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Heme/ Lymph-AC > 3- Introduction to White Blood Cell Disorders, Reactive and Neoplastic Myeloid Processes > Flashcards

3- Introduction to White Blood Cell Disorders, Reactive and Neoplastic Myeloid Processes Flashcards

1
Q

WHat WBCs are in the bone marrow?

A

Pluripotent stem cells

Lymphoblast

Myeloid blast Erythroid precursor

Megakaryocyte

Myeloblast

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2
Q

What WBCs are in the peripheral blood?

A

Monocyte

Neutrophil

Eosinophil

Basophil

Mature Lymphocyte

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3
Q

Where are WBCs distributed?

A
  • bone marrow
  • peripheral blood: granulocytes, monocytes, lymphocytes (B, T, NK)
  • Lymph nodes, thymus, spleen, tonsils, adenoids, peyer patches
  • Mucosa-associated lymphoid tissue (MALT): Lung, GI tract
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4
Q

What are benign leukocyte disorders? And how do we classify them?

A

Definition: NOT neoplastic (clonal)

  • Classified as:
    • Qualitative (structural/functional) disorders
    • Quantitative (numerical) disorders
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5
Q

What are the 2 different types of quantitative (numerical) disorders?

A

Increased-cytoses

Decreased-cytopenias

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6
Q

What is a leukemoid reaction?

A

NOT leukemia! (benign) exaggerated response to infection

Absolute leukocyte count >50,000/uL

May involve neutrophils, lymphocytes or eosinophils

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7
Q

What are 3 common etiologies of leukemoid reactions?

A

Perforating appendicitis: Neutrophils

Whooping cough (Bordatella pertussis): Lymphocytes

Cutaneous larva migrans (nematodes): Eosinophils

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8
Q

What is a leukoerythroblastic reaction? What 2 things can it be due to?

A

Immature bone marrow cells in the peripheral blood (PB)

  • Due to: BM infiltrative disease
    • infiltrative disease: Fibrosis or metastatic breast cancer
  • ​Due to severe BM stress
    • ​sepsis or growth factor
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9
Q

What is neutrophilia? Wat are 3 possible etiologies? What are 2 mechanisms?

A

Absolute neutrophil count >7,000/uL

  • Etiology
    • infection (acute appendicitis)
    • Sterile inflammation with necrosis (acute MI)
    • Drugs (steroids, catecholamines, lithium)
  • Mechanism
    • increased production
    • decreased margination
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10
Q

What is neutropenia?

A

Absolute neutrophil count <1,500/uL

  • Etiology
    • chemotherapy
    • aplaastic anemia
    • immune destruction (SLE)
    • septic shock
  • Mechanism
    • decreased prodtuction increased estruction or margination
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11
Q

What is eosinophilia? What are 4 possible etiologies? What is the mechanism?

A

Absolut eeosinophil count > 700/uL

  • Etiology
    • Type I hypersensitivity (bronchial asthma, penicilin allergy, hay fever)
    • Invasive helminths (stongyloidiasis, hook worm)
    • Hypocortisolism (Addison’s disease)
    • Neoplasm (Hodgkin lymphoma)
  • Mechanism
    • increased production (induced by interleukins)
    • increased tissue recruitment by chemotactic factors
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12
Q

What is basophilia?

A
  • Absolutel Basophil >200/uL
  • Etiology
    • Chronic myeloid leukemia (and other myeloproliferative neoplasms MPN)
    • Hypersensitivity/inflammatory reactions
    • Hypothyroidism
    • Infections (TB, certain viruses)
    • Chronic Kidney disease
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13
Q

What are the 2 Neoplastic leukocyte disorders?

A

Leukemia: Proliferation of neoplastic cells, primarily in BM and PB

Lymphoma: Proliferation of neoplastic cells, primarily in LNs and extramedullary lymphoid tisue

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14
Q

What are myeloid neoplasms? What are teh WHO classification criteria?

A

Neoplastic stem cell disorders, may involve one or more cell lineages

WHO: Morphology, Immunophenotype, Genetic features, Clinical features

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15
Q

What are 4 Myeloproliferative neoplasms?

A

Chronic Myeloid Leukemia, BCR-ABL1 posiitve (CML)

Polycythemia vera (PV)

Primary Myelofibrosis (PMF)

Essential thrombocytopenia (ET)

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16
Q

What are general features of MPN?

A
  • Clonal hematopoietic stem cell disorders
  • Proliferation of one or more of the myeloid lineages
    • Granulocytic
    • Erythroid
    • Megakaryocytic
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17
Q

At what age do people usually get MPNs? Describe the cellularity of the bone marrow? Is it effective or ineffective hematopoiesis? What are 2 physical results? What are we worried about?

A
  • Common in adults (5th-7th decade)
  • Hypercellular BM with effective hematopoiesis (increased PB granulocytes, RBCs and/or platelets)
  • You see splenomegaly or hepatomegaly
  • Potential for progression (BM fibrosis or acute leukemia)
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18
Q

What is the difference between MPN and MDS?

A
  • MPN: Hypercellular BM with effective hematopoiesis
    • increased PB counts- cytoses
    • clonal abnormalities increase cell proliferation
  • MDS: Hypercellular BM with ineffective hematopoiesis
    • decreased PB counts: cytopenias
    • clonal abnormalities promoote cell death
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19
Q

What is the epidemiology of Chronic myelogenous leukemia (CML)?

What is the pathogenesis? What are the clinical findings?

A
  • Epidemiology: peak at 40-60 years
  • Pathogenesis:
    • Neoplastic expansion of the pluripotential stem cell
    • BCR-ABL1 fusion gene (produces protein with tyrosine kinase activity)
  • Clinical findings:
    • ​Hepatosplenomegaly
    • fatigue, wekaness, weight loss, anorexia
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20
Q

What are the laboratory findings for CML?

A

Leukocytosis with immature myeloid cells

Few myeloblasts (2-3%)

Basopilia

Thrombocytosis (40-50% cases) or thrombocytopenia

Hypercellular BM (~100%) with granulocytic hyperplasia

Philadelphia chromosome: t(9;22)

BCR-ABL1 fusion gene (FISH or RT-PCR)

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21
Q

What is the equation for what BM cellularity should be?

A

100-age

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22
Q

What is the clinical course of CML?

A

3 stages

Chronic phase (~3 years)

Accelerated phase (~1 year)

Blast phase= acute leukemia (myeloid or lymphoblastic)

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23
Q

What are the therapies for CML?

A
  • Allogenic stem cell transplant
  • BCR-ABL tyrosine kinase inhibitors
    • Gleevec (imatinib mesylate)
    • Dasatinib
    • Nilotinib
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24
Q

What is polycythemia vera (PV)? What mutation is associated?

A

Neoplastic explanation of the pluripotential stem cell

increase in RBCs granulocytes and platelets

Janus 2 Kinase gene (JAK2) mutation in virtually all cases

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25
Q

What are the 4 clinical findings of PV?

A
  • Splenomegaly
  • thrombotic events due to hyper-viscosity (eg hepatic vein thrombosis)
  • gout (increased uric acid due to increased cell breakdown)
  • signs of increased hiatamine (released from mast cells in the skin)
    • ruddy face
    • pruritis after bathing
    • peptic ulcer disease
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26
Q

What are the 6 laboratory findings associated with PV?

A

Increased RBC mass

leukocytosis

thrombocytosis

decreased erythropoietin (EPO)

Normal oxygen saturation (SaO2)

hypercellular BM with fibrosis in later stages

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27
Q

What are the major and minor diagnostic criteria?

A
  • Major
    • hemoglobin > 16.5 g/dL in men, 16.0 g/dL in women or other evidence of increased RBC volume
    • BM biopsy showing hypercellularity for age with trilineage growth (panmyelosis) with prominent erythroid, granulocytic and myeloid proliferation with pleomorphic mature megakaryocytes
    • presence of Jak2 mutation
  • Minor criterion
    • serum EPO level below the normal reference range
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28
Q

What is the clinical course of PV like?

A
  • Conservative treatment (eg phlemobotomy) median survival of > 10 yrs
  • most pts die fo thrombosis or hemorrhage
  • 15-20% of pts. evolve to “spent phase” which is similar to primary myelofibrosis
  • 2-3% of pts develop MDS or AML
    • (without cytotoxic therapy; >10% if history of cytotoxic therapy)
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29
Q

What therapies are used for PV?

A

Phlebotomy

Low dose aspirin

Cytoreductive therapy: i.e. hydroxyurea, in high risk patients

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30
Q

What is primary myelofibrosis (PMF)

A
  • Rapid development of BM fibrosis and extramedullary hematopoiesis (EMH) in the spleen, liver and lymph nodes
  • Clinical findings
    • fatigue, splenomegaly, hepatomegaly, fever, bone pain, night sweats
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31
Q

What are the laboratory findings in PMF?

A
  • JAK2 mutation in 50-60% of cases (also CALR, MPL)
  • BM fibrosis and clusters of atypical megakaryocytes
  • peripheral blood leukocytosis
  • thrombocytosis (early)
  • normochromic, mormocytic anemia
    • teardrop cells
    • leukoerythroblastic reaction
32
Q

What is the clinical course of PMF?

  • Median survival
  • How many patients develop AML
  • Major causes of morbidity and mortality
A
  • Survival
    • 3-7 yrs in fibrotic stage
    • >10 yrs in early (prefibrotic) stage
  • 5-30% of patients develop AML
  • Major causes of morbidity and mortality
    • BM failure (infection, hemorrhage)
    • thromboembolic events
    • portal hypertension
    • cardiac failure
    • AML
33
Q

What is the therapy for PMF?

A

Symptom based

hematopoietic stem cell transplant

34
Q

What is essential thrombocytothemia?

A
  • ET is neoplastic stem cell disorder with proliferation of megakaryocytes
  • platelet count> 450,000/uL atypical platelet morphology
  • normocellular to occasionally hypercellularity BM with abnormal megakaryocytes
35
Q

What are these pictures showing?

A

large/giant hypogranular platelets

36
Q

What are 2 clinical findings for ET? What mutation is seen? What is the typical life expectancy ?

A
  • Clinical findings:
    • Bleeding or thrombosis, splenomegaly
  • JAK2 mutation in 50-60% of pts. or CALR, MPL
  • Most patients: normal life expectancy
  • treatment: aspirin or cytoreductive therapy (hydroxyurea)
37
Q

What are Myelodysplastic syndromes (MDS)

A
  • clonal hematopoietic stem cell disorders
  • cytopenias, dysplasia (one or more myeloid cell lineages) ineffective hematopoiesis, and increased risk of development of AML
  • ENhanced apoptosis contributes to cytopenias
  • myeloblasts < 20% (PB and BM)
38
Q

What are the laboratory findings for MDS?

A
  • cytopenias (uni-, bi- or pancytopenia)
  • leukoerythroblastic reaction
  • dysplastic features
  • hypercellular BM
  • ring sideroblasts
  • increased myeloblasts
39
Q

What is dysplasia? What is the difference between normal neutrophils and dysplastic neutrophils?

A

abnormal morphology!

  • Normal neutrophils
    • segmented nucleus (~3)
    • granular cytoplasm
  • Dysplastic neutrophils
    • hyposegmented nucleus
    • hypogranular cytoplasm
40
Q

What is the difference between normal platelets and dysplastic platelets?

A
  • Normal
    • small size
    • normal granulation
  • Dysplastic platelets
    • large size
    • hypogranular
41
Q

What is this?

A

Dysplastic erythroid precursor

42
Q

What is this?

A

dysplastic megakaryocyte

*simplified nuclei with a single lobe

43
Q

What is shown in these images?

A

ringed sideroblasts!

they have chunky granules that surround the nucleus

associated with MDS

44
Q

What is a monosomy 7 mutation associated with?

A

MDS!

45
Q

What is the clinical course of MDS?

  • who gets it
  • what are symptoms
  • medan survivial
  • what does it progress to and what causes mortality
A
  • elderly individuals (50-80)
  • weakness, infections, hemorrhage or asymptomatic
  • median survivial: 9-29 months, t-MDS: 4-8 months
  • progression to AML in ~30% of cases
  • Mortality: infection, bleeding (due to cytopenias)
46
Q

What is the therapy for MDS?

A
  • supportive: blood products, antibiotics, growth factors
  • hypomethylating agents: not curative (decitabine, azacitidine)
  • allogenic stem cell transplant
47
Q

What is acute leukemia and what are the 2 categories?

A

Neoplastic proliferation of imature cells (blasts) recapitulating progenitor cells of the hematopoietic system

two main categories: Myelobastic (myeloid)-AML and Lymphoblastic (lymphoid)-ALL

48
Q

What is the difference between acute and chronic leukemia? How long do people typical live without treatment?

A

Acute Leukemias:

  • Immature cells (blasts)
  • untreated natural history of weeks to months

Chronic leukemias ( and MPNs)

  • Mature cells
  • untreated natural history of months to years
49
Q

Who typically gets AML

A

3 cases/100,000 per year

primarily adults, median age is 60 yrs. It is 80-90% of acute leukemias in adults

equal male to female ratio!

50
Q

Who typically gets ALL?

A
  • most common in children, but may be seen in adults (75% under 18yo)
  • 1.4 cases/100,000 ppl
  • M:F= 1.4:1
51
Q

What are therapeutics for ALL and AML based on?

A

morphology, cytochemistry, immunophenotyping, genetics

52
Q

AML

  • blast size
  • chromatin
  • nucleoli
  • cytoplasm
  • auer rods
  • myelodysplasia
A

AML

  • blast size: large and uniform
  • chromatin: finely dispersed
  • nucleoli: 1 to 4 often prominent
  • cytoplasm:moderately abundant granules often present
  • auer rods: 60-70% of cases
  • myelodysplasia: often present
53
Q

ALL

  • blast size
  • chromatin
  • nucleoli
  • cytoplasm
  • auer rods
  • myelodysplasia
A

ALL

  • blast size: small to medium; variable
  • chromatin: coarse
  • nucleoli: absent or 1 or 2; indistinct
  • cytoplasm: scant to moderate granules lacking
  • auer rods: absent
  • myelodysplasia: absent
54
Q

What is a cytochemical stain? Which 2 are the most useful?

A

they exploit the presence of intracellular enzymes that produce a colored product

Myeloperoxidase (MPO): myeloblasts

Non-specific esterase (NSE): monocytic blasts in AMLs with monocyte differentiation

55
Q

What are the 4 roles of immunophenotyping?

A
  • differentiates ALL from AML
  • distinguishes B-ALL from T-ALL
  • Identifies subtypes of AML (megakaryocytic, monocytic etc)
  • treatment and prognostic groups determined partly by immunophenotype

*using antibodies specific to antigens on the cells. they are used in situ (in tissue sections) or to bind to single cells in flow cytometry

56
Q

What are the lymphoid antigens? which are associated with T lineage vs B lineage?

A
  • T lineage: CD1a, CD2, CD3, CD4, CD5, CD7, CD8
  • B lineage: CD19, CD20, CD22
57
Q

What are the generic myeloid anitgens?

A

CD13, CD15, CD33, CD117, MPO

58
Q

What are the immunophenotypic markers of immaturity? What diseases are they seen in?

A

CD34 (AML and ALL)

TdT (mostly seen in ALL)

CD117 (AML)
CD1a (restricted to immature T cells)

59
Q

What do we use cytogenetics for?

A

classification: AML vs ALL associcated abnormalities

subgroups of both AML and ALL are defined by cytogenetic abnormalities (biologic and prognostic)

60
Q

What is AML?

A

Heterogenous set of disorders with a generally poor outcome? (25% long-term survival)

Systemic neoplasms of myeloid progenitor cells that primarily involve blood and bone marrow but may involve extramedullary sites

61
Q

What are the clinical features associated with AML?

A
  • Generally related to cytopenias (weakness, fatigue, petechiae, infections)
  • less common findings ( organomegaly, lymphadenopathy, infiltration of other extramedullary tissues)
  • coagulopathy in specific variants
62
Q

What are the general pathologic features that are required to call something Acute leukemia?

A
  • >20% myeloid blasts in blood or marrow
  • BM usually hypercellular
  • variable blast morphology, depending on sub-type
  • maturation may be towards any of the myeloid lineages (sometimes more than one)
    • Granulocytes, Monocytes, Megakaryocytes, Erythroid precurosors
63
Q

What is this red line pointing to?

A

The Auer rods found in AML!

64
Q

What are the 2 hematologic features of AML?

A

Severe leukopenia to marked leukocytosis

anemia and thrombocytopenia

65
Q

What are the 4 WHO classification of AML?

A

AML with recurrent cytogenetic abnormalities

AML with myelodysplasia-associated changes

AML, therapy related (and t-MDS, t-MDS/MPN)

AML not otherwise specified

66
Q

What happens in AML with recurrent cytogenetic abnormalities (“de novo” AML)?

A

generally reciprocal translocations

generally flat incidence rate over differenet age groups

distinctive morphologic features

no antecedent myelodysplastic syndrome

generally favorable prognosis

67
Q

What is another name for AML with 1(15;17) PML-RARA? hat is the morphology?

A
  • “Acute promyelocytic leukemia” and is 5-8% of AMLs,
  • Morphology:
    • generally hypergranular (minority of cases “microgranular”)
    • reniform/bilobed nuclei
    • singel cells with mulitple Auer rods
  • usually Leukopenic (low WBC count) but microgranular variant often manifests leukocytosis
    *
68
Q

What condition is associalted with APL? What therapy does it respond to?

A

Frequent DIC at diagnosis causes early morbidity and mortality

responds to all-trans retinoic acid (ATRA)

69
Q

What does a t(15;17) produce? How do we fix it?

A

produces PML-RRARa fusion gene

retinoic acid is important for myeloid maturation (disruption of receptor produces maturation arrest at the promyelocyte stage)

all-trans retinoic acid (ATRA) administration overcomes blcok and essentially matures the cells and quickly corrects the coagulopathy

APL is only AML that is responsive to ATRA

70
Q

What is AML with Myelodysplasia related changes likely related biologically to? What is the prognosis?

A
  • Likely related biologically to MDS, and may be antecedent MDS
  • MDS-type cytogenic abnormalities (complex karyotypes, losses of chromosomes or parts of chormosomes)
  • increasing incidence with age
  • prominent multilineage dysplasia
  • poor prognosis
71
Q

What is Therapy-related AML (t-AML) (and t-MDS, t-MDS/MPN) ?

A

AML (or MDS, MDS/MPN) occuring in patients previously treated with chemotherpay and/or radiotherapy

Alkylating agent related

Topoisomerase

ionizing radiation (involving bone marrow)

other agents

72
Q

What is langerhans histiocytosis?

A

a histiocytic condition that stains for CD1a and langerin

distinct clinicopathologic entities

Birbeck granules (“tennis racket” appearance on EM)

BRAF mutations

73
Q

What are the 3 kinds of langerhans cell histiocytosis?

A
  • Multifocal multisystem
    • often >2yrs old
    • aggressive
  • Unifocal/unisystem
    • often involve bones
    • treatable; sometimes spontaneous regression
  • Pulmonary
    • associated with smoking, may regress after quitting
74
Q

WHat is Hemophagocytic lymphohistiocytosis/ hemophagocytic syndrome (hyperinflammatory condition)?

A
  • non-neoplastic but aggressive (often fatal) clinical pathologic syndrome
  • uncontrolled systemic activation of macrophages, cytotoxc T cells, systemic inflammation
  • Primary (genetic) HLH: defects in genes involve in T/NK cell cytotoxic granule formation/relase (ie perforin)
  • Secondary HLH: Infection (EBV), Neoplasms (lymphomas)
75
Q

What are the 8 diagnostic criteria for hemophagocytic lymphohistiocytosis/ hemophagocytic syndrome (hyperinflammatory condition)?

A

1 genetic link or 5 out of the 8 below criteria

  • Fever (>38.5 for 7 days)
  • Splenomegaly (palpable spleen >3cm below costal margin)
  • Cytopenias involving> 2 cell lines (Hb<9, ANC <100, platelets<100,000)
  • Hypertriglyceridemia or hypofinbrinogenemia (fasting TG>2 mmol/L, fibrinogen<1.5g/L) *or 3SD away from typical for age
  • Low or absent Natural Killer Cell activity
  • Serum ferritin >500uG/L (usually 1000s)
  • Elevated soluble interleukin-2 (CD25) levels (>2400U/mL or high for age)

Heme/ Lymph-AC (24 decks)

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