Dr. Kait Nevel talks with Dr. Katharina Schmidbauer about primary CNS T-cell lymphoma, highlighting diagnostic challenges, imaging characteristics, and treatment approaches for this rare disease. 

Read the related article in Neurology®. 

Disclosures can be found at Neurology.org. 

Podcast Transcript:

Dr. José Merino: This is José Merino, editor-in-chief of the Neurology Family of Journals. The Neurology Podcast provides practical information to neurologists and other clinicians to help them provide better care for their patients. Thanks for listening and have a great week.

Dr. Kait Nevel: Hello, my name is Kait Nevel. Today, I am interviewing Katharina Schmidbauer on her article, «Clinical Manifestations of Primary CNS T-Cell Lymphoma.» Welcome to the Neurology Podcast. And Katharina, I would love to hear a little bit about you.

Dr. Katharina Schmidbauer: Thank you, Kait. Thank you for having me. It’s a pleasure. I am a neurologist with a great research interest in neuro-oncology, working at the University Hospital of Munich.

Dr. Kait Nevel: Wonderful. Thank you for that. What do you think the most important takeaway is from your article for the practicing neurologist?

Dr. Katharina Schmidbauer: Primary CNS T-cell lymphoma is very rare and the diagnosis is often really difficult to establish. In this study, we present hallmarks of the disease that could help with the diagnosis in the future. And our case series really illustrates many diagnostic challenges. The first important message would be how to deal with diagnostic uncertainty. If you have a progressive tumefactive CNS lesion and the clinical course, the imaging, and pathology don’t quite fit together, CNS lymphoma and also T-cell CNS lymphoma need to remain on the differential, even if the first biopsy is inconclusive. And in this context, it’s also important to avoid, of course, steroids before biopsy because they could cause regression of the lesion and therefore make the biopsy non-diagnostic, which is not the same as a negative biopsy.

Dr. Kait Nevel: Thank you for that. And before we get into some more of the details of the findings of your study, could you give us a brief overview of the background and methods of your study?

Dr. Katharina Schmidbauer: Sure. Primary CNS T-cell lymphoma is very rare and an aggressive subtype of CNS lymphoma. Most primary CNS lymphomas are B-cell lymphomas, but for T-cell lymphoma, we have very little systematic data. In fact, there are only three case series so far, and therefore we performed a multicenter retrospective study across three centers in Munich, Heidelberg, and Boston. And there we identified 16 adult patients with histologically confirmed primary CNS T-cell lymphoma without systemic disease treated between 2008 and ’24. We looked at several levels of the disease, the clinical presentation, of course, histopathology, immunophenotype, T-cell receptor gene rearrangement testing, and if available, next-generation sequencing. And we also gathered MRI and PET imaging, treatment regimes, and of course outcome data. We also centrally reviewed the imaging and histopathology results in a multidisciplinary setting. And the study is mainly of course descriptive. However, we also tried to find associations that are relevant for outcome.

Dr. Kait Nevel: Getting into some of the things that you found or discovered through this study, what’s one thing that surprised you?

Dr. Katharina Schmidbauer: One surprising finding of the study was the heterogeneous presentation on MRI and the high number of misdiagnosis on MRI in more than half of the patients. If you look into the imaging figures in the paper, these tumors can present as like any other disease. They can mimic neuroinflammatory disease, high-grade glioma, small vessel disease, and even meningioma or leptomeningeal disease. So the most common misdiagnosis was high-grade glioma, and indeed these lesions often showed very infiltrative growth patterns and almost streaky or perivascular patterns of contrast enhancement. And another interesting finding was the PET imaging. You might expect an aggressive tumor to show very high metabolic activity on FET PET, such as in high-grade glioma. But in our small subgroup of patients who underwent FET PET imaging, uptake was often relatively low to moderate or also completely photopenic, especially on FDG PET.

Dr. Kait Nevel: Yeah. I found that part of your findings fascinating that the imaging is so unlike what we see in the much more common diffuse large B-cell lymphoma that we see in the CNS. It’s much more common than T-cell lymphoma. Was there any understanding of why the imaging looks so different, particularly on the PET and FET imaging, as you mentioned?

Dr. Katharina Schmidbauer: CNS lymphoma is a very heterogeneous entity itself. And we also know that from other PET imaging studies and CNS lymphoma that it can present heterogeneously with low or moderate, but also high uptake. And on MRI, we also know that in the CNS lymphoma, it’s not always the common picture and the involvement of subcortical or deep brain structures. So it’s a mimicking disease also in other studies, but in this rare subtype of T-cell lymphoma, this was pretty striking. Yeah.

Dr. Kait Nevel: One thing that you’ve already mentioned that stood out to me was the number of initial misdiagnoses before reaching a diagnosis of primary CNS T-cell lymphoma. How do we work as a team, do you think, when we’re evaluating these patients to reach the correct diagnosis more quickly? Is there anything that we should be doing differently?

Dr. Katharina Schmidbauer: I feel the solution is early multidisciplinary discussion. We need to involve all disciplines pretty early, neuroradiology, neuropathology, and neurosurgery of course, and plan the diagnostic steps together, especially the biopsy. In some cases, we also used FET PET imaging to look for potential hotspots within the lesion that might provide a more representative biopsy target. Interestingly, of course, the uptake was only moderate in our cases, but I would potentially give it a try to have additional information when to plan and where to plan the biopsy. Of course, also histopathology needs to be regarded when we talk about misdiagnosis. I don’t have a good explanation for why even when we obtain enough tissue, some characteristic findings we would expect such as T-cell receptor clonality were simply not detected. Yeah, this is not solved so far.

Dr. Kait Nevel: Has anything you discovered in your results changed the way that you evaluate patients with brain lesions that have yet to be diagnosed or maybe the patient who has an unusual imaging or unusual clinical history coupled with imaging that maybe isn’t totally typical for anything?

Dr. Katharina Schmidbauer: Yeah, there are several things. I would be cautious about the diagnostic approach and sometimes especially the imaging or also the histopathology creates some uncertainty. If CNS T-cell lymphoma or CNS lymphoma in general is suspected, I would try very hard to obtain tissue before the application of steroids. This is maybe the first point. And next is how I deal with an apparently negative biopsy. I would distinguish between a truly negative biopsy and a non-diagnostic biopsy. So the histopathology findings show non-specific inflammation. For example, I would ask, was the patient exposed to steroids? Was enough viable tissue obtained? Was the right part of the lesion sampled? Was there necrosis? And also what you mentioned, how is the imaging pattern and does it fit also the clinical course? Is it relevant like the lesion behaves? Is it like an inflammatory disease? Does it regress and recur or progressively enlarge? If these questions leave you uncertain, then I would plan to reperform another biopsy. But what sometimes happens in the retrospective of the study, in some cases you jump to the next plausible diagnosis and of course, such as an inflammatory tumefactive CNS lesion that may also have responded to steroid treatment in the beginning, you could also go with another plausible diagnosis. So we need to be careful to reassure is it really a negative biopsy or is it a non-diagnostic one and how to proceed?

Dr. Kait Nevel: What did you learn about outcomes in your patient cohort and do you think that we can use your results to guide treatment decisions for patients with primary CNS T-cell lymphoma?

Dr. Katharina Schmidbauer: Yeah, of course we looked also at associations with outcome based on the treatment regimens that we found in our study. However, in my view, our results provide somehow supportive evidence, but I would be careful about using the small retrospective series to recommend specific treatment regimes. In our cohort, MTX-based treatment was commonly used and patients who received high-dose MTX-based treatment with autologous stem cell transplantation had longer overall survival, which is of course consistent with general treatment principles we know from primary CNS B-cell lymphoma. But of course we have only 16 patients and there is obviously substantial selection bias. Younger and fitter patients are more likely to receive intensive treatment and transplantation. So overall, I would say that our results support MTX-based treatment, including stem cell transplantation in selected patients as an important therapeutic strategy.

Dr. Kait Nevel: Do you think that it is important or helpful to get next-generation sequencing on the samples of patients who have established primary CNS T-cell lymphoma?

Dr. Katharina Schmidbauer: I would say molecular characterization is really important, but I would not say that every patient needs broad NGS. In my view, it’s extremely valuable when you have an unusual histological phenotype, diagnostically difficult case, disease relapse, or when the result could potentially change treatment. And of course our ALK1-positive case is a good example. She had a fast progressive subtype and of course knowing about the mutation that changed the treatment algorithm, but in other cases we look at our small NGS subgroup. We also found variants of uncertain significance and we cannot term them as pathogenic mutations. So I would go for it if you have the facility to do it, but maybe not in every case.

Dr. Kait Nevel: That makes sense. And it sounds like important to consider because as you highlight in our conversation and in your paper, you can uncover something that could be potentially pretty impactful to treatment for some patients. What do you think that we could do to learn more about this very rare oncologic condition? I mean, in your study, this was a multicenter. There were three different centers involved over a decade, almost 14-year timeframe, I think it was, or 16 years.

Dr. Katharina Schmidbauer: Yeah, exactly.

Dr. Kait Nevel: And you identified 16 patients, so about one patient per year over three academic centers, so pretty rare. What can we do or what do you think we should do as a neuro-oncologic community maybe to understand this group of heterogeneous, somewhat heterogeneous diseases better?

Dr. Katharina Schmidbauer: The biggest challenge is of course the rarity of the disease and to gain any evidence that is useful. So as a single center, we would have never had enough patients and international collaboration of course is key for gaining any evidence. Yeah, I’m also really thankful for the great work and collaboration with the centers in Heidelberg and Boston. But yeah, we need larger registries for rare CNS tumors and ideally prospective standardized data sets to gather all the relevant information. And of course, I believe there are many distinct molecular subgroups of primary CNS lymphoma. They may behave differently or respond differently to treatment. And the next step in my view would be to really focus on the molecular subtypes and also aim for biology-driven treatment. But still the first steps, the number of misdiagnosed cases is maybe also not that low and should in the first place aim for not to miss any diagnosis of primary CNS T-cell lymphoma and to remember to keep it on the differential.

Dr. Kait Nevel: Yeah, that sounds like a good goal. And your article and this podcast hopefully is a call out to people to remember this in the differential diagnosis for patients who have brain lesions, that it’s not really clear what they are and diagnosis has been elusive to keep this in the list of possibilities.

Dr. Katharina Schmidbauer: That would be great. Yeah.

Dr. Kait Nevel: Great. Thank you so much for talking with me today, Katharina, and thank you for sharing more information about your study with us and educating all of us about primary CNS T-cell lymphoma.

Dr. Katharina Schmidbauer: Thank you so much for having me.

Dr. Kait Nevel: So again, I’ve been talking with Katharina Schmidbauer about her article, «Clinical Manifestations of Primary CNS T-Cell Lymphoma.»

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