John P. Leonard, MD (Host): Welcome to Weill Cornell Medicine CancerCast, conversations about new developments in medicine, cancer care, and research. I'm your host, Dr. John Leonard. And today on the podcast, we will be talking about pathology and the role this important specialty area plays in diagnosing and treating cancer.

Our guest for this episode is Dr. Amy Chadburn, someone who I have worked with for many years. Dr. Chadburn is the type of pathologist known as a hematopathologist who evaluates diseases of the blood cells. As a hematopathologist, Dr. Chadburn and her colleagues use a variety of techniques to then help guide treatment approaches alongside hematologists and oncologists. In addition to her clinical work, Dr. Chadburn conducts research on lymphoproliferative disorders and has authored numerous papers and articles throughout her career. She's also been very involved in teaching and administration. I'm really excited to speak with her today about her expertise.

John P. Leonard, MD: So, this is really a great chance, I think, to enlighten our audience a little bit about what happens behind the curtain in pathology and hematopathology. Patients get biopsies. And then, this complicated process goes on. And these reports and analyses and ideas get issued. And this is used very commonly to guide therapy or to establish a diagnosis that leads to a therapy for patients. How did you get into pathology as a specialty? It's kind of a distinct area within medicine.

Amy Chadburn, MD: Well, where I went to med school, students tended to either go into surgery or immunology. I went down the surgery route. But I decided if I did not want to stay in surgery, I would switch to pathology. I did like surgery, but I realized it wasn't the field for me. I knew I couldn't do two or three types of cases my whole life, and I needed to be in a field where one could ask questions. And really, that's pathology. I like to ask questions. I ask a lot of questions. And to me, questions is a very broad term. It includes understanding the biology of the disease, but it also includes what tasks I need to do to make the right diagnosis and what I can do to help the clinician better treat the patient.

How did I get into hematopathology? I did this project and I fell in love with lymph nodes. It was a study of HIV lymph nodes. And, those lymph nodes are still cases I use today for some of my research projects.

John P. Leonard, MD: I find it very interesting, your comment about asking questions. You have many skills as a pathologist and we've shared patients and cases and discussions over probably decades at this point. But one of the things that really, I think, distinguishes you is the issue of asking questions. A great skill or attribute of outstanding pathologists is that aspect of asking questions because, often in medicine, we're kind of siloed, where people are working in their own area. And the idea of "Tell me a little bit about this," or "I saw this patient's biopsy, and I'm thinking this could be this, or could be that." And, something that patients don't necessarily understand and appreciate is the importance of having an outstanding pathologist who asks the right questions, looking at their material and participating in their care.

Amy Chadburn, MD: I do think that asking questions is a key part of pathology. We have tons of tools to work up cases. But you have to ask, which tool is the best tool? What am I trying to figure out? How can I put all these pieces together? That's one of the beauties of pathology, is that you can ask these questions. You can go on these adventures to get the information to try to make the right diagnosis. And really trying to make a diagnosis is asking a question. What is it? So, I think pathology really is an asking question field.

John P. Leonard, MD: To a patient or to a layperson, how do you describe the field of pathology and the role of a pathologist?

Amy Chadburn, MD: I don’t think many people understand how broad it is. I think a lot of people think about it as CSI, but we’re much more than that. We do do autopsies, which can be very informative and help families understand why their loved ones have died, but we also look at tissue biopsies. We evaluate blood samples like CBCs, and that’s your blood counts, including your hemoglobin, your white cell count, and your platelets. We do the chemistries like sodium and potassium. We do SPEPs to find monoclonal proteins. We do coagulation studies, which are important for people on warfarin and other anticoagulants. We do bacterial cultures for people who are sick. We do molecular studies, mostly for cancer patients, but we also do them for detecting viruses and varied problems with coagulation factors. And we do cytogenetics, which is important in cancer care and in patients who have fertility issues and patients who have genetic diseases. So, pathology is really, really broad. It depends what you’re talking about and what you’re focusing on. We supply about 70% of the medical record. So pretty much every time a patient seeks medical care, in some way, in some form, they’re touched by pathology.

John P. Leonard, MD: I think most people probably think about pathologists as dealing with biopsies and analyzing biopsies. But how do you think of it from the cancer perspective? And how has that evolved over the years, because it strikes me that certainly the depth and the level of involvement seems to be getting more and more over time.

Amy Chadburn, MD: I think it is. And what we’re able to do has also greatly expanded. When I was a resident, we basically looked at glass slides. That was it. We looked at the tissue sections, the H&E sections, which are the glass slides that people pick up for second opinions. But now, we have so many different tools that we can use to help figure out what those cells are. We can get much more specific. We can look at proteins with immunohistochemistry. We can do flow cytometry, which also looks at proteins on the cells or inside the cells. We do molecular studies to look at the genetic makeup. We have many more cytogenetic studies than we used to have. So, there are many, many different techniques and ancillary studies that we can do to better tease out exactly what’s going on with the tumor cell. And when we can better characterize the tumor cell and put it into a category, then you as the clinician, can better pick the therapy to treat the patient. So, I think that's very, very important, that we’ve been able to expand what we’re able to do and give you more information for you to make therapy decisions, but also for the patient to have an idea of what their tumor is like. Is it something that’s relatively indolent or is it something very aggressive?

John P. Leonard, MD: For a patient getting a biopsy, the patient is there, they get the surgical procedure, a needle biopsy, or in some cases, a blood specimen or some other sort of procedure.Tell us a little bit about the process that happens after that. The patient may see the material, the tissue, going into a bottle or a tiny specimen container, and then it gets put in a bag and sent off. What happens after that until ultimately the report or the information comes?

Amy Chadburn, MD: I’m going to talk about a lymph node biopsy, because they’re a little bit bigger. The problem with the core biopsy is that we’re a little bit limited on what we can do with that sometimes. But if we get a lymph node biopsy, the first thing we do is we look at it. And we look at it grossly. We can sometimes tell quite a bit about what’s going on just by looking at the piece of tissue. For example, some types of Hodgkin lymphoma, you can actually get a really good idea that that’s what’s going on, because you can see bands of collagen and you can see the tissue pop up in between. So, you get this nodular pattern. We also do touch preps before we even process the tissue, just to see what’s going on.

If we see lymphocytes or Reed-Sternberg cells, we’ll take some of that tissue and put it in suspension, meaning that we smash the tissue in and get individual cells out and put them in fluid so we can run flow cytometry. We take a piece of the tissue and we put it into formalin, which is a type of fixative. Formalin cross-links proteins so the tissue won’t autolyze or die so we can look at tissue sections of this later on. And we often, if we have enough tissue, freeze a little bit away. And the reason we do that is because some molecular studies are better done on frozen tissue. It gives us more flexibility in the testing that we can do. Sometimes we also freeze some cells away if we have enough material. And we try to think well ahead of what we might need in the future. And so, we try to save material for all of these different types of tests.

In our laboratory, when we get a piece of tissue and we put it in a fixative, we actually fix it overnight. We don’t submit it for processing in large tissue processors the same night. We do it the next day because we have studied our immunostains and found that we get the best results if we fix the tissue overnight in formalin in a cup. It’s a fluid that fixes the tissue. It goes through the tissue processor. They put it into what we call a paraffin block. And I kind of think of the paraffin block like a loaf of bread. It’s something you can slice sections off of. And those slices are what we use to make H&E stain sections where we can see the cells, but we also can cut sections off to do immunostains.

The slides come down, we look at the slides, we have the flow cytometry results, and we put this all together. We decide whether or not we need more immunostains. Now, the immunostains are actually antibodies that detect proteins on the surface on the cell. They help us identify the cell types, like if they’re a T cell or a B cell or a myeloid cell. We look at those, again, with the tissue sections and with the flow results. We then decide whether we need more immunostains, if we need molecular studies, or if we’re able to sign out the case.

Now, what’s signing out the case? It’s what the patient sees. Making the report that has the diagnosis, it has the gross description, which we’ve already done in the very beginning. The microscopic that we saw off of the routine histologic sections, those purple slides you pick up, it will have the results of the immunostaining and the results of the flow cytometry. So, all of that goes into the report to give support to the diagnosis that's in the report, as well. We also sometimes do molecular studies, but those come in a separate report. And often, we do an addendum to the original report to include these molecular studies and cytogenetic studies, so, the patient has one report with all the information about the tissue biopsy in one spot.

John P. Leonard, MD: One question patients might ask is, why does it take so long? They’re worried, they want the answer, and sometimes it can take a week or two.

Amy Chadburn, MD: It takes a long time for a variety of reasons. But the main reason is that we want to get the best answer. But if we get a core biopsy, for example, we sometimes have to do things sequentially, because we don’t have a lot of tissue and we want to use the tissue in the best manner we can. We may do some stains and then look at those and then decide to do other stains, but that adds time onto it. Cases that are difficult means that we have to do more testing. Cytogenetics can be very, very crucial in making the right diagnosis. Cytogenetics you have to grow the cells, so that takes a while usually, like a week. Molecular studies can be very crucial in making the right diagnosis. Molecular studies can also take a significant amount of time. With respect to the molecular studies, it’s not even just doing the test, doing the PCR or the NGS, you also have to put it through a pipeline and then align all the base pairs, et cetera, in order to find the abnormality. So, a lot of this just takes time. And we would all like to do it faster. We are getting faster. For example, immunostains are much, much faster than they used to be, and they are much more reliable, because we’ve put them on machines rather than doing them by hand. So, we have made some progress in some of our ancillary testing modalities to make it much faster. But some of it, it just takes a while.

John P. Leonard, MD: Tell us a little bit about second opinions. I have been working here at Weill Cornell with you and your colleagues. We have lots of pathologists and lots of specialists in different areas. And I know that you all provide each other second opinions because you look at things together, as well. But tell us about the importance of second opinions in pathology and how often diagnoses get changed or people differ in their opinions for pathology.

Amy Chadburn, MD: First of all, before we talk about second opinions from institution to institution, I think it’s important that everybody realizes that when we make a new diagnosis, even in our own division, we show it around. We have to get another person to agree with us on the diagnosis. It’s a quality control to make sure that we’re doing the right thing, or we didn’t miss a test that might change the diagnosis.

The diagnosis, every once in a while, it's changed.There are times that you do change somebody else's diagnosis. I always try to do sufficient testing to confirm what I think it is in contrast to what the other group did. You want to make sure you have all the data that will support your diagnosis. It doesn't happen very often. I think it actually happens less now, because instead of just looking at glass slides, we have ancillary studies. We have the immunostains. We have the flow cytometry. We have molecular testing. So at least in hematology-oncology, we have all of these additional studies that help us confirm what we see on the glass slide.

However, second opinions are important because it does confirm that that's the diagnosis. If you're going to get treated in another institution, you should have your pathology reviewed there. And it's really important, if somebody has recurrent disease or comes back and has another, say for example, lymph node biopsy and it's benign, you want to know for sure what the original looked like, so you can do a comparison. So, we do do comparisons with previous specimens all the time to make sure that what we're seeing is the same or different as the case may be. So, second opinions are very, very important for that reason as well.

John P. Leonard, MD: Looking at pathology reports is complicated, particularly in blood cancers, but in lots of areas as well. What advice do you have for people about the report, and the key elements of what's going to be in a report? Is it mostly just make sure you have your doctor interpret it or any other thoughts around that part of things?

Amy Chadburn, MD: Well, I think it's important to have your physician interpret it with you or go through it with you to explain the different things. I really try with our trainees to impress upon them that this report is not just being read by people in the medical field. You need to spell out all the words so people can at least look them up to see what they are.

It's important that patients go through the report with their clinicians, so they completely understand what's going on. But the report has many parts that are important. And I think at this point in time, different diseases have things that are specific for the diagnosis, and it's important for the patient to know that those are there in their diagnosis.

The report is complicated. It's only going to get more complicated, unfortunately, as we do more and more tests. But I think as we do more and more of these sophisticated tests, particularly along the molecular line. We're going to be able to better classify and characterize the lesions. And that means you can better treat them. So, I think it's a double-edged sword. And instead of having a simple one-line diagnosis now, it is very complicated. But again, I think, the best thing is to go through it with a physician and get the definitions of the different words. I think most of us try to make it readable, but medicine's a separate language.

John P. Leonard, MD: One area that comes up a lot is the idea of molecular testing. I've had patients come in and say, "I would like the pathologist to do molecular testing on my specimen." And I think that often people have a specific test or there is a specific test that's very relevant to their situation. But often, it's just the concept that molecular testing sounds like it must be good and must be helpful. How would you explain that to people and kind of where does that fit in a general sense, recognizing it may differ based on the diagnosis and the disease we're talking about?

Amy Chadburn, MD: I think in the myeloid neoplasms, molecular testing is becoming more and more important. And so, in a way, that's a reasonable question to have answered. I think right now, because we use molecular so much for classifying myeloid neoplasms, we actually do it up front a lot of times. So, for certain diseases, the molecular testing really is going to be crucial in making the diagnosis. And even now in some instances, it is really the classifying, defining feature. Also, molecular genetics, cytogenetics, they're different ways of looking at the same thing, or different ways of looking at the genetic composition of the tumor. And sometimes cytogenetics also is important. But the thing is that we can do molecular studies, but it’s not necessary in all cases. For example, patients with mantle cell lymphoma, yes, we could look at them, at the molecular level, we have primers to look for a BCL1 rearrangement, but actually those primers are not as sensitive as doing FISH or doing immunostaining for the BCL1 protein. We try to do the best test for the question we're asking. Patients may come in and say, "Oh, I want molecular done on my specimen," but it really depends on what diagnosis the patient has, or you suspect they have. Molecular testing is great, but at least at this point, it's not the end all.

John P. Leonard, MD: Before we wrap up, I want to ask you what's on the cutting edge in pathology or what kind of research is happening that you think patients should be aware of that perhaps, in the coming years, will be important to know about as it may influence care? What are you excited about in this area?

Amy Chadburn, MD: Well, I think the genetics really is kind of the cool stuff right now. At least for diffuse large B cell lymphoma, I am positive – well, 99. 9% positive – we’re   going to be subclassifying these lesions using genetic markers. Myeloid neoplasms, again, genetic markers are helping us classify them into different groups so we can better treat them. And by doing the genetics, we can also identify abnormalities that we may have targeted therapy to and also, we can develop antibodies against. So like Rituxan and CD20, that was a breakthrough. But there's also things like BCR-ABL, where we now have TKI inhibitors to inhibit that alteration.

Other things that are coming down the pike, there's cell-free DNA, which we will be able to look at the blood to see if we find tumor DNA. This is going to be really, really helpful for monitoring patients after they're diagnosed. It'll be less invasive, easier for the patient. Also, our understanding about tumor biology, we now know that it's not just the neoplastic cells, but also the microenvironment around the tumor that's important for tumor development. So, we're doing a lot of work in that with multiplex immunostaining to understand the microenvironment and how it plays into tumor behavior. MRD testing – minimal residual disease testing – we now do a lot of it by FLOW, specifically for chronic lymphocytic leukemia, myeloma, and B lymphoblastic leukemia. But we're also beginning to do more of that at the genetic level with deep sequencing and clonoSEQ. We need to develop MRD testing for other types of diseases until we get the cell-free DNA up and running. Development of antibody targets and inhibitors, I think that it's so wonderful that we're not having to treat every single person with chemotherapy, that we can actually target the problem in the cell with an antibody or an inhibitor. Specific treatment is so much better. So, I think there's a lot of things going to be really, really helpful for us and for the patients.

John P. Leonard, MD: Well, Dr. Chadburn, thank you very much for joining us today. It's been a great discussion. I'd like to invite our audience to download, subscribe, rate and review CancerCast, on Apple Podcasts, Spotify, or online at weillcornell.org. We also encourage you to write to us at cancercast@med.cornell.edu with questions, comments, and topics you'd like to see us cover more in depth in the future. That's it for CancerCast, conversations about new developments in medicine, cancer care, and research. I'm Dr. John Leonard. Thanks for tuning in.

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