The Complete Hematopathology Guide Web Sample Long1 (1)

About th is guide If you’re reading this introduction, it means you are probably either a) covering hematopathology in your pathology class right now, or b) studying for boards. Either way, you’ve come to the right study guide! Inside, you’ll find a comprehensive (but not oppressive) review of both benign and malignant hematopathology, neatly summarized and nicely illustrated. Whether you have a read-the-text-straight-through kind of mind, or a looking-at-pictures mind, or a question-working mind, you’ll find it easy to work your way through this guide. Extra help If you are stuck, or frustrated, or if something just doesn’t make sense, feel free to email me at [email protected]. I’ll do my best to get you unstuck and back on track.

© 2013 Pathology Student

The Complete (but not obsessive) Hematopathology Guide page 2

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Table of Contents 1. Introduct ion…………………………………… p. 5

2. Anemia………………………………………… p. 12

3. Benign leukocytoses……………………….. p. 39

4. Leukemia……………………………………… p. 46 Acute myeloid leukemia………………….. p. 48 Myelodysplastic syndromes……………… p. 59 Acute lymphoblastic leukemia…………… p. 60 Chronic myeloproliferative disorders…….. p. 65 Chronic lymphoproliferative disorders…… p. 72

5. Myeloma……………………………………….. p. 78

6. Lymph node disorders………………………. p. 80 Benign lymph node disorders……………. p. 80 Non-Hodgkin lymphoma…………………. p. 83 Hodgkin disease………………………….. p. 93

7. Reference sect ion……………………………. p. 96

8. Study quest ions………………………………. p. 102

List of Diseases

Anemia Iron-deficiency anemia Megaloblastic anemia Hemolytic anemias Hereditary spherocytosis G6PD deficiency Sickle cell anemia Thalassemia Warm autoimmune hemolytic anemia Cold autoimmune hemolytic anemia Microangiopathic hemolytic anemia Anemia of chronic disease Anemia of chronic renal disease Anemia of chronic liver disease Aplastic anemia

Benign leukocytoses Benign neutrophilia Benign lymphocytosis Other leukocytoses

Leukemia Acute myeloid leukemia

AML with genetic abnormalities AML with FLT3 mutation AML with multilineage dysplasia AML, therapy-related AML, not otherwise classified

Myelodysplastic syndromes Acute lymphoblastic leukemia

T-cell ALL B-cell precursor ALL Burkitt leukemia

Chronic myeloproliferative disorders Chronic myeloid leukemia Chronic myelofibrosis Polycythemia vera Essential thrombocythemia Chronic lymphoproliferative disorders Chronic lymphocytic leukemia Hairy cell leukemia Prolymphocytic leukemia Large granular lymphocyte leukemia

Myeloma

Lymph node d isorders Benign lymph node disorders Non-Hodgkin lymphoma Small lymphocytic lymphoma Marginal zone lymphoma Mantle cell lymphoma Follicular lymphoma Mycosis fungoides/Sézary syndrome Diffuse large B-cell lymphoma Lymphoblastic lymphoma Burkitt lymphoma Adult T-cell leukemia/lymphoma Hodgkin disease Nodular lymphocyte predominance Nodular sclerosis Mixed cellularity Lymphocyte rich Lymphocyte depletion



Chronic Leukemias

Chronic leukemias are very different from acute leukemias. Chronic leukemias are for the most part diseases of older adults (acute leukemias occur in both children and adults). They appear in an insidious fashion and have a relatively good prognosis (as opposed to acute leukemias, which have a stormy onset and poor prognosis). In addition, chronic leukemias are composed of fairly mature-appearing hematopoietic cells (as opposed to acute leukemias, which are composed of blasts). There are two kinds of chronic leukemias: myeloid and lymphoid. Instead of being reasonable, and calling them “chronic myeloid leukemias” and “chronic lymphoid leukemias,” the powers that be dubbed the two divisions “chronic myeloproliferative disorders” and “chronic lymphoproliferative disorders.” These names are not so great, in my opinion, since these are not just “disorders” – they are real leukemias! But no one asked me. Pathophysiology The chronic leukemias are malignant, monoclonal proliferations of mostly mature myeloid or lymphoid cells in the bone marrow (and blood). These leukemias progress more slowly than acute leukemias. So early on, the marrow is involved – but not totally replaced – by malignant cells. Still, it is hard for the normal white cells to function properly. The lymphoid cells, in particular, have a hard time making normal immunoglobulin in certain chronic lymphoproliferative disorders. One of the major causes of mortality in these patients is infection. As the chronic leukemias evolve, more and more of the marrow is replaced by tumor, and eventually there is little room for normal white cells to grow. Cl inical Features Chronic leukemias present in over a period of weeks or months. Patients might have splenomegaly (which shows up as a dragging sensation or fullness in the left upper quadrant of the abdomen), lymphadenopathy, or a general feeling of malaise and fatigue. Some patients are asymptomatic at diagnosis, and the disease is picked up on a routine blood smear or CBC. Likewise, the clinical course is different in chronic leukemia. In many cases of chronic leukemia, patients can live for years without treatment at all.



Chronic Myeloproliferative Disorders

The chronic myeloproliferative disorders are malignant clonal proliferations of a pluripotent stem cell that lead to excessive proliferation of myeloid cells in the blood and bone marrow. What that means in plain English is that a stem cell somewhere way back (before it’s even committed to the neutrophil line, or red cell line) goes bad and starts proliferating like crazy – so you wind up with a marrow packed with cells from all the myeloid lineages (the official name is “panhyperplasia”). Usually, one particular myeloid lineage predominates in this growth fest – so you’ll see a ton of all the myeloid cells, but the majority are neutrophils, or red cells, or megakaryocytes. So the chronic myeloproliferative disorders have been divided into four types according to what is proliferating most:

• Chronic myeloid leukemia (tons of neutrophils and precursors) • Polycythemia vera (tons of red cells and precursors) • Essential thrombocythemia (tons of platelets and megakaryocytes) • Chronic myelofibrosis (tons of everything…then nothing! See below.)

We’ll consider each of these separately because they are very different clinically and morphologically. But they do have some common features: all of them have a high white count with a left shift, a hypercellular marrow, and splenomegaly. Chronic myeloid leukemia Chronic myeloid leukemia (CML) is a chronic myeloproliferative disorder characterized by a marked proliferation of neutrophils (and precursors) in the bone marrow and blood. All cases have a t(9;22), also known as the Philadelphia chromosome (it’s the 22 that’s officially the Philadelphia chromosome). Cl in ical Features CML frequently occurs in patients who are around 40 or 50. It does not occur in children (though there is a separate disease similar to CML, called juvenile CML, that does occur in kids). Usually, the onset is slow, with a long asymptomatic period, followed by fevers, fatigue, night sweats and abdominal fullness. On physical exam, patients usually have an enlarged spleen. Hepatomegaly and lymphadenopathy may also be present.

CML, PV, ET, and Chronic myeloproliferative disorders:

chronic myelofibrosis

CML has a t(9;22).



There are three clinical stages, or phases, of CML: chronic phase, accelerated phase and blast crisis. Patients generally present in chronic phase and then progress to one or both of the other phases.

Chronic phase • High but stable number of neutrophils and precursors. • Stable hemoglobin and platelet count. • Easily controlled by therapy. • With traditional treatment (not imatinib, see below), usually lasts 3-4 years; is then followed

by accelerated phase and/or blast crisis.

Accelerated phase • Characterized by a change in the patient's previously stable state. • Usually see increasing leukocytosis, decreasing hemoglobin and platelet count. • May terminate in this stage, or may progress to blast crisis. • Usually fatal within several months.

Blast cr is is • Characterized by a marked increase in blasts (myeloblasts or lymphoblasts). • Usually fatal within a few weeks or months.

Morphology Blood The blood smear shows a marked neutrophilia with a left shift. The left shift is a little weird in that it is not evenly distributed between all the neutrophil stages. There are tons of neutrophils at all stages of development, but there are relatively more myelocytes and segmented neutrophils (and relatively less of the other stages). There are a few myeloblasts around (which you don’t see in normal blood, of course) but they don’t number more than 2 or 3%. Here’s an interesting thing: patients with CML almost always have a basophilia. That’s actually one of the first things that happens in the development of the disease! There are few if any other reasons for a basophilia. So if you see this in a patient, even if they don’t have the typical findings of CML (big white count with lots of neutrophils and precursors), you should rule out CML! The platelet count may be increased (because of all the megakaryocytes around in the bone marrow).

Chronic myeloid leukemia: marked neutrophilia,

left shift, and basophilia

CML: blood



Bone marrow The bone marrow is hypercellular, with a pan-myeloid hyperplasia (all the myeloid cells are increased – neutrophils and precursors, red cell precursors, megakaryocytes). However, if you look closely, you’ll see that the neutrophils and precursors make up the bulk of the cells. Later in the course of the disease, the marrow may become fibrotic. You can detect this using a reticulin stain. This is not a good sign. Pathophysio logy All cases of CML have a translocation between chromosomes 9 and 22, resulting in what’s commonly known as the Philadelphia chromosome (Ph). This designation refers to the new chromosome 22 that results from the translocation. Nobody talks about poor chromosome 9. The translocation places the c-abl proto-oncogene on chromosome 9 next to the bcr gene on chromosome 22. A new, fusion gene is created: the bcr-abl gene. The bcr-abl gene encodes a protein called p210, which increases tyrosine kinase activity and disrupts the cell cycle. Here’s a weird fact: the Philadelphia chromosome is found not only in the myeloid cells, but also in some B lymphocytes! That’s weird, considering that this is a myeloid lesion with no apparent changes in the lymphoid cells. This probably means that the initial bad cell (the one that became malignant) was a very early stem cell, one that hadn’t even committed itself to myeloid or lymphoid lineage yet, and the Philadelphia chromosome is present in all the descendents of that cell. Further supporting this idea is the fact that when patients enter blast crisis, the blasts can be lymphoid! Treatment and Prognosis In the old days, CML was treated with myelosuppressive agents like hydroxyurea, and then if the patient had a match and could tolerate it, allogeneic bone marrow transplant was performed. That was the only hope for a cure. Recently, a new drug called imatinib (or Gleevec) was developed that targets the messed-up tyrosine kinase receptor activity in CML. It has been like a miracle for many patients – even patients in the later stages of the disease. In fact, we don’t even know what the typical prognosis of CML is anymore, because these patients are still living with the disease. This drug has turned CML into a chronic but treatable disease, like diabetes, for many patients. It’s one of the happiest leukemia research stories ever.

CML: bone marrow



Chronic myelof ibrosis Chronic myelofibrosis, also called idiopathic myelofibrosis or agnogenic myeloid metaplasia, is a chronic myeloproliferative disorder characterized by panmyelosis, bone marrow fibrosis, and extramedullary hematopoiesis. In real words: the bone marrow at first is markedly hypercellular, but over time, it becomes fibrotic, and the hematopoietic cells go elsewhere (most often, to the spleen) to try to make a home. Cl in ical Features Like the other chronic leukemias, chronic myelofibrosis is a disease of older adults. The peak age is in the late 50s. The disease presents over a relatively long period of time, with symptoms of splenomegaly (left upper quadrant pain and fullness, epigastric pressure) and anemia (weakness, fatigue, and palpitations). A small number of patients are asymptomatic at diagnosis. Physical examination shows massive splenomegaly in most patients, as well as signs of anemia (pallor, tachycardia). Morphology Blood The blood smear shows a leukoerythroblastosis (remember this term from benign leukocytoses? If not, see page 41). There are lots of teardrop red cells in the blood due to the tight spaces (fibrotic marrow, big spleen) the red cells have to squeeze through. The platelets are often weird looking (large and hypogranular). Bone marrow Early on, the marrow is hypercellular, with a pan-myeloid hyperplasia. Megakaryocytes, in particular, are markedly increased in number. Later on, the marrow becomes fibrotic, and in the end stages of the disease, it is entirely replaced by fibrotic tissue, with very few remaining hematopoietic cells. Pathophysio logy The cause of the fibrosis is still not completely worked out. The fibroblasts are benign – so why are they so active? It’s probably a result of megakaryocyte stimulation. Megakaryocytes are known to release cytokines that stimulate fibrosis – and in chronic myelofibrosis, there are tons of megakaryocytes around. So this seems like a plausible explanation.

Chronic myelofibrosis: marrow fibrosis,

extramedullary hematopoiesis and teardrop red cells

Chronic myelof ibrosis : blood

Chronic myelof ibrosis : bone marrow



Treatment and Prognosis Chronic myelofibrosis has a relatively long course (mean survival is 5 years). Treatment usually consists of supportive measures (like red cell transfusions) and myelosuppressive therapy (like hydroxyurea) if the patient can tolerate it. The cause of death in patients with chronic myelofibrosis is usually marrow failure. A small number of patients undergo leukemic transformation (meaning that they develop an acute leukemia – like the blast crisis phase we talked about in CML). Interestingly, the acute leukemia can be either myeloid or lymphoid! Polycythemia Vera Polycythemia vera (PV) is a chronic myeloproliferative disorder characterized by panmyelosis, with an erythroid predominance. In real words: the marrow is stuffed with myeloid cells, and most of them are red cell precursors. The blood shows a markedly increased red cell count. “Polycythemia" just means an increase in red blood cell mass. It may be:

• Primary (polycythemia vera or true polycythemia): increase in red blood cells caused by an intrinsic abnormality of myeloid cells (no ↑ in erythropoietin).

• Secondary: increase in red blood cells caused by ↑ secretion of erythropoietin, which may be appropriate (e.g., high-altitude living) or inappropriate (e.g., a paraneoplastic syndrome related to a solid tumor).

To distinguish between primary and secondary polycythemia, and to differentiate PV from other chronic myeloproliferative disorders, a polycythemia vera study group came up with the following Polycythemia Vera Study Group Criteria (how creative). To diagnose PV, you need either (1) A1, A2, and A3, or (2) A1, A2, and any two from B: A (major) cr i ter ia A1 Increased RBC mass A2 Normal O2 saturation in blood A3 Splenomegaly B (minor) cr i ter ia B1 Thrombocytosis B2 High WBC without infection B3 Increased leukocyte alkaline phosphatase (see box at right) without infection B4 Increased serum B12 level

Things to make you look smart Q. What is leukocyte alkal ine phosphatase (LAP)? A. LAP is an enzyme present in normal neutrophils. It is strangely absent in the neutrophils in CML – so it was used in the olden days (before cytogenetics) to distinguish between a benign neutrophilia and CML. LAP is expressed at normal levels in the neutrophils in PV. Why is that? Who knows! But it’s important – because if you have a lot of neutrophils around, and you think it’s a chronic myeloproliferative disorder, you could do an LAP. If it was low or zero, that would be a pretty good indicator of CML. If it was increased, it could be PV (you’d still have to rule out infection though). Nowadays, we use other means to diagnose these disorders. But you’ll still hear people (and books) talk about the LAP. So now you know.

Polycythemia vera: tons of red cells



Clin ical Features Polycythemia vera, like the other chronic leukemias, is a disease of older adults; the mean age at diagnosis is 60. Symptoms and signs are related to the massive increase in red cell mass. Patients may have headaches, weakness, pruritis and dizziness (from increased blood volume); they may also have symptoms of vascular stasis, thrombosis or infarction (from increased blood viscosity). Physical examination may show hepatosplenomegaly, and something called “plethora,” which means ruddiness or redness of the head and neck.

Morphology Blood For most of the course of the disease, the red cell count is markedly increased. So are the white cell count and the platelet count. Towards the end stages of the disease, though, the marrow can become pooped out (the official name for this is “spent phase”) and quit making red cells. Then the patient’s red cell count goes down, and the patient may even become anemic. Bone marrow The marrow is hypercellular, with a pan-myeloid hyperplasia. Red cells make up the bulk of the myeloid cells in the marrow. Towards the end of the disease, however, the marrow may become fibrotic, and red cell production may decrease.

Pathophysio logy Recently, a unique genetic abnormality was found to be present in virtually all patients with polycythemia vera. There is a normal signaling pathway present in all kinds of organisms, from slime molds to humans, called the JAK-STAT (Janus kinase-signal transducer and activator of transcription) pathway. It’s a pretty cool pathway because it transmits signals from outside of the cells (like growth hormone signals) to the nucleus of the cell without the need for second messengers (which most other receptors need to use). It turns out that myeloid growth and development is mediated, in part, by this pathway. Patients with polycythemia vera have a mutation in the JAK part of this pathway (specifically, in the JAK-2 gene), which makes the JAK think it’s getting signals when it’s not. So cells with this mutation are constantly getting signals to grow! The mutation has been found in virtually all cases of polycythemia vera (making it a great tool for differentiating primary from secondary polycythemia), and in a significant number of patients with chronic myelofibrosis and essential thrombocythemia too.

Treatment and Prognosis Treatment usually involves phlebotomy, with or without myelosuppressive drugs. Survival is long (average 9 - 14 years). Dangers include thrombosis, hemorrhage, and transformation into acute leukemia.

Virtually all cases of

JAK-2 mutation polycythemia vera have a



Essential Thrombocythemia Essential thrombocythemia (ET) is a chronic myeloproliferative disorder characterized by panmyelosis, with a megakaryocytic predominance. Meaning: the marrow is stuffed full of myeloid cells, and the predominating cell is the megakaryocyte. The blood shows a markedly increased platelet count. The diagnosis of ET is basically one of exclusion. You have to rule out benign causes of thrombocytosis and all of the other chronic myeloproliferative disorders. Here are the criteria:

• Platelet count must be >600 x 109/L (normal = 150 – 450). • Hgb must be <13 g/dL or RBC mass must be normal (excludes PV). • Philadelphia chromosome must be absent (excludes CML). • Marrow must lack fibrosis (excludes chronic myelofibrosis). • All other causes of thrombocytosis (e.g., iron deficiency anemia, cancer) must be excluded.

Cl in ical Features ET usually occurs in patients over 50, but occasionally it occurs in young women. Symptoms are those related to thrombotic phenomena (like myocardial infarction, stroke, and deep venous thrombosis). Some patients also have excessive bleeding, which you wouldn’t expect, if you have all those platelets around. The cause is a secondary (or acquired) von Willebrand disease! Weird. Physical examination may reveal mild splenomegaly, pallor and tachycardia (if the patient is anemic), and purpura and ecchymoses (if the patient has developed a secondary von Willebrand disease). Morphology Blood The blood shows a ton of platelets - usually the count is over a million. The platelets usually look abnormal; they are often large and/or hypogranular. Bone marrow The bone marrow shows normal to increased cellularity, and tons of megakaryocytes, which are often described as being “back-to-back.” Treatment and Prognosis The main aim of treatment is to reduce the chances of hemorrhage or thrombosis. Usually platelet pheresis or myelosuppressive drugs are used to lower the platelet count. Aspirin is also used to decrease the risk of clotting. Most patients survive at least 5-8 years. Death is usually related to hemorrhage or thrombosis, but a small number of cases undergo leukemic transformation.

tons of platelets

ET: bone marrow

ET: blood

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