Heme 02: Wbcs, Reactive-Neoplastic Myeloid, Leukemia

Front 1

Where are WBCs distributed?

Back 1

- Bone marrow
- Peripheral blood
- Lymph nodes, thymus, spleen, tonsils, adenoids, Peyer patches
- Mucosa-Associated Lymphoid Tissue (MALT) in lung and GI tract

Front 2

Where does WBC maturation begin? With what?

Back 2

- Starts in bone marrow
- With Pluripotent Stem Cell

Front 3

What lineages can the Pluripotent Hematopoietic Stem Cell in BM differentiate into?

Back 3

- Myeloid
- Erythroid
- Megarkaryocytic
- Lymphoid

Front 4

What are the types of Myeloid WBCs?

Back 4

- Monocytes
- Neutrophils
- Eosinophils
- Basophils

Front 5

What kind of cells are these?

Back 5

Neutrophils

Front 6

What kind of cells are these?

Back 6

Basophils

Front 7

What kind of cells are these?

Back 7

Eosinophils

Front 8

What kind of cells are these?

Back 8

Monocytes

Front 9

What kind of cells are these?

Back 9

Lymphocytes

Front 10

What is the term for NON-neoplastic conditions affecting WBCs?

Back 10

Benign Leukocyte Disorders (clonal disorder)

Front 11

What are the types of Neoplastic conditions affecting WBCs? Location?

Back 11

- Leukemias: proliferation of neoplastic cells, primarily in BM and PB

- Lymphomas: proliferation of neoplastic cells, primarily in Lymph Nodes and extramedullary lymphoid tissue

Front 12

What are the types of Benign Leukocyte Disorders?

Back 12

- Qualitative (structural or functional) disorders
- Quantitative disorders (increased WBCs = cytoses; decreased WBCs = cytopenias)

Front 13

What is the term for a Benign Leukocyte Disorder with increased WBC number?

Back 13

Cytoses

Front 14

What is the term for a Benign Leukocyte Disorder with decreased WBC number?

Back 14

Cytopenia

Front 15

What are the types of Quantitative Benign Leukocyte Disorders?

Back 15

- Cytoses (increased WBCs)
- Cytopenias (decreased WBCs)

- Leukemoid Reaction
- Leukoerythroblastic Reaction

Front 16

What happens in a Leukemoid Reaction?

Back 16

- Benign, exaggerated response to infection
- NOT leukemia

Front 17

What are the blood cell counts in Leukemoid Reaction?

Back 17

- ↑ Leukocytes > 50,000 / µL
- May involve neutrophils, lymphocytes, or eosinophils

Front 18

What change in WBCs will a severe infection in perforating appendicitis cause?

Back 18

Neutrophilic Leukemoid Reaction:
- Benign Leukocyte Disorder
- Absolute leukocyte count usually >50,000/µL
- Specifically elevated neutrophils

Front 19

What change in WBCs will whopping cough cause?

Back 19

Lymphocytic Leukemoid Reaction:
- Benign Leukocyte Disorder
- Absolute leukocyte count usually >50,000/µL
- Specifically elevated lymphocytes

Front 20

What change in WBCs will a nematode infestation, such as cutaneous larva migrans cause?

Back 20

Eosinophilic Leukemoid Reaction:
- Benign Leukocyte Disorder
- Absolute leukocyte count usually >50,000/µL
- Specifically elevated eosinophils

Front 21

What are the types of Leukemoid Reactions? Causes?

Back 21

- Neutrophilic: severe infection in perforating appendicitis
- Lymphocytic: whooping cough (Bordetella pertussis)
- Eosinophilic: nematode infestation (eg, cutaneous larva migrans)

Front 22

What happens in a Leukoerythroblastic Reaction?

Back 22

- Benign Leukocyte Disorder
- Presence of immature bone marrow cells in the peripheral blood
- Immature WBCs (blasts) or RBCs (nucleated RBCs)

Front 23

What can cause a Leukoerythroblastic Reaction?

Back 23

- Bone marrow infiltrative process such as bone marrow fibrosis or metastatic cancer
- A severe bone marrow stress d/t benign conditions such as sepsis or growth factor administration may also cause a similar phenomenon
- Leads to immature WBCs (blasts) or RBCs (nucleated) to be released into the peripheral blood

Front 24

What is the blood count in a Neutrophilia? What can cause a Neutrophilia?

Back 24

- Absolute Neutrophil count > 7000 / µL
- Infection (eg, acute appendicitis)
- Sterile inflammation w/ necrosis (eg, acute MI)
- Drugs (eg, granulocyte colony stimulating factor (G-CSF), steroids, catecholamines, lithium)

Front 25

What drugs can cause Neutrophilia?

Back 25

- G-CSF (granulocyte colony stimulating factor)
- Steroids
- Catecholamines
- Lithium

Front 26

What happens to neutrophils during an infection?

Back 26

- Increased neutrophils = neutrophilia
- Neutrophils are not only increased in number, but also have prominent blue primary granules (instead of usual orange secondary granules) = Toxic Change

Front 27

What happens during a "toxic change" to neutrophils?

Back 27

During infection, prominent neutrophil granules go from orange secondary granules to blue primary granules

Front 28

What is the blood count in a Neutropenia? What can cause a Neutropenia?

Back 28

- Absolute neutrophil count < 1500 / µL
- Aplastic Anemia
- Immune destruction (eg, systemic lupus erythematous)
- Septic shock
- Chemotherapy for various malignancies

Front 29

What is the blood count in a Eosinophilia? What can cause a Eosinophilia?

Back 29

- Absolute eosinophil count > 700 / µL
- Type I hypersensitivity rxn (eg, bronchial asthma, penicillin allergy, hay fever)
- Invasive helminths (eg, strongiloidiasis, hookworm)
- Hypocortisolism (eg, Addison's disease)
- Neoplasms (eg, Hodgkin's lymphoma)

Front 30

What is the blood count in a Basophilia? What can cause a Basophilia?

Back 30

- Absolute basophil count > 200 / µL
- Chronic Kidney Disease
* Chronic Myelogenous Leukemia (and other myeloproliferative neoplasms)

Front 31

What blood count abnormality is most frequently encountered in Chronic Myelogenous Leukemia?

Back 31

Basophilia ( > 200 / µL )

Front 32

What are the types of Myeloid Neoplasms?

Back 32

- Myeloproliferative Neoplasms (MPNs)
- Myelodysplastic Syndromes (MDS)
- Acute Myeloid Leukemia (AML)

Front 33

What type of disorders are Myeloproliferative Neoplasms (MPNs) and Myelodysplastic Syndromes (MDS)? What kind of cells are affected?

Back 33

- Myeloid neoplasms
- Neoplastic stem cell disorders
- May involve one or more specific cell lineages

Front 34

What kind of data is necessary to diagnose a Myeloproliferative Neoplasm (MPN) or a Myelodysplastic Syndrome (MDS)?

Back 34

Combination of:
- Morphologic features
- Immunophenotypic features
- Genetic features
- Clinical features

* With rare exceptions, in order to make a diagnosis we need to synthesize information from various sources

Front 35

What characterizes Myeloproliferative Neoplasms (MPNs)?

Back 35

- Clonal hematopoietic stem cell disorders
* Proliferation of one or more of myeloid lineages (granulocytic, erythroid, megakaryocytic, or mast cells)
- Early precursor cell is affected, but one specific cell lineage may be primarily affected downstream

Front 36

What are the most common types of Myeloproliferative Neoplasms (MPNs)? What cell lineage is involved?

Back 36

- Chronic Myelogenous Leukemia, BCR-ABL+ (CML) = neutrophils or monocytes
- Polycythemia Vera (PV) = RBCs
- Primary Myelofibrosis (PMF) = neutrophils or monocytes
- Essential Thrombocythemia (ET) = platelets

Front 37

Which Myeloproliferative Neoplasms (MPNs) cause proliferation of neutrophils and monocytes?

Back 37

- Chronic Myelogenous Leukemia, BCR-ABL positive (CML)
- Primary Myelofibrosis (PMF)

Front 38

Which Myeloproliferative Neoplasms (MPNs) cause proliferation of red blood cells?

Back 38

Polycythemia Vera (PV)

Front 39

Which Myeloproliferative Neoplasms (MPNs) cause proliferation of platelets?

Back 39

Essential Thrombocythemia (ET)

Front 40

When do Myeloproliferative Neoplasms (MPNs) more commonly occur? How common?

Back 40

- Adults: 40s-60s
- Relatively rare: 6-10 / 100,000 / year

Front 41

What are the commonalities of the Myeloproliferative Neoplasms (MPNs)?

Back 41

* Hypercellular BM
* Effective hematopoiesis → ↑ numbers of peripheral blood myeloid derivatives (WBCs, RBCs, platelets) = Cytoses
- Splenomegaly and/or hepatomegaly
- Potential for disease progression to either BM fibrosis or acute leukemia

Front 42

What can the Myeloproliferative Neoplasms (MPNs) progress to?

Back 42

- Bone Marrow Fibrosis
- Acute Leukemia

Front 43

What kind of genetic/molecular abnormality do the Myeloproliferative Neoplasms (MPNs) have?

Back 43

- Cytogenetic or molecular abnormalities
- Leads to expression of protein w/ increased tyrosine kinase activity

Front 44

What disorders are commonly affected by increased tyrosine kinase activity?

Back 44

Myeloproliferative Neoplasms (MPNs):
- Chronic myelogenous leukemia (CML)
- Polycythemia vera (PV)
- Primary myelofibrosis (PMF)
- Essential thrombocythemia (ET)

Front 45

What kind of state can you consider Myeloproliferative Neoplasms (MPNs) and Myelodysplastic Syndromes (MDS)?

Back 45

Pre-Acute Leukemic state (neoplastic condition)

Front 46

What is the overall effect of Myeloproliferative Neoplasms (MPNs)?

Back 46

Increased Cell Proliferation

Front 47

What are the primary features of the Myeloproliferative Neoplasms (MPNs)?

Back 47

* Hypercellular bone marrow
* Ineffective hematopoiesis → ↓ peripheral blood counts = Cytopenias

Front 48

What is the overall effect of Myelodypslastic Syndromes (MDS)?

Back 48

Increased Cell Death

Front 49

What are the most significant differences between Myeloproliferative Neoplasms (MPNs) and Myelodysplastic Syndromes (MDS)?

Back 49

- MPN: hypercellular BM + ↑ PB counts (↑ cell proliferation)
- MDS: hypercellular BM + ↓ PB counts (↑ cell death)

Front 50

What kind of disease is Chronic Myelogenous Leukemia? What genetic/molecular change occurs?

Back 50

- Type of Myeloproliferative Neoplasms (MPNs)
* BCR-ABL fusion gene → produces a protein w/ Tyrosine Kinase activity
* t(9;22) → Philadelphia Chromosome → BCR-ABL fusion gene

Front 51

What symptoms do patients with Chronic Myelogenous Leukemia have?

Back 51

Non-specific symptoms:
- Fatigue
- Weakness
- Weight loss
- Anorexia
- Hepatosplenomegaly

Front 52

What are the peripheral blood cell count changes in Chronic Myelogenous Leukemia?

Back 52

- ↑↑↑ Leukocytosis (>100,000 / µL)
- Neutrophilia (>7000 / µL)
- Immature myeloid cells, rare myeloblasts (2-3%)
* Basophilia
- Thrombocytosis (50% of cases)

Front 53

What are the bone marrow cell changes in Chronic Myelogenous Leukemia?

Back 53

- Hypercellular (~100%)
- Granulocytic hyperplasia (predominance of the precursors that form neutrophils, basophils, and eosinophils)

Front 54

What gene change results from a t(9;22) translocation? Implications? What disease?

Back 54

BCR-ABL fusion gene → Philadelphia chromosome → ↑ tyrosine kinase activity
(Chronic Myelogenous Leukemia)

Front 55

How do you detect the BCR-ABL translocation t(9;22)? Diagnostic of?

Back 55

- FISH, rtPCR
- NOT specific for Chronic Myelogenous Leukemia, ALSO seen in Acute Leukemia (both myeloid and lymphoblastic)
= CML, AML, ALL

Front 56

What are the stages of Chronic Myelogenous Leukemia? Length of time?

Back 56

1. Chronic Phase - 3 years
2. Accelerated Phase - 1 year
3. Blast Phase (equivalent to AML or ALL, >20% blasts in PB or BM)

Front 57

How do you treat (not cure) Chronic Myelogenous Leukemia? Response?

Back 57

Administer BCR-ABL tyrosine kinase inhibitors:
*Imatinib mesylate (Gleevac)*
- 85% have good response, but this does NOT cure, so must be taken continuously for life

- Also some other tyrosine kinase inhibitors

Front 58

How can you potentially cure Chronic Myelogenous Leukemia? Response?

Back 58

Allogeneic stem cell transplant (only for patients with a matched donor that can tolerate this procedure) - possibly a cure

Front 59

Which Myeloproliferative Neoplasm is associated with increased RBC mass? Mutation? Implications?

Back 59

Polycythemia Vera (PV):
- Janus 2 Kinase (JAK2) gene (tyrosine kinase) mutation involved in signal transduction pathways → constitutively active
- Leads to increased proliferation of RBC precursors

Front 60

What are the symptoms of Polycythemia Vera (PV)?

Back 60

- Splenomegaly
- Thrombotic events d/t hyperviscosity (eg, hepatic vein thrombosis)
- Gout (↑ cell breakdown → ↑ uric acid)
- Ruddy face, pruritus after bathing, or peptic ulcer disease (d/t ↑ Histamine released from mast cells)

Front 61

What are the lab findings of Polycythemia Vera (PV)?

Back 61

- ↑ RBC mass → ↑ [Hb] and/or ↑ RBC count
- Leukocytosis
- Thrombocytosis
- ↓ Serum [Epo] in presence of normal SaO2

Front 62

How do the levels of Epo help in diagnosing Polycythemia Vera (PV) compared to other conditions that may cause erythrocytosis (increased RBC mass)?

Back 62

- PV: ↓ serum [Epo]

- Other conditions causing erythrocytosis may be d/t exogenous Epo production or d/t ↑ Epo production secondary to ↓SaO2

Front 63

Polycythemia Vera:
- RBC Mass?
- Plasma Volume?
- SaO2?
- Epo?

Back 63

- ↑ RBC mass
- ↑ Plasma volume
- Normal SaO2
- ↓ Epo

Front 64

Polycythemia / Erythrocytosis d/t COPD, cyanotic congenital heart disease:
- RBC Mass?
- Plasma Volume?
- SaO2?
- Epo?

Back 64

- ↑ RBC mass
- Normal Plasma volume
- ↓ SaO2
- ↑ Epo

Front 65

Polycythemia / Erythrocytosis d/t Ectopic Epo (eg, renal disease):
- RBC Mass?
- Plasma Volume?
- SaO2?
- Epo?

Back 65

- ↑ RBC mass
- Normal plasma volume
- Normal SaO2
- ↑ Epo

Front 66

Relative Polycythemia / Erythrocytosis d/t volume depletion:
- RBC Mass?
- Plasma Volume?
- SaO2?
- Epo?

Back 66

- Normal RBC mass
- ↓ Plasma volume
- Normal SaO2
- Normal Epo

Front 67

What are the diagnostic criteria for Polycythemia Vera?

Back 67

- JAK2 mutation (↑ tyrosine kinase activity)
- Hypercellular BM w/ Erythroid Hyperplasia

Front 68

What is the clinical course and prognosis of Polycythemia Vera?

Back 68

- Median survival > 10 years
- Most patients die of thrombosis or hemorrhage

Front 69

How do you treat Polycythemia Vera?

Back 69

Managed w/ conservative treatment (eg, phlebotomy)

Front 70

What can Polycythemia Vera progress to? How often?

Back 70

- 15-20% evolve to "spent phase" which is similar to primary myelofibrosis
- 2-3% develop MDS or AML

Front 71

What are the characteristics of Primary Myelofibrosis (PMF)? What kind of disease is it?

Back 71

- Rapid development of BM fibrosis and extramedullary hematpoiesis (EMH) in spleen, liver, and lymph nodes
- Myeloproliferative Neoplasm

Front 72

What are the symptoms of Primary Myelofibrosis (PMF)?

Back 72

Splenomegaly → Portal HTN

Front 73

What happens in the early and typical stages of Primary Myelofibrosis (PMF)?

Back 73

- Early: pre-fibrotic stage shows peripheral blood leukocytosis
- Typical: fibrotic stage shows peripheral blood normochromic, normocytic anemia w/ frequent teardrop cells, and a leukoerythroblastic reaction

Front 74

What happens early on in Primary Myelofibrosis (PMF)?

Back 74

- Pre-fibrotic stage
- Peripheral blood leukocytosis

Front 75

What happens later in Primary Myelofibrosis (PMF)?

Back 75

- Typical / fibrotic stage
- Peripheral blood w/ normochromic, normocytic anemia
- Frequent teardrop cells
- Leukoerythroblastic reaction

Front 76

What does a BM biopsy in Primary Myelofibrosis (PMF) show?

Back 76

- Fibrosis
- Clusters of atypical megakaryocytes
- Generally increased platelet count, may be variable

Front 77

What genetic/molecular abnormality is associated with Primary Myelofibrosis (PMF)?

Back 77

JAK2 mutation found in ~50% of cases (↑ tyrosine kinase activity)

Front 78

What is the prognosis of Primary Myelofibrosis (PMF)? Causes?

Back 78

- Pre-fibrotic / early stage: > 10 years
- Fibrotic / typical stage: 3-7 years

- BM failure (w/ infections and/or hemorrhage), thromboembolic events, portal HTN, or cardiac failure

Front 79

What can Primary Myelofibrosis (PMF) progress to? How common?

Back 79

- 5-30% develop AML
- BM failure (w/ infections and/or hemorrhage), thromboembolic events, portal HTN, or cardiac failure

Front 80

Which Myeloproliferative Neoplasm is characterized by proliferation of Megakaryocytes?

Back 80

Essential Thrombocytopenia (ET)

Front 81

What are the peripheral blood abnormalities in Essential Thrombocytopenia?

Back 81

- Elevated platelet count >450,000/µL
- Platelets have atypical morphology (large/giant, hypogranular)
- Mild neutrophilic leukocytosis

Front 82

What are the Bone Marrow abnormalities in Essential Thrombocytopenia?

Back 82

- Hypercellular
- Abnormal megakaryocytes

Front 83

What are the symptoms of Essential Thrombocytopenia?

Back 83

- Bleeding tendency
- Thrombosis

Front 84

What genetic/molecular abnormality is associated with Essential Thrombocytopenia?

Back 84

JAK2 mutation in 50% of cases (↑ tyrosine kinase activity)

Front 85

What is the prognosis for Essential Thrombocytopenia?

Back 85

Median survival: 12-15 years

Front 86

How do you treat Essential Thrombocytopenia? Effect?

Back 86

Alkylating agents or similar drugs to lower platelet count

Front 87

What characterizes Myelodysplastic Syndromes (MDS)?

Back 87

- Clonal hematopoietic stem cell disorder
- Cytopenias
- Dysplasia (morphologic abnormalities) in one or more myeloid cell lineages
- Ineffective hematopoiesis

Front 88

What myeloid cell lineages are affected by Myelodysplastic Syndromes (MDS)?

Back 88

One or more myeloid cell lineages:
- Monocytes
- Neutrophils
- Eosinophils
- Basophils

Front 89

What happens to the hematopoietic precursors in bone marrow in Myelodysplastic Syndromes (MDS)?

Back 89

- Increased proliferation of hematopoietic precursors → hypercellular BM (but myeloblasts < 20%)
- Ineffective hematopoiesis and enhanced apoptosis → cytopenias in peripheral blood

Front 90

What are you at increased risk for if you have Myelodysplastic Syndrome (MDS)?

Back 90

Acute Myelogenous Leukemia (AML) in 30% of cases

Front 91

Which syndrome/disease is associated with cytoses? Cytopenias?

Back 91

- Cytoses (↑ peripheral blood counts): Myeloproliferative Neoplasms
- Cytopenias (↓ peripheral blood counts): Myelodysplastic Syndromes

Front 92

What lab findings are associated with Myelodysplastic Syndromes (MDS)?

Back 92

* Cytopenias (uni-, bi-, or pancytopenia)
- Leukoerythroblastic Reaction
* Dysplastic features
* Hypercellular BM
- Ring sideroblasts
- ↑ Myeloblasts
- Chromosomal abnormalities in 50%

Front 93

What genetic abnormalities are associated with Myelodysplastic Syndromes (MDS)? How common?

Back 93

- Monosomy 5 or del5q
- Trisomy 8
- Monosomy 7 or del7q

- 50% of cases

Front 94

What are Red Sideroblasts? When conditions are these associated with?

Back 94

- Red cell precursors w/ frequent iron granules surrounding the nucleus
- Abnormal iron accumulation in functionally impaired mitochondria

- Associated with Myelodysplastic Syndromes (MDS) and other non-neoplastic conditions like alcohol consumption, drugs (isoniazid), or other toxins

Front 95

Who is more likely to get Myelodysplastic Syndromes (MDS)?

Back 95

Elderly (50-80 years)

Front 96

What are the presenting symptoms of Myelodysplastic Syndromes (MDS)?

Back 96

- Weakness
- Infections
- Hemorrhage (d/t cytopenias)
- OR asymptomatic

Front 97

What is the prognosis for Myelodysplastic Syndromes (MDS)? What can it progress to? Causes of death?

Back 97

- Median survival: 9-29 months (t-MDS is 4-8 months)
- Progression to AML in 30% of cases

- AML, infections, bleeding can all cause death

Front 98

How do you treat Myelodysplastic Syndromes (MDS)?

Back 98

- Some get aggressive chemotherapy but it is difficult to cure and may be intolerable

Supportive therapy:
- Blood products
- Antibiotics
- Growth factors
* Hypomethylating agents

Allogeneic stem cell transplant (potentially curing MDS)

Front 99

When are hypomethylating agents used? Effect?

Back 99

Myelodysplastic Syndromes (MDS)
- They are not curative
- Can reduce bone marrow cellularity, percentage of blasts, and improves cytopenias

Front 100

What is the effect of Allogenic Stem Cell Transplant in Myelodysplastic Syndromes (MDS)? Concerns?

Back 100

- Only potential method to cure MDS
- Lack of matched donors and relatively high morbidity and mortality associated with this procedure limit those that may benefit from this

Front 101

What are Acute Leukemias? Chronic Leukemias?

Back 101

- Acute: neoplastic proliferations of immature cells (blasts)
- Chronic: neoplastic proliferations of mature cells

Front 102

What are the types of Acute Leukemias?

Back 102

- Myeloblastic or myeloid
- Lymphoblastic

Front 103

What is the natural history of untreated Acute Leukemias? Chronic Leukemias?

Back 103

- Acute: weeks to months
- Chronic: months to years

Front 104

Which type of Acute Leukemia is more common in children? Adults? Males/Females?

Back 104

- Children (<18y): 80-85% have ALL (can also occur in adults) (equal in males and females)
- Adults: 80-90% have AML (incidence increases with age, median age = 60 y) (slight male predominance)

Front 105

What clues do you make the differential diagnosis of AML vs ALL based on?

Back 105

- Morphology
- Cytochemistry
- Immunophenotyping
- Genetics

Front 106

Acute Myelogenous Leukemia:
- Blast size
- Chromatin
- Nucleoli
- Cytoplasm
- Auer rods
- Myelodysplasia

Back 106

- Blast size: large and uniform
- Chromatin: finely dispersed
- Nucleoli: 1 to 4 often prominent
- Cytoplasm: moderately abundant, granules
- Auer rods: 60-70%
- Myelodysplasia: often

Front 107

Acute Lymphoblastic Leukemia:
- Blast size
- Chromatin
- Nucleoli
- Cytoplasm
- Auer rods
- Myelodysplasia

Back 107

- Blast size: small/medium and variable
- Chromatin: coarse
- Nucleoli: absent or 1 or 2; indistinct
- Cytoplasm: scant to moderate, lacking granules
- Auer rods: absent
- Myelodysplasia: absent

Front 108

How does blast size compare for AML or ALL?

Back 108

- AML: large and uniform blasts
- ALL: small/medium and variable blasts

Front 109

How do the chromatin compare for AML or ALL?

Back 109

- AML: finely dispersed
- ALL: coarse

Front 110

How do the nucleoli compare for AML or ALL?

Back 110

- AML: 1-4 often prominent
- ALL: absent or 1 or 2, indistinct

Front 111

How do the cytoplasm compare for AML or ALL?

Back 111

- AML: moderately abundant, granules often present
- ALL: scant to moderate, granules lacking

Front 112

How does the frequency of Auer rods compare for AML or ALL?

Back 112

- AML: 60-70% of cases
- ALL: absent

Front 113

How does myelodysplasia compare for AML or ALL?

Back 113

- AML: often present
- ALL: absent

Front 114

What does cytochemistry for diagnosing AML vs ALL rely on?

Back 114

Takes advantage of presence of intracellular enzymes which generate a differently colored product when exposed to a substrate

Front 115

What are the cytochemistry tests for diagnosing AML? What do they show if positive?

Back 115

- Myeloperoxidase (MPO - generates a black intracellular product)
- Non-specific esterase (NSE - generates a brick-red intracellular product

Front 116

If you are concerned for AML and use a Myeloperoxidase (MPO) cytochemical test, what would be a positive result?

Back 116

Generates a black intracellular product

Front 117

If you are concerned for AML and use a Non-Specific Esterase (NSE) cytochemical test, what would be a positive result?

Back 117

Generates a brick-red intracellular product

Front 118

What are the methods of assessing for AML vs ALL with immunophenotyping?

Back 118

- Immunohistochemistry
- Flow cytometry

Front 119

What are the benefits of immunophenotyping (immunohistochemistry or flow cytometry) in differentiating between AML and ALL?

Back 119

- Differentiates between AML and ALL
- Identifies subtypes of AML
- Used to establish a fingerprint for minimal residual disease assessment

Front 120

What is the method of Immunohistochemistry?

Back 120

Uses tagged antibodies that recognize antigens expressed by cells in tissue sections

Front 121

What is the method of flow cytometry?

Back 121

- Uses tagged antibodies that recognize antigens expressed by cells in a cell suspension
- Assesses more than one antigen at at ime
- Usually for antibodies designated by CD#

Front 122

How does immunohistochemistry (IHC) compare to Flow Cytometry?

Back 122

Flow cytometry can assess more than one antigen at a time

Front 123

What are the important antibodies to remember for AML? What are they markers of?

Back 123

- CD34 and CD117
- Markers of immaturity

Front 124

What is the function of cytogenetics in assessing AML vs ALL?

Back 124

Distinguishes sub-groups of AML, based on cytogenetic abnormalities that have biologic and prognostic significance

Front 125

What is the prognosis for AML?

Back 125

- Poor outcome
- Overall long-term survival of ~25%

Front 126

What kind of cells are involved in AML? Location?

Back 126

- Myeloid progenitor cells
- Peripheral blood, bone marrow, may also involve extramedullary sites

Front 127

What are the symptoms of AML?

Back 127

- Cytopenias cause weakness, fatigue, petechiae, infections
- Less common: organomegaly, lymphadenopathy, and infiltration of other extramedullary tissues
- Coagulopathy in some variants (acute promyelocytic leukemia)

Front 128

Which subtype of AML has coagulopathy (clotting disorder)?

Back 128

Acute Promyelocytic Leukemia

Front 129

What is the main diagnostic criterion for AML?

Back 129

Greater than 20% myeloid blasts in blood or marrow

Front 130

What are the laboratory findings in AML?

Back 130

- Myeloid blasts >20%
- Hypercellular BM
- Severe leukopenia to marked leukocytosis
- Anemia
- Thrombocytopenia
- Maturing cells of myeloid lineages may be dysplastic

Front 131

What is true of the blasts in AML?

Back 131

- >20% in BM or PB
- Blasts have limited ability to mature beyond blast stage
- Maturation may be towards any of the myeloid lineages (*granulocytes, *monocytes, megakaryocytes, or erythroid precursors)

Front 132

What are the types of AML?

Back 132

- AML w/ recurrent cytogenetic abnormalities
- AML w/ myelodysplasia-related changes
- Therapy-related myeloid neoplasms (including AML)
- AML, not otherwise specified

Front 133

Why is it important to classify the types of AML?

Back 133

Biological correlates to classification

Front 134

What are the features of AML w/ recurrent cytogenetic abnormalities?

Back 134

- Generally reciprocal translocations
- Generally flat incidence rate across age groups
- Distinctive morphologic features
- Dysplasia of maturing lineages is not prominent
- No antecedent myelodysplastic syndrome

FAVORABLE prognosis

Front 135

What are the features of AML w/ myelodysplasia-associated changes?

Back 135

- Related biologically to MDS
- MDS type cytogenetic abnormalities (complex karyotypes, loss of chromosomes, or parts of chromosomes)
- Increasing incidence w/ age
- Prominent multilineage dysplasia

POOR prognosis

Front 136

How does the prognosis compare for AML w/ recurrent cytogenetic abnormalities and AML w/ myelodysplasia-associated changes?

Back 136

- AML w/ recurrent cytogenetic abnormalities: favorable prognosis
- AML w/ myelodysplasia-associated changes: poor prognosis

Front 137

What are the genetic abnormalities associated w/ AML w/ recurrent cytogenetic abnormalities?

Back 137

- t(8;21)
- inv(16)
- t(15;17) - PML/RARα gene fusion

- 11q23 (MLL) rearrangement

Front 138

Which of the recurrent cytogenetic abnormalities associated w/ AML have a favorable prognosis?

Back 138

- t(8;21)
- inv(16)
- t(15;17) - PML/RARα gene fusion

Front 139

Which of the recurrent cytogenetic abnormalities associated w/ AML have an intermediate to unfavorable prognosis?

Back 139

11q23 (MLL)

Front 140

How common is AML w/ t(8;21)? Prominent features? Prognosis?

Back 140

- 5-12%

- Prominent granulocytic maturation
- Prominent Auer rods
- Extramedullary involvement relatively common

- Favorable prognosis

Front 141

How common is AML w/ inv(16)? Prominent features? Prognosis?

Back 141

- 10-12%

- Similar to myelomonocytic leukemia - dual differentiation towards granulocytes and monocytes
- BM contains eosinophils w/ dysplastic features
- Extramedullary involvement is common

- Favorable prognosis

Front 142

How common is AML w/ t(15;17)? Prominent features? Prognosis?

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- 5-8%

- Acute Promyelocytic Leukemia (APL)
- Atypical, hypergranular promyelocytes (rarely microgranular)
- Reniform nuclei
- Multiple prominent Auer rods ("****** cells")
occassionally
- Leukopenia assoc. w/ hypergranular/typical forms
- Leukocytosis assoc. w/ microgranular forms

- Disseminated intravascular coagulation (DIC) at diagnosis → early morbidity and martality
- Favorable prognosis

Front 143

What fusion gene is generated by t(15;17)? How do you treat AML w/ t(15;17)?

Back 143

- Generates the PML-RARα (retinoic acid receptor alpha) fusion gene
- Responds to all-trans Retinoic Acid (ATRA) - favorable prognosis
- Matures the cells and also corrects the coagulopathy

Front 144

What are the implications of the formation of the PML-RARα fusion gene? What causes this?

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- Caused by t(15;17) translocation
- Retinoic acid is important for myeloid maturation
- Disrupting its receptor produces maturation arrest at promyelocyte stage
- Treatment w/ all-trans Retinoic Acid (ATRA) overcomes the block and essentially matures the cells

Front 145

For what disease is ATRA (All-Trans Retinoic Acid) used?

Back 145

t(15;17) variant of AML because this causes a PML-RARα fusion gene

Front 146

How common is AML w/ 11q23 (MLL) rearrangements? Prominent features? Prognosis?

Back 146

- 5-6% of AML
- Prevalent among infantile AMLs

- Monocytic features
- Hyperleukocytosis
- Extramedullary tissue infiltration

- t(9;11) translocation has intermediate prognosis
- Other translocations involving MLL gene have intermediate to poor prognosis

Front 147

When does AML w/ myelodysplasia related changes occur? Prognosis?

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- May follow an Myelodysplastic Syndrome (MDS)
- May occur without antecedent MDS
- Primarily in older adults

- Unfavorable prognosis

Front 148

What are the prominent features of AML w/ myelodysplasia related changes?

Back 148

- Dysplasia in >50% of 2+ lineages AND/OR
- Myelodysplasia-associated cytogenetic abnormalities (eg, monosomy 7 / del(7q), monosomy 5 / del(5q), or complex karyotypes)
- Unfavorable prognosis

Front 149

What are the myelodysplasia associated cytogenetic abnormalities? Prognosis?

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- Monosomy 7 / del(7q)
- Monosomy 5 / del(5q)
- Complex karyotypes

- Unfavorable prognosis

Front 150

What can cause therapy-related AML and MDS?

Back 150

- Patients previously treated w/ chemo and/or radiotherapy
- Two main classes of chemo drugs: alkylating agents and topoisomerase II inhibitors

Front 151

What can alkylating agent and topisomerase II inhibitor chemotherapies both lead to an increased incidence of?

Back 151

Therapy-Related AML and MDS

Front 152

When does Alkylating Agent Related AML/MDS occur? What is risk for developing this related to?

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- Occurs ~5 years after treatment
- Risk related to total dose and patient age

Front 153

What are the features and prognosis of Alkylating Agent Related AML/MDS?

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- Multi-lineage dysplasia
- Cytogenetic abnormalities (aberrancies of chromosomes 5 and 7) in nearly 100% of cases
- Very poor prognosis
- Similar to AML w/ myelodysplasia-related changes

Front 154

What type of AML is Alkylating Agent Related AML/MDS similar to?
What type of AML is Topisomerase II Inhibitor Related AML/MDS similar to?

Back 154

AML w/ myelodysplasia related changes

De Novo AML w/ 11q23 (MLL) gene rearrangements

Front 155

When does Topoisomerase II Inhibitor Related AML/MDS occur?

Back 155

Occurs 2.5-3 years after exposure

Front 156

What are the features and prognosis of Topoisomerase II Inhibitor Related AML/MDS?

Back 156

- Monocytic or myelomonocytic morphology
- 11q23 (MLL) balanced translocations are most common cytogenetic abnormalities
- Poor prognosis
- Similar to De Novo AML w/ 11q23 (MLL) gene rearrangements

Front 157

How do you categorize AML if it does not fulfill criteria of the other three groups (AML w/ recurrent cytogenetic abnormalities; AML w/ myelodysplasia-related changes; or therapy-related AML)?

Back 157

AML not otherwise specified (NOS)

Front 158

How do you categorize AML not otherwise specified (NOS)?

Back 158

- 3 categories based on degree of maturation
- 5 categories based on lineage of differentiation

Front 159

What kind of tumor is a Myeloid Sarcoma?

Back 159

Extramedullary tumor of immature myeloid cells

Front 160

How does Myeloid Sarcoma related to AML?

Back 160

Myeloid Sarcoma can occur after, with, or preceding an AML diagnosis

Front 161

How do you treat Myeloid Sarcoma? Why?

Back 161

- Treat in same fashion as AML
- Because it is assumed that progression to systemic disease would eventually occur even if BM and blood are sometimes not overtly involved

Front 162

What are the variety of responses to treatment for AML?

Back 162

- Ranges from cure to refractory disease
- Prognosis in individual patients cannot be estimated accurately, meaning that very good patients may relapse while very poor patients may be cured

Front 163

What are the new prognostic markers for AML that are attempting to refine the risk stratification? Prognosis?

Back 163

- FLT3 - poor prognosis
- NPM1 - favorable prognosis

Front 164

What kind of molecule is FLT3? Marker of what?

Back 164

- Receptor Tyrosine Kinase
- Has a role in hematopoietic progenitor survival and proliferation
- Activating mutation caused by internal tandem duplications of juxtamembrane domain occurs in ~1/3 of AMLs → POOR prognosis

- New prognostic marker for AML (seen in various subtypes)

Front 165

What kind of molecule is NPM1? Marker of what?

Back 165

- Nucleocytoplasmic shuffling protein
- Mutated NPM1 seen in 50-60% of AML w/ NORMAL karyotype
- Favorable prognosis in cases w/o mutated FLT3

Front 166

What happens if you have both FLT3 and NPM1 mutations?

Back 166

Mutated FLT3 (poor prognosis) trumps the good prognostic effect of a mutated NPM1

Front 167

What do "histiocytoses" refer to?

Back 167

Variety of proliferative disorders of dendritic cells or macrophages

Front 168

How severe are Histiocytoses?

Back 168

- Some are very rare and highly malignant
- Others are completely benign and reactive

Front 169

What are the types of Histiocytoses?

Back 169

- Histiocytic Lymphomas (very rare and malignant)
- Histiocytic proliferations in lymph nodes (benign and reactive)
- Langerhans Cell Histiocytoses (tumors made of Langerhans cells)

Front 170

What are Langerhans cells? Where? Function?

Back 170

- Immature dendritic cells found in the epidermis
- Function to capture antigens and display them to T cells

Front 171

What do Langerhans cells express in Langerhans Cell Histiocytoses?

Back 171

- MHC Class II antigens
- CD1a
- Langerin

Front 172

What is Langerin? Where is it found? What does it look like?

Back 172

- Transmembrane protein
- Found in Birbeck granules (cytoplasmic pentalaminar rodlike tubular structures)
- Look like tennis rackets (characteristic periodicity and a dilated terminal)

Front 173

What do proliferating Langerhans cells in Langerhans Cell Histiocytoses look like?

Back 173

- Do not resemble their normal dendritic counterparts
- Instead, they have abundant, often vacuolated cytoplasm and vesicular nuclei
- Appearance more akin to tissue macrophages (called histiocytes)

Front 174

What are the three relatively distinct clinicopathology entities of Langerhans Cell Histiocytoses?

Back 174

- Multi-system Langerhans Cell Histiocytoses (Letterer-Siwe Disease)
- Uni-system Langerhans Cell Histiocytoses (Eosinophilic Granuloma)

Front 175

When is Multi-system Langerhans Cell Histiocytoses (Letterer-Siwe Disease) more likely to occur? Signs?

Back 175

- Children < 2y
- Multifocal cutaneous lesions that grossly resemble seborrheic skin eruptions
- Hepatosplenomegaly
- Lymphadenopathy
- Pulmonary lesions
- Later, destructive osteolytic bone lesions

Front 176

What happens to the skin in Multi-system Langerhans Cell Histiocytoses (Letterer-Siwe Disease)?

Back 176

- Multifocal cutaneous lesions
- Grossly resemble seborrheic skin eruptions
- Composed of Langerhans cells

Front 177

What happens to the bone marrow in Multi-system Langerhans Cell Histiocytoses (Letterer-Siwe Disease)? Implications?

Back 177

- Extensive infiltration
- Leads to pancytopenia
- Predisoposes to recurrent infections like otitis media and mastoiditis

Front 178

What is the prognosis of Multi-system Langerhans Cell Histiocytoses (Letterer-Siwe Disease)? Treatment?

Back 178

- Rapidly fatal if untreated
- With extensive chemo, 50% survive 5 years

Front 179

What are the characteristics of Uni-system Langerhans Cell Histiocytoses (Eosinophilic Granuloma)? Location of lesions?

Back 179

- Unifocal (skeletal system) or multifocal
- Expanding, erosive accumulations of Langerhans cells, usually within medullary cavities of bones (or less commonly in skin, lungs, or stomach)
- Any bones in skeletal system: calvaria, ribs, femur most commonly

Front 180

What do Uni-system Langerhans Cell Histiocytoses (Eosinophilic Granuloma) lesions contain?

Back 180

Langerhans cells, admixed w/ variable numbers of lymphocytes, plasma cells, neutrophils, and eosinophils, which are usually, but not always prominent

Front 181

What are the symptoms of UNIFOCAL Uni-system Langerhans Cell Histiocytoses (Eosinophilic Granuloma)? Treatment?

Back 181

- Most often involves the skeletal system
- Asymptomatic or may cause pain, tenderness, and pathologic fractures

- Indolent disorder that may heal spontaneously or be cured by local excision or irradiation

Front 182

What are the symptoms of MULTIFOCAL Uni-system Langerhans Cell Histiocytoses (Eosinophilic Granuloma)? Treatment?

Back 182

- Usually affects children
- Typically manifests w/ multiple erosive bony masses that sometimes extend into the soft tissues
- 50% involve posterior pituitary stalk of hypothalamus which leads to Diabetes Insipidus
- Calvarial bone defects + Diabetes Insipidus + Exophthalmos = Hand-Schüller-Christian Triad

- Many have spontaneous regressions, others treated effectively w/ chemotherapy

Front 183

What is the Hand-Schüller-Christian Triad? When is it seen?

Back 183

Combination of:
- Calvarial bone defects
- Diabetes Insipidus
- Exophthalmos (abnormal protrusion of the eyeball or eyeballs)

Associated with Multifocal Uni-system Langerhans Cell Histiocytoses (Eosinophilic Granuloma)

Front 184

What genetic abnormality is associated with the Langerhans cell tumors?

Back 184

- Acquired mutation in serine/threonine kinase BRAF
- Valine to glutamate substitution in residue 600 that leads to hyperactivity of kinase
- BRAF is a component of Ras signaling pathway that drives cellular proliferation and survival, effects that likely contribute to the growth of the noplastic Langerhans cells

Front 185

What is an acquired mutation in serine/threonine kinase BRAF associated with?

Back 185

- Langerhans cell tumors (Histiocytoses)
- Hairy cell leukemia
- Benign nevi
- Malignant melanoma
- Papillary thyroid carcinoma
- Some colon cancers

Front 186

What kind of condition is Hemophagocytic Lymphohistiocytosis (HLH)?

Back 186

Potentially fatal hyper-inflammatory condition

Front 187

What can cause Hemophagocytic Lymphohistiocytosis (HLH)?

Back 187

- May occur as primary (genetic) condition d/t mutations in genes (Eg, perforin) important in the cytolytic secretory pathway
- Causes perforin and granzymes to induce apoptosis in target cells

* Familial HLH (HLH is the only manifestation of the disease)
* Other genetically caused HLH (HLH is one of several clinical manifestations)

Front 188

Identical clinical findings of Hemophagocytic Lymphohistiocytosis (HLH) may be caused by what?

Back 188

Secondary to infectious, rheumatologic, malignant, or metabolic conditions = Secondary HLH

Front 189

How does the type of Hemophagocytic Lymphohistiocytosis (HLH) affect treatment?

Back 189

Whether primary (familial) or secondary (infectious, rheumatologic, malignant, or metabolic), HLH therapy needs to be instituted promptly to prevent irreversible tissue damage

Front 190

What end of the spectrum is Hemophagocytic Lymphohistiocytosis (HLH) of the hyper-inflammatory disorders?

Back 190

Severe end of spectrum when the immune system starts to damage host tissues

Front 191

What are the clinical features diagnostic of Hemophagocytic Lymphohistiocytosis (HLH)?

Back 191

There is no single clinical feature alone diagnostic of HLH, you need the entire clinical presentation to make the diagnosis

Front 192

What is hemophagocytosis? How does this relate to Hemophagocytic Lymphohistiocytosis (HLH)?

Back 192

- Hallmark of activated macrophages
- Neither specific nor sensitive for HLH, its presence should only be considered supportive of HLH

Front 193

What can hemophagocytosis be indicative of?

Back 193

- Supportive of a diagnosis of Hemophagocytic Lymphohistiocytosis (HLH)
- Also seen as secondary disorder in association with severe infections, malignancies, rheumatologic disorders, and some metabolic diseases

Front 194

What is the most common infectious cause of Hemophagocytic Lymphohistiocytosis (HLH)?

Back 194

EBV - may trigger HLH in patients w/ familial disease

Front 195

What is the most common malignant cause of Hemophagocytic Lymphohistiocytosis (HLH)?

Back 195

Lymphoma (most common) or leukemia of T or NK cell lineages

Front 196

What is the prognosis for Familial Hemophagocytic Lymphohistiocytosis (HLH)?

Back 196

- Before the initiation of modern therapeutic regimens, 1-year survival rate of children was close to 0%
- With introduction of stem cell transplant (SCT) and increased experience, survival has improved to 92%

(delay in diagnosis and multi-organ involvement associated w/ worse prognosis)

Front 197

What is the prognosis for the different types of Secondary Hemophagocytic Lymphohistiocytosis (HLH)?

Back 197

Mortality varies from:
- 8-22% in rheumatologic-HLH (better prognosis)
- 18-24% in EBV-HLH (worse prognosis)

(delay in diagnosis and multi-organ involvement associated w/ worse prognosis)

Front 198

Which condition is associated with a very high Ferritin?

Back 198

Hemophagocytic Lymphohistiocytosis (HLH)