Diagnosis and Co-management of Hematologic Malignancies for the Primary Care Provider
Previously Recorded: Thursday January 25th 2024 | 5:30 – 7:00 PM EST
Join subject matter experts from Roswell Park Comprehensive Cancer Center for an interactive live educational event: “Diagnosis and Co-Management of Hematologic Malignancies for the Primary Care Provider." This event aims to arm primary care physicians and APPs with essential knowledge pertaining to identification and collaborative management of a variety of hematologic malignancies. Our expert speakers will delve into the latest techniques in diagnostics, treatment modalities, and interdisciplinary approaches, providing attendees with valuable insights to enhance patient care and outcomes. Don't miss this opportunity to expand your expertise and contribute to a collaborative approach in addressing hematologic malignancies within the primary care setting.
Assistant Professor of Oncology
Department of Medicine, Lymphoma
Department of Cancer Genetics & Genomics
A Basic Approach for Patients with the Possible Diagnosis of Lymphoma
Director, Lymphoma Research
Professor of Oncology, Department of Medicine
Head, Lymphoma Translational Research
Associate Professor, Department of Immunology
How to Approach the Abnormal CBC
Director of MDS
Clinical Disease Team Leader
Director for Liquid Tumor, Center for Early Phase Clinical Trials
Department of Medicine
Plasma Cell Dyscrasias: When to Suspect. How to Detect?
Professor of Oncology and Internal Medicine
Chief of Myeloma
Good evening, all and thank you for joining us. My name is Doctor Matt Cortez. I'm an assistant professor of oncology, specializing in lymphoma and chronic lymphocytic leukemia at Russell Park Comprehensive Cancer Center here in Buffalo New York. It gives me great pleasure to welcome you to tonight's events, diagnosis and co management of hematologic malignancies for the primary care provider. I'm looking forward to serving as your moderator this evening where we have three excellent presentations prepared by experts in their fields. The first talk will feature Doctor Francisco Hernandez Eliza La Toi titled a Basic approach for patients with the possible diagnosis of lymphoma. Next will be Dr Elizabeth Griffiths who will be discussing the initial evaluation of myeloid disorders focusing on leukemias and myelodysplastic syndromes. We will wrap up the presentations with Doctor Jens Hillings discussing plasma cell dyscrasias when to suspect and how to detect the three talks will be presented sequentially with a live question and discussion period to follow. You are encouraged to submit your questions at any time throughout the presentation as they will be collected and reviewed following the presentations. As always, we here at Roswell Park. Appreciate the opportunity to produce these educational series uh as a means to connect with our peers in the community as well as our colleagues at other institutions. It is our hope that you'll find this program informative and we ask that you please provide your honest feedback when prompted again. Thank you for joining us tonight as we welcome Doctor Francisco Hernandez, Eli la toi. Doctor Hernandez. Good evening. I'm Doctor Francisco Hernandez Salit Tore. I'm the director of the Lymphoma Research Program at Rosel Park Comprehensive Cancer Center. I would like to talk to you a little bit briefly about what is the general approach for patient that we suspect to have lymphoma. So I want to start this presentation with a small case, uh something that we sometimes can see in general practice. So this is a 6660 years old African American male who presented to the primary care office campaign of a large uh submandibular mass uh that he noticed two weeks ago during shaving, he also have been having some um um kind of fatigue but no symptoms. And I think that is usually the way that patients with lymphoma sometimes present uh to uh physicians in general practice, you know, and in general, you know, um the the severity of the symptoms of patients with lymphoma will depend in um the kinetics in which the lymphoma is growing uh the location and, you know, sometimes the type of the lymphoma. So that's something we have to be um having in mind, um lymphoma is really a generic term that we use to describe cancers that are arising within the immune system of our bodies. Um in, you know, lymphomas is really a very heterogeneous group of malignancies and each one has different um pathogenesis, um kind of genetic drivers of uh of, of, of the development of progression, clinical manifestations, treatment and prognosis. Um So it's a little bit challenging to understand, you know, lymphomas. But a good understanding, understanding of the biology of lymphomas really results in a better management for patients who they suffer from this kind of disorders. And in general, um we depend a lot in our pathology. Colleagues to really um you know, um determine the type of lymphoma the patient may have. In addition to that, we depend also from colleagues. So they have surgical capacities to able to secure an uh you know, proper tissue uh to make the correct diagnosis in these patients. So when we look at lymphomas, you know, as I said before, it's a very heterogeneous group of malignancies and uh they are arising from different areas of the lymph nodes. And I think this is a slide that show uh the anatomical um areas of uh the lymph node that you can see there are some icelands that we call follicles that are. So by darker um purple areas that we call uh the cortex of the of the the paraf areas. And they are immune cells in between. So it's interesting that you know, out of these areas, they have different type of lymphoid cells. And when uh mutation occurs in the cells that they have, they, they live in these sections of the lymph node, patient may develop different type of lymphomas. You know, and I think so again, when you look at a patient that has a lymphoma and we do a biopsy of the abnormal lymph node, you will see that sometimes this normal architecture is destroyed by the expansion of the abnormal cells that are arising from one of those three different sections. Now, um um lymphomas, as I said before, um they are categorized based on how they look at the microscope and you know, what kind of uh biological, diverse um you know, forces, you know, they have, you know, they can be classified different type of lymphomas. Currently, we recognize more than 80 different type of lymphomas and each one has different uh prognosis, different treatments. Um This is a diagram that kind of uh describe a simple way to classify lymphomas into two big families. Uh No hodgkin lymphomas which are by far more common. And Hodgkin lymphomas, it's a very small group of lymphomas affecting usually either young patients or elderly patients. Um hon lymphomas can be divided in 45 different subtypes. Uh four classical hodgkin lymphomas subtypes and what uh nor lymphoid doina hodgkin lymphoma that non hodgkin lymphoma is a more heterogeneous group of malignancies that is divided in two types based on what is the cells given birth to the lymphoma that we have a VSA lymphoma, which are by far more common, 80% of the lymphoma that we see in our country. They are bal in nature. And then we have TLRNK cell lymphomas, bal lymphomas, they can be further divide based on the uh the pace of the disease into high grade or low grade lymphomas. Large beal lymphoma is by far the most common hy grade lymphoma that we see in the United States, which is also abbreviated as the L BC L and follicular lymphoma is the most common subtype of internal lymphoma that we see um in the United States. T A lymphoma is a very heterogeneous group of malignancies and some of them have a very aggressive behavior. Uh The most common type is what we call mycosis fos which is a skin um located lymphoma of lymph of T cell lymphomas that they are present in the lymph nodes or inside the patient's body. Uh you know, the most common subtype is peripheral t cell lymphoma, not otherwise specified. So why there are so many type of lymphomas? Well, it's because our immune system is quite complex and you know, one of the functions of our immune system is to really kind of fight um you know, um micro organisms that we get exposed on a day to day basis So our immune system is formed, you know, by different uh uh blood cells, you know, um and they all start in the bone marrow where we have what we call the PLU report and the stem cells and those stem cells at one point, they differentiate into big into two big uh kind of stem cells. Lympho, the stem cells or myelo stem cells, lympho the stem cells, they will be further divided during a process of what we call immune moderation into different type of either B cells or T cells that we can see in this complex diagram. You know, normally those are kind of pre uh or B or T stem cells. They start migrating from the bone marrow into the lymph, no glas, the thus of the spleen where uh the proby cells or the uh of the pro thy T cells will mature and they will eventually develop uh or they will become mature B cells into plasma cells or mature T cells that they will be able to um fight macro organisms by us. Now, during that process of miration, uh each immune cells going to different genetic changes in order for those cells to learn to fight infections. And during that process of maturation is uh some of the cells are going into a weak and somatic hyper mutation phases in which the chromosome of these cells they get open and closed in order to um change the expression of different receptors. In each immune cells that will lead to a normal mature uh immune effector cell. Unfortunately, each of these steps, errors in the process can happen and that's when patients may develop a lymphoma. So, depending on the cell that develops the abnormality and the phase in which that error is happening that, but it leads to the type of lymphoma that the patient may be affected with. You know, and um this is kind of a small cartoon that it kind of tell us that as normal B cells uh move into the dation process from being a pro B cell, which is kind of like an undifferentiated B cell to a fully working plasma cell that is able to fight the infection for us, the surface of the immune cells change in the terms of protein expression. You can see here, there are several receptors that they are either absent at the beginning of the process of the differentiation and they are acquired towards the end of the differentiation process of a normal B cell. But they also can be present in cancer cells. And that allows to develop treatments that are directed against each of these receptors. Now, this is kind of a highlight in which when we look at the kind of lymphoma that patients may develop depending on where the the effect on the proliferation occurs. So, when uh the mutations occur at the bone marrow space, when the vessel is very undifferentiated patients, and developing a weaker lymphoblastic leukemia or lymphoma. When sometimes the uh the differentiation process is is abnormal in the cells that they are already in the lymph nodes. And they are going through the process of somatic hyper mutation. Depending on the abnormality. Seen, patients may develop either manto cell lymphomas, follicular lymphomas or large cell lymphomas. And if the mutations occur at the terminal differentiated state, that's when patients may develop multiple myeloma plasma cyto plasma cell leukemia. No, the same kind of process happened in T cells. T cells. They also differentiate from precursors T cells to a fully moderated T cell. And during that process, they either acquire receptors or they lose uh enzymes like TDT, for example. And again, you know, this kind of uh changes allow the cells to fight infections. But also as clinicians that we treat lymphomas allow us to uh to develop therapeutic target for patients. They suffer from either B or T A lymphomas. And again, just like in these lymphomas depending on where the abnormality happens in the differentiation process of the T cells is a kind of T cell lymphoma. The patient may develop, there are some T cell lymphomas, they develop in the T cells being uh kind of like living in the bone marrow space. That's when patients develop T lymphoblastic leukemia. Um when the T cells are still immature, but they live in what we call the liver or the spleen. Those are when patients develop elastic T cell lymphomas. And you know, when the abnormalities happen in T cells that are already in the tissues or in the lymph nodes, et cetera. That's when patients develop other forms of rare T cell lymphomas, like per tal lymphomas, anaplastic large lymphomas, et cetera. So, as you can see, lymphoma is just not one word, it's really, it's a very complicated group of malignancies that a lot of physicians will get to see in a day to day practice. So when a patient goes to, to see a physician, because he's concerned that the patient may have or not an enlarged lymph node that could result in a lymphoma. Usually the patient is enter the system through the primary care office, um complain of enlarged lymph nodes or other constitutional symptoms related to the possible lymphoma. Those patients normally are evaluated and some of them are sent to uh a medical oncologist and hematologist. And at that time, you know, in general, we need to basically do some radiological imaging studies to see the size of those abnormal lymph nodes, the location and the relationship with other structures. In addition to that, we need to start uh talking to surgeons or interventional radiologists to develop uh an a diagnostic approach that for the most part requires a biopsy. And once the biopsy is obtained, then, you know, it has to be processed by a group of not only technologies but hematologists that they integrate many diagnostic tools to give us the correct diagnosis in um lymphoma, the foundation of the treatment, uh the treatment of the patient and the prognosis of the patient is really based on the type of lymphoma that the patient has. So it is very important to get the correct diagnosis. Uh The uh the fastest possible way to do it with uh the least amount of risk to the patient, you know, and again, it does require a group of physicians and a skilled technicians that we have to work together so we can get to the proper diagnosis, you know. So and again, you know, normally we look at these patients, uh we do a complete history and physical examination. We order some labor testing, laboratory testing, we do diagnostic imaging and then we perform the lymph node biopsy. And again, in general, in contrast to the type of cancers, a fine needle biopsy is not enough. We normally require either a core biopsy which is using a thicker needle or removing one of the normal lymph nodes. And again, you know, as we are developing better diagnostic tools, the biopsies normally are submitted to different technologies that include float Tory cytogenetics gene sequencing uh routine, you know, paraffin uh and be two develop hne and the moos chemist sustaining and the pathologist use all of these kind of tools or, or or diagnostic techniques to gather the information to try to basically tell us what kind of lymphoma we are dealing with, you know. So for an example, flos atom Mery is um a quick analysis of the surface of proteins present in normal and malignant cells in general, you know, uh lymphomas which are vessel in nature, they will express some uh vsel markers, you know, and you know, sometimes abnormally they, they express tel markers. A good example of that is chio lymphocyte leukemia. These type of patients, they normally express V markers like CD 20 C 19. But they also express abnormally CD five, which we normally only see in normal T cells. Now, when we look at the T cell lymphoma, this uh kind of cancers that are usually characterized by expressing some of the T cell markers, but they tend to lose a lot of them. So sometimes we see in the microscope abnormally looking T cells that they should express all the markers that you can see in the right in single T, but they may only express two or three of them. And that usually raise a flag to the pathologist that we are dealing with the T A lymphoma. So this is an example of how we use some of the techniques that you know, um that we have available to try to somehow guess, you know what kind of lymphoma the patient is suffering. The most important uh tool is the morphology, which is how do the cancer cells look and how do they look in relationship to the other normal cells surrounding the lymph nodes that once the patient is diagnosed with a lymphoma, there are other things that we need to collect that allows to assess the the degree of involvement of the patient with the cancer and how healthy the patient is and what other precipitating factors could affect the lymphoma. So we normally order standard uh CBC C MP L DH set rate for hodgkin lymphomas. We normally do an HIV serology tear virus, hepatitis B and C ology for diagnostic and therapeutic purposes. Some patients uh the lymphoma is driven by viruses. You know, there are some patients who come very sick with signs of systemic inflammatory uh processes, something that we call hemo foc cytic syndrome or HLH. This is usually present in patients with T A lymphoma. And usually if we suspect of it happening, we have other laboratory studies like ferritin soluble cept levels, DS C profile, et cetera. Of course, we need to do cat scans and pet scan because that allows to stage the patient properly as well as a bone marrow function. A bone marrow biopsy. Finally, we do uh an echocardiogram and put my function test, especially we're going to use agents, um therapeutic agents that can produce heart or lung dysfunction in general. This is kind of the overview of how a patient comes into the doctor office. You know, what kind of informa they may have. How do we integrate imaging studies and pathological studies to secure a good biopsy, but to get a diagnosis and what kind of testing we do after this is kind of the things that we do at our institute. And again, this is something that we don't do alone. We have a team of lymphoma doctors that they are part of the lymphoma service or the solar therapy service. We as a partner with radiation doctors and surgeons and again, this is the contact information you want to talk to us about patients and we we're happy to help you. Good evening everyone. Um My name is Elizabeth Griffiths. I'm an associate professor of oncology here at Russell Park. My clinical focus is on patients with bone marrow failure disorders and acute leukemias. And um I'm currently an Associate Professor of Medicine at the Rossell Park Conference of Cancer Center. Today, we're gonna talk a little bit about the approach to an abnormal CBC and patients you might be seeing in clinic. Um When should you refer those patients? And what should you do about those findings uh when you do see them? So these are my disclosures. So what is a CBC? A CBC is a complete blood count? It's an actually an electronic measurement of what cell types sizes and shapes are present in a particular volume of blood when we draw blood from the peripheral uh from the periphery in your arm or your hand or where have you um those cells show up and those reflect the production from the bone marrow. An automated CBC uh also can provide a differential for what types of white cell are white cells are present in the blood. Um Remember when we think about white cells, those are generic, anything with a cellular nucleus will be present and will be counted as a white cell. Um Sometimes you can actually see nucleated red blood cells counted as white cells. And so sometimes you might see a correction to an automated differential where they apparently report elevated white cell count, which turns out to be nucleated red cells. Um It allows us to identify the relative percentage of the different types of nucleated cells in the blood neutrophils are usually the most dominant cell type in the peripheral blood. These are the infection fighting foot soldiers as I affectionately refer to them when I talk to patients about them, lymphocytes, usually B and T cells, sometimes NK cells and other mononuclear cells monocytes or um and eosinophils, which are sort of the special forces of the immune system. And basophils again, um relatively less frequent uh members of the peripheral blood and elevations of these relatively less frequent cell types can signal something abnormal. Uh We also have directly measured values that come to us on the CBC. These are the hemoglobin and the hematocrit effectively. These are now interchangeable in the old days when we used to draw blood, we would spin the blood down in a capillary elective rhesus tube. And then we would measure the amount of red blood cell mass or the amount of red cells compared with the total amount of blood volume. And this would be reported as the hematocrit. These days, we use light to determine how much hemoglobin is present in a sample. And that's actually reported as a specific value. But these are, are, are essentially interrelated with a um with a um an equation. Um 10 to 20% of CBC S will be reported or flagged as abnormal. And so it's important when you're seeing patients in clinic and you see an abnormality to know when that abnormality should be something to be concerned about and when you can just ignore it. So red cells, when you see red cells, it's hard to know what to focus on. They have a lot of different things that get reported as part of the red cell report. Um The first thing is the hemoglobin or the hematocrit. Um This value is reflective of how much red cell or hemoglobin is present in a particular sample of blood. And this is effectively the oxygen carrying capacity. Um When we look at red cell indices, there is a report of something called the mean corpuscular volume, which is how big or how small the red blood cells are. And this is a key factor for classification of different anemias. Um Additionally, there's something on there called the red cell distribution with. And this is a distinction that this is a description of how big and small or how different in size the red cells are. So when you have somebody who has a primary problem with the bone marrow, you often have difficulty with quality control. And so you can see very big or very small sizes of red cells. And there are particular diseases or particular genetic subtypes of disease which are related to the size of the red cell. And then the last thing that I think is important to focus on is the reticulocyte count. This isn't always reported in a standard CBC but is usually performed as an automatic part of the CBC when it's done on the machine. And this reflects the number of relatively younger cells in the peripheral blood reticulocytes are um red blood cells that are still undergoing hemoglobin organization. And so they still contain a little bit of RN A and they look a little purple under the microscope, they're usually slightly bigger than a standard red cell. And if you have a um a hemolytic anemia or something in which red cells are being actively destroyed or patient is bleeding, you can see an increase in the reticulocyte count which can correspond with an increase in the M CV because these cells are bigger and you often see an increase in the red cell distribution with again, reflecting the fact that the reticulocytes are representing a larger percentage of the number of cells in the peripheral blood or the red cells in the peripheral blood. So white cells again, uh white cells are generic term, they're divided into the different subclasses of white cell. And um when you see an elevation in the white cell, you have to ask the question, which of the different lineages of white cells are elevated. Um White cell evaluation is useful for identification of both acute and chronic leukemias. And it's important sometimes when you see an elevated white cell to ask the the lab to go back and do a manual differential, which is where there is a tech who looks under the microscope at a slide where they can identify the different subtypes of the blood under the microscope. So when you consider the underlying patient, you have to ask yourself the question is this CBC value that you see for the white cell count, specifically new or different for the patient you're seeing in front of you. Does that patient have something that might be driving an inflammatory situation like an autoimmune disease or an infection? In that case, you would expect to see a high white cell count with a high neutrophil count because those neutrophils are designed to fight infection. Um By contrast, if you see someone who has an elevated white cell count and it's mostly lymphocytes. The differential diagnosis for that process is quite different. Um race and sex can actually affect what's considered normal. So there are many people who run around with white cell counts that are considered abnormally low, but they don't have infections and they don't have anything wrong with them. And if you look back all their lives, they've had this white cell count and it's actually just normal for them. And, uh, I think the other thing is, what's the context of the patient you're seeing? Are they sick or? Well, do they have something going on? Um, these are all important aspects when you're thinking about the white cell number. So I mentioned before that white cell count normals actually vary quite widely between individuals. You can see here for males and females, the normals in terms of hemoglobin numbers, uh M CV S, platelets, white cells and neutrophils are actually quite different and these are quite distinctly different in individuals of African ancestry. Ok. And the majority of our normal ranges, certainly those done at Russell Park Conference of Cancer Center are largely based on a, on a on a biased white, mostly male population of patients. Uh Many individuals, many female individuals, whether white or African American actually suffer and chronic blood loss anemia due to heavy menstrual bleeding. And so the relative normal ranges for hemoglobin are actually substantially lower for women and this probably reflects a degree of iron deficiency. And you can see here also that normal ranges for white cell counts are quite different, depending on the population you're looking at. So the most type of cells that you see in the peripheral blood are actually your red cells. Normal erythropoiesis is a very, very tightly controlled process and actually represents the bulk of the heavy lifting that's done by the bone marrow within the bone marrow hematopoietic stem cells differentiate into a common myeloid progenitor and then they differentiate into a blast forming unit erythroid which then uh further differentiates into a colony forming unit erythroid and these colonies are sensitive to erythropoietin. Ok, erythropoietin is a hormone manufactured in the kidney, which can be increased or decreased in the context of kidney dysfunction or the kidney perceiving low oxygen. And this these drivers can increase production of red cells quite dramatically under normal healthy circumstances. Red blood cells live in the circulation between 100 and 10 and 100 and 20 days and you make almost a billion new red blood cells every single day. This can be rapidly up regulated in the context of bleeding or hemolysis with decreases in the red cell lifespan. So things that can diminish the ability to effectively produce red cells include things like inadequate building blocks from vitamin deficiency. Um drug intervention, various drugs can cause lowering of the blood counts and um interruption with normal production of building blocks. Um primary bone marrow disorders like myelodysplasia or AM L and fibrosis can all mitigate the ability to effectively produce red cells and things like invasive cancer can also invade the bone marrow and prevent the normal function of the marrows production of, of red cells. So, fundamentally, erythropoiesis being stable, depends on an equal amount of production and destruction. And so you have decreased production, you will develop anemia over time. Usually people tolerate anemia better. If it happens over a longer period of time, we can accommodate to lower levels of hemoglobin more effectively and more easily if it happens over a course of months or weeks or months rather than if it happens overnight. If I take someone and I make their hemoglobin go from 13 to 9 overnight or in a, in a few hours, they will become extremely sy symptomatic and short of breath and feel horrible. Whereas if I do that over the course of three months, they might tolerate it very well. So what is anemia, anemia is a persistently decreased hemoglobin. And we use the red cell size assessed by the MC B to help us to distinguish what could be the cause of that anemia. And again, I think it's important to recognize that anemia is important in the context of of time. So if somebody is anemic and you're seeing them for the first time in clinic, um you don't know how long that anemia has been present. It's important to look back in the record and see is this person, somebody who's been anemic their whole life. People with small red blood cells, microcytic disease with a size less than 80 femto liters are more often people who have either iron deficiency usually uh acquired over a long period of time or a genetic abnormality, which results in small red cells. Classically, thalassemias or thalassemia traits can cause uh small size of red cells. People with a normal red cell size between 80 100 femto liters have a really very broad differential diagnosis. This can be happening in the context of bleeding which is incorrectly incompletely corrected with nutritional supplementation. You can have a mixed picture. If somebody has, for example, a gastric bypass, they might have both iron deficiency as well as folate or B 12 deficiency. You can have anemia of chronic disease where people have chronic kidney disease and they just don't produce quite enough epo people can sometimes have hemolysis where they have an acute decrease in their hemoglobin as a result of some directly in direct injury to the red cells or the red cell membrane like glucose, six phosphate deficiency patients. Or they could have a primary bone marrow problem when people have big red cells, uh macrocytic. So, so as we call it uh with a size of red cells, greater than 100 femto liter. This really suggests a red cell production defect and this can be caused again for a broad number of causes. But the things we worry all the time about are things like primary bone marrow problems. Alcohol and liver disease are classic causes of macrocytic red cells. Um but you can also see this as I mentioned before in the context of hemolysis or bleeding where we see an increase in reticulocytes. And in this case, a peripheral blood smear would help you to distinguish if you saw a large number of reticulocytes and you had a high retic count um with a, with a macrocytic picture that would go along with a bleeding situation when you look at these patients and you see them and they initially present with anemia. You ask the question, are the reticulocyte counts high or low if the reticulocyte count is high, um that indicates that the bone marrow is probably functioning reasonably well, right. That says that the production facility is good, but that we're losing our red cells in some way, this can happen from destruction like hemolysis, it can happen as a result of bleeding. Clues for hemolysis would be an increased bilirubin. Bilirubin is a breakdown product of red cells. Um That's metabolized by the liver. You can see L DH which is an enzyme normally present inside of red cells. And when those cells lice in circulation, you see an increase in the enzyme in the blood. And um you can order something called a haptoglobin, which is a, which is a binding protein that binds up free uh hemoglobin. And if the haptoglobin is low or has been consumed as a result of free red cells or free hemoglobin that will help to distinguish and suggest a hemolytic picture. So under the microscope, you can see fragmented red cells in certain disorders. If they don't have evidence of moses, you can look at the possibility of G I blood loss and the microscope. If you see fragments, you would think about microangiopathy or direct damage or sometimes people who have uh Thalia can look like fragments. Um If you don't see microangiopathy, you could think about a um A ad A T or autoimmune hetic anemia or a primary membrane defect. If the patient does not have an increased reg reticulocyte count, then you have to ask yourself, what was previously normal for this patient. Is this new, what's the size of the red cell? If they're macrocytic, you worry about um vitamin deficiency. Um If you exclude vitamin deficiency states, then you worry about primary bone marrow disorders like mylod dysplasia or hypothyroidism. If the previous, if the CV C was previously not normal, then you think about more genetic causes and congenital causes of anemia, things like genetic disorders which can present through the course of the life. So the patient might be having this low hemoglobin. I have a patient in my clinic who presented at age one with anemia and has been chronically transfusion dependent since that time. So these are, these are things to think about. Um obviously, they wouldn't necessarily come in the door as your as your patient. Um But actually, we have picked up patients with um fanconi anemia who presented in, in, in middle age or in, in, in their late twenties. So it's always important to think about this. If you see microcytosis or a small size of, of red cells, then the the chief thing on the differential there is iron deficiency which is extraordinarily common, especially in women. So, in the context of microcytic red cells, the first thing to check is a ferritin, ferritin is reasonably easy to obtain, it turns around really quickly. And additionally, we rec recommend iron studies which will give you the uh transparent saturation, the serum iron and um the um and and the other indices of iron loading. Um If the ferritin itself is very low, historically, we've said low, less than 15. But increasingly we recognize that probably less than 50 is a better cut off for identification of people with mild iron deficiency. Um or even less than 100. In the context of somebody with inflammation, the patient probably has iron deficiency. We could look for G I bleeding, we could look for other malabsorption. Um I have picked up many people who actually have um who actually have malabsorption as a result of occult or sub acute um some acute gluten intolerance, which is like a very common problem. Um I've also seen several patients presenting as a result of autoimmune alo hadria um or because of chronic use of PPIs where they don't produce acid in the stomach. And so they are poorly able to absorb iron if the ferritin is normal or high, um that could be an acquired state. We often see this in the context of anemia of chronic disease. It's important to recognize that abnormal ferritin or higher ferritin. Um with low percent saturation, less than 30% can be a functional iron deficiency state because you actually have difficulty mobilizing iron stores when there is inflammation present. And so this is important to think about and to consider supplementing iron in those patients sometimes and, and sometimes ivy iron is the best way to go. Um The other option is if it's chronic, you would wanna look for um potentially an occult malignancy. So, if you have a normal or macrocytic anemia, again, this is a more complicated problem if the patient, sometimes you would look for splenomegaly. So, if the patient has an increased size of the spleen, that's uh probably an indication to consider referral to hematology. Hypersplenism can happen for a variety of reasons, liver disease, lymphomas, uh systemic lupus or um or uh rheumatoid arthritis. Um if they don't have splenomegaly, the the differential is a little bit more cancer focused. So, myelodysplastic syndrome, multiple myeloma plastic anemia are all in the differential. And so those are conditions where a bone marrow biopsy is indicated. So, again, referral to hematology, if you see. So if um the platelets and the white cell count are normal and that you have a, you have an, a low hemoglobin or hematocrit if the white cell count um and the platelets are increased. Um You worry about things like inflammation. But you can also see this in chronic leukemias, like chronic myelogenous or chronic um or chronic myeloid neoplasms. Um increased platelets can also be present actually in the context of iron deficiency. So you can see shunting from the, from the lineage um into the platelet lineage because you just don't have enough building lucks to make red cells. And then if the white cell count is normal and the plates are normal or low, um ask the question about reticulocytes. And if those reticulocytes are increased, consider uh bleeding events, if you have an Ormoc cytic anemia, you want to rule out treatable causes. So look for nutritional anemia, deficiencies. As I talked about, check the ferritin and homocysteine levels, look for hemolytic anemia. And um we often see anemia in the context of renal insufficiency as you can see here. And again, um if you think there's hemolysis that warrants a referral to hematology, if you don't think that there's evidence of hemolysis, think about anemia of chronic disease or a primary bone marrow disorder. Again, consider calling us. So the, the the next thing we talk about is not anemia, but the opposite of anemia, which we call erythrocytosis or an elevated hematocrit or hemoglobin. Um This is defined in men as a hemoglobin a greater than 18.5. Uh or in women as a hemoglobin greater than 16.5. Uh depending on the context. Um The first thing to consider here is hypoxia, um sleep apnea and COPD and poor oxygen delivery in the context of heavy smoking, uh is actually relatively common and high testosterone, especially in people who are getting testosterone supplementation. All of these can drive erythrocytosis if you do an epo level, if you decide to do one and you see that the epo level is read out as normal, but it's above 10. Uh in the context of a high hemoglobin that is strongly suggestive of a secondary polycythemia. Um primary polycythemia would be suggested by a very low epo level or a suppressed epo level, which means that the kidney is sensing adequacy of uh oxygen delivery and suppressing production of epo but nevertheless, red cells are being produced in excess. Um Things that would also suggest PV would be a high white cell count, presence of splenomegaly. Uh complaints of what we call aquagenic perdu, which is itching when you get out of the shower or the presence of AJ T mutation in the peripheral blood. So the big question here, when you see a high red cell count is, is it polycythemia or is it a secondary cause the primary polycythemia? There are a secondary cause. So again, looking at the serum epo is how we distinguish this as I as I alluded to before. If the epo level is low, think about J two and primary polycythemia vera. Um if the epo levels are normal, uh this can be a little bit of a conundrum. You have to remember that um normal is not normal if the hemoglobin is very high. Um And if the clinical or laboratory clues suggestive of polycythemia vera, then a bone marrow biopsy is warranted. Um If there are no evidence or nothing to suggest a pylos theia vera, then repeat the CBC in three months and ask questions about what drugs the patients on. Um There are actually genetic causes which result in um epo insensitivity and epo independent colony growth and and these people often tend to do very well in endurance sports just naturally. Um but um this is important to be aware of. Um and then poly diagnoses are unlikely in the context of people who have hypoxia driven high epo levels. Um impaired oxygen delivery from heavy smoking people who smoke more than a pack a day or epo overproduction, which can be seen in specific cancers like renal cell cancers. And sometimes cysts can produce this uh renal artery stenosis and other other events. So finally, we can come to the white cell count and the various different types of white cells that we can see in that are elevated in the blood. So, neutrophilia is defined as any white cell count, any neutrophil count greater than 10,000 and things that would be red flags in terms of calling Hema hematology for a consultation would be if you had a CBC reported immature looking forms in the peripheral blood or if you saw a white cell count that was over 20,000 and it was new, right? Very often with CBC S, it's the change in the CBC over time. So if the white cell count previously was normal and all of a sudden it's gone up to 20 there's nothing precipitating, no infection, nothing else that would make me a little concerned. Um Things that can increase the white cell count in people. Sort of as a general rule are heavy smoking as a result of inflammation can drive an elevated white cell count and actually obesity itself. Um um there's some evidence to suggest that um that fat cells can produce G CS F. Um testing is done to rule out neoplasm or to rule out um mutational events that are driving increased heat of Weis. So, for CML, we do uh chronic myeloid leukemia, which is, which is uniformly associated with a mutation in BC rabl and a chromosome 922 or a Philadelphia chromosome. We can fish that on the peripheral blood and we can make that diagnosis very quickly if you see um elevation in the white cell count as well as hemoglobin platelets. Um You would think about a polycythemia or a or AJ two mutant um myro neoplasm. Um We would normally consider a bone marrow in patients who had an abnormal hemogram and an elevated white cell count without another explanation. Um The differential for high neutral count is pretty broad but the common things, obviously, infections, rheumatologic conditions, uh obesity, smoking can double the white cell count. Pregnancy can drive the white count higher and lower and steroids. Uh can cause demargination um of the white cell count. And if you have endogenous steroid producing tumor like Cushing syndrome, you can see a high white cell count from that. Obviously, you don't wanna miss acute myelogenous leukemia, your um CBC or the place that reads, it should be able to look under the microscope. And if they see blasts, they should call you. And if you see blasts in the peripheral blood, that is never normal and that should always be referred urgently. Um When you get that call, you get the result, you call us right away. One of us is available all the time. Somebody is available, don't stop calling until you get a person on the phone and you get the patient in to be seen. CML often happens over some period of time. So the patient might be have a sort of slowly increasing white cell count and you might notice that there's an increase in basophils. Remember I told you those special forces type cells um or eosinophils in the peripheral blood, um You also can sometimes see splet amely and patients can complain of non-specific symptoms like bone pain and sort of generally feeling unwell and sometimes these people can present with CML. And then there is a rare entity called chronic neutrophilic leukemia uh which is associated with specific mutational events. Um And um these patients probably need to be seen by hematology. So the other thing we sometimes see is neutropenia where the white cell count is low. Um Many people have actually what we call benign neutropenia where the A NC is less than 500 but they don't have any infections and their counts go up in the context of them getting infections. Sometimes these are due to autoimmune causes where you get anti neutrophil antibodies that essentially lower the circulating white cell count or the neutrophil count. But don't impact the function of the bone marrow and don't impact the ability to produce infection, fighting neutrophils in the context of infectious process. We can also see autoimmune uh destruction of neutrophils by large granular lymphocytes. And here on the right, you can see a picture of an LGL cell in the peripheral blood. These are frequently seen in association with autoimmune diseases like Felty syndrome and then relatively rare. But, but something important to be aware of, there is an abnormality called a hairy cell leukemia, which is a chronic um B cell neoplasm usually involving the spleen uh which can cause low blood counts. Um and which is a which is, which is very, very treatable but can sometimes be just observed. So these are all things that you should be aware of. If you see a patient with neutropenia, very reasonable to refer them for evaluation. Um And we can always do a bone marrow if we find nothing. Um We can simply watch that patient and I have patients in my clinic that I follow who are chronically neutropenic and I see them once a year in the absence of infections, we just leave these people alone. There are rare genetic causes of neutropenia where the, the there's a genomic germline event which causes decreased production of neutrophils. Um Some of these patients actually do reasonably well and don't have a lot of infections, others respond to G CS F. Um But that's a very unique subset of patients. So generally rules of thumb. If the neutropenia is sudden and the patient is sick, call us, call us right away, we'll admit the patient don't stop till you get us. Just like if you see a blast. Ok. Um, neutropenic can happen in the context of medications. So if there are new medications avail and the patients started on it and they suddenly are neutropenic, stop the new medication and consider starting a preventive antibiotic like Levaquin. But please don't give G CS F until we've had the chance to see the patient. Um, and really important to call us. Um If you see blasts as I as you can see in this picture on the right side of the screen that's abnormal and, and again, that patient should be referred to hematology. So what about if the platelet count is high, high platelet count and low platelet count are probably the most common cause. Uh The most common reason for referral to hematology. Um the most common cause of thrombocytosis or an elevated platelet count is actually reactive. So, by far and away, the most common cause is that somebody has an infection, they have an inflation inflammation, they got scared, they, they got injured. Um These are all causes iron deficiency can cause an elevated platelet count. As I mentioned before. Um you can look at the CBC, if you a specter that it's a reactive process, just monitor the CBC, check it again and if you see it go down, you can feel comfortable. It's probably something that was a trigger. If you don't think it's reactive, you can always check the ferritin and the CRP or the sed rate and look at a peripheral blood smear. Um if it looks like the patient has sort of doly bodies in the peripheral blood and the neutrophils that look like an inflammatory reaction or something in the context of infection, it's probably that if you don't think that it is uh reactive where there's no real clear explanation, then refer the patient to hematology, right? Those are people who might have AJ two B 617 F mutant myeloproliferative neoplasm, they might have chronic myelogenous leukemia and um if you're concerned and the thrombosis doesn't resolve, then send the patient to us. Um eosinophilia again, relatively common, seen in a lot of conditions, rheumatologic conditions, neoplasm, neoplasm allergy and asthma patients who have chronic asthma who have chronic eosinophilia. It's very common. Addison's disease. Parasitic disease is classically, although in our society, we are largely exempt from that problem. Um hyperopia is very rare. Um but it's interesting and it's very treatable um because it's responsive to thin kinase inhibitors which are given by mouth. So we like to keep an eye on this. Um clinically, these patients can present with a very high Sinop count greater than 1.5 or 2000 and they sometimes can be very sick um with cardio cardiac uh complications, skin involvement, clots, lung disease and neuropathy. So, these are patients important to identify um elevated monocyte count can also go up with any inflammation if the monocyte elevation is persistent, greater than 1000 or greater than 1500 for a long period of time. And or if you see abnormal looking monocytes, those patients should be referred. Um The most common cause of this in the chronic situation is chronic. My myelomonocytic leukemia CMML is an M DS spectrum disorder and this is a particularly of concern if the other white cell count um if the other counts are low. So if the neutrophil count is low or if the platelets are low or if the hemoglobin is low. So, lymphocytosis is also relatively common. Um You should be worried or think about it. If the, if the patient has a persistently elevated lymphocyte count, greater than 5000, up to 4 to 5% of the population will have clonal lymphocytes in the peripheral blood. Uh This is now termed monoclonal B cell lymphocytosis. And um these are cells that are designed to expand in response to infection in order to protect us, but sometimes they can acquire a mistake that results in that particular population of B cells persisting and expanding excessively. Um CLL is the most common cause. If you see something called smudge cells in the peripheral bladder, you look under the microscope and the the the bone marrow or the lab reports that there are these things called smudge cells. Those are mature B cells that have um that have kind of been smashed under the uh under the process of making the smear. Um And that's very, very common in CLL. Um The other thing that can happen is if somebody has had a spleen removed for an accident or for some other reason, um you can see an increase in lymphocyte count which is normal and uh it can be a reactive process. So I have a patient I saw in clinic the other day who is in remission from his blood cancer and is doing very, very well. But all of a sudden his white count was 14,000 and he had an elevated lymphocyte count and because he's post chemotherapy and treatment, we always worry. Um but he had had a viral in the last two weeks before. And so that was, we did a flowy tome here. That was entirely that um and it's now come back to normal. So, um the differential for development of low platelet count is actually extremely broad. Um And the most important aspect for thrombocytopenia is actually how quickly did this thrombocytopenia occur if the patient had a normal white cell count, a normal platelet count two weeks ago. And now their platelets are five. That's important. A production defect in platelets is relatively rare as a cause of isolated thrombocytopenia. You usually see it in the context of either a high or a low white cell count and also anemia. Um hypersplenism or sequestration in which uh platelets are removed from circulation by the spleen can happen in the context of liver disease. And um perhaps the most common cause of low platelet counts is actually an immune thrombocytopenia in which usually a viral illness precipitates the development of an antibody which binds erroneously to the platelets and takes them out of circulation. These people usually have a normal bone marrow, but in the context of this immune activation, their platelets are killed early and so the platelet volume is usually high because just like reticulocytes are bigger. Um young platelets are bigger too. Um Another event is non immune destruction by say, for example, TT P thrombotic thrombocytopenic pur, this is a much more important and more serious problem can be seen in the context of um people who have acute kidney injury or mental status changes. And that's an, that's not actually an emergency, a hematologic emergency. So, acute thrombocytopenia, if the patient shows up with a very low platelet count, the differential is based on how low is the platelet count. So the lower it is um it's more likely to be ITP or drug induced. Uh very low platelet counts. These are, these are usually more benign causes. Although things like a PL or acute primacy leukemia can show up with very low platelet counts as well. This is a cancer, a very unique cancer which is very, very curable but can kill you as a result of bleeding in the first period, right around the diagnosis. Platelets between 10 and 50,000 can be from disseminated intravascular coagulation, which can happen in the context of acute illness. Uh TT P thrombotic thrombocytopenic pur which is um mediated by lack of an enzyme called Adam ts 13. Um more often presents in the spring often in African American women or in people who have autoimmune history, um can be very life-threatening can be associated with increased creatinine or abnormalities. Itp can happen with the platelet count here. And um um heparin thrombocytopenia can cause platelets counts in this range platelets between 50 100,000. Much less likely to be um a clear clinical problem uh or clearly an an emergency seen in the context of liver disease, seen with ITP, seen with TT P and H and myos plasia. It really also depends on the clinical context. How sick is the patient that you're seeing? And are they bleeding? So if the patient is sick or they are bleeding, that patient with thrombocytopenia should be urgently evaluated and worked up if the platelet count is less than 20 you don't have a good explanation and you don't feel comfortable that this is like most likely an ITP, then it's very strongly, it's very reasonable to consider admitting that patient until you figure out what's going on. Um It is also important to ask about recent heparin exposure. Um One should look at the peripheral blood smear in these patients and look to see are there giants playlets that would make you feel more comfortable that it was an itpitp is usually benign and usually respond to steroids. So for example, I had a patient who was referred to me by a primary care doctor who had received a vaccination against, I think it was RSV. And um three or four weeks later, he presented for a routine CBC and he was noted to have a platelet count of 10. He was pretty asymptomatic. He had a little bit of bruising, but he felt fine and um he had been reluctant to get the vaccine. And then after that he never wanted to get another vaccine again. Um But we looked at him in the, we had him come into the clinic, we looked at his peripheral blood smear. He did have giant platelets. And in that case, we started him on steroids without admitting him to the hospital because he absolutely refused to come in and his platelets responded very nicely. In that case, if you decide not to admit that patient, you should do it in the context of uh referral to hematology. And sometimes you start the steroids and the platelets can come up within a few days. Um If you see in the peripheral blood abnormal cells on the right, you can see a picture of a patient who has acute promyelocytic leukemia. Um These are blasts with many hour rods in the cytoplasm. Um That's those long skinny um lines in the cytoplasm that you can see here. And you can see these cells have an extremely large n nucleus. Um They have dense granular Granules in the cytoplasm and they have a nucleolus and the nucleus and the nucleoli are large. Um Those look like blasts, that patient should be referred urgently for admission. If you were to see schistocytes or broken red cells or red cells that look like there are pieces cut out of them that's concerning for something called TT P or acute um or um atypical hemolytic uremic syndrome. If the patient is pregnant, you'd be worried about help syndrome. Um That's also a matter of urgency that patient needs to be treated uh right away. Um If the platelets are low, but the patient is pretty asymptomatic. A splenic ultrasound might help you. You could see if the liver uh and abdominal ultrasound. You can see if there's a normal liver texture and if the spleen is enlarged. In that case, you might think about a liver liver abnormalities. Um You should also ask about whether the patient has a rheumatologic history. Acute drops in platelets can be seen in the context of um diseases associated with rheumatologic conditions and clotting. Um and those are very important to identify. So when do you need to do a bone marrow biopsy? For sure if you see circulating ab abnormal immature cells, if you have a new or progressive petopia that's happening in front of your eyes, if you see a very lower T count. So that suggests that there's a primary bone marrow problem, nucleated red cells plus or minus. I have a patient I saw recently who tells me that all of his life, he's had mild anemia. His sister has mild anemia. His father had mild anemia. He had his, his father has spleen out for unclear reasons when he was a young man. The patient tells me he had this abnormality with increased reticulocyte count and he doesn't know why. Um In fact, the man that gentleman had a spherocytosis, which is a genetic abnormality in which the red cell membrane is abnormal. And so the red cells get removed from circulation early uh by the spleen. And so, splenectomy is actually the, the historical treatment. But these days, we just make sure that they're on supplements for vitamins. Um for people who have specific types of malignancy, a bone marrow is indicated to do staging. So, lymphomas generally require a bone marrow as part of the staging work up for M DS and AM L. We also require bone marrow. And if you have an unexplained anemia, especially a microcytic anemia, a macrocytic anemia or unexplained or progressive or new cytopenia or cytosis of any lineage in concert with significant symptoms. So I think the most important thing that I can say to you is for patients when they have an abnormal CBC, you should not hesitate to call us. It really costs nothing if you're concerned to give us a call and we're more than happy to review those CBC S in concert with you. Um Specific red flags as I've identified here um are important to keep in mind. But in general, if the cell counts are substantially different from the way they were on previous checks, that's worth calling and discussing. Thank you for your time. And I'm happy to take any questions. Hello. My name is Jen Silga and I'm the chief of myeloma at Russell Park Comprehensive Cancer Center in Buffalo. I would like to talk about blasphemous cell discretions today when to suspect them and how we can detect them as you know, multiple myeloma is a malignant disease. Obviously, Rossville Park, we are treating cancer. So it's a malignant disease of plasma cells. The median age diagnosis is around 69 years. So that's kind of the age group where you should suspect patients to develop the disease. It's more common in male than in female, but not that much. So it should not really influence the decision if, if we look for multiple myeloma or not. And um we have patients who are much younger and we have patients who are much older. So the age alone should not really keep us from looking for multiple myeloma. If we have a suspicion, it's a proliferation of plasma cells. As I mentioned cells of the immune system in the bone marrow, but the symptoms and I will get to the symptoms in more detail are not really oftentimes reflected by the bone marrow infiltration only but show other things that I will come later in my talk, it's an incurable disease. Currently, we think we will be able to cure it at one point. But at this time, it's considered to be incurable. At least in the majority of patients in older patients, we can treat them very well and sometimes they live and pass away from another disease or from another reason. But in general, multiple myeloma is considered incurable. At this point, the overall survival rates are around five years. It's 55 to 75%. It's getting better every year because we have a lot of new treatment options. So please um think of it because when I went to med school, we had two drugs. Now we have about, I think 17 treatment options that are available. So multiple myeloma is not curable but very well treatable. And I think that's very important to keep in mind, the incidence is about 70 100,000 per year. So not very common but also not super rare. And that kind of ends up being 35,000 patients. Uh, new cases in the US per year. What I think is very important is the distribution amongst races. It's double the frequency in African Americans and our clinic does reflect it to a certain degree but not as it should based on the numbers. So I think, uh, often times it's under reported or under um diagnosed in, in African Americans. So it's about double the frequency in African Americans compared to Caucasians to whites. Um, and it's less frequent in Asians. Again, this should not keep us from looking. Uh, if the disease is there, if we have um, strong suspect, suspecting it strongly. But, um, we should be aware that African Americans definitely have a higher risk. The um, improvements over the course of years is depending on the younger patients versus older patients. And if you look here, it becomes more common with age as you can see. And then in the older age, of course, other diseases are more common and patients are not that frequently diagnosed anymore. But you can see here the um the, the increase of, of the frequency in patients is the highest in African Americans as well. The multiple myeloma has been shown to be preceded by a precursor disease. Um, most patients are not diagnosed with that but if they present without symptoms and we look for other reasons. Oftentimes there's a diagnosis or diagnosis of the so called monoclonal demy of undetermined significance or MGUS where there is this monoclonal protein that is produced by these plasma cells. Um but they don't have any symptoms yet or at least not symptoms that are really related to these plasma cells. There are very rare occasions where symptoms can be related to the MGUS. Then we call it monoclonal gammopathy of clinical significance. The symptoms can be neuropathy, tingling, numbness in the fingers or toes or can be renal insufficiency where these proteins that are produced by chance, basically damaged tissues in the body. So MGUS is still relevant. It's actually fairly common. The incidence of MGUS is about 10% in the elderly population. Um So it's not uncommon to find an MGUS. But then the job would be to figure out if this is only MGUS, which is, has a risk of progression of about 1% per year versus is it already multiple myeloma. And then there's this gray zone in between smoldering, multiple myeloma where the patients also don't have symptoms. But they already fulfill a few criteria. Like for example, the plasma cell percentage in the bone marrow when we do bone marrow biopsy. And that because called smoldering myeloma, we are still going back and forth if we should treat those patients, not treat those patients. There are, there's a lot of discussion in the community going on. At this point, we are mostly not treating smoldering myeloma patients because their risk of progression is about 10% per year. So about 90% don't progress per year. So we don't over, don't want to overtreat, but as soon as they show signs of progression, then we consider them to be multiple myeloma, then we would treat the patients. So what we try to figure out is what is really an early, multiple myeloma and what is a kind of a late angus. Um So we want to get rid of this moldering myeloma stage, but we still have it right now because we cannot really with the current technology, we have, we cannot really differentiate it completely. The pathophysiology which is reflected in the symptoms of the disease is as I mentioned, the infiltration of the plasma cells in the bone marrow where they actually usually recite, but they proliferate and kind of replace the normal hematopoiesis. So the patients can have cytopenias can have anemia, low white count low platelets. The anemia is kind of what we look for most. Um but there are other symptoms like bone destruction, which is in our experience. The most common reason why patients come to us usually back pain if there's an osteolytic lesion, where the reason for these osteolytic lesions is that these myeloma cells are over activating osteoclasts or bone eating cells in the bones. The bone eating cells themselves are not really sick, but they are over activated by the myeloma cells, which then leads to bone destruction in the sense of punched out focal lesions, which then can lead to fractures in some patients. It can also cause something like an osteoporosis. It's not the real osteoporosis. But those patients kind of have very tiny osteolytic lesions which then can cause fractures as well. And that's oftentimes the reason why patients present to our clinic hypercalcemia is related to the same mechanism. These osteoclasts get calcium out of the bone and into the bloodstream and then patients can be very tired, can be confused. Um but oftentimes that's a very late stage. And oftentimes patients have other symptoms before that. And then the fourth symptom is renal insufficiency, the monoclonal proteins that are produced by these plasma cells um can clot kind of the kidneys which then leads to renal insufficiency, which can also be a first presentation for patients with multiple myeloma. Here's a retrospective analysis where um it was kind of looked at which races develop which symptoms first. And as you can see here in African Americans, anemia seems to be the most common symptom at diagnosis. But this is not, again, should not really change our approach. But I think it's an interesting finding that different races seem to have a different presentation at first diagnosis, which is again, something to keep in mind. The, um, estimated new cases, as I mentioned is about 35,000 per year and the death rate is about 2.1% of all cancer deaths and about 12,000 of these patients. So as I mentioned, the five year relative, survivor was 20 until 2019 was about 60%. Now, I think it's a bit better because we have new treatment options even since 2019. So as you can see, patients can live a very long life with multiple myeloma if they are treated early and adequately. The diagnostic. Of course, first, we do medical history. We see if the patient has any systemic issues if they have. Mostly as I said, most first presentation is pain, frequent infections can be related to these low counts. So that's something that we should think about, especially nowadays that we have winter, a lot of people have infections. So not everyone might have myeloma. But if patients have more frequent infections, for example, more than three episodes per year, that would be something they would at least look deeper into potentially hematological disease. These symptoms are not very common in myeloma, but they can happen, neuropathy, as I mentioned, can be related to the monoclonal protein. And as you know, neuropathy is fairly common because diabetic patients can have neuropathy. So sometimes it's just important to figure out if this is related to another disease or if it's really related to the monoclonal goopy or to the multiple myeloma physical examination, we focus on infections. As I mentioned, pain, localization of pain. Again, most common is the spine, but they can also have fractures of the extremities. So, but that's something to definitely keep in mind blood work. Definitely a CBC to see if there are any changes in the blood counts. As I mentioned with the replacement of the bone marrow serum protein in serum protein electrophoresis are important because that shows us this monoclonal protein which is a very specific type of symptom in multiple myeloma than for the kidney function. Obviously, creatinine and then sodium calcium potassium because that can be off especially the calcium related to multiple myeloma. More specific tests are the immunization which differentiates between the monoclonal protein and another, for example, inflammation related high protein in the blood. The immunization would give us the answer if this is a monoclonal protein and then serum free light chain is a specific type of the monoclonal protein. And that's something that can be ordered in the labs, which then also is very specific for multiple myeloma 24 hour urine is something we do. Um It's definitely good to do because we see the protein excretion over the course of the day can change. And the total protein urea is relevant in myeloma, but specifically the urine protein electrophoresis, where we again see this monoclonal protein which can be excreted through the urine. And the immunization again would be the technique to figure out is this really a monoclonal protein or is it another kind of protein that is excreted? Imaging? We try to avoid X ray because it's not very sensitive. There have been old studies comparing X rays with CT and it's about CT is 25% more sensitive for a first screen. I think it's OK. But I would in our clinic, we don't do X rays conventional X ray anymore. We already switched to CT or pet CT an MRI, especially in the, if there are spinal fractures and if there's pain or maybe even neurological issues, then definitely MRI would be the technology to use switching gears a little bit related to multiple myeloma but much even less common is a l amyloidosis or amyloid light chain amyloidosis, which is related to myeloma in a sense that the monoclonal protein in that is produced by this malignant or sometimes even by the benign cells that are not malignant. Yet, if they produce the monoclonal protein in this protein is misfolded on a molecular level. So the body basically doesn't know what to do with it and cannot excrete it and just puts it somewhere and this somewhere can be basically all tissues of the body. The most relevant ones are the heart, cardiac amyloidosis is a very severe disease. It can be the nerves. So patients can have neuropathy. The problem with amyloidosis, it can cause almost all symptoms and all symptoms can be amyloidosis related. But again, amyloidosis is rare. So we would offer that we work up these patients if there are any concerns with neuropathy with cardio cardiac issues. And we have a very good collaboration with oral cardiologists. If they have a suspicion that there is amyloidosis in the heart, then they send us the patient and we do the work up because there are also other types of amyloidosis, which we don't treat. But we also diagnose which is also a misfolded protein, but it comes from a different source. In this case with the al amyloidosis. The source is these plasma cells that are also causing multiple myeloma or MS. And this is what I was mentioning. There's another type called a tr amyloidosis which can be hereditary. It can also be a wild type and there the protein doesn't come from the plasma cells, but it comes from the liver and is produced there. And again, the misfolding happens and the body doesn't know what to do with it. Those proteins aggregate and are deposited in certain areas of the body. We do work up for that we collaborate with our cardiologists, with our nephrologists neurologists to figure out which kind of amyloidosis is there. If there's really a concern about this and symptoms, as I mentioned, Emily doses can almost cause everything. Things that kind of trigger. In my my mind is heart failure should at least have an echocardiography where you can see the thickening of the heart with this accumulation of the protein there. Um neuropathy is a reason to think of amyloidosis patients who have, who kind of get dizzy when they, when they get up, they have a risk for am amyloidosis can cause that because the amy amyloid can be in the blood vessels, orthostasis was the word I was looking for and in the blood vessels. So when they, when they get up, the blood vessels cannot contract fast enough and then they become dizzy and sometimes they even pass out. So those are symptoms. Macroglossia is a very specific symptom for, for amyloidosis. Um It's very rare, but if it happens, that's something that should also trigger a work up for amyloidosis. And with this, I thank you for your attention and I'm looking forward to collaborations. Hello, everyone and good evening. Welcome to our hematology review series for primary care providers. I'd like to introduce Doctor Jen Singas, Doctor Francisco Hernandez, Eliza La Tori and Doctor Elizabeth Griffiths here with me today. Um If you have any questions, please feel free to type them in the chat and we'd be happy to answer them. Um With that, I will dive in with our first question of the evening. Uh My first question from the audience is for Doctor Hernandez. Uh You had mentioned that there are some large uh lymph nodes that would typically uh raise um suspicion and for lymphoma as an example, and they warrant a heic consultation. Uh I was wondering if you could speak to other red flag symptoms or findings that would prompt primary care providers to refer patients for lymphoma work up and it was an excellent talk and thank you. Uh Thanks again, thanks for uh attending the lecture. I'm glad that you find the content uh of use. Um I think that uh when we look at what red flags, you know, primary care doctors may use to call, you know, us in case that you guys need some uh consultation. I think the the size of the lymph node enlargement and the duration of the enlargement of the lymph node is important. Um in general, sometimes patients may have small enlarged lymph nodes in the neck that could be related to throat infections. Those ones may go away within two weeks and they don't need a further work up. But if uh a lymph node has been enlarged for more than two weeks, especially despite antibiotics, that's something that is warrant further evaluation. There are some locations that we should think quickly about cancer, primarily lymph nodes in the super cappi area. Um in addition to that patients who they have constitutional uh, symptoms that we cannot explain like night sweats, primarily drenching night sweats or fever, weight loss that cannot be accounted for unexplained bruising, you know, recurring infections. Those are things that, that maybe are trying to tell you that the patient's immune system maybe is having some problems and they need some uh further work up some of the symptoms that patients with lymphoma have. You know, they are related to the locations of where the lymphoma is. So we have to put some attention to G I symptoms or respiratory symptoms. Uh But again, I think certainly the clinical suspicion is important. And uh and again, it's important to kind of maintain an open dialogue, communication between the primary care doctors and the consultants. So patients can move through the system quickly and effectively. Thank you very much. Any other thoughts on lymph endopath and other things that would raise suspicion for a cancer for lymphoma? Yes. Well, again, other thing will be blood test, but those are kind of more results of if you see a patient that is taken and you order some blood testing, a normal blood counts, increase count, uh low platelets, low hemoglobin. Um those are concerning uh an enlarged spleen, you know, sometimes could be the first indicator of rare type of uh lymphomas like for example, her leukemia. Uh but again, certainly those are, you know, things that we're looking for. Um another area that is important are skin rashes. You know, there are some lymphomas of the skin that present very similarly to psoriasis or eczema. I think what is very interesting about these type of situations is that normally patients with the skin lymphomas at the beginning, they may look like psoriasis, but usually the lesions are in areas that are covered by the sun instead of areas that are exposed to the sun. So you have a patient that has a, that has been there for a while. That is not in an area that is exposed to the sun. That should certainly raise a flag to maybe refer the patient for dermatological evaluation and get a skin biopsy. So that's incredibly valuable. Thank you, Doctor Hernandez. Um The second question we have from our audience is where does CLL and SLL fit in? And I would say this, this goes between Dr Griffiths, Doctor Hernandez and of course, myself to introduce myself, my name is Matt Ortiz. I'm a chronic lymphocytic leukemia doctor. That's what we mean by CLL and a small lymphocytic lymphoma or SLL um Doctor Hernandez. You wanna take that first, my friend? But again, so I'm happy I appreciate you are very well qualified to talk about it. So, uh and of course, you know, maybe we're gonna grassle down Doctor Griffin a little bit about this. Uh But I think so coronial focal leukemia is really falls into the family of lymphoid malignancies. And, you know, um if we go by textbooks, it falls into the category of uh non hodgkin's lymphomas. I think uh some patients that depends on where you practice and depends of the um the healthcare network. Some patients with currently facility leukemia are evaluated and treated by Leukemia doctors. Uh some patients are evaluated and treated by lymphoma doctors like in our group. Uh But again, a lot of patients with CLL, they are managed perfectly well in the community. Uh So general oncologists or general hematologists, you know, can evaluate and treat these patients as well, especially early in the course of the disease. So, but I think for practical purposes and academically speaking, they are considered like lymphoid malignancies just like multiple myeloma. It's a very politically savvy question. I like it. Doctor Griffiths. Any comments on on CLLSOL, does it belong in Leukemia lymphoma or both for you? So it's a mature B cell malignancy, right? And it's an expansion of clonal cells that one can see in the peripheral blood. And many times people present with an isolated increase in the lymphocyte count and those people are pretty thick on the ground, right? And so um in many cases, there's nothing to be done. I believe you correct me if I'm wrong. Um But in in those cases, when you look under the microscope, you can see characteristic features, um those cells tend to be bigger than average and they tend to be crushed, um, under the microscope when you make a, when you make a, a peri, a peripheral blood smear. And so the pathologist or the lab may call and tell you that there are a lot of smudge cells on the smear. And, um, when you see that, that's sort of a cardinal feature of people who have AC LL, uh, process and, and for many people, there's really nothing at all to do. I would agree. Although I would say anyone with CLSL should see an, an expert, especially if you're being told things that don't make sense. Um And certainly there are criteria for treatment. So any symptomatic lymphoma or leukemia or disease in general, frankly, if there are symptoms, we should be treating and, and evaluating, I will say that CLL and SLL tend to have an excellent prognosis overall. Um We can often work together with primary care physicians. It's like for lab uh count monitoring things like that. Uh red flags with patients with CLL, you can get more benign hematologic conditions. So things like um ITP you can get uh autoimmune hetic anemias, you can get um your red cell plasia. So if you see worsening anemia in these patients, we always do comprehensive anemia panels as doctor great, ultimately explained in her talk. Um but I would also say even a simple reticular site count if it's zero, I would also look for something like Parvovirus B 19 for example. So this, these folks can be very immunosuppressed as well. Um So I would say it belongs in both uh lymphoma and leukemia is confusing. It's in our wo fifth edition guidelines um published in May of last year. Um And it is under our lymphoid malignancies uh group. So it's closer to my heart there. I would say as a as a biased perspective and one more thing, I mean, those patients, as you mentioned, have a tendency to be relatively immunocompromised in terms of their ability to respond to viral illness, not just par virus but vaccination against pandemic COVID-19, uh RSV, et cetera. And those people are at higher risk for complicated illness from those, from those viral illnesses. And so identifying them and offering them appropriate prophylaxis and um considering them immunocompromised and, and finding them. And even if the approach is just monitoring every six months, having them done, having them, followed by somebody who's familiar with the disease, uh really can help to uh negotiate those periods when they might have unusual phenomenon related to their low grade process, which may not require chemotherapy or oncologic treatment but may require different and nuanced supportive care, agree 100%. And to be back on that Griffiths, I appreciate you saying that number one, thank you for leading our COVID vaccination efforts. Um So, Doctor Griffiths was one of the first to identify in our group at Russell Park. Um The unique sensitivity of our patients uh with heic malignancies, particularly CLL and SLL uh to COVID and their failure to respond to vaccinations. And a large percentage of patients, especially those who are on active treatment or who have uncontrolled and highly advanced disease. And uh thank you for that. Well, I can't take that was a project that I did. I ended up in concert with Doctor Hernandez. So we really, it was a group effort with, with all of you. So well, we were together. So thank you all. And um one thing I think it important especially for uh primary care doctor. I think we have CLL they have very exquisite predisposition to develop other type of cancers during that 10 year with the leukemia. That is a reflection of the po immune system. And they have a higher risk to develop lung cancer or skin cancer like melanoma or s common cell carcinoma. So those patients, they, we need to be very careful about smoking, sensation, skin examination with dermatology and really kind of be on the top of all the preventive measurements that we normally do for other healthy patients, you know, because they do benefit from the early detection and treatment of other cancers. So that's a great point. Excellent point. Um The last thing I want to say with this, if I may and before we move on to the next question is um with respect to frequent infections in your patients, one thing to check for, for me would be a quantitative immunoglobulin panel um and consider things like a serum protein electrophoresis as well. Um So an acquired hypo game globm can also be a tell of CLL and other um he like malignancies including plasma cell neoplasms and other uh lymphoid leukemia, for example, including CLL. So something that to throw in the panel, if you see frequent upper respiratory tract infections or infections uh for a primary care doc, it's a good IgD level. Um Doctor Griffiths, I believe this next question is for you. Um for patients with M DS and thrombocytopenia, if the bone marrow biopsy shows normal megakaryocyte. And uh is it correct to say if the hematologist says that the low platelets cannot be due to M DS if the normal uh mega carys are seen on a bone marrow biopsy and that there must be some other cause like ITP. Is that true or no, in your opinion? Oh, that's a complicated question. Um I guess first things first, uh it's my practice never to bet against the cancer. So it is my general feeling that if the cancer is possibly causing something, then it's certainly possible that it could be the cause. Um And so if somebody has a a really a true diagnosis of myelodysplastic syndrome, um the bone marrow findings can be somewhat challenging and the the assessment of dysplasia or funny looking findings within the mega Cary lineage can be so much somewhat nuanced and can be difficult to assess. And so I would first ask the question, what type of M DS, what's the molecular features of the disease? And was the quality of the bone marrow assessment adequate to really entirely exclude mega car acidic dysplasia? And because almost never, is it the case that the bone marrow meter sites are totally normal in someone with M DS? And so, um thrombocytopenia is a cardinal feature of patients with myelodysplasia. And so we do see that as a common uh finding in people who have an M DS diagnosis. Um there can also be ITPs and other thrombocytopenia, other thrombocytopenia causes in people with M DS. Um Doctor Hernandez and I actually have shared several patients like this who, who come to see me who have a bone marrow that demonstrates a myelodysplastic process, which is of low grade and they have throm cytopenia and we follow him over time and eventually they get diagnosed with something else. Like we had a patient who had a lymphoma diagnosis in the spleen. Um and when we treated the lymphoma, the the platelets came up. But unfortunately, after the treatment for lymphoma, he actually developed a leukemia from his my plate. So, you know, there are a lot of things going on here. These are complicated patients. Um I think um that's why it's important to refer patients with mildest plastic syndrome to a specialized center um in the United States. And actually uh worldwide, we have M DS Centers of Excellence. And Rossell Park is, is lucky to be designated by the M Ds Foundation as an M Ds Center of Excellence. And really what that means is that we see enough patients. Um and that we have a comprehensive clinical pathologic correlations being done where we have a close interplay between our molecular pathologist, our Hema pathologist and our clinicians, uh all of whom getting to get able to get together to render an accurate diagnosis and um to offer patients really sort of the cutting edge of what's known about the diagnosis. Excellent. Thank you so much. And I will say a large degree of that center of excellence is due to you as our, as our M DS specialist. I think all of my colleagues are excellent M DS doctors. II, I like to, I like that's my area of particular enthusiasm. So um thank you very much. Uh The next question. Um So what should be the sequence of test performed in private practice? This for doctor Hilling? I should have mentioned um What should be the sequence of test performed in private practice if there's a concern for multiple myeloma or amyloidosis? Yeah, that's an excellent question. And that's oftentimes the, the question that people actually ask me when, when I'm in touch. And I think the most important thing is when, when you have usually there is already a CBC C MP available which points in this direction, total protein can already be a sign. If total protein is elevated, it's not PAG noon, but it can still be a sign of myeloma. Then the next step would be, as you mentioned earlier. Also, the immunoglobulins are, they are usually easy to interpret. And if there is, if they are really off, that is signed to go any to go further. And then the next step, I think would be the serum electrophoresis because that's also easy to assess. And then if there's an M spike, I think, then the referral should be made just because myeloma is very well treatable. And um we should treat it early enough so that the patients don't have these ominous scrap criteria that they don't have bone fractures if we can avoid it, that they don't go into anemia or even renal failure or hypercalcemia. So I think it's important to refer to the referral early but to, as the question was kind of referring to um do the the first few steps and then that helps us to already know. OK. Is it, is it urgent to see the patient? We have to see the patient tomorrow because they have a kidney failure or is it OK to see the patient maybe in a week or two in the worst case, if we, if you don't have availability, which we usually try to have. Um I think those would be the first steps, oftentimes patients also present with back pain, which makes it very challenging because a lot of us, a lot of people have back pain and not many people have myeloma. So that's a bit more challenging. And what I do recommend if the back pain is getting worse over time and not otherwise explained, an X ray is already a good start. We do much more sophisticated imaging in myeloma nowadays. But a simple X ray can show if there is a fracture that we would not expect based on age or based on comorbidities uh from, from that. And I think imaging, the first X ray just have a lower threshold to do that as well. Can I just comment? I mean, I think in when I was a fellow many, many years ago now, um you know, one of the things we we would see in our primary care care of patients would be unexplained fractures. So anybody who has a fracture and you don't know why or they had a fracture out of the context if they just bumped themselves and they got a fracture, I think those are really red flags for malignancy in general, not just hematologic malignancy. And actually, you know, you and I are sharing a patient recently where we have a patient who was seen by an excellent hematologist in our community who had a bone marrow biopsy. And then the question was whether there was a concomitant myelodysplastic syndrome and a myeloma. And so these can be complicated patients, complicated cases and, and the results, especially now with all these complicated molecular and cytogenetic results that we get back um can be really confusing, especially if you're not doing this all day, every day. And so I think, you know, working in concert with our community colleagues um both in the primary care setting as well as people who are working in community practice. Um really is a, is a critical aspect of what we do so much. Doctor Dennis, anything to add on? Um ok. Um Let's see. Um So this question is for Doctor Griffiths, um is splenomegaly alone enough to warrant a hematology consultation. Uh And then there's an example here. So for instance, what about incidentally found splenomegaly on CT scans in a patient with an acute process such as cholecystitis? And I'll open this question up to everyone to comment on if I may. Um or say for example, if there's patients with another explanation for splenomegaly, things like uh systemic lupus, uh eryth mitosis or patients who are wise established with the rheumatologic condition. Uh Thank you so much. Uh very valuable talk for primary care providers. Oh, well, I'm glad I, yeah, I, I think isolated splenomegaly uh depends a lot on the context. Uh if it's truly an isolated event and there's no other explanation for what's going on. Um If the patient has a completely normal hemogram, I would probably just follow it and repeat as an imaging procedure. I think ultrasound would be probably an adequate imaging procedure because you could spare the person radiation um in, you know, a month or so to follow it up. There are many causes of splenomegaly that are transient, things like viral infection. CMV, Epstein Barr virus, all these things can cause splenomegaly and those should be transient and should get better. And if they do uh then probably it's not something to be worried about. But if you see a patient who has substantial splenomegaly, um in association with either an elevated hemoglobin or in association with um anemia or other abnormalities of the hemogram. I think that's something that would warrant um referral, especially if that patient is clinically ill. Many times, people with say myeloproliferative neoplasm will have um bone pain or fatigue or other symptoms associated with cytopenias. People with polycythemia vera would have splenomegaly in association with potentially an increased risk for blood clots um or unusual thrombotic events in the, in the splenic circulation or in the, in the cerebral cerebral veins. Um Those are people who should be evaluated. Certainly, rheumatologic conditions can cause splenomegaly. And so if you have somebody who has lupus or rheumatoid, and they don't have an abnormal hemogram and they have splenomegaly and it's mild and it's stable, probably no need to refer specifically to hematology for that. Um But those people are also having immunity defects and are at increased risk for development of things like lymphoma. So I think it's always important to have a reasonable index of clinical suspicion and to monitor things over time. I mean, fundamentally the the spleen is like a big lymph node, right? So it will react and increase in size in the context of any immune activating event. Um but as long as that goes down within two weeks, probably it's benign. So I, I agree with you, I think in the, it depends on the clinical context and the laboratory abnormalities. And I think if you have an acute process that can explain uh the astronomically and there is not a specific cystic lesions or a particular solid mass. For the most part, you can attribute that to the acute illness. And if it's an acute illness, it will resolve, you know, I think uh things to be worried is that when that doesn't uh resolves if it progress in terms of size, it also has to do with how big is the spleen. A lot of times the patient comes to the emergency room, get ac A T scan done and they call you because the patient has sperli, but the lymph node is only measured like 1314 centimeters. That's a different call that if the patient has ac a schedule a 25 centimeter spleen. So again, so I think the size of the spleen matters, um I think that's important usually when um there are conditions in which uh patients can develop either acute infections or rheumatological processes that they can predispose them to develop. Not only lymphoma that can be manifested by the large spleen, but also they can develop a hyperactivy of the immune system that we seldom see. But we call it hemogo syndrome that is usually associated with a constellation of abnormal parameters in the blood tests in the blood counts, the liver and other problems. But that kind of problems can be a life threatening situation than it does when that is happening. It has to be identified. And definitely a consultation with an expert in that kind of condition is is very important because those patients, unfortunately, they do require urgent specialized care. Um um They are rare type of lymphoma that can present with isolated large splint, primarily lymphomas, uh like margins or lymphomas of the splint. Sometimes we have rare t cell lymphoma. But if, what is the context, you know, um it depends of, you know, the size of this, explain the context and you know, but certainly if, if, if the clinical picture is concerning, you should trust your instincts and your clinical skills and never be afraid to grab a phone and call. So no here, Jordan J doctor. Anything else you'd like to add? That really was great summary. I have nothing to add. All right, we'll move along. Um I believe um in fact, this might be our last, I think we're actually done with questions. Is that correct? Yes. Um If, if there are no more questions from the audience, I'll give you another 30 seconds or so to get your fingers flying. Um, but I do want to say it's been a pleasure uh to work at Roswell Park with these fine colleague physicians. Um We are always available to help. Um Just please pick up the phone and call, um, use our websites. Uh We, we try to be very readily available. Um I would say as well that um you're never alone frankly. I just wanna say you, you see a lot of complicated folks in primary care. Um I think your breadth and wealth of knowledge is absolutely mind blowing. And you see the full uh depth and breadth of medicine and uh for that, I commend you and um we're here to help you as specialists and, and uh as colleagues as well. Um I do wanna give it a shameless plug to our um ash Review, our American Society of Hematology. We do have a uh review series. If anyone is interested, there should be an online option as well. This will be March 16th and 17th in Niagara Falls actually. And uh it should be a wonderful event. It's gonna be co-hosted by the Bear Foundation, uh which is a nonprofit organization to help build hospitals in Nepal. And um we would love to see you there if you, you're um so inclined, we'll do a comprehensive review. Um If there are no other questions. Um Thank you all very much for joining. Um I would like to let my colleagues have the opportunity to have any closing arguments that they might like to make as well. Yeah, I think it was great to interact. And um as Matt already said, we are happy to help if, if there are any questions really low threshold, give us a call, we are happy to help. Kind of the same kind of echo, the same feeling. So again, as I said before, well, I was one phone call away. So any questions, you know, again, we're here to help and um hopefully we'll see you in March. Sounds good. I, you know, I would say again, uh one who can't, one can't go wrong, trusting your instincts. If you're worried about someone, then you should be concerned. And it's important that it's caring, you know, that you care enough that you call and you trust your guts and not let that lap go away and she will come back, it will come back. It's a little bit of a haunting way to close this. Thank you everyone. Thank you for coming. Thanks for all that you do. Um We're here for you. Have a great night.