as our hematopathologists. And they were able to make the confirmatory diagnosis that it was a diffuse large basal lymphoma, as we suspected.

In this situation, we sent right away to Dr. Dixit, was able to do body scans. And at that point, did not have any MRI findings, and so didn't need to go to Dr. Magill. At this stage, we are continuing to monitor closely. Her situation because it was just found in the eye and nowhere else. She's receiving methotrexate intravitreal injections. Within three months, you know, all of her intraocular lymphoma has resolved and she's now on active surveillance and she's completing a one year protocol, and she's doing very well.

As Dr. Dixit said, this is one of those things where we need to have close followup and management. You know, so having this team here where we can quickly communicate with one another provides actually a lot of security to our patients knowing that we're actively watching, we have a team, and we're prepared. And I think it's one of those things that I know brought me here to Northwestern knowing that we have the experts that really care about the people. It's really a family and not only do we consider the patients our family, but we're families to each other.

Dr. Karan Dixit: You know, what's challenging with something so rare is there's no guidelines really, because there's just so few patients. And so, there's no guidance of how often do you surveil the nervous system, how often do you do an MRI, how often do you examine someone. So, it just kind of comes down a lot to, you know, the more you see, the better you get at it or the more experience you have. And you kind of form like a very focused expert opinion on these things just kind of seeing more and more of these cases. I think as we see more, as we learn more, you know, we develop our own internal guidelines, our own internal sense of like, how often should we do things appropriately for patients. And then, we present these as a larger group to the community and kind of see how can we change the field, or how can we change the management of this disease. And this is kind of something that we meet as groups, you know, locally, and also kind of internationally, nationally.

And so, you know, it's only by pooling our expertise, our insights. And then, you know, just kind of working really close together, I think really helps with something so, so rare. It's one of those things that I didn't think of as a medical student. Like, you didn't know it was a thing, and now I'm so focused on. It's like, "Oh my goodness," I joke with my residents, it's like, "You got to prove to me it's not a lymphoma." It's like, "Why is it not that?" You know, we just get so focused on something.

I think it benefits patients really well when you have kind of a really tight-knit group where we can just quickly assess things very fast and kind of make them feel at ease that someone is always there. Are the patients we share know, like, hey, if there's an issue, they can call someone? It's not like they're calling, you know, one day, "Hey, I'm noticing my cognition is affected. I'm noticing my memory is not as good as it used to be." Now, we've met, we've established care with the patient. They know if they have anything concerning. We talk to them, like, "Hey, this is what we need to look out for. If you have any of these. Let us know immediately." We can get them in real fast. Having that base connection really helps. The other way as well, you know, when we have patients who have brain disease with no eye involvement, but they have visual symptoms, you know, I can't do anything. You know, an MRI will be slightly helpful, but getting them to see Dr. Bowen is going to be super helpful because he can actually see what the eye looks like. So, having that connection in the beginning really helps patients. I think they feel really at ease and they feel comforted that they have a fully kind of team approach as kind of the standard of care here. I mean, it's been my only job, but it's really great. I assume it's like this everywhere, but I know it's not. So, it's really, really nice.

Melanie Cole, MS: Thank you so much, Dr. Dixit, for that. And Dr. Magill, give us your final thoughts. Where do you see this going and what would you like other providers to take away from this?

Stephen Magill: Yeah, I think the takeaway is it's a rare disease. It's difficult to diagnose, and getting a patient to a team of specialists who can do an accurate diagnosis, whether it's intraocularly, whether it's imaging, or whether it requires a brain biopsy is really important. In these rare diseases, having a multidisciplinary team where we see a fair number of these patients, even though they're rare, really helps build experience, so we can build data to create new therapies in the future and really advance things forward. So, I think that's really where we see it going. And on the surgical side, just always pushing minimally invasive as much as possible so that the patient isn't spending time recovering from surgery, but they're spending their time getting the definitive treatment that they need for their lymphoma.

Melanie Cole, MS: Dr. Bowen, last word to you. In your experience, what have been some of the most significant advancements and breakthroughs? Give us a little blueprint for future research. Tell other providers what you would like them to know from this physician panel today.

Dr. Chris Bowen: Well, first of all, I think vitreoretinal lymphoma and the management of vitreoretinal lymphoma, it's not a single person. It's a united team effort of experts working together to provide the best outcomes for both life and vision. And that's why we need to work together, both from the neuro-oncology side, the neurosurgical side, the cytology side, radiation-oncology, hematopathology, all these experts working together to come up with this common goal.

It's really exciting because, within the field of ocular oncology, the treatments, the methods, the surgeries are all advancing actually very, very quickly. The options to even do liquid biopsies to obtain these additional genetic analyses and tests, they're very minimally invasive. It's just very exciting for us already at this stage. Also, our surgeries for vitrectomies are becoming easier and easier, less risks. The yield in getting our samples are becoming easier. And we're looking, you know, as Dr. Dixit was mentioning, how do we pool all of our experts together, you know, from the ocular oncology side throughout the country? You know, we have annual meetings, we have international meetings on clinical trials moving forward on the best management, minimizing ocular toxicity, maximizing benefit from visual outcomes. Because as you know, number one, getting a diagnosis of cancer is a very scary thing. It's a humbling thing. And then, also hearing that your vision, which is an important sensory organ, may be going as well, all kind of cause a lot of distress and concern. And so, being able to provide both minimally invasive diagnostic measures, effective treatments that have reduced risks is definitely our aim and our goal. And the exciting thing is that it's not just a want, but we're actually actively, proactively moving forward and making these decisions on improving them.

Just the other day we were talking with Dr. Dixit about, you know, how we can minimize corneal toxicities to the methotrexate and we came up with some ideas and some ideas moving forward for clinical trials. And it's just exciting. Just when we have an idea or thought, it's just like, "Let's make a plan of action."

Dr. Karan Dixit: Yeah, it was a single email. I was like, "Wait, what about this? Let's do this." So, I mean, these kinds of conversations become ideas, become practical studies, and they become something that we can actually help patients with. So, you know, just kind of having people who think about it. You know, when something is rare, you just don't think about it, but someone who's like their day to day, that's all they think about, it's really, really helpful to kind of try to advance the field a little bit. So, it's really exciting to be part of this group.

Melanie Cole, MS: Thank you all so much for being a part of this thought leader conversation in this physician roundtable. Thank you again. And to refer your patient or for more information, please visit our website at breakthroughsforphysicians.nm.org to get connected with one of our providers. That wraps up this episode of Better Edge, a Northwestern Medicine podcast for physicians. I'm Melanie Cole.