Intro to WBC disorders

Question 1

Monocytes, neutrophils, eosinophils, basophils all come from what type of blast?

Answer 1

Myeloblast

Question 2

What three cell lines result from myeloid blasts?

Answer 2

Eyrthroid precursor, megakaryocyte, myeloblast

Question 3

What areas are white blood cells distributed in?

Answer 3

Bone Marrow, Peripheral blood (granulocytes/monocytes/lymphocytes)

Lymph nodes, thymus, spleen, tonsils, adenoids, Peyer Patches

MALT–in lung and GI tract

Question 4

Benign Leukocyte disorders are NOT neoplastic thus not:

Answer 4

Clonal

Question 5

In benign leukocyte disorders, we see Qualitative and Quantitative disorders…

What types of quantitative disorders do we see?

Answer 5

Increased: cytoses

Decrease: cytopenias

Question 6

Normal range for WBCs

Answer 6

4,000 to 10,000

Question 7

Reference range for :

Neutrophils

Lymphocytes

Monocytes

Answer 7

 Neutrophils = 1,500 – 6,000
 Lymphocytes = 1,000 – 3,500
 Monocytes = 100 – 600

Question 8

Reference range for:

Eosinophils

Basophils

Answer 8

 Eosinophils = 0 – 450
 Basophils = 0 – 200

Question 9

 NOT leukemia (benign, exaggeratedresponse to infection)
 Absolute leukocyte count > 50,000/mL
 May involve neutrophils, lymphocytes oreosinophils

Answer 9

Leukemoid reaction

Question 10

Three causes of leukemoid reactions?

Answer 10

Perforating appendicitis (neutrophils)

Whooping cough (lymphocytes)

Cutaneous larva migrans (eosinophils)

Question 11

Describe leukoerythroblastic reaction

Answer 11

immature bone marrow cells in the PB d/t BM infiltrative disease (such as fibrosis or metestatic breast cancer) or from severe BM stress (such as sepsis or Growth factor)

Question 12

What defines neutrophilia and when do we see it?

Answer 12

absolute neutrophil count > 7,000

seen in sterile inflammation with necrosis (acute MI)

Infection (like acute appendicitis)

Drugs (steroids or catecholamines, lithium)

Question 13

What is the pathogeneis of neutrophilia?

Answer 13

Increased production and decreased margination

Question 14

Define Neutropenia:

Etiology:

Pathogenesis

Answer 14

Absolute neutrophil count: <1,500

Etiology of neutropenia: chemo, aplastic anemia, immune destruction, septic shock

Pathogeneis of neutrophenia: decreased production, increased destruction/margination

Question 15

Describe Eosinophilia:

Etiotology

Answer 15

Absoulte eosino count >700

 Type I hypersensitivity (e.g., bronchialasthma, penicillin allergy, hay fever)
 Invasive helminths (e.g., strongiloidiasis, hookworm)
 Hypocortisolism (e.g., Addison’s disease)
 Neoplasms (e.g., Hodgkin lymphoma)

Question 16

Pathogenesis of eosinophilia

Answer 16

Increased produciton (induced by interleukins)

Increased tissue rectruitement by chemotactic factors

Question 17

Describe Basophilia:

Etiology of Basophilia:

Answer 17

absoulte basophil count of >200

 Chronic myelogenous leukemia or CML (and otherchronic myeloproliferative neoplasms)
 Chronic kidney disease

Question 18

 Proliferation of neoplastic cells, primarily in BM and PB

Answer 18

Leukemia

Question 19

Proliferation of neoplastic cells, primarily in LNs and extramedullary lymphoid tissue

Answer 19

Lymphoma

Question 22

Myeloid neoplasms are neoplastic _______ disorders

Answer 22

stem cell

**can involve more then one cell lineage

Question 23

What are the 4 key WHO classification criteria in Myeloid neoplasms?

Answer 23

Morphology

Immunophenotype

Genetic Features

Clinical features

Question 24

What are the three types of myeloid neoplasms?

Answer 24

 Myeloproliferative neoplasms (MPN)
 Myelodysplastic syndromes (MDS)
 Acute myeloid leukemia (AML)

Question 25

What are the four myeloproliferative disorders we need to know?

Answer 25

Chronic myelogenous leukemia: BCR ABLpositive (CML) Polycythemia vera (PV) Primary myelofibrosis (PMF) Essential thrombocythemia (ET)

Question 26

Myeloproliferative neoplasms, General features: \_\_\_\_\_\_hematopoietic stem cell disorders Proliferation of one or more of the follwing myeloid lineages:

Answer 26

Clonal hematopoeitic stem cell disorders Lineages: Granulocytic/ Erythroid/ Megakaryocytic/ Mast cell

Question 27

MPN is common in what decade? How common?

Answer 27

MPN seen in 5th - 7th decade Incidence: 6-10/100,000/year

Question 28

MPN is: Hyper or Hypocellular BM with effective or ineffective hematopoesis

Answer 28

Hypercellular BM with effective hematopoiesis (increased PB counts = cytoses) \<= clonal abnormalities increase cell proliferation

Question 29

MDS is: Hyper or Hypocellular BM with effective or inneffective hematopoesis

Answer 29

Hypercellular BM with ineffective hematopoiesis (decreased PB counts = cytopenias) \<= clonal abnormalities promote cell death

Question 30

Chronic Myelogenous Leukemia (type of myloproliferative disease) Epidemiology: Pathogenesis:

Answer 30

peak at 40-60 years Pathogenesis: 1. Neoplastic expansion of the pluripotentialstem cell 2. BCR-ABL fusion gene (produces protein with tyrosine kinase activity)

Question 31

What 5 key clincal findings do we see in CML?

Answer 31

Hepatosplenomegaly, fatigue, weight loss, weakness, anorexia

Question 32

Lab findings show Leukocytosis with immature myeloid cells, few myeloblasts (2-3%) and basophilia... what would we expect to find on FISH or RT-PCR?

Answer 32

BCR-ABL fusion gene~~ common in CML

Question 33

expected lab findings for CML

Answer 33

Leukocytosis with immature myeloid cells  Few myeloblasts (2-3%)  Basophilia  Thrombocytosis (40-50% cases) or thrombocytopenia  Hypercellular BM (~100%) with granulocytic hyperplasia

Question 34

Chromosome and gene responsible for CML

Answer 34

Philadeplphia Chromosome: t(9;22) BCR-ABL fusion gene (FISH or RT-PCR)

Question 35

What should a normal bone marrow core biopsy look like?

Answer 35

100-age rule ex: if you are 30 yo you should have 70% cellularity and there should be adipocytes in there

Question 36

What are the three stages seen in CML if left untreated?

Answer 36

Chronic phase~ 3 years Accelerated phase~ 1 year Blast phase = acute leukemia (meloid or lymphoblastic) \*all end up in blast phase if left untreated

Question 37

What is the ideal type of treatement for CML?

Answer 37

BCR-ABL tyrosine kinase inhibitors - Gleevec - Dasatinib - Nilotinib \*can't cure CML but staying on this therapy you can see 95% event free survival

Question 38

Pathogenesis:  Neoplastic expansion of the pluripotential stem cell  Increase in RBCs, granulocytes and platelets  Janus 2 kinase gene (JAK2) mutation in virtually all cases

Answer 38

Polcythemia Vera

Question 39

We see expansion of \_\_\_, _____ and _____ in polycythemia Vera

Answer 39

increase in RBC, granulocytic, and platelets

Question 40

What mutation is present in virtually all cases of polycythemia vera?

Answer 40

Janus 2 kinase gene (JAK2) --constitutional activation of JAK/STAT will cause activation of genes important in proliferation and survival~ in this case constant proliferation of red cells

Question 41

PV – Clinical findings

Answer 41

 Splenomegaly  Thrombotic events due to hyperviscosity (e.g. hepatic vein thrombosis)  Gout (increased uric acid due toincreased cell breakdown)  Signs of increased histamine (releasedfrom mast cells in the skin)  Ruddy face  Pruritus after bathing  Peptic ulcer disease

Question 42

Your patient comes in with splenomegaly, is itchy after they bathe and was recently diagnosed with peptic ulcer disease. The Lab shows they ahve increased RBC mass. What would you suspect of their EPO and SaO2 levels

Answer 42

This is describing polycythemia vera EPO is decreased Normal oxygen saturation

Question 43

In most polycythemias, there is an increase in EPO, why is polycythemia vera different?

Answer 43

In the other polycythemias, the increased EPO is driving the overproduciton of RBCs In PV, it is the JAK/STAT2 mutation that is upregulating the transcription of RBCs, NOT the EPO

Question 44

What are the major criteria for polycythemia vera?

Answer 44

Hemoglobin \> 18.5 g/dL in men, 16.5 g/dL in women or other evidence of increased RBC volume Presence of JAK2 mutation

Question 46

PV – Clinical course  Conservative treatment (e.g., phlebotomy); median survival of:  Most patients die of:

Answer 46

\> 10 years thrombosis or hemorrhage

Question 47

In PV, 15-20% of pts evolve to what phase? 2-3% of PV pts develope what diseases?

Answer 47

evolved to 'spent phase' devo MDS or AML

Question 48

Rapid development of BM fibrosis and extramedulary hematopoiesis (EMH) in the spleen, liver and lymph nodes

Answer 48

Primary myelofibrosis (PMF) ~ type of myeloproliferative neoplasm

Question 49

What are the clinical findings seen in: Primary myelofibrosis (PMF)

Answer 49

Splenomegaly with portal hypertension Splenic infarcts with left-sided pleural effusions

Question 50

What mutation is found 50% of the time in PMF?

Answer 50

JAK2 seen in 50% cases

Question 51

What do we see on a blood smear in a patient with Primary myelofibrosis?

Answer 51

**BM fibrosis and clusters of atypical megakaryocytes**  Peripheral blood leukocytosis (early stage)  Variable platelet count  Normochromic, normocytic anemia \***Teardrop cells** \*Leukoerythroblastic reaction

Question 53

Median Survival for PMF:

Answer 53

3-7 years in fibrotic stage \>10 years in early (prefibrotic) stage

Question 54

5-30% of patients with PMF will develop:

Answer 54

AML

Question 55

Major causes of morbidity and mortality in PMF:

Answer 55

 BM failure (infection, hemorrhage)  Thromboembolic events  Portal hypertension  Cardiac failure  AML

Question 56

Essential thrombocythemia (ET): Neoplastic stem cell disorder with proliferation of\_\_\_\_\_\_\_\_\_\_

Answer 56

megakaryocytes

Question 57

Platelet count in Essential throbmocythemia is:

Answer 57

\> 450,000/mL

Question 58

In this disease we see atypical platelet morphology Mild neutrophilic leukocytosis Hypercellular BM with abnormal megakaryocytes

Answer 58

Essential Thrombocytopenia

Question 59

Describe what you see in Essential Thrombocythemia on HE

Answer 59

more platelets that are larger in size (they shouldn't be larger then RBCs) See large/giant, hypogranular platelets

Question 60

Clinical findings of essential thrombocythemia

Answer 60

bleeding or throbmosis splenomegaly Jak2 mutation in 50% pts

Question 61

Common mutation in ET pts? Median survival: Tx for ET

Answer 61

JAK2 in 50% pts median survival: 12-15 years Tx: alkylating agents or simular drugs to lower platelet count