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Yes um So in terms of how these things develop, this is a little diagram here of, for everything from our multi potent stem cell, which is what everything starts from and from there, I think divide into myeloid, lymphoid and from there into different types of cells, you see myeloid also gives us our red cells and platelets um and lymphoid cells differentiate towards lymphocytes and plasma cells. Also NK cells as well now different leukemias arise from abnormalities in different cells. So acute leukemias tend to revise from the top of this food chain. Um All these couple of cells beneath that TML actually arises arises from this common myeloid progenitor or something around there and we'll come onto later you get an excess of all these cells beneath that there are few other conditions. I've mentioned here, So CLL and lymphoma both arise from lymphocytes and myeloma arises from plasma cells now. Um how do these things present, so the in terms of our sort of rough, four categories acute versus chronic, is the first differentiation of discuss, so acute leukemias tend to present with what's happening is there's a rapid proliferation of cells and that causes the normal bone marrow content, which is all this good stuff we see at the bottom of this diagram above is not being produced, so you tend to get what we call pancytopenia, so you get anemia from the cytopenia and neutropenia so low um hemoglobin, low platelet count and low neutral counts. Those center developed quite rapidly with acute leukemias, they will develop eventually with chronic leukemias, but it will take a lot longer for that to happen. Um Splenomegaly is much less common in acute leukemias than chronic leukemias and the reason for that is it takes a lot of time to feel spleen to enlarge that much. The next thing I listed here is bone pain, so because the bone marrow has got a rapidly producing group of cells in there. The bones can get painful during the presentation of acute leukemia. Most of our patients who present with acute leukemias actually present with infections as well or bleeding manifestations as well so as I pointed out the main thing for huge leukemias is they'll present with pancytopenia. It's important to differentiate the term pancytopenia here from the fact some of these patients may have an elevated white blood cell count, but you'll notice most of them will have a low neutrophil count um so they may have a total white count of 30 or 40 or higher, but the neutral count will usually be low, not always, though in most of these cases it will be low Now the chronic leukemias uh said you got a slur, a proliferation of cells so you get a slightly different pattern of disease so for the lymphoid um so CLL tends to present with small volume lymphadenopathy um and splenomegaly as well. And CML so chronic myeloid leukemia tends to present classically with splenomegaly. Because um the spleen starts cooling lots of cells and starting to um work hard to make new cells as well. You tend to get less burden of disease in the bone marrow and there's no more normal bone marrow contents. You tend to get less effect of these things above sea, less anemia, less thrombocytopenia, and less neutropenia, but they will develop eventually, given enough time, just one quick thing I'll touch upon As well is it with all the leukemias is, there's an emergency and hematology, which is lucas stasis. That is when you've got a very high white blood cell count and the blood is very viscous and very thick and you can get end organ damage, so you can get um lung infiltrates and you can get bleeding as well um And you also get thrombosis because it's very thick blood. As such, um this can happen at relatively low blood counts for AML, um particularly um but for things like CLL, it takes a lot longer for this to happen and the reason for that is is through the size of the cell and also how how sort of sticky that salads some AML cells are very big and very sticky so very few of them needed relatively to to cause these problems, whereas patients with CLL often people who are not used to dealing with these patient's will see a white blood cell count 300 get quite surprised by that, but they they will often have no symptoms even with a white count of 300 because the cells is small and they don't cause the sort of reaction to these people do have um so for the patient's who do present with lou cost asus. We have to either get rid of the white cells by leukapheresis, or we take it out by a bit of a complicated method where he was basically taken out by um through a machine or we give them chemo is the table here just explaining the sort of acute versus chronic divide, and the sort of symptoms you tend to find in both of these. As I said before, this is the four sort of main categories you think of as a student. Actually there are a lot more categories than that and we can divide things much further, breathe, even the ones I put here, um but you don't need to know about that particularly this stage. There are few extra conditions. I will briefly touch upon in this talk, um which the one of the, which is under a ml here, just will not come up very well on my phone version of this, but it's a pl, keep promyelocytic leukemia um and I briefly touch as well upon CMML, which is a slight variant of cml. I'm listening to go briefly and talk about the the four types of leukemia in in detail, um So, I'll start off with the acute leukemias. History for these is largely similar like I said before, It's mainly characterized by the cytopenia is the pancytopenia. A. L. L. Tends to affect classically exams children. It does affect adults as well, but it's one of the commonest childhood cancers um They tend to get hepatosplenomegaly, they can often present with bone pains and limping, and that a significant proportion then we'll have CNS symptoms as well, another thing they can present with as well as testicle disease, which is nothing to look out for um adults. Again, similar is mainly the symptoms of pancytopenia. Now the way it is many diagnosed is through blood tests, so with acute leukemias. I said before, the the idea of leukemia is you have white lots of white blood cells in the blood but actually not always is that the case and sometimes people have a normal white blood cell count or even a low white blood cell count and still have acute leukemia um The thing that is abnormal is there's usually the presence of we call blast cells in the peripheral blood um and in your exam. Questions, hopefully, they'll point out somewhere there are some blast cells, circulating blast cells are not normal. There are a few conditions apart from acute leukemia that can produce them, but for the purposes of the exams, the most common thing is acute leukemia, so blast cells going back up to our diagram here are essentially are stem cells. We shouldn't be seeing in the peripheral blood and these guys have proliferated out of control and replace the bone marrow contents and they're in the peripheral blood. This is what they look like on a peripheral blood smear, so normal lymphocyte should be about the same size as the red cell. These here are many times the size of the red cell. Um I put out a few of the other features there, but you don't need to worry about that too much. The diagnosis of acute leukemias is very difficult just from looking at a blood film. It would be very difficult to tell that from a ML, so we rely a lot on other testing, so particularly call flow cytometry. What you mean a phenotyping, which is why we look at the markers on the cells. I don't think you particularly to know this um as medical students, and indeed I don't think anybody apart from hemotologists, particularly to know this, but the path they sometimes put random things in, so, I just put a few things about what we normally see on flow cytometry for these patient's um so that the immature cells are typically marked by see you 34 being positive, which is a marker for stem cells. Um Along with that there'll be a few other markers, so cd 19 is the commonest B cell marker and c. D. Three is one of the T cell markers, but again this is something I don't think you particularly to know about. I've also put a slide in front of the interested about the genetics of LL um which is not particularly relevant for Path one thing. I will point out there for the adults. A. L. L. Is that a proportion of them in quite a significant proportion have this mutation called the bcra b. L one mutation um because of the night translocation between chromosome nine and 22 Now some of you may have recalled this is the same mutation that causes CML and I will cover that later. Um The reason being that this mutation can happens quite early on in the sort of development of these white blood cells, and depending on various number of factors, patient's with this mutation can go on to develop either CML or acute leukemias um but it's worth noting for exam purposes that if somebody has a history is consistent with acute leukemia and something like this and blast cells in the blood film, it may be a l. L instead of CML that should hope to be apparent though from other features. Treatment of a. L. L. Is again beyond the scope of this, but essentially we give them a lot of chemo for a long period of time up to about three years. They get treatment for um I keep my Lord leukemia is um the other acutely kenya, now again the sort of clinical features are very similar. The incidence of this doesn't increase with age, it's unusual and children that does occur. Um The main other things to point out is that a lot of these patient's some of them will have had a pre existing myelodysplastic syndrome and the proportion of them as well will have had uh previous chemotherapy. This is often chemotherapy related as well, but most of the time this is idiopathic. I we have no idea what's caused it again with blood tests. You see this picture of what we call pancytopenia, so a low neutrophil count, a low platelet count, uh low hemoglobin, the white cell count can be anything, it can be zero, it can be 100 but like I said if it's going to, if it's high, then the abnormal cells are going to be these blast cells and not normal cells go on to morphology, so the blood film appearances The typical thing that everyone remembers for exams is our rods. This is a cell here with a lot of our rods In you can get other cells with just single hour rods by spray and find one there we are this guy here is an hour rod in that that blast there. Um so the presence of our roads is abnormal and pretty much diagnosed AML. Without much other information, not all mLS will have our rods though only about 20 or 30% will actually have these present, so again we'd have to go back to immunophenotyping, what we call flow cytometry and look for these markers. Again, mother said 34 is this marker for immature cells and these ones below are things that are typical of myeloid cells as this m. P. O. As well mhm, The treatment of a ML is very similar to l. L. In terms it involves chemotherapy, but it's usually a shorter duration of any about four months. If people respond, be there are a few targeted drugs we have for ML now and also particularly for a PML, which is acute promyelocytic leukemia. This is a particularly unusual type of leukemia in that patient's who survive past the first month. It's almost 90% of the time it is a cure curable condition um that is curable pretty much with just this one agent, which is atra, which is basically just vitamin A. I won't go into why that is, but um these patient's have this particular translocation between chromosomes 15 and 17, which causes a fusion fusion of a gene called PML with with the RARA gene um but it's a very good prognosis in the longer run, but in the short term, they can present with d. I. C. And sometimes very catastrophic bleeding including intracranial bleeding and things like that so, I've offer you questions for this talk. Um I don't know how many of you guys on the line, the sorry, uh I think everyone wants to just write in the chat with you. The answer this this question would be so which of these things is most concerning for an acute leukemia. There's five options there just give you a few seconds to think about that highjack. This is an um just wondering if while people are answering you'd like me to screen share from my laptop or you want to continue like this, uh you can yeah maybe personal laptop that if it works okay great, um So anyway I was quickly continue, have you had a chance to think about that. Um so number four here is the correct option so um okay once the next slides a year, so just going on to a group of conditions called m. P. N. S. Now which is sort of the reason I'm talking about these is because CML is one of these and I'm going to talk about chronic leukemia. Is next, this is increased production of these particular group of cells here in the myeloid lineage well, let's move on to the next one. Um So again, I think if people want to write in the chat, I'll give people a few seconds or people just think about it um about things that can cause a high platelet count, but the interest of time we'll move on to the next slide as well um fine, so essentials from besides Southie me A. Is one of these conditions we call m p. N. There's four of them, I'm going to briefly go through um so e. T, percent of people with a high platelet count and no other cause of that. Your other, I'll point out in a minute. The main causes of high platelet count are not e. T. E. T. Is quite a rare condition, um but most of them will be associated with the mutations below so jack, to, in kalar um So the other thing about e. T. And all all these conditions that we call m p. N. S. Is they have a high risk of thrombosis as well, but sometimes they do present with unusual thrombotic events and young ages um So we can move onto the next slide um So just going through the causes of a high plate accountant for exams. I've seen some of the previous questions that they ask you to rank um sort of things that would cause the high platelet count. Things like that the most common things were going to see are going to be acute infections and chronic inflammation. The minority of patients who have a high platelet count is going to be the cause is beneath that um but patient's who are well and don't have any chronic infection or inflammation should be investigated for this um particularly for soy dog, a malignancy as well which goes the next slide. Polycythemia vera is a condition of theirs over production of the red blood cells um There's also a bit of over production of the platelets students commission as well. Um Most of these patient's do have a Jack T mutation, so 95% of them will have a Jack T mutation, and the remainder of that often have a different type of mutation in the same sort of gene. Um These also have a high risk of thrombosis and there's also a risk transformation to a ML, which is um slightly more than with e. T. To treat these patient's. We give them aspirin to reduce their risk of stroke and we sometimes venn, effect them I just take out some blood from them. They often have a high platelet count as well as a high hematocrit. He's going to next slide the other causes of a high hematic writ. So the main things again, we'd be ruling out secondary causes so this respiratory diseases such as sleep apnea and cyanotic heart disease, um and often we check an e. P. O. Level as well to check for your risk, a protein secreted cancers and and see if it's an approach for e. P. O. Level. Um So these are things we have normally checked people have a high platelet count and a high hematocrit, so again with platelet count, which I'm checking, there's no inflammation somewhere that's causing that um And if there isn't we'd be sending off this panel for these mutations hi, hematocrits Again, we're looking to exclude another course so respiratory conditions and renal cancers and things like that we're checking e. P. O. Level as well and if it's persistent with me sending a mutation panel for Jack too, um people who don't have a jakti mutation, occasionally, we've got a strong suspicion, we'll do other things like look at the kidneys and referring to respiratory teams as well, so the next thing, next third of these four conditions is mild fibrosis, This can actually result from either of the previous two and they can transform into mild fibrosis. It's a sort of inflammatory condition where the there's over the production of all these cells in the model lineage, but also they produce some unusual cytokines which make the brain marrow by bra tick um Now with the brain verified, braces that impairs its ability to make blood cells and it also causes these cells. We called teardrop poikilocyte, which we can see in the blood film and the other characteristic thing an exam questions A sort of a buzzword is the dry tap on bone marrow is often indicative of severe bone marrow fibrosis. What that means is we put the needle in and we can't get anything out to the bone marrow because it's all fibrotic and dry. Um These patient's have a risk of transformation to a. M. L. As well and often the best treatment for them is a stem cell transplant if they have severe disease. The final one of these things you know the next side is CML um So this is classified as an m. P. N. As well. It's related to the other conditions as well, but the mutation is slightly different and we've touched upon it before we're still on the next slide from here. The classic things for CML that tends to affect middle aged adults, there is a slight male predominance as well. Um it tends to present with splenomegaly and there are a few questions a few causes of sort of massive splenomegaly and exam questions which are typically CML and mild fibrosis. The other catholic third one is leishmaniasis, which we don't really see very often. Um Most of the patient will be asymptomatic and picked up on routine blood testing nowadays, um Although historically they may have presented with more symptoms such as um symptoms have lifted listed there. It's very rare to see an accelerated or blast phase phase now, but they will occasionally present with those. So on the next slide of put put the sort of usual blood counts for somebody with CML and the white cell count will be elevated in the chronic leukemias, so they keep leukemias it can be anything but the chronic leukemia is, it will always be elevated and it'll be made up of mature cells not blasts. There may be occasional blast cells in um CML. There'll be a minority on the bottom. I put this maturation of the normal myeloid cells from blast cells either stem cells all way through to mature neutrophils. In cmL, we see all these cells in the blood films. They usually have preserved hemoglobin and platelet count, but sometimes the platelet count will be a bit high and in more severe disease, they might become a bit anemic. The other thing to point out as well is that the basic pill count will probably be elevated. It's quite unusual siarhei ba seville count. We always when we see that we worry about um these conditions such as TML on the next side just pointed out the things we've investigated for a high white blood cell count. Most common things, I get called about people who got infections you've got slow to resolve white blood cell counts or people on steroids as well, but there are other things that can cause it as well, such as hematological, hematological conditions, you can just go on to the next slide. Um So occasionally you can see some of these precursor cells in severe infections, but if you're seeing a lot of them and you're seeing elevated basophilic, the eosinophil council is quite concerning for CML and the next one yeah this is the blood film for CML, So this is just showing the with a lot of white blood cells in the blood film, which you might not be able to appreciate. I have not seen too many of them before you should have a lot more red blood cells and white blood cells um So the white blood cell count of this person is probably in the hundreds. It's what we call a left shift, so we see this precursor cells a number of different stages of maturation. You know the next slide I've got another example of her blood film as well slightly lower white blood cell count here, but again you can see a full spectrum of different types of cell, not just mature neutrophils so diagnosed. The CML is um purely made on sort of nowadays using his modern techniques looking at this particular mutation, because we know that 99% of CML will be associated with this mutation, so the b c r a b l one fusion clean is what comes from this philadelphia chromosome translocation. It's different, there's three terms open and bolder, all interchangeable. Essentially, there is some slight nuance difference between them, but for example purposes they are the same thing most of these patients we diagnosed in chronic phase nowadays they've actually removed the accelerated phase from the classification last year um And I'm very small minority will be found in blast phase, which presents a bit basically like ML but um it's very rarely seen nowadays. The treatment for CML is nowadays with these modern drugs called tyrosine kinase inhibitors which worked very well, and uh most patient's will not leave anything apart from these, about 70% will respond to the first drug. They're given and as you can see the nine the 10 year survivors 90% which is quite fantastic for something that we would have been telling people need the bone marrow transplant through 30 or 40 years again, so next we're coming on to the chronic lymphocytic leukemia, which are closely related to limb famous. It begins the next slide. Um CLL is quite lymphocytic leukemia. Again, this will present with a high white blood cell count. It's usually asymptomatic and it's usually in older adults, it's quite unusual to see in people under 50 and again it's got a slight male predominance. Then these patient's will have lymph nodes that powerful, although usually they're quite small and a small proportion will have immune complications of this. They can have a high higher risk factor, doing i. T. P, so immune mediated, low platelet count basically and hemolytic anemia. There's an autoimmune problem there causing anemia um So CLL will tend to have a high white blood cell count has there, has to be a white blood cell count over five for the lymphocyte count of five to diagnose it, but most of these patients will have white blood cell counts of close to 100 often um a diagnosis even if they're asymptomatic and these will be made of purely lymphocytes pretty much. They'll have a preserved mutual account usually underneath that um and normally they have a normal hemoglobin and platelet count. If those things are affected, that signifies more advanced stage disease, so the next slide just yeah just chose a blood film of someone with CLL. The classic thing that's mentioned exams is smear cells or smudge cells, which these sort of smeared cells you can see quite fearful this blood film the normal lymphocytes, the small purplish cells are similar size to red blood cells um So nowadays we diagnose it by again using I mean a phenotyping says technique where we look at what the markers are on the blood cells um and we look for clonal population that expressed markers typical for CLL um confusing. There's another condition called small lymphocytic lymphoma, which has the same pathology essentially, but just they don't have an elevated white blood cell counts. They'll have limit. They'll have lymphadenopathy. They may have a small population of lymphocytes in the blood, but they have a low white blood cell count of less than five. There's a similar condition. Um Next treatment of Cll again, most these patient's don't need treatment to start with and in their lifetime a third of patients will never need treatment at all um So often, we watch and wait and decide to treat them when they've got symptoms of the disease, or they've got significant involvement um of either lymph nodes or the bone marrow and the treatment nowadays. Um I saw there was actually a question on this and one of the past papers, but it was a bit unfair, but they the there's a few different drugs we give nowadays, so we tend to give either rituximab with chemotherapy and for some patient's and other patient's, we give targeted drugs such as a brutal nip, patient's who have this tp 53 mutation tend to respond a bit worse to chemotherapy and have a higher risk of problems with chemotherapies we tend to give than ibrutinib or a calibrated up these btk inhibitors, um but again, I don't think this is particular thing you need to know, I can move on to the next slide. Um I don't know if it's with me going through some of these yeah one second, so again let's have a look at these people can reviews on their own time as well after the lecture, but the, I got an example of a few different blood um sort of panels here, so in terms of CML, so like I said with chronic leukemia is they always have a high white blood cell count that would immediately exclude number three and number four um secondly with a chronic leukemia CML, I'd be expecting a high neutral account um so that would leave me with numbers um five and number one. The thing that we most in keeping here is the fact there's a high baseball count. I need a cynical account with number one that is probably the most likely diagnosis here. The high platelet count also grows with CML because you get slightly over production of platelets as well as the white blood cells in the early phase of the disease, so number one is the right answer here. On the next side, I think I just um suggested what the diagnosis would be for two, so here we've got a high white blood cell count as well, but we've got a high lymphocyte count, a normal neutral account, This would be typical for chronic lymphocytic leukemia, Cll, um number three. Um Again, they've got this, this one has a low white blood cell count. They've got a low hemoglobin and a low platelet count. They've got a pancytopenia here with a low neutrophil count. This would be quite concerning for a lot of different things and I'll come onto that. I think on the next slide, the patient with a pancytopenia there's lots different causes, lots of different causes of this. Um When people ring us up about this, the first things we always ask them to check the hematinic so, at b 12 and folate and also iron as well. Um. The second thing is take a good drug history because there are some medicines that will cause this as well, particularly a couple I've listed there, um but the thing that we most worrying would be a malignancy, so acute leukemia can present with pancytopenia and low white blood cell count as well, the reason being sometimes all the disease from the leukemia is in the marrow, and the bone marrow may be packed with AML or a. L. L, but they it's not spilled out into the blood yet. The second thing is BURMA infiltration from other reasons, so others like solid cancers as well, can do that um a plastic conditions, so there's autoimmune conditions where the body destroyed the same bone marrows, but they're quite rare and occasional can be virus rated with pump virus, myelodysplasia. I'll come onto in a minute um but it's a sort of precursor condition to AML where the body is not producing the normal blood cells the normal way it's producing abnormal cells. Mother fibrosis can also cause the same picture, um but occasionally will cause. Um you sometimes will get a high white little account with that as well that's in within the differential diagnosis here, so the next slide, I'm just summarizing um sort of typical findings for acute and chronic leukemia's, I've put at the bottom as well that the bone marrow is the ideal test for a lot of these conditions, particularly the acute leukemias, particularly if they've not got particularly high white blood cell count for some of these patient's, with a pancytopenia that like that previous slide, we need to do a bone marrow biopsy if they have a high white, high blast percentage in the bone marrow that would be diagnostic of acute leukemia. So Mds confuse everybody as a medical student because it's a sort of pre malignant condition but has quite significant impact on some patient's if they have significant disease, it's a dysplastic condition, so it means that the body is not producing um normal white blood cells and red blood cells and platelets, and there's often under production as well, so there's two parts to it um they can affect all three lines, so it can affect by three lines, I mean the myeloid cells, the neutrophils, the red blood cells, and the platelets, or it can just affect one or two of those. There's a risk of progression. Two ML, which is significant for some patient's and so some patient's is much lower. The center present with incidental cytopenia so low blood counts, but sometimes they can present with infections or symptoms of anemia. Um On the next slide, it just sort of um points out that the anemia and MDS tends to be macrocytic um so as hematologist we tend to get a bit more worried about macrocytic anemia's that are not b 12 and folate deficient. The patient have macrocytic anemia that's gotten and they've got normal b 12 and folate levels. We often see these patient's in clinic because of this concern, so mds, we get these abnormal changes in the blood film and also the bone marrow tests um So these are these are bone marrow slides actually here, but the they're not things you particularly to know, there are a few sort of buzz words that you may hear one of which is pseudo pell gah neutrophils, sudeep elga anomaly which is in the bottom left. This diagram you get these neutrophils that have a sort of dumbbell shaped their nucleus. The bilobed, the new normal neutrophils have 3 to 5 lobes, um whereas an md s sometimes they just have to so abnormal. The rest of these changes again uh not particularly important to know, um but you get these dysplastic changes basically on the next slide. I'm just talking about the classification of MGS. I think in the past day we may have the old classification in there from the previous Whre classification 2016. They've actually updated it quite recently, um but the, and I sort of again, I don't think I need to know the classification I/O in fact that something I need to know for my exams, but the main things I just point out that the prognosis and MDS is related to these things. I've listed there, so in the bone marrow, lots of patients with MDS will have a percentage of blasts, so abnormal cells if they have over 20% blasts, that is by definition a ML, but some patients will have sort of 15% blasts, which signifies the quite high risk of progression two ML um that's one of the significant things, for instance, so about 30% will progress to a. M. L. But it does depend on these scoring systems that we use to look at prognosis, so some patients have a much higher risk than that and some will have a much lower risk. The treatment is not really important for Year five Path, but again we give a combination of some patients are a high risk. We will give them chemotherapy even though it's a sort of pre malignant condition, and we will often try for younger patient's to do a stem cell transplant before they transform to AMl mhm, coming towards the last couple of topics. I'm going to touch upon so first of all in favor and secondly myeloma, the lymphoma is um pretty much The original diagram towards the faster lecture come from these, these lymphoid cells uh with your lymphoid cells mainly um which passed through lymphoid follicles and through those various stages. Sometimes things go wrong now, There's two main classifications, which is the Hodgkin's and non Hodgkin's lymphoma. Is this is quite an old through outdated way of looking at it because Hodgkin's is sort of a disease that zone uh non Hodgkin's, in famous. It's a it's a big category of lots of different diseases. Hodgkin's tends to present in young patient's. I see you get lots of people under the age of 30 with Hodgkin's and then you get a smaller peak in older people as well, Hodgkin sense to affect the mediastinum bit more than the non Hodgkin's lymphomas um and it tends to be aggressive and curable disease. The next slide I've spoken about the non Hodgkin's lymphomas and sort of a few categories of those, so you can subject them in lots different ways and there's about 50 different types of lymphoma, but the broadest way of thinking about the most t cell and B cell. In famers, t cell lymphomas are quite rare. B cell ones are much more common. Then within B cell lymphoma is the commonest ones. We group into low grade, high grade, and sort of very high grade follicular lymphoma is an example of a low grade diffuse large B cell lymphoma, which I've abbreviated the d. L, b. C. L is a high grade lymphoma, which is one of the commonest and Burkitt's lymphoma is a very, very, very high grade lymphoma, so it's going through these in some detail, each in a minute, but first just the staging of lymphoma. This does occasionally come from the exams um the ANN arbor stating which we still use nowadays. So this is um so patient with one nodal group involved. It's just one side of the diaphragm is stage one if you've got to nodal groups involved, but they're the same side of the diaphragm that stage two or more than two, even as long as the same side of the diaphragm. As soon as you got disease on both sides of diaphragm that stage three disease and to have stage four disease, it means you've got infiltration of another organ that's not a lymph node such as the spleen or the bone marrow, or anything else like the lung or um the bowel, For instance, the second part of the staging is would be assigned letter A or B. If they have any of these symptoms listed here, then we call it stage 12, or three or four and then be which indicates a slightly worse prognosis, mhm, stage. In the case, the absence of these um So Hodgkin's, as I said there's two peaks, the biggest peak is in the younger people who are under 30 and a site smaller peak in your, in older adults. The classic thing for exam questions is these weeds sternberg cells, which are large cells have to nucleus usually or even more, and um these are actually one thing is unusual for Hodgkin's, for other malignancies, the malignant cells, the minority of the cells, and the biopsy usually because these hodgkin's cells he'd read Sternberg cells you may only have a few of them in each lymph node that's sufficient to diagnose Hodgkin's lymphoma thing on the next night, I've got a picture of one of them in a minute, maybe not get a little bit later. Actually um there's a few different types of Hodgkin's in favor, but they're mostly treated with chemotherapy. Essentially there's a very good chance of cure, the next type of in famous non Hodgkin's in famous and again like you see in the graph. They they're mainly in older adults and they're less common in younger adults. Let's go talk about subtypes bit briefly as the first subtype we're going to talk about is um the indolent types of indolent means slow growing, so folliculin famer is the most common example of this um can. I put a few details about it there, but essentially they present with very slow bering in fluids um and there is, although there's a risk of transformation to high grade lymphoma a lot of patient's with folliculin famer will never need treatment. The difficulty comes with low low grade lymphomas, they're not very terrible and they will keep coming back and relapsing and remitting rather than high grade lymphomas that once you've got them in remission, they won't come back again. The next one speaker as mantle cell lymphoma. That's an example of follicular lymphoma on path. Uh huh um mantle cell lymphoma is sort of a high grade in famer, but again it's a bit variable and not all of them are some of them a bit lower grade and the mental cell lymphoma has this typical translocation between 11 and 14 and it's a bit unusual and it can it can present with a sort of leukemic picture. When you get these abnormal blood cells in the peripheral blood, the more common high grade learning fame is diffuse large b cell lymphoma, um which tends to present quite aggressively and responds very well to chemotherapy as well. Um So the mental cells have these sort of cleft and then they look a bit like a heart to the nucleus um so that's that's the sort of typical features on in the blood, but not all patients will have blood involvement at diagnosis sort of leukemic involvement um to fuse large pizza lymphoma. We, we currently cheap have been treating with R chOP chemo um and it's associated with e. B. V. Virus although not all patients will have that as well. The example here a very high grade lymphoma is burke. It's in favor now the classical history of burke, instant fame is a very fast growing lump usually either in the abdomen or the neck. Um It's associated with HIV as well and also eBv, it tends to occur younger adults mainly there's a very high risk of tumor lysis syndrome with treatment for these patient's um so they have to be managed appropriately for that and hydrated well. They sent it. This is what we call starry sky appearance on histology, so you can use sort of bright bright whites with pearly vac you all's we call them in the lymphoma cells amongst the sort of see a very bluish cells. We call it a starry sky appearance. Um T cell and framers are quite rare. I just included a bit of details here about a t. L. L, which has these sort of flour resells and also um you can get some cutaneous t cell lymphomas, which present with rashes, which are a bit unusual um a t l l associated with the virus for htlv one, which is endemic or commoner in the in sort of japan, in countries in the area of the world. It's also in the caribbean as well the most patient's will be from those demographic, but not all, um so just um a question here just showing the ranking question about what the sort of thing they might ask you in the path exam, ranking the amitabha staging for patient's so stage one is patient's with one area of disease so that would be option number four here um State number to be two areas on the same side of the diaphragm, so for instance, uh mediastinal auxiliary state number three would be the example of number three and then state number four be with the bone marrow involvement the next slide um I just give an example here of something that I think they call them on the papers. I've seen on the paper bank. Um patient's the buckets in fame. I have a very high risk of um complications when they start treatment. This patient had chemotherapy six hours ago and his cracking the shot up the potassium has shot up. His calcium has gone down. His phosphate has gone up quite a lot. The diagnosis here. I don't know if anybody wants to take it in the chat. If not all yep say, do you realize this syndrome that is definitely what this is so this is humanized syndrome um is important to be aware of this and this is something you may encounter when you start working at some point um the treatment for this. There's a number of different options we can do this patient here with a chatting with seven you'd be wanting to get them treatment with a drug called rasburicase, also treat the hypochelemia. Of course, they probably end up needing renal replacement therapy as well. There's a number of different things we give in lymphoma patient's and other other hematological patient's to prevent this. Allopurinol is the communist agent we use with patients who are higher risk. We give them a drug called rasburicase, which directly depletes uric acid levels and which is what we would give us treatment as well, um but some patient's despite that will still go into renal failure, this is one of these sort of hematological emergencies. For the next slide, we could go onto the last condition that I touched point, which is multiple myeloma. This is a condition of plasma cells that sort of your memory B cells essentially um so normally secrete immunoglobulin, so antibody um If you get too many of them, they also create same antibody rather than secreted in a nice variety of antibody. We call this. Um we see this sort of peak, which is the far right peak of the gamma globulin and the gamma zone, the the graph on the top right, um and we call that a pair of protein it's a monoclonal protein of one particular type of antibody essentially in the year in. We sometimes can detect this protein as well, which we call it Ben's jones, protein on the next side. I just touch upon this bit more so um we can type these proteins, so the the graph from the top left shows the sort of normal curve versus with myeloma on the bottom right. It shows what we call immunofixation when they check what type of preparation, this is and what type of immunoglobulin the thing is secreted. This patient is decreasing, i g, it's got CAPa uh restrictions, so it's got kappa light chains um myeloma can progress from m gas or smoldering myeloma, and these are sort of pre malignant conditions. MgA's has a progression rate about 1% per year were Smoldering myeloma is that in the order of 10 to 20% a year depending on the risk. Um So my name itself the diagnosis of this requires a number of things, first you have to demonstrate the clonal bone marrow plasma cells, um so his patient's will need the brain right to diagnose them. They have to vary 10% plasma cells in the bone mary, but the second thing that's very important is they have to have evidence of end organ damage yes they have to have one of these crab criteria and so high calcium, renal impairment, anemia, or bone lesions with the lytic lesions. It's very important to point out here that the they can't they at least have to be juice to myeloma, so somebody's anemic because of my inefficiency that doesn't count as a crab symptom, if the hypercalcemic brings another reason that's not a crab symptom as well um The second thing is well is there's also slim criteria. Some patient's do have um mri involvement, which is I just touched upon there, which also counters crab criteria as well, but they're less common and less like to be tested in your exams. Put in so um moving myeloma is sometimes called asymptomatic myeloma. Because you have the evidence of clonal plasma cells and um in the bone marrow, or you have a high monoclonal protein, but there's no end organ damage, which is a crucial crucial thing and the reason is is the key distinction is because there's no benefit in treating these patient's and that's been shown in multiple trials, these patient's will eventually progress to myeloma, but we know that there's no point treating them until they do. Um Finally, m, gas is just a condition where you got less than 10% close pen cells in the brain marrow, but you have a monoclonal protein that protein can range anywhere from 1 g to 29 g. If it's over 30 g, then by definition is smoldering myeloma at least yeah and again they must have no crab symptoms. It's important to remember that patient with myeloma as the next year. Next side's fine patient with myeloma can present with any carrier protein level. It's often over 30 but some patient's do not have a population over 30 as long as they fulfill the other criteria, are you having crab symptoms and having over 10% plasma cells in their bone marrow and they can still be diagnosed with multiple myeloma. Um There's also rare conditions. I just mentioned the bottom, which is called walls and strongest macroglobulinemia, which is similar to this, but they tend to have an eye gm power protein. It has a similar sort of mechanism of disease. They don't tend to get crab symptoms um and it's it's something you don't need to know particularly much about basically because it's a sort of lymphoid it's a sort of lymphoma type condition. Um If they, if the paraproteins anti gm then that's more likely to be waldenstrom's than the myeloma let's slide um let's share a blood film of myeloma. Um. Now the area on the center is pointing towards what we call rouleau, to the sort of stacking of the red blood cells due to sort of them being sticky and inflamed. The other arrow is pointing towards plasma cell. We don't normally see them in the blood and in fact it's actually quite poor prognostically to see them in the blood of a myeloma patient um We usually see them in the bone marrow, but this particular patient does have some the next slide. I think I just point about the management of this, so MGA's we advise gps normally to manage this with annual blood tests. Smoldering myeloma would usually be under a hematology clinic and we would monitor every three months until they progress and patient with symptomatic multiple myeloma. We would usually treat them unless there's um that's a very frail um on the next side of listed a few treatments, there are quite a lot of different treatments nowadays. Um Most of these patients end up having what we call an autologous stem cell transplant when we give them high dose chemo, followed by their own stem cells. Um The next slide do a yes just a few of the examples of drugs on this slide As well again, it's not particularly important for Year five Path, but these are some of the things we're using nowadays, so we're coming towards the end now, I do have a few questions towards the end of this, which you can go through in your own time. I'll just quickly go through this case as well, so this patient, this patient here the six year old man and they've got i. G. A. I. G, lambda paraprotein 25 now as I said before this, this could be anything. This could actually be MGA's it could be smoldering myeloma, it could be myeloma because with myeloma, you can have any level of power protein on the next time. I think I just explained some the investigations I would do for this patient. I haven't actually um any of these, so basically anybody with a paraprotein over um 10. This i. G. I. G. A. Or anything over 15. That's i. G. Gps, get advised to refer them into hematology clinic and most of these patients will get imaging to look for bone lesions and also they get a bone marrow biopsy as well um to check that's, that's what we do mhm. At the very end of this talk, I spoke, I have a couple of slides about stem cell transplant there's autologous and allogeneic stem cell transplants. The principle of this essentially is that we we know if we give very high dose of chemotherapy, it's got a higher chance of killing the problem sell we're trying to get rid of the leukemia or lymphoma or the myeloma, but sometimes the limiting factor is that we wipe wipe out the patient's bone marrow by doing that. What we do is, we harvest some stem cells either from the patient themselves or from somebody else and then we give the patient a very high dose of chemotherapy, following that we then give them rescue with term cells, so um they get re infused with them cells. The 10% mortality figure there is referring to allergenic stem cell transplant with, with autologous stem cell transplant, it's much closer to 1% than that till the next slide. Um Yeah some people with stem cell transplants um well crop up in and he's all over the place, but they are at risk of certain things. It's always worth discussing with their particular transplant center they're particularly risk of GVHD and also infections that slide. I've got a number of questions here. Um I don't know if you want to go through them in their own time or you want to go through them now. Um I don't know what's easier cause, I'll see you over a little bit later than I wanted to uh it's up to you jack, jack okay um Maybe I'll quickly just talk through a couple of the features of a couple of these things okay um So you and you can have a look through them. There's a few variations some of these questions as well, so this first question is looking at um myeloma diagnosis, essentially so this patient's got a cap, a power operating of 37 now power posting over 30 means it can only be smoldering myeloma or whack or myeloma, so we have to look for are crab symptoms um. This patient here has a hemoglobin of 90 which is. There's no other cause for that that would indicate myeloma, symptomatic, multiple myeloma, so the answer would be be if they didn't have um hemoglobin of 19, they had a higher hemoglobin. It could be smoldering myeloma um so those would be the two options here, it's more likely going to be be the next slide yes. This is a example again of this is acute leukemia, example, um again you can look through sort of this a bit more later uh. This patient has the key things here. This patient has 27% blasts in the bone marrow, anything over 20% defines acute leukemia by definition. The only question here is whether this is my, lord or lymph, it or lymphoblastic. It's quite difficult to tell this. On exam, questions and your stage didn't know if they'd necessarily be expecting to know that it might be sort of more difficult question, but essentially here, the the flow cytometry, the cd 19 is a basal marker and t. D. T. Is a lymphoid precursor marker. This is linda plastic. Uh the trans location 9 22 is the one that you get with CML but like I said it's it's present in almost a third of a l l adults cases as well, this is a l. L. Um This one here is another acute leukemia and the blood film helpfully has a single hour rod in one of those cells, you have to believe me in the cell in the very center, but it's a variation of the previous question essentially, NPR is a myeloid cell marker to be with the next question such as this is, this is so and you had a picture somewhere of a particular type of cell. If you uh the, the next next one is fine um so, a young man with drenching night sweats, so that's concerning for lots of hematologic conditions, particularly in famous, his blood count is largely quite normal. Actually um he had a biopsy of one of his lymph nodes and shamed this particular cell now multi nucleated cells like this. This is a read Sternberg cell or Hodgkin reese, read Sternberg style, it's got two nuclei um It's a very large cell compared to the cells around, and this is Hodgkin's lymphoma and like you said you may see a few of these on a biopsy, but they are diagnostic my next question um So again, this is somebody with splenomegaly, There's a few differentials for splenomegaly and the hematological causes tend to be CML and mild fibrosis. Um In this particular case, they've got an elevated white blood cell count now you can see that with both those conditions, um but the left shifted granular sites with favor CML and the fish showing the pcr a. B. L. One gene would be diagnostic of CML. This is CML at the very end of this lecture and you'll have to get a slide, so the number of blood films I think I put the diagnosis at the bottom of them. All if you have a look through if you're interested, I'm not sure they'll put blood films in the examination. I think they did put a couple in my year, but I think they haven't put that many in the last few years, but it's in if you are interested there at the end of the lecture, I also have a little document with a few perhaps exam questions which I will send round as well. Um When I just tie this up a little bit does anybody have any questions if anyone's got any questions feel free to put in the chat or unmet yourself, but otherwise, if okay, yeah we've got we've got one in the chat now it's okay uh the white blood cell count um so acute leukemia starts off in the bone marrow essentially is the way I think of it. Um So the first thing you get with a ML or a. L. L. Is you get the suppression of the normal bone marrow production of things and sometimes the blast cells and the team be a don't really come out to the peripheral blood very much. You can sometimes get very packed bone marrow full of blast cells and you see that you see the effects of that in the peripheral blood, so you see low low blood counts, um low hemoglobin, low platelets, and low neutrophils, but you may not see any blast cells or you may see very few um as things progress. Eventually, that those will spill out until into the peripheral blood, so they're not always so although we often do see a high white blood cell count. It's not always as high in acute leukemias. I hope that answers that um Question three. This is so this is another sort acute leukemia example. Um This is a ML because there's for a couple of reasons, so that's sort of history is same as the same Question too, 27% blasts is also the same question, too, we're trying to focus on here, just the different slight differences in the question so that the photo tom, a tree showing MPO is diagnostic of a ML, the other thing as well as there's an hour rod and that's one of those cells on the, on the slide of, after this one, if you go one side, after you probably see a bit closer up the hour rod, it's very small um with these blast cells showing hard rods, there's actually one in the one at the cell above as well um is that the ML all right, thanks everyone. I am putting a link for some feedback in the chat itself be very grateful. If you guys can fill it in. I'm also going to share a screen with the qr code. Please fill in the feedback for this talk. Um Any questions or anything, please email us uh Thank you very much for coming and thank you to Jack, as well, um for the talk, sorry for the technical problems. In the beginning, we we try to preserve probably my fault, my laptop being rubbish, no worries at all. Thank you very much. Thank you. Bye.