|
Slide #1
JONATHAN SAID,MD: My apologies for that. What I particularly am pleased about being here today is for an opportunity to talk to the public and talk to patients, because pathology, as you may realize, is not one of the glamor specialists in medicine, and we very rarely have an opportunity to interact with the patients, which is a great pity. I do think this is changing now, and I think because patients are better educated and aware of questions in the pathology of lymphoma, I get more and more patients wanting to talk to me and coming to see me to discuss their pathology, and I think that's a terrific thing. I'm always happy to talk with patients, to give them the kind of advice I can give as a pathologist or insights into the disease. So I think that's a very positive thing, and it's important that the pathologist is really part of a team. We like to feel that we're part of the management team and contributing to the patient's treatment and the success of that treatment, so we don't like to be isolated in our little laboratories, and we're very pleased to be involved in this kind of forum.
Slide # 2
So what does a pathologist do, and how does the pathologist play a role in the diagnosis and, in fact, the management of a patient with lymphoma? Well, firstly, we're usually the point where everything starts, because lymphoma is usually diagnosed in some kind of biopsy, whether it's bone marrow or blood or tissue, and we're called in to identify the disease, to make the diagnosis.
Lymphoma is a very special disease and requires very special handling. So what we do, then, is we collect this tissue, and we collect it in a way that is going to be suitable to make the best diagnosis, to make the best characterization of the disease, and also that we'll have tissue for specific markers and for specific therapeutic decisions or for entry into specific therapeutic trials.
The good news about lymphoma, and what's very exciting to me in this century, the year 2002, to be involved in lymphomas, is that there are new therapies coming out all the time, and therapies that are specifically targeted against a specific abnormality and a specific kind of lymphoma. But to enable one to be able to apply those therapies, the pathologist has to be able to identify very specifically what subtype of disease the patient has, and has to have the tissue available. For example, if it's immunotherapy, we have to be able to have the tissue in such a way that it can be suitable to go into a trial to develop immune antibodies against the patient's lymphoma. So I think we're more and more important in how we collect the tissues at a biopsy and how we handle it. So everything is done in an optimal way for the patient.
Slide #3
And this is just to show you some of what we do, and when we get a lymph node in a patient with a question of lymphoma, we have a team of pathologists and fellows and residents, and we're just waiting in the wings for the surgeon to call us to the operating room. We will take the tissue and we will divide it up and try to get the most use of it. So we'll want tissue for diagnosis, we'll want tissue for electromicroscopy, for markers, for immune markers, for immunotherapy, frozen tissue available for clinical trials, for immunotherapy and other aspects, for microbiology, for virology, because some lymphomas may be viral- or bacterial-related.
So we have to know up front. We have to be part of the team where the surgeon tells us, which they always will do, this is a patient who possibly may have a lymphoma, and your team has to be there and ready and waiting to do all these studies. And that's the way we do it at UCLA and at, I think, most major medical centers.
Slide #4
Now, the classification of lymphomas is critical because lymphoma, as you know, is not just one disease. It's really many diseases, and they're treated differently. And as we get more therapies, this is going to become more and more critical. The classification of lymphomas is highly complex, and as I've mentioned, really requires special expertise right from the beginning with the handling of the tissue.
This is a quote from a famous pathologist from 1948, and he said, "Nowhere in pathology has the chaos of names so clouded clear concepts as in the subject of lymphoma." And that's as true today as it was in 1948. However, light came at the end of the tunnel with the World Health Organization. The World Health Organization realized that this was a Tower of Babel in terms of lymphoma classification, and they decided to fund a proposal where pathologists throughout the world and clinicians throughout the world would be able to get together and really agree on what these diseases were and how to classify it. And many -- probably all the speakers in this room were involved in that WHO effort to try and get some sense into the classification of lymphomas, and they were very successful, and the success of that classification is based on the realization that lymphoma really is a disease with morphologic features that you can see down a microscope, immunologic features, genetic. It's a genetic disease, and it's a clinical disease as well, and we need to consider all of this as a whole in order to make the best diagnosis to determine the best treatment for each one of our patients as an individual. Each patient is an individual, and each disease is slightly different.
Slide #5
So this WHO resulted in major agreement among hematopathologists about entities that we can recognize and techniques we can use to distinguish between these specific entities, and the accurate diagnosis requires morphology, looking down the microscope, immunophenotype, immunology, genetics, either molecular genetics or cytogenetics, when we look at the actual chromosomes, as well as the clinical features of the disease.
Slide #6
There are broad categories of lymphomas, as Dr. Horning mentioned: Hodgkin's lymphoma, non-Hodgkin's lymphoma and lymphoid leukemias. And really, in terms of lymphoid diseases, the separation between lymphoma and leukemias is highly artificial. In most cases, it's the same disease. It just depends how the patient may present.
Slide #7
Here, for example, is a very clear-cut difference between a Hodgkin's lymphoma over here -- and the malignant cell is called the Reed-Sternberg cell, with these Li nuclei -- and this is a non-Hodgkin's lymphoma, which is made up of nodules, hence the term follicular or nodular. So these nodules are then non-Hodgkin's lymphoma. So that's the first distinction we have to make as a pathologist: Is it a Hodgkin's or a non-Hodgkin's lymphoma?
Slide #8
How do we do this? Well, in many cases morphology may be sufficient, but in many cases we now rely on more objective parameters. In other words, it's not just me or some other person looking down a microscope and making a diagnosis. We want a full armamentarium. We want to know the immunology, we want to know the molecular changes, the cytogenetics, and all this has enabled us to make much more accurate and reproducible classification and characterization of lymphomas. Again, the goal is to get the best therapy for our patients.
The clinical features will have to be known. Part of each lymphoma definition is the constellation of clinical features, so in every single case, my colleagues, the oncologists, will come to me or I'll call them up and we'll chat, and I'll say, "This patient presented in such and such a way, and this is the distribution of the disease," and he'll tell me or she will tell me all about the patient, and I will say, "Well, this is my pathologic findings," and we correlate everything together. So we're part of the team in management of the patient, and I think that's really important.
How the patient presents is very important. We don't only look at lymph nodes. Lymphoma can involve any tissue in the body, and we frequently look at lung biopsies, bone marrow biopsies, GI, stomach biopsies, colon biopsies. We make a diagnosis of lymphoma, and we have to be aware of changes in any organ of the body.
Slide #9
Now, as we've said, lymphoma is not a continuous spectrum of disease. There are many different diseases. Each one has its own particular peculiarities. Many distinct lymphoma entities have a range of histologic grades and aggressiveness. So just because a patient has a follicular lymphoma, they're not all the same. They're grade I, they're grade II, they're grade III. Some of them may have diffuse components. We have to be aware of all these subtle little details, and the good news is, these little details are making a difference as more therapeutic modalities come about. So very subtle differences that the pathologist can appreciate within these different subtypes can make a difference in determining the best effective therapy for our patients.
Slide #10
The main clinical groupings which we place these lymphomas into as pathologists are indolent lymphomas with long survivals, aggressive lymphomas. We have to determine nodal versus extranodal disease, and pathologists are involved in staging of lymphomas, which Dr. Horning mentioned. We're the ones that usually determine, is the disease in the bone marrow, in the liver, in the spleen, and the distribution. So we're important not only in making the diagnosis, but in determining the stage of the disease.
Slide #11
Here, for example, is a bone marrow biopsy. Many patients with lymphoma undergo a bone marrow biopsy, and that's a very important specimen to us. We realize that there's a certain amount of discomfort in this procedure, and we want to do our best to make sure that we will get the best results from these bone marrow biopsies. This is a patient with a follicular lymphoma, and you can see the lymphoma cells here next to the bone, which is where they characteristically hang out in their follicular lymphomas.
Slide #12
Now, fortunately, we have a number of things in our armamentarium which enable us to, instead of just looking -- in the old days, pathologists would just look through the microscope and make a diagnosis. We don't do that anymore. The diagnosis of lymphoma requires a lot of special methods and techniques that enable us to be much more specific and much more reproducible in our diagnosis, and one of the most helpful things is immunostaining. This is one of those Reed-Sternberg cells that I showed you earlier, and now instead of just having to look down the microscope and say, "Well, that looks like a Reed-Sternberg cell to me," we now can take this antibody called CD15, and that antibody will beautifully and specifically home into that Reed-Sternberg cell and stain it brown, some people call these brown stains and then we can say, "Well, yes, we know this a Reed-Sternberg cell not because I say so, but because it's expressing these antigens." So that's a major breakthrough. In addition to immunohistochemistry, we have molecular genetics, we have cytogenetics, we have a whole armamentarium now.
Slide #13
Now, what about clinical trials and novel therapies? Again, the pathologist is the key, because many of these trials require the pathologist to identify, say, a specific target that the therapy may work about. A good example is rituximab. The clinicians want us to tell them, "Yes, this patient's lymphoma really expresses the CD20, so your treatment, anti-CD20, is going to work." So they're relying on us not only to diagnosis the lymphoma and characterize them, but to tell them whether this specific therapy is going to work for this individual, single patient.
If a patient wants to have immune therapy, if that's a possibility, the immune therapist is going to want us to handle that tissue to determine what type of immune antigens are present on that lymphoma, what the idiotype is, for that single patient's lymphoma so they can put the patient into that trial and develop the antibody. If we're not doing things right and handling the tissue right right from the beginning, then we're not going to be able to do that. So in terms of clinical trials, again, the pathologist is one of the keys to placing the right patient in the right trial where it's likely to make a difference.
Slide #14
This is CD20. The rituximab antibody that we're all so excited about specifically will react with cells that express the CD20 antibody. Here we've taken our brown stains, and we can show specifically that that malignant cell, that happens to be a Reed-Sternberg cell, but that particular malignant cell is expressing CD20. And yes, this patient is likely to benefit from this type of treatment.
Slide #15
What about the pathologist as a consultant? Most of my calls from patients are, "I have been diagnosed with lymphoma, and I have some concerns, and I would like another opinion on the pathology. Do you think that's a good idea? Who should I send it to?" That's a question that I would like to try to answer for you. I think the point about this is that diagnosis of lymphoma is a complicated procedure. It's much harder, actually, than most of the other aspects of pathology, in my opinion. Now, there are specialist hematopathologists. There are many of us in every city, every major medical center. We call ourselves "lymphomaniacs." [LAUGHTER] I think that in a disease like this, it is worthwhile, perhaps, having your pathology reviewed at a major medical center or by a pathologist who really has an interest and a specific career in this disease and knows about all the various subtleties. So I think second opinions are a good idea, and that having a real expert hematopathologist involved is a very good idea.
What about conflicting opinions? You will get conflicting opinions in some cases, and the reason is there are gray zones in pathology. I think the standard of pathology in America is extremely high, but nevertheless there are areas when is this a Hodgkin's lymphoma or a non-Hodgkin's lymphoma becomes a very difficult opinion, and then it helps to have other experts. Sometimes even is it a benign disease or a malignant one can be difficult.
Slide #16
I'll show you one example. Here we have a MALT lymphoma, one of these lymphomas of the stomach that are related to the bacterium H. pylori. Here we have a peptic ulcer, and really they look very similar. You need an expert pathologist sometimes to be able to look at that and say, "Yeah, that's the peptic ulcer, and this is the MALT lymphoma." So correct and accurate diagnosis, obviously, is critical.
Slide #17
Here's another example. Here are two types of lymphomas. This is a follicular lymphoma, and this is a mantle cell lymphoma. Even as someone who has spent the last 30 years looking at lymphomas all day long every day, I can tell you just looking at those two slides is very, very difficult. That one has a prognosis entirely different from this kind of lymphoma. In this case, we can use a specific molecular marker, cyclin D-1, to really identify which one is the mantle cell lymphoma, because that one will express the cyclin D-1. So it's really important, I think, that accurate and specific diagnosis is made, and that may require an expert pathologist and a lot of ancillary expert techniques -- immunohistochemistry, molecular techniques, whatever.
Slide #18
What about banking tissues? Is that something we should think about? When we have our biopsies, what's going to happen to that tissue? I think we might think about what happens if down the line someone comes along with a very specific therapy that may require us knowing what my lymphoma actually showed, what exact antigens were present in my lymphoma -- not just anybody's my own very special lymphoma. And also, for people wanting to do studies, it's very important to be able to have, say, 50 cases of one kind of lymphoma, and I think what's happening in pathology, very important, is the setting up of lymphoma banks, and there are a number of those in the U.S. right now. The one at UCLA we have was funded both by the Lymphoma Research Foundation of America and by the National Institutes of Health, which is a wonderful organization in this country, and I think more and more of these banks are set up. And then we keep the patients' tissue for use in treatment protocols, and then again this is a very valuable scientific tool for further trials.
Slide #19
So just a final summary slide. I just wanted to mention that, yes, pathologists are a very important part of your treatment, and we're always happy to get to know you, to chat about various pathology problems. They're a diverse group of diseases that are highly complicated. They arise from the immune system, and in order to diagnosis them, we need a combination of the morphologic features, the immuno features, the clinical features, the molecular features, the genetic features. And although that sounds very complicated, it's not as bad as I've said, because although there are many, many types of lymphoma, actually most patients, there really are a small number of diseases that affect most of the patients.
Slide #20
What is the role of the pathologist? Accurate diagnosis and classification, of course, but may require a specialist. We're happy to be consultants, and we have to ensure availability of tissues for clinical trials and special treatments, and we're involved in the clinical trials and also in research in lymphomas. Thank you. [APPLAUSE]
Sandy is allowing me, kindly, to answer questions if there are any. Yes?
JONATHAN SAID, MD: That's a very interesting question.
The question is, is there a relationship between breast cancer and malignant lymphoma, and particularly Waldenström's macroglobulinemia. And perhaps reassuringly, I can say that there really is no known link between breast cancer and lymphoma, but very interestingly, there is an increased incidence of -- Waldenström's is part of a disease of so-called plasma cell dyscrasias. There's an increased incidence of these diseases in patients who have had breast implants, interestingly. No one really knows exactly why. It may have something to do with the immune reaction to the breast implant in patients who have had breast reductions and implants. But I'm not aware of any direct link between lymphoma and breast cancer.
I think we know lymphoma is a genetic disease, and we're always concerned, what about our loved ones? Is this is a genetic disease? Because I have this disease, are my children going to be affected? And all those questions are very important. But actually, the direct genetic link between lymphomas is only in a few diseases. There's not a strong genetic link, and I think that's quite reassuring to many of us.
Q: My question has to do with -- I'm still in the stage of trying to understand as much as possible. What does the CD15s and CD20s -- I know that they're markers.
JONATHAN SAID, MD: Yes.
Q: But can you explain like what CD stands for?
JONATHAN SAID, MD: Sure.
Q: What do all those numbers stand for?
JONATHAN SAID, MD: A good question, an excellent question. Let me explain. Various lymphoma cells have various markers, and they're called antigens, and we're able to identify them. In the early days of mono -- of antibodies, which -- it's really exciting, because I just started getting interested in this when this became done -- everybody in the lab would make an antibody to a marker, say, and I would call mine, you know, Jonathan Said 1, and Stanford would call one Levy 1, and it got to be chaotic.
So what happened, there was a group of meetings held, and they said, "We're going to take all the markers that recognize one antigen and give them a number, and we're going to call them CDs for clusters of differentiation. So we're going to take all the markers that recognize this kind of marker on a Reed-Sternberg cell and call that CD15. That means we can talk to each other. I can tell a pathologist anywhere in the world that this tumor is CD20 positive, and he knows what I mean. Now, I might use a number of antibodies to identify that CD20. So it's just a way of standardization of things, standardization of antigens, basically. And there are hundreds of CD groups. Every year they come up with more. There are hundreds of them. There are big books published each year with these classes of differentiation.
Q: I have kind of a group of questions all based on the pathology report. What details should be listed on a report? As a patient, when I read these things, I'm not sure what I should be looking for.
JONATHAN SAID, MD: It's interesting.
Q: So what details should be listed on the report, and how do you know if the disease is in the liver and spleen if you haven't had a biopsy section of the liver or the spleen? And should the report show everything that was checked during the process, or what do you look for?
JONATHAN SAID, MD: Excellent question, and the answer -- it's an easy one to answer, because there's a group called the Association of Directors of Anatomic and Surgical Pathology, and what they did was get a committee together -- and I was one of the members of this committee; Elaine Jaffe at the NIH, some of you may have heard of, was the chair -- and we actually sat down, and we got together in a meeting and we defined exactly what should be in a path report on lymphomas. I'd be happy to give anybody here who wants a copy of it, and that is going to be published very soon in multiple journals of pathology. So we now have a standardization of what this committee of expert hematopathologists thinks should be in that report. And it's quite complicated. It's a several-page document, so I can't -- I don't have time now, but I would be happy, anybody who wants a copy of that document, if they just e-mail me, I'd be very happy to e-mail them back a copy of it. But standardization is very important, and path reports are highly variable, so I think that's a very good question.
In terms of your second question, how do you tell if the liver and spleen without doing a biopsy? That's a question better for the clinicians, because there are ways, by clinical tests, there's scans, there's ways to determine disease without actually putting in a needle and looking at it. Fortunately, there are other ways to do that, but that's -- pathologists don't do that. Dr. Horning and her colleagues do that, so I won't answer that. Sir?
Q: Yes. How unusual is it for an indolent form of lymphoma to kind of morph into a more aggressive type, and is that to be expected over a period of time?
JONATHAN SAID, MD: These are such good questions. I'm really impressed by the knowledge. Most indolent or low-grade lymphomas will transform, and it's one of -- For the last three years, actually, my research at UCLA has been in looking at transformed lymphomas to try and understand how this happens, because it seems to me it's fine, a patient with an indolent lymphoma, particularly if they're older, they might go a natural lifespan with this disease, but they nearly all will transform eventually if the patient lives long enough. And if a young person has an indolent lymphoma, it's very likely that they're going to see some kind of transformation event. So I would say that practically all low-grade indolent lymphomas have this capacity to transform.
We know a lot about how some of them do it. We don't know much about how others do it. But I think this is a very fertile form of research, and it's really been the basis of my personal research for about the last three years. So I'll be happy, if we have more time, to go into it.
Q: Has the way that the pathologist comes to a decision, has that changed since nine, ten years ago? And would you suggest that when there's a recurrence of the lymphoma that a new biopsy be done and it be sent to the pathologist and also to the tissue bank?
JONATHAN SAID, MD: Well, what's changed in diagnosis has been the new techniques. So many -- we're so much better now today. When I look back, what we were doing ten years ago and what we're doing today, it's a quantum leap. And it's not that we're smarter, it's that we have all these new tools now to make more accurate diagnosis, so we're much better now. I sort of shudder when I think about how I did things ten years ago, and I'm so grateful now that we have these tools that are more objective.
In terms of a second biopsy, again, that's often a clinical decision, and the questions arise, has this lymphoma transformed? Is it still the same? Those are the kind of questions. The good news is, we can do a lot now on what are called fine needle. I didn't go into this, but there are techniques such as fine needle aspirations where, instead of having to undergo a biopsy, you can just put a skinny needle. It's an outpatient procedure. It takes only a few minutes, but you can just put a needle into the lymph node and withdraw a few cells. That may not be enough for a de novo diagnosis when you want to exactly characterize it, but that's often enough for me to say, "Well, yeah, this patient's lymphoma is still the same." Well, yeah, it has transformed. We need to do something differently.
So I think the clinical parameters -- and Dr. Horning -- again, I don't like to talk about clinical things, but there are indications for doing some kind of procedure to try and characterize a recurrent lymphoma. But fortunately, things like FNA are often suitable for that, and that can save the patient another procedure.
Q: But would you suggest getting enough tissue to go to a tissue bank?
JONATHAN SAID, MD: Again, you see, I always think having a procedure -- you know, I have to consider the patient, how they feel about having the procedure. I would say as pathologists we always want tissue. When the surgeons say, "How much do we want," we always say more. [LAUGHTER] So if you say yes, sure, I would like tissue, but will I get enough information from that to make it worthwhile, you, the patient, having the procedure, when perhaps I can tell just from an FNA. But let's consider -- say you want to go into a therapeutic trial, and then they may really need tissue to sort of characterize your specific lymphoma for that trial. So it's a very complex question. You know, I think you always have to consider what I want as a pathologist or as a researcher -- sure, I want tissue -- against, you know, you're the patient. I have to consider the morbidity and mental, whatever strain of having to undergo a procedure. So it's always a payoff, you know. One more question, please.
Q: Doctor, would you mind elaborating on what the term diffuse means when you're describing follicular lymphoma?
JONATHAN SAID, MD: Absolutely. So the way the WHO classifies follicular lymphoma is predominantly follicular lymphoma, follicular and diffuse, and then predominantly diffuse, because what happens with follicular lymphomas, they may stay off -- and I don't know if you remember that picture I showed you with those nice nodules. It was a very good follicular lymphoma. What happens is, either at the start or with time they start to lose that nodular appearance and they start to become more diffuse. Now, that has an impact on prognosis. As a single factor, diffuse lymphoma generally might be more aggressive than a follicular one.
So when I get a biopsy on a follicular lymphoma, I do not just want to tell is it follicular, I want to tell the clinician, tell Dr. Horning, "Yeah, this is a follicular lymphoma, but 50% of it actually is diffuse," indicating perhaps a more advanced disease, because it's transforming from follicular to diffuse. So whenever we see a follicular lymphoma, there's always some component of nodularity or follicularity. There's always some component of diffuseness, and we have to try to quantify it. Less than 25, we call it follicular. 25 to 50%, we call it follicular diffuse. Greater than that, we call it predominantly diffuse. So it's a subtype with follicular lymphoma. Does that --
Q: Yes, thank you.
JONATHAN SAID, MD: Thank you very much. I really appreciate those questions. [APPLAUSE]
|
SUMMARY
