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Peter Martin, MD: Hello. I'm Dr Peter Martin from the Lymphoma Program at Weill Cornell Medicine in the Meyer Cancer Center in New York City. Welcome to Medscape's InDiscussion series on mantle cell lymphoma. Today we'll be discussing key topics in the pathology of mantle cell lymphoma. I'd like to introduce my guest, Dr Eric Hsi, professor of pathology and chair of the Department of Pathology at Wake Forest University. Eric, welcome to InDiscussion.
Eric D. Hsi, MD: Thanks for having me.
Martin: I think those of us who are on the treatment side of clinical medicine probably pay a lot of attention to the management of different lymphomas, and we can, without thinking, name a few people who published heavily on the topic. We all probably recognize the huge role that pathology plays and have close relationships with the pathologists in our own institution, but unfairly, we probably might struggle to name some of the internationally recognized pathologists that are in the world doing all of the work on behalf of our patients. When I think of internationally recognized pathologists, your name definitely rises to the top. You've been at the top of the game for a long time with the College of American Pathologists, the American Society for Clinical Pathology, and the American Society of Hematology. We first met 15 years ago at the Alliance for Clinical Trials in Oncology, where you were chair of the pathology committee. You might not remember, but you actually gave me one of my first opportunities to get involved in pathology research in mantle cell lymphoma when we worked together to describe the characteristics of leukemic nonnodal mantle cell lymphoma.
Hsi: It's been a long time. I think it was called CALGB at that time, right before it was the Alliance even. That was a great opportunity for me to work with people like you. Most pathologists sort of stay in the basement in their offices, doing their work, and don't get let out to interact a lot with clinicians, which is so important for pathologists to have a much better feel for your world and your problems. It makes us better pathologists, I think.
Martin: Is it that kind of clinical experience that drew you into studying mantle cell lymphoma, or was it something more behind the scenes that led you to looking into it?
Hsi: It's a little bit of both. It's an interesting biology. A clinical problem I learned from people like you is how there needs to be new treatments. Many forms of mantle cell lymphoma are really incurable. We're still searching all these years later for better therapies.
Martin: I came up with a different format for this podcast episode, and hopefully you'll humor me. I came up with a list of statements, not intended to be true or false, but just to provoke discussion. Hopefully you can let me know what you think of them and we can get into them in a little bit more depth. The first one: SOX11 is an important diagnostic marker in mantle cell lymphoma.
Hsi: Yes, SOX11 is interesting. It's a molecule where its absence is associated with a particular form of mantle cell lymphoma. We use it diagnostically to recognize some forms of mantle cell lymphoma that lack a cyclin D1 overexpression translocation, so called cyclin D1–negative mantle cell lymphoma. That's something we just learned about in the past decade or so. SOX11 was an important marker to allow everyday pathologists the ability to diagnose that. I think it is an important marker, particularly in recognizing those cyclin D1–negative mantle cell lymphomas. But then as you know, it's a marker of so-called nonnodal forms of mantle lymphoma where you basically have a lack of SOX11. When you're confronted with things as a pathologist that you think are that nonnodal form, you're reaching for that SOX11 marker as well. It's something that many labs have brought up in the past decade because it became important to recognize and maybe confirm your clinical impression when you're seeing a patient. Do you look for that marker when you're reading reports?
Martin: It's a good question. In the cyclin D1–negative cases, SOX11 is definitely really helpful. Otherwise, I found it to be more confusing than anything. Maybe some of that is the history of it. Initially it seemed to have prognostic significance, but there was one group that reported that it was associated with negative prognosis. Another group reported that it's associated with a positive prognosis. It was really confusing for a while.
Hsi: I think the problem with the nonnodal disease is that it is indolent, and by the time you see a patient, they may have had it for 10 years and no one ever really knew. So now they are presenting at a more advanced stage where that nonnodal designation is less clinically relevant. Because now it clinically manifests as a more aggressive lymphoma. Maybe it has other molecular abnormalities along with it that turn it into a more aggressive form that now presents. But the patient could have had it for years before and not known it. That gets confounded in the survival analysis and things like that.
Martin: You start out with what are two distinct pathobiologies: the leukemic nonnodal and the classic nodal mantle cell lymphomas. They're clearly different, but eventually they end up in the same place, which is not a good place toward the end. That brings up the question of leukemic disease in general. Is leukemic disease always an indolent mantle cell lymphoma?
Hsi: I don't think so. I think we probably know that there's a high percentage of patients that present with circulating disease at the time when you look for it that are conventional type. I think that's been known. Then it just depends on how hard you look. I think using leukemic disease as the marker for nonnodal mantle cell lymphoma is probably not the right thing to do.
Martin: Is there a better way for us to distinguish between these subtypes. I guess the bigger question eventually is, will it be relevant? But right now, is there a better way to distinguish between them?
Hsi: I think it still comes down to the clinical-pathologic kind of correlation, and you can use SOX11 to support this as long as you realize that you may be seeing patients at different parts of their journey at presentation, and you don't know what happened before. You're sort of handicapped in trying to figure out that they biologically were nonnodal because there's just really not a great way to know. There are gene signatures now that some groups have identified, but those are not really clinically available. They probably need more validation too, as in, is that signature frozen and does it change over time as patients progress?
Martin: Yes. That's the NanoString assay from Elias Campo's group. The funny thing that I always come back to when thinking about that is that the cases were selected by clinical characteristics, as you say. You still come back to the clinical characteristics and then say, okay, these are the leukemic nonnodal cases. It's hard to get away from the collaboration between clinicians and pathologists there.
Hsi: I think the interesting thing is when you get to low levels. We've talked about that instance where you have a very low level, you detect it's CD5-positive, but there are not enough cells present to do FISH and you're not going to necessarily just do a bone marrow because you're curious to see whether it's a case of the precursor of CLL [chronic lymphocytic leukemia], monoclonal B-cell lymphocytosis of CLL phenotype, which is also CD5 positive. You have a similar thing, but maybe that case is a super-early indolent mantle cell lymphoma. But there's no good way — routinely, at least — to look for the translocation and things like that unless you were doing a research project. There are probably people walking around with what we call MBL, monoclonal B cell. You think it's like a CLL type, but in reality what they actually have is an early form of mantle cell lymphoma.
Martin: That's a good segue to another discussion point, and that is, in situ mantle cell neoplasm is underdiagnosed. Can you explain what that actually is?
Hsi: In situ mantle cell lymphoma is diagnosed when there's an incidental finding in a lymph node biopsy. You're just standardly working up your case and you do a cyclin D1 stain and then you see cyclin D1–positive cells, lymphocytes, which doesn't happen normally. They're distributed where you find normal mantle cells, in the mantle, and they're just scattered cells. They don't distort to the lymph node or anything. Around the same time we recognize the concept of in situ follicular lymphoma. Those things kind of came up together. But we know some things about in situ mantle cell lymphoma. We know that it's significantly less common — maybe 10 times or more less common — than in situ follicular lymphoma or in situ follicular neoplasia. It is uncommon. We don't go around looking to diagnose it. Usually it's just an incidental thing. Is it underdiagnosed? It probably is. Then that begs the question, does it matter? I'm not so sure it matters, but we don't really understand it very well because it is uncommon and we haven't had long population-based follow-up studies like you can do with monoclonal B-cell lymphocytosis, for example, because there are tens of thousands of samples in population databases and in bank samples. You can do those longitudinal follow-up studies to see who develops CLL out of a monoclonal B-cell lymphocytosis of CLL phenotype, but that's much harder to do with in situ mantle cell lymphoma because you have to have a tissue biopsy.
Martin: Do you ever see mantle cell in the gastrointestinal tract? Mantle cell lymphoma is, in some reports, found in the gastrointestinal tract 90%-95% of the time. Do you ever just accidentally find something like mantle cell neoplasm in situ in a colectomy specimen?
Hsi: I don't think I've ever seen that. It's possible that you would do that. But in situ, mantle cell lymphoma could be underdiagnosed because people just aren't looking for it. If a colon comes out positive for colon cancer and you're just looking for lymph nodes from metastasis, you're not staining all cases just to see if there is in situ mantle cell lymphoma present. There was a study by the German group that helped to find what the incidence is. They took over 1000 all-comer reactive lymph node biopsies and then went back and just stained them all and found no cases. We don't do that. We don't go looking in all the sample lymph nodes for in situ mantle cell lymphoma by immunostaining when you're really looking for metastatic disease, which you can just do on a hematoxylin and eosin — H&E — without doing any kind of extra staining. Whereas to find in situ mantle cell lymphoma, you would have to do immunostaining. [The German study showed that the incidence is very low (less than 1 in 1000).]
Martin: Next topic: FISH [fluorescence in situ hybridization] for 11;14 translocation should be performed in all CD5-positive lymphomas.
Hsi: I don't think you need to do that when you have a tissue biopsy because essentially you have the immunostain, which basically is a surrogate for that. It's a very good surrogate because that translocation drives the cyclin D1 expression. In a way, that is your FISH result. I don't think you need to do FISH in cases of mantle cell lymphoma. I think you do need to do FISH in cases of CLL or just to make sure you're not missing a case of mantle cell lymphoma with an unusual phenotype and mistaking it for CLL. That's probably not a bad idea. Many places have added 11;14 FISH into their routine CLL panel. I don't know if you do that at Weill Cornell, but many places do.
Martin: I don't think we do it routinely here for all cases that are more clearly CLL.
Hsi: You can do a very good job with a good flow panel and be pretty sure you're dealing with CLL. There are always these cases that are a little bit unusual. I think it's definitely worth FISH in cases like that.
Martin: I have a few cases. Recently we've had a run of lymphomas where we had two lymphomas, CLL, and mantle cell lymphoma in the same person, and we wouldn't have caught it had we not looked for it. They had two clones that were not otherwise really easy to distinguish. We have somebody else with marginal-zone lymphoma and mantle cell lymphoma at the same time. There are cases where it is really confusing if you see CD5, which sometimes can be present in marginal-zone lymphoma.
Hsi: That's why I am a big proponent of doing panels when you do immunostaining. If you're only thinking of one thing and then you order the stains just for that, guess what? You're going to see just that. You can miss things that are subtle. I'm a big fan of standardizing your practice and just doing the panel for different kinds of subtypes of lymphoma.
Martin: Related question: Any CLL with an 11;14 translocation is mantle cell lymphoma? There used to be this theory that other entities might have an 11;14 translocation — not specifically multiple myeloma, but other lymphomas.
Hsi: There are these rare reported cases where you have a secondary 11;14 translocation, and they've been pretty well documented. They start out as one thing and then that same clone, for whatever reason, adds an 11;14 translocation. That would be an interesting problem. What do you do with that? It started out as CLL. It really was CLL. And then you got a 11;14 translocation and is that going to drive a different biology? That's an interesting question.
Martin: This is interesting when you think of the timing, because I think most mantle cell lymphomas acquire their 11;14 translocation during VDJ (variability, diversity, and joining) rearrangement. But I saw this hypothesis that some patients with hypermutated IGHV may acquire their 11;14 translocation during germinal center reaction. They're clearly arising in different stages, and I guess that's consistent with what you're saying — that it can be acquired later on.
Hsi: Yes. There's really just a handful of cases reported like that.
Martin: I wasn't aware of that. That's interesting. New topic: splenic lymphomas, which now we know can sometimes be mantle cell lymphoma. Should splenic biopsies be done more often to diagnose splenic lymphomas?
Hsi: Well, you've got to remember what you're asking. You're asking a pathologist. When have I ever turned down tissue? I would love to get splenic biopsies because if it's important to get a specific diagnosis, I think that's the only way to do it. Of course, there are risks in doing splenic biopsies. You know more about that than I do. There are some entities within the splenic marginal-zone lymphoma and splenic diffuse red-pulp lymphoma. With these unclassified lymphomas, you really need the spleen to be the arbiter of what it is. A lot of times I think it comes down to you as a clinician, your judgment about how important it is. If you know the possibilities and it could be one of these three things, how important is it to go with your next plan of action in terms of therapy?
Martin: When we are doing a core needle biopsy of a lymph node — which I know pathologists never love, but sometimes clinicians are stuck doing it because it's either that or a massive surgery for a retroperitoneal lymph node or something — you still want the biggest core possible. I think none of us are super-keen to poke a big needle into a spleen, but is a really fine-needle core or FNA [fine-needle aspiration] sufficient for a spleen biopsy? I imagine the architecture is important for certain lymphomas but maybe not for others. And how does that fit in with the spleen?
Hsi: If you're looking for classification, you need architecture. You probably run into these situations. Sometimes I've seen this more often in CLL, but it is important in mantle cell lymphoma where there's not leukemic disease, but you want to know where there's a p53 mutation in a small lymphocytic lymphoma, for example. And there is no other way to get cells other than in the blood because there just aren't enough cells. If all you really wanted to do is get a molecular answer, then we don't need architecture for that and a needle biopsy would work. But in these classifications of splenic lymphomas where architecture is important, you want to know, is it in the red pulp or is it not in the red pulp? Is it nodular? Is it not nodular? The only way to answer those questions is with a piece of tissue with enough surface area — or acreage, as I call it — to be able look at it and make a judgment on the architecture pattern.
Martin: Molecular testing is a good segue to the next topic, which is: Immunohistochemistry (IHC) is sufficient for p53 staining, and sending all cases for TP53 sequencing is a waste of money.
Hsi: It's been shown that IHC is very good at predicting mutational status in mantle cell lymphoma. It's very specific. It's not entirely sensitive. The numbers I've seen are 80% sensitive but close to 100% specific. That's pretty good. How many tests in medicine are like that? Then the question is, what are the clinical stakes of maybe missing a case if your sensitivities are 80%? That then becomes a value judgment around embarking on this really expensive toxic therapy that actually has a lot of benefit. The patient's IHC is negative. I know the sensitivity is not 100%. There's a small chance that they actually do have the mutation. Is it worth it to go and do sequencing in a case like that? Maybe it is.
Martin: Do you think that we're approaching an era where the specific type of TP53 mutation will become relevant, or are they all pretty similar? Do we have any way of evaluating which alleles have this TP53 mutation and whether it is present in two alleles or one allele of a cell?
Hsi: That's a really good question. I don't know if we're there yet, but that would be a great question for people that really do a lot of p53 research. Certainly if there are drugs that we are improving that only work for certain domains of the p53 molecule, that would obviously become important. I'm not aware if there are drugs that are that specific. We're just lucky in that we think it's targetable, at least to some degree. The question of whether it is present as a biallelic thing or are there copy number losses is sort of addressable by next-generation sequencing methods. This is asking a lot of the technology. There are new ones coming out where you're actually long-sequencing a single molecule. Then you really can understand: Is it biallelic? Is it not? For those technologies, I think the PacBio platforms can give you that answer. But those are not clinical instruments. There may be somebody running that clinically, but I'm not aware of anyone doing it.
Martin: We've been doing a lot of sequencing here, with Selina Chen-Kiang running the basic science side of a mantle cell lymphoma program, and finding, interestingly, that the mutational burden of mantle cell lymphomas early on really is not that impressive. It really seems like copy number alterations are going to be a lot more relevant in the future. The last big topic is proliferation, which I think is an important one. So: Ki-67 is the best and only marker of proliferation. It's a two-part question that is applicable to all tissue types.
Hsi: Yes, Ki-67 is the best marker of proliferation that we have. Everybody has it in a clinical lab and does it for many different reasons — not just in lymphoma, obviously. I would say there are very good studies that are coming up with basically the same information, that Ki-67 index is a good prognostic marker in mantle cell lymphoma, and the cutoffs at 30% have sort of been validated in different treatment settings. I think Ki-67 a really good marker. It is now standard of care. Everybody should probably be doing it because it's pretty well documented. It is not applicable in all tissue types. It is technically possible in liquid samples, but no one does that. In blood samples or liquid bone marrow and body fluid samples, we really couldn't do that unless we got paraffin-embedded formalin-fixed tissue.
Martin: Are there any proliferation markers? I can't think of any off the top of my head that are applicable to blood. It is kind of frustrating. A third of these mantle cell lymphomas are leukemic, nonnodal, and we can't estimate this thing that's a pretty relevant prognostic marker, as you mentioned.
Hsi: There are flow cytometry–based methods that are certainly not standard of care. They used to do a lot for breast cancer, as you may remember back in the day. There are maybe still some labs doing proliferation, S-phase fraction, and cell-cycle analysis, which you can do in pulling nuclei from paraffin or in freshly isolate cells. But that's never been huge in pathology. Breast cancer was the real application. That's sort of fallen away, as far as I know. It was done for acute leukemias back in the day. There are ways to do it. It just hasn't caught on as a real prevalent use case that people would bring up assays for.
Martin: There is still some room for improvement there, for maybe another paper on copy number alterations looking at p16, CDK4, and RB.
Hsi: Their imaging tools are becoming more available too. Should we be getting away from what is actually easy, which is obviously to just eyeball-read? On a lymph node, it's fairly reproducible. But if you had a nonnodal and you did bone marrow, you would need to do multiplex IHC or immunofluorescence to find the tumor cells and then get a Ki-67 index of that. It's doable, but no one is really doing this right now.
Martin: We have a project where we're working on that, and hopefully I'll be able to share it soon. These were great topics. Eric, thanks to you for going over them with us. Today we've talked with Dr Eric Hsi about the pathology of mantle cell lymphoma. Thank you for tuning in. If you haven't done so already, take a moment to download the Medscape app, and listen and subscribe to this podcast series on mantle cell lymphoma. This is Dr Peter Martin for InDiscussion.
Resources
College of American Pathologists
American Society of Clinical Pathology
American Society of Hematology
Alliance for Clinical Trials in Oncology
Diagnostic Accuracy of SOX11 Immunohistochemistry in Mantle Cell Lymphoma: A Meta-analysis
Prognostic Role of SOX11 in a Population-Based Cohort of Mantle Cell Lymphoma
Cell Cycle Dysregulation in Mantle Cell Lymphoma: Genomics and Therapy
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Cite this: Pathology of Mantle Cell Lymphoma: Biopsies, Diagnostic Markers, and Options for Clinicians Treating This Disease - Medscape - Apr 27, 2023.
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