Tapan Kadia, M.D.
The University of Texas MD Anderson Cancer Center
Hello, everyone. My name is Tapan Kadia. And today, I will be talking to you about hematologic malignancies, the diagnosis and staging. I am an Assistant Professor at the Department of Leukemia at the University of Texas MD Anderson Cancer Center. And as part of this, the first part of this lecture, we will talk about leukemias and myelodysplastic syndrome. But before we start, we are going to talk about the normal hematopoietic system, the production of red blood cells, white blood cells, and platelets; go on to disease states such as cytopenias, and then on to leukemias.
So, these are some of the objectives for the entire module. Upon completion of this lesson, we should be able to talk about: the normal hematopoietic system; identify common presenting symptoms for hematologic malignancies; and then discuss initial diagnosis and staging for leukemias, MDS or myelodysplastic syndrome, lymphomas, and multiple myeloma.
As part of the first module, as I mentioned, I will go over the normal hematopoietic system. We will discuss the presentation, diagnosis, and staging for acute myelogenous leukemia or AML, acute lymphocytic leukemia or ALL, chronic myelogenous leukemia or CML, and chronic lymphocytic leukemia or CLL. And we'll also talk about the difference between myelodysplastic syndrome and acute myeloid leukemia, and the specific diagnostic characteristics to distinguish between the two.
So, blood: blood is a mixture of plasma and cells and blood cells are made in the bone marrow. Throughout the adult life, bone marrow is mainly sequestered in the pelvic bones and the sternum. During birth, the bone marrow is sequestered in most long bones in the body. The bone marrow produces three types of cells, which make up the blood. And these are white blood cells, red blood cells, and platelets; each having their own function, which we will go into more detail in just a bit.
So, this is a typical peripheral blood smear, which represents the normal peripheral blood. As you can see there are three types of cells illustrated here. The red blood cells are listed here --- are illustrated here. These larger cells with multiple nuclei are white blood cells; in this case specifically polymorphonuclear leukocytes, which we'll get into in a bit. And these tiny little specks, which almost do not seem like cells, are in fact the platelets. Each one of these cells has its own function in the blood, which we will get into and then we will talk about disease states where these cells are low or malignant.
So red blood cells: red blood cells are those cells that are packed with hemoglobin, which is the molecule that is responsible for carrying oxygen and carbon dioxide between the lungs and the rest of the body. And so the red blood cells, they become oxygenated when they are transported to the lungs, when we take a deep breath. And then its oxygen is delivered to the rest of the body, the tissues that need oxygen such as muscles, brain, etc. The red blood cells and hemoglobin also pick up carbon dioxide, which is released from cellular metabolism, and bring them back to the lung where we are able to expire and release these toxic or waste gases into the rest of the atmosphere.
Platelets are actually small pieces of a large precursor cell called the megakaryocyte, which is a factory type of cell, which exists in the bone marrow. Platelets are produced when portions of the cytoplasm of the megakaryocyte break off and go into the blood ---go into the blood stream. Platelets are very important in providing hemostasis and to prevent bleeding. And so low platelets can lead to bruising, bleeding, and other complications.
Now, white blood cells are the most important part of our immune system. There are several different types of white blood cells that are specialized to fight different types of infection; and they are the first cells to present at the sites of inflammation. The different types of white blood cells are listed here: neutrophils, lymphocytes, eosinophils, monocytes, and basophils. We will briefly go through each of them and describe their function in a little bit of detail.
Neutrophils are known by many different names. They are also called granulocytes or segs because of their segmented nuclei as can be seen here. They are also called PMNs or polymorphonuclear leukocytes or simply polys by hematologists. Neutrophils are often considered the "Marines" of the immune system because they are usually the first cells that appear at the site of an infection or inflammation. They fight common bacterial infections by several different mechanisms. Among them include phagocytosis, which literally means eating the cell, which they engulf foreign bacteria or other particles; elaboration of toxic oxygen metabolites, meaning they release things like hydrogen peroxide into the bacterial cell wall that kills the bacteria. And finally they are also able to produce anti-bacteria enzymes, which can digest bacteria and other organisms. As I mentioned, these are the first white blood cells to appear at sites of infection or inflammation. And, in fact, these are the cells that make up pus that we often see in cuts or --- other types of injuries. As I mentioned, neutrophils are most often nonspecific. They attack all types of inflammation. And most need that the targeted antigens are coated with antibodies or complement for better and efficient killing.
As opposed to the lymph --- the neutrophils, the lymphocytes are more specific and more targeted. They are the "Special Forces", if you will, when describing it to kids. Since they are more specific, they are able to be differentiated and able to recognize different types of viruses, different types of virus-infected cells, and even different types of bacteria and fungi. There are two main types of lymphocytes: T-cells and B-cells. T-cells and B-cells are all derived from the original stem cell that helps derive hematopoietic cells. Later on in life as they mature, precursors of the T-cells go to the thymus gland and mature into T-cells, where precursors for the B-cells go into the bone marrow and mature later into B-cells. T-cells are mainly divided into two major categories, what we call CD4 type or helper T-cells, and CD8 type or cytotoxic T-cells. They are both involved in cell-mediated immunity. This means that the T-cells in fact associate directly with the foreign bacteria, virus-infected cell, or fungi to exert its cytotoxic effect. They can release cytokines, which can cause other immune cells to come to the site of infection and help in killing the foreign organism. B-cells on the other hand are not really involved in cytotoxic or cell-mediated immunity, but are involved in humoral immunity. What this means is that B-cells produce antibodies as directed by the T-cells that we just described. As a result, there are millions of types of B-cells each producing its own specific type of antibody, each directed at specific antigens, which the patient may or may not have been exposed to before. B-cells are the types of cells that give us long-lasting memory to many of the different type of childhood infections that we have had. And B-cells are the types of cells that react to vaccinations that we have had both in childhood and as adults. A subset of T-cells known as natural killer cells are a specialized type of T-cell, which can kill infected cells and attack cancer cells and are also active by cell-mediated or cytotoxic immunity.
Next, we go on to the monocyte lineage. Monocytes are larger white blood cells, which are different than lymphocytes and neutrophils. And they play an important role in killing yeast, fungi, and usual intracellular bacteria, such as listeria. They are also responsible for causing granulomatous infections, such as tuberculosis in patients who are infected with those. They often engulf the bacteria, or viruses, or fungi, or yeast, and form granuloma around them as their type of inflammation. Macrophages are a type of monocyte-derived cell which is more involved in phagocytosis. And they primarily resolve --- reside in various tissues, such as the lung or the soft tissue; whereas monocytes are often seen circulating in the blood stream. This is a picture of megakaryocyte, for example, that is engulfing various cells around it. As you can see here, this small cell within the cytoplasm of the megakaryocyte represents a polymorphonuclear leukocyte, which has perhaps been dying after being --- after attacking a foreign organism.
Next, we have eosinophils. Eosinophils are very easy to spot in the peripheral blood smear as they have a very red-looking cytoplasm. And on higher magnification you will notice that these red cytoplasms are actually made up of small red granules which are full of enzymes that help the eosinophil do its job. Eosinophils are very important in the immune reaction against the parasites such as worms and other things. They are also very involved in allergic response. Therefore, in patients with a very elevated eosinophil count, it is always important to look for, or think about parasitic infection or a recent allergic response.
Finally, we have basophils, also involved in allergic response because they release the different chemical mediators. And basophils are suspicious cells, which are not often seen in normal peripheral blood smear, but are elevated in certain malignant conditions such as chronic myelogenous leukemia.
Before we go on, let us talk about the normal lymphatic system. Now, we know that the normal lymphatic system is made up of lymphocytes, which are the T-lymphocytes and the B-lymphocytes. They not only reside in the bone marrow, but they have many other sites throughout the body. The thymus, which we know is the area where T-cells mature, lymph nodes, which are present throughout our body as shown here in this diagram. The green nodules here represent the lymph nodes, which are up and down our body and are connected by a series of channels, what we call lymphatic circulation. The spleen is also an important site, which is located in the left upper quadrant, but it is an important site for --- lymph node --- trafficking. Finally, the tonsils and adenoids are also lymphoid glands. And the entire digestive and respiratory tract are lined with small patches in the --- small Peyer's patches and other nodules, which contain large amounts of lymphocytes, which work to help surveillance against infections and local localized inflammation. Lymphocyte circulation occurs between these lymph glands, the spleen, the gastrointestinal system through the lymphatic channels, which I described.
So, now that we've talked a little bit about the normal hematopoietic system and where these cells reside, we should talk about some of the disease states. And, of course, one of the main disease states we need to discuss are cytopenias or low blood counts. This is often a common presentation that is seen in many patients in internal medicine offices or even patients who are seen by hematologists. The three types of cytopenias obviously are low white blood cell count or leukopenia, low red blood cell count or anemia, or low platelet count or known as thrombocytopenia. Low white cells can predispose patients to infections by other different organisms. Low red blood cell count will lead to anemia and will lead to shortness of breath, fatigue, and cardiovascular complications, as there will be a mismatch between the amount of oxygen needed and the amount of oxygen that is able to be transported by the blood. Low platelet count, as we mentioned before, puts you at a very high risk for bruising, bleeding. And this can result in bleeding gums, epistaxis, petechiae or small red rash all over your body, ecchymosis, or bruising, and internal bleeding. So, it is very important to watch for low platelet count, especially when they drop below 50,000, as this puts you at a very high risk for bleeding, spontaneous bleeding, especially the worrisome intracranial hemorrhages.
So, how does one evaluate cytopenias? And the first step we often do after doing the CBC and realizing there is cytopenia is to look at a peripheral blood smear. There are many clues in the morphology of the red blood cells, the white blood cells, and sometimes even clumping of the platelets that gives us an idea why the cytopenias may be occurring. The next step often is to look at a bone marrow aspiration or biopsy. And the reason for this is to try to figure out the etiology of the cytopenia, whether it is due to underproduction, where the bone marrow is not producing good blood cells or whether it is due to increased peripheral destruction. In other words, is the bone marrow completely normal and producing normal cells? And are these cells being destroyed elsewhere in the body? So this is an important distinction that needs to be made in the initial evaluation of cytopenias because the diseases are very different and the treatments are very different. Certain examples of underproduction are: myelodysplastic syndrome, which we will talk a little bit about later; aplastic anemia, in which the bone marrow is completely empty and devoid of any hematopoietic elements due to many different causes; vitamin deficiencies, such as iron deficiency, B12 deficiency ,or folate deficiency, which can all lead to anemia and some can also lead to leukopenia and thrombocytopenia; viral infections, such as HIV, hepatitis A, B, and C as well as CMV and Epstein-Barr virus, and other childhood viruses can actually lead to bone marrow damage and destruction on a temporary basis leading to a relatively aplastic marrow and low blood counts. Finally bone marrow infiltration is an important thing to realize when doing a bone marrow aspiration and biopsy in the evaluation of cytopenias. The bone marrow can be infiltrated with many different things including infections such as yeast or histoplasma; malignancies such as breast cancer, prostate cancer, thyroid cancer, and others; or a fibrosis in the case of myelofibrosis.
The other arm of evaluating cytopenias: if it's not underproduction in the bone marrow then we look for peripheral consumption and destruction. Usually in these states, the bone marrow is actually relatively normal or even hypercellular, meaning that the bone marrow is trying to compensate for the low cytopenias. And this can occur due to: autoimmune destruction, where the immune system outside the bone marrow is destroying the blood cells; sequestration in patients who have a large liver or spleen where the blood cells are residing and, therefore, out of the circulation; DIC or disseminated intravascular coagulation, in which the body is clotting incessantly and using up or consuming platelets and other factors causing a lower blood count; or mechanical problems, such as heart valves or other things, which cause shear stress and destroy these red --- destroy these blood cells on a more mechanical or physical level.
So just as a review, before we go on to the malignant portion of this talk, looking at the malignant types of hematopoietic disorders, let's go over the family tree, if you will, of hematopoietic lineage. On the left, we have what is called the very immature or early precursors of the different types of blood cells, and [on] the right side we have the mature or functional or active arm of the hematopoietic system. As we go from the immature and grow or mature into the more mature forms we lose proliferative capacity meaning they are able to --- they are less able to proliferate and divide rapidly, but we increase their functional capacity; in this case, fighting infection or engulfing organisms, or in this case, producing antibodies. So, if we start off there is hematopoietic stem cell, which often divides into myeloid and lymphoid lineages, the myeloid lineage, which can later on give rise to myeloid malignancies, such as AML or CML, can differentiate into red cells or granulocytes --- granulocytes/monocytes and give rise to these as mature cells. The lymphoid derivative of a stem cell often gives rise to T-cells and B-cells and can also give rise to lymphoid malignancies such as ALL or CLL.
So, leukemia, in general, is a group of neoplastic diseases characterized by abnormal proliferation of white blood cells because they are malignant and they are no longer subject to the normal cell division processes.
So, the different types of leukemias are acute leukemias and chronic leukemias. Acute leukemias are generally rapidly progressive diseases that are characterized by proliferation of immature precursors in the bone marrow and the blood, and immature meaning, if you remember the left side of that particular family tree, the earlier precursors. Chronic leukemias, on the other hand, are characterized more by proliferation of the mature precursors. So the defect in the actual leukemic cells is later on in the family tree where the actual white blood cell has matured somewhat. Myeloid leukemia as we talked about characterized by cells with characteristics similar to myeloid cells or their precursors. And lymphoid leukemias are characterized by cells with characteristics similar to lymphoid cells or their precursors.
This is an example of a peripheral blood smear of someone with acute leukemia. Notice that these are very immature-looking cells because they are large. They have very large nucleus with some nucleoli within them. And this is often a rapidly progressive disease.
So, the four major types of leukemia, as we outlined before: ALL, AML, CML, and CLL. We will briefly go through these in the next few slides.
So, the symptoms, in general, of leukemias are presented here. They're very nonspecific. Acute leukemia symptoms are generally not subtle. They are usually very, very aggressive and patients often present very sick to the hospital with symptoms such as: severe malaise and fatigue; high fevers; symptoms of anemia such as shortness of breath and severe fatigue; bone pain, as the leukemia is growing rapidly within the bone marrow, stretching the cortical bone causing severe bone pain. Many may have flu-like symptoms. Many may have opportunistic infections due to the immune defect that is associated. And in many cases, due to severe thrombocytopenia or DIC there may be bleeding complications. Chronic leukemia patients, on the other hand, may be somewhat asymptomatic in many cases. And the finding of leukemia may be an incidental finding, especially in the cases of CLL. But once again many of these patients especially in the more advanced stages will present with malaise, fatigue, weight loss. And, in --- unlike the acute leukemias, more commonly present with things like splenomegaly and lymphadenopathy, which are associated with CML and CLL, respectively.
So, on diagnos - on diagnosing leukemia, the peripheral blood cell can often reveal elevated white blood cell with mature or immature forms like we saw in the previous --- two slides ago. We can also see anemia and thrombocytopenia on the peripheral blood. The diagnosis of these diseases is confirmed by a bone marrow aspiration looking at a --- a monotonous infiltrated immature blasts in the case of acute leukemias or mature white blood cell forms in the case of chronic leukemias that replaces the normal hematopoiesis that should be there.
So, ALL or acute lymphocytic leukemia, is the most common leukemia in children. Although there are more adults with the disease than there are children with the disease because of the --- because of the longer life of adults, and the fact that many patients --- many children with ALL are often cured of the disease. The older classification is the FAB classification is what is used currently, but is slowly being --- teased out --- phased out. It has basically three different subcategories that we call L1, L2 and L3, and they basically describe the morphology. As we become more advanced with our biological or molecular biologic techniques, it has become more important to look at the flow cytometry of these cells as well as the cytogenetics or the chromosomes and some molecular markers. Phenotypically, we can talk about three big categories of ALL or acute lymphocytic leukemia, and these are pre-B ALL, which is perhaps the most common. These are often positive for markers such as TdT, Calla, and cytoplasmic IgG. Pre-T-cell ALL, or ALL that is derived from T-cell lymphocyte or early T-cell lymphocytes, are often positive for these markers. And clinically they often present with a large mediastinal mass, as the only site of disease. Finally, we have what is called the mature B-cell ALL, also known as Burkitt's leukemia/lymphoma, which is a very rapidly progressive disease that can be life threatening and must be treated immediately. Burkitt's leukemia/lymphoma is characterized by characteristic translocation involving chromosome 8, which has the myc oncogene. So we often see translocation t(2;8), t(8;14), or translocation t(8;22) as part of the disease that helps confirm the diagnosis of Burkitt's leukemia.
ALL is notable in that it has a high incidence of CNS disease or disease involving the central nervous system. Factors associated with/or prognostic for CNS involvement is a high initial white blood cell count at presentation and a high LDH at presentation. As a result of the CNS disease, just as an aside, the treatment of ALL involves the treatment --- involves intrathecal therapy or therapy within the cerebral spinal fluid to not only treat, but also to prevent further infiltration into the CNS. ALL can also present very commonly with extramedullary disease. Often sites of involvement are gonads, mediastinal mass, as we talked about in T-cell ALL, as well as lymphadenopathy.
This picture illustrates the demographics and the incidence of mortality of patients with ALL. As you see, there are two big peaks: a peak in the very young age, as you can see in this peach-colored background, and a peak in the elderly. However, what you will see in the solid blue line is that the mortality increases as you get older and the mortality is relatively low in patients with young age because, in fact, the leukemia, ALL in younger adults or in kids is very responsive to chemotherapy, has a better prognosis, and a very high cure rate.
The clinical presentation of ALL is listed here: again signs and symptoms of pancytopenia, such as risk of infection; bleeding; severe fatigue; bone pain, due to progressive leukemia; organomegaly, as we discussed; and the leukemia can infiltrate the liver, spleen, and lymph nodes. SVC syndrome or superior vena cava syndrome can occur from mediastinal lymphadenopathy that can often happen as the presenting sign of T-cell ALL. Neurologic symptoms may also be presenting signs such as a facial droop, aphasia, or other stroke-like symptoms because of CNS disease. Leukocytosis may occur with white counts of 100 to 200,000. But leukostasis, where the elevated white blood cell count causes neurologic or pulmonary symptoms is pretty rare. There are also metabolic abnormalities associated with advanced leukemia such as Tumor Lysis Syndrome. We have elevated potassium, elevated uric acid, and sometimes worsening kidney function.
Cytogenetics or chromosomes are very important in the diagnosis and now as well in the treatment of leukemia, not only ALL, but many other acute leukemias as well as chronic leukemias as we will be able to see in the next few slides. This pie chart shows a relative distribution of different cytogenetic abnormalities in adult ALL, which are important. I will point out a few that are quite important. As you can see, the most common is diploid or no cytogenetic abnormality. But the second most common is translocation t(9;22), also known as the Philadelphia chromosome. This is important because this translocation portends a very poor prognosis in patients of adult ALL and these patients, after receiving chemotherapy, should move forward with a stem cell transplant in their first remission. Other important subtypes are translocation t(4;11) or translocations involving 11q23, which in some incidences include translocation t(4;11). This is another subgroup of patients that also has a relatively poor prognosis and should consider getting aggressive high-dose therapy followed by stem cell transplant after they achieve a remission. On this end, translocation t(12;21), in fact, is associated with a better prognosis, as most often seen in younger kids.
This is a table looking at the types of chromosomes and the prognosis that they portend. As you can see, Philadelphia chromosome, which is not very common in kids, is much more common in adults and has a very low cure rate. Hyperdiploid or having more than 46 chromosomes has a high incidence in pediatrics and is also associated with a higher cure rate. Translocation t(12;21), another one that is associated with high pediatric incidence and a relatively high cure rate.
Now we will turn to AML or acute myelogenous leukemia. It's much more common in adults than ALL. And this is the FAB or French-American-British Classification that we have used for many, many years. And is currently used as more of a historical marker rather than used in treatment, except with the exception of M3 or APL, which is treated much differently and now has a very high cure rate. These are the FAB Classifications listed here.
Again, the clinical presentation is similar to other acute leukemias, rapidly progressive and worsening clinical symptoms. A bone marrow that has greater than or equal to 20% blasts of which more than --- greater than or equal to 3% are myeloperoxidase or MPO positive. This gives you the diagnosis of AML. This 20% blast is important because if it's less than 20% blasts, similar myeloid diseases are known as myelodysplastic syndrome according to the current classification system. This is an important way to distinguish acute myeloid leukemia from high-risk MDS. The comp --- the other presenting signs again are complications of pancytopenia that we discussed previously, bone pain due to progressive leukemia, leukocytosis or very elevated white blood cell count. The difference between AML and ALL is that, in patients with AML with a very high white blood cell count, they are at risk for leukostasis. And this essentially means that they can have complications in their pulmonary system, their neurologic system, and other areas due to very high white blood cell count, as the white cells are thought to be a little bit more "sticky" [quote-unquote] and because they have better adhesion to the endothelial cells and cause problems related to sludging in the arteries and capillaries. A relatively uncommon presentation of AML is something called a myeloid sarcoma in which there is an extramedullary presentation or mass associated with AML. And this can be anywhere in the body. They can also appear on the skin and this is known as leukemia cutis.
The prognosis of AML is relatively poor. The median overall survival is about 12 months on average. Over the past 15 to 20 years we have been improving the treatment of AML. And in younger patients the overall survival has improved somewhat to an average of 21 months. But in patients above the age of 55, the median overall survival is still grave of 6 to 8 months. And so further therapies are continued to be developed for this particular population. The maj --- In addition to age, the other major prognostic characteristics are cytogenetics or chromosomes and they are divided into three categories known as favorable, intermediate, or adverse. And we will talk about that soon in the next slide. Performance status is an important determinant of prognosis. The better performance status you have, the better you do. And finally, newer things are on the horizon, such as molecular subtypes, the so-called "FLIT3" or FLT3 mutation, which is presented in about a third of AML. Patients who have FLT3 mutations are known to have a very proliferative and aggressive disease. There is a high risk of relapse and a relatively adverse prognosis. This is a population which we would recommend getting a stem cell transplant in first remission. NPM mutation in approximately a third of AML is associated with a favorable prognosis in patients who have an NPM1 mutation but who do not have FLT3 mutation. CEBPα is also another mutation that helps associate with the prognosis.
So, these are the cytogenetics categories I was talking about. Favorable include three, translocation t(15;17) or APL, inversion 16, and translocation t(8;21); the last two known as core binding factor leukemias. The unfavorable are known are minus 5 or monosomy 5, monosomy 7, 11q23, among others. And the rest of them fall into the intermediate category. Complex cytogenetics or any cytogenetic karyotype having three or more abnormalities is also considered an unfavorable karyotype.
What we realized over the years is that we can divide patients --- divide patient's survival according to their cytogenetics. And so in patients who have so called "favorable" cytogenetics they have a very high median duration of remission of about 2 years with about 50% cure fraction. Whereas people with "adverse" or "bad" cytogenetics that we saw on the previous slide, have a very poor duration of remission as you see, 3 to 6 months, with a very low cure rate. And so it is important to stratify these patients by cytogenetics so that their treatments can be appropriately targeted.
Next, we move on to chronic myelogenous leukemia or CML. This is a rare disease with a peak incidence about 40. However, the prevalence of this disease is increasing because more and more people with CML are living, due to the advent of new drugs known as tyrosine kinase inhibitors. CML is characterized by elevated white blood cell count with mature neutrophils that are in the peripheral blood and the bone marrow. Sometimes the platelet count may be elevated. This is often associated with Phila --- with splenomegaly, but the hallmark of this disease is the positivity for Philadelphia chromosome or the translocation between 9 and 22. There are three phases of CML known as chronic phase, accelerating phase, and blast phase, which are treated slightly differently. Most people present in chronic phase and the blastic phase is more of an acute leukemia type of presentation which requires chemotherapy usually in addition with the tyrosine kinase inhibitor.
This is a Karyotype. We're looking at chromosomes 9 and 22 and the Philadelphia chromosome is often associated with a translocation of 9 and 22.
The translocation between these two chromosomes leads to the fusion gene product of BCR-ABL, but which is an abnormal gene product which is constitutively active and drives the CML process. Small molecule tyrosine kinase inhibitors such as imatinib, nilotinib, and dasatinib have revolutionized the treatment of this disease and are currently the front line of care for these diseases.
Chronic lymphocytic leukemia is currently the most common adult leukemia in the western world. It has co-expression of CD5, 19, and CD23, but is CD10 negative and is very unique for most B-cell neoplasms having this, where it shares this particular phenotype only with mantle cell lymphoma. There are several stages here listed: where the highest stage in people who have thrombocytopenia; isolated anemia is known as Rai stage 3; having splenomegaly is Rai stage 2; and having lymphadenopathy alone is Rai stage 1.
Much like the other leukemias, we have to do all prognostic indicators. These indicators including staging of the disease that we just discovered --- discussed, Rai stages 0 through 4; elevated doubling time, meaning that the lymphocyte count in the peripheral blood doubles at a quicker pace; and in cytogenetics, as we discover --- discussed previously in other leukemias, 13q in this case. 13q deletion is considered favorable, 17p deletion or 11q23 abnormality are both considered unfavorable, whereas trisomy 12 is considered an intermediate prognosis. ZAP70, which is often done by immunohistochemistry or by flow cytometry, suggests that the disease is more aggressive and carries a more adverse prognosis if it is positive in lymphocytes.
The immunoglobulin heavy-chain gene mutation is also an important prognostic characteristic in chronic lymphocytic leukemia. In patients who are unmutated, defined as less than 3% change from the germline, the disease is usually considered more aggressive with an adverse prognosis; whereas mutated is considered or carries a better prognosis. A CD38 positivity, a higher percentage of the positivity by flow cytometry, considers --- portends a more aggressive disease and beta-2-microglobulin is a serum marker. The higher level often correlates with the higher bulk of disease and a more adverse prognosis.
Finally, we will talk about myelodysplastic syndrome or MDS. And this is an interesting disorder because the incidence of MDS has increased significantly over the past 5 to 10 years, perhaps due to a greater recognition of this disease. It is a heterogeneous group of malignanc --- clonal stem cell disorders characterized by an ineffective and disordered hematopoiesis usually resulting in peripheral blood cytopenias. Therefore, in this particular disease, in the bone marrow, you often see a hypercellular bone marrow with lots of cellular elements, but low blood counts peripherally. There is usually not peripheral destruction but that the bone marrow precursors themselves are not able to mature sufficiently and, therefore, the hematopoiesis is ineffective. MDS is often known as pre-leukemia in many cases by many people.
The clinical presentation of MDS: most of the patients with MDS are greater than 70 years of age. So it is a disease usually of the elderly, half of the patients usually have no symptoms and often just present to their doctor for normal blood clots and find to be anemic or slightly thrombocytopenic or leukopenic. Most common symptoms that people present for are due to anemia, due to fatigue. Some people present with bleeding or infection and physical findings are usually uncommon and splenomegaly is not very common. Some patients may present with fever due to underlying leukopenia and concomitant infection.
The laboratory evaluation of MDS is listed here. Bone marrow we described earlier, the presence of ineffective hematopoiesis. About half of the patients present with some cytogenetic abnormalities that we discussed previously, but are somewhat, a little bit different in MDS and these include chromosomal deletions or extra chromosomes. And there is also dysplasia in one or more cell lines, and dysplasia is abnormal-appearing cells that do not mature into functional blood cells.
So, cytogenetics changes in MDS are listed here. The most common: monosomy 7, monosomy 5, trisomy 8, 5q minus, and less common ones are also listed there. There is also an entity called treatment-related MDS, which is becoming more recognized. And this is a type of myelodysplastic syndrome that occurs in patients who have been treated previously for another malignancy with things such as alkylating agents or topo-II --- topoisomerase-II inhibitors and their associated cytogenetics are listed here.
This is the FAB Classification which had been used previously. And this gives you an idea of the lower risk MDS, which is refractory anemia, and refractory anemia with ringed sideroblasts to the higher more aggressive MDS type of categories. What is interesting here is looking at the bone marrow blast percentage and how this is changed with a WHO Classification. In the past, patients who had refractory anemia with excess blasts in transformation were considered MDS, but in fact anyone who has 20% or greater blasts currently in the WHO Classification is considered AML.
This is the current classification. The ones listed in green here are the lower risk MDS. And as you go down into the red, it is considered high-risk MDS with a higher proportion of blasts in the bone marrow and the peripheral blood as well as more adverse cytogenetic abnormalities and more cytopenias.
This is an important tool that is currently used clinically called the International Prognostic Scoring System for MDS. And it gives us an idea to tell patients about their overall prognosis and three major characteristics are used. One is a percentage of bone marrow blast, the second is karyotype or cytogenetics, and the third is the number of cytopenias. Using these three variables, we give --- we give each patient a score as listed in this table. The cytogenetics are listed here. And depending on their - depending on their number of points they are put into different categories, such as low risk, intermediate 1, intermediate 2,or high risk. The reason this is important is that the overall survival of these patients' ranges from about 6 years in patients with low-risk MDS all the way up to 6 months in patients with high-risk MDS.
And finally, in conclusion, as a summary, we have reviewed the normal hematopoietic system. We have talked about some of the diseases and the presentation of various hematologic malignancies such as leukemia. In the next section, we will hear about lymphoma, multiple myeloma. And hopefully you have been able to distinguish myelodysplastic syndrome from acute myeloid leukemia. Thanks again for listening. If you have any feedback or questions, please let us know.
Hematologic Malignancies: Diagnosis and Staging, Part 1 video
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