Myeloproliferative Neoplasms (MPNs) & Myelodysplastic Syndromes (MDS) Flashcards Preview

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Flashcards in Myeloproliferative Neoplasms (MPNs) & Myelodysplastic Syndromes (MDS) Deck (83):
1

myeloproliferative neoplasms definition:

heterogeneous group of CLONAL myeloid neoplasms characterized by sustained PROLIFERATIONG of one or more cell types in the peripheral blood, with minimal dysplasia (EFFECTIVE HEMATOPOIESIS) and variable progression to acute leukemia

2

myeloproliferative neoplasms features:

-chronic bone marrow disorders
-excess growth in myeloid cell line (RBC, WBC, PLTS)
-similar signs and symptoms with some overlap

3

common features of all myeloproliferative neoplasms:

1) insidious nset
2) initial chronic and relatively indolent phase
3) progressive erythrocytosis/leukocytosis/thrombocytosis
4) BASOPHILIA, SPLENOMEGALY
5) variable bone marrow fibrosis and failure
6) transformation to acute leukemia (blastic phase)
7) underlying molecular events knows -BCR/ABL1, JAK2

4

Chronic myelogenous leukemia (CML) -
1) what gene associated?

t(9,22) - philadelphia (Ph) chromosome - BCR/ABL1 fusion gene

5

most common MPN?

chronic myelogenous leukemia

6

1st leukemia described?

Chronic myelogenous leukemia

7

1st leukemia associated with chromosomal abnormality?

Chronic myelogenous leukemia

8

Disease for which "leukemia" (white blood) is coined?

Chronic myelogenous leukemia

9

Chronic myelogenous leukemia
-mediam age of diagnosis?

-median age 46-53 years at Dx but can occur at any age*

10

Chronic myelogenous leukemia
-clinical features:

-FREQUENTLY ASYMPTOMATIC*
-weakness, fatigue, lethargy, WL
-fever, NS, gout (hyperuricemia)
-bleeding, pallor, dyspnea
-splenomegaly
-tri-phasic disease: chronic-accelerated - blast

11

Chronic myelogenous leukemia - pathologic features of blood smear in chronic phase:
1) granulocytes?
2) neutrophils? other granulocytes?
3) blasts?
4) platelet/clotting related?

1) Severe left-shifted granulocytosis at all stage - 30K to 100K
2) neutrophilia with "myelocyte bulge" ; eosinophilia, monocytosis, basophilia; basophils <10%
3) blasts 1-2%
4) thrombocytosis common, thrombocytopenia rare

12

myelocyte bulge- think which sample and disease?

-Chronic myelogenous leukemia - CHRONIC PHASE = neutrophilia

-blood smear

13

Chronic myelogenous leukemia - pathologic features of bone marrow biopsy & aspirate in chronic phase:
1) cell number?
2) Myeloid:Erythroid (M:E) ration?
3) Blasts % and basophils %?
4) megakaryocytes appearance?
5) special cells? where are normally seen?

1) markedly hypercellular bc granulocyte & megakaryocyte proliferation
2) >10M:1E (normal is (2-3M):1E)
3) blasts

14

dwarf megakaryocytes - which sample and which disease?

-Chronic myelogenous leukemia - CHRONIC PHASE

-bone marrow aspirate and biopsy

15

How are pseudo-gaucher cells seen on bone marrow aspirate? what does this mean?

sea-blue histiocytes

-really high cell turnover

16

What are the ancillary studies involved in CML?

1) conventional cytogenetic analysis (karyotype) - cell in metaphase state: find 9,22 translocation
2) fluorescence in situ hybridization (FISH) - find 9,22 translocation - MORE SENSITIVE TEST!
3) qualitative/Quantitative polymerase chain reaction - find BCR/ABL1 mRNA

17

CML - Chronic myelogenous leukemia-
-Pathophysiology:

-9,22 translocation = BCR/ABL1 protein tyrosine kinase is
-constantly active bc it can transfer a phosphate activating group to itself and generates signals that mimic the effect of growth-factor activation
-cells are less dependent on normal growth factor receptor signals for growth
-proliferative and differentiate unchecked
-anti-apoptotic effects

18

Chronic myelogenous leukemia - CML:
-three different gene regions of BRC:
-most common?

-Major p210 breakpoint: vast majority of CML* w/ conventional pathological characteristics
-Minor p190 breakpoint: seen in Ph chromosome ALL and CML with monocytosis
-p230 Breakpoint: CML with thrombocytosis

19

***Which BCR gene region is most common in CML?

p210 breakpoint***

20

p210 breapoint disease associations?

conventional CML with usual pathologic characteristcs

21

p190 breakpoint diease associations?

Ph chromosome ALL and CML with monocytosis

22

p230 breakpoint disease associations?

CML with thrombocytosis

23

CML - accelerated phase disease basically means? Other features?

-if left untreated the blasts and basophils will continue to increase
*-Peripheral blood or bone marrow blasts: inc to 10-19% (must be less that 20%)
*-peripheral blood basophils: inc to >20%

-persistent thrombocytopenia or thrombocytosis (unrelated or unresponsive to therapy)
-worsening leukocytosis, splenomegaly
-clonal evolution by cytogenetic analysis

24

Acute leukemia definition? related to CML accelerated phase?

-acute leukemia has >20% blasts while CML-accelerated has 10-19% increase

25

CML-blast phase:
-characteristics?
-myeloid vs lymphoid blasts pregression? significance?

-Peripheral blood or bone marrow blasts >20%

-myeloid-blast phase- 50-60%
-lymphoid blast phase- 15-30%
-Myeloid blast phase more often than lymphoid (this cancer can jump lineages)

26

How to distinguish lymphoid and myeloid lineage CMLs? which phase?

-immunophenotyping via flow cytometry
-blast phase CML

27

CML Treatment:

-tyrosine kinase inhibitors (Imatanib/Gleevac)
-stem cell transplantation for younger patients

28

CML prognosis:

-if chronic phase=6 years chronic phase
-if blast phase=terminal
-imatanib (Gleevac): prolonged survival
-goal to eradicate clone in Chronic Phase (CP), prevent AP (acute/accelerated phase)/BP (blast phase)

29

imatanib is treatment for?

CML

30

CML - differential diagnosis for chronic phase and for accelerated/blast phase?

1) Chronic Phase:
a) leukemoid reaction
b) other MPNs, aCML, CMML

2) Accelerated/Blast:
a) MPN/MDS
b) AML
c) ALL

31

What is a leukemoid reaction?

reactive benign neutrophilia due to infection or inflammatory state

32

What do you see in a benign leukemoid reaction vs a neoplastic CML?

Leukemoid /// CML
-Nml response to infection /// Clonal MPN
-WBC30-60K
-Segs and bands /// myelocyte bulge
-no basophilia or splenomegaly /// Yes to basophilia and splenomegaly
-explained clinically /// unexplained
- LAP (leukocyte alkaline phos) score elevated /// LAP score decreased
-normal megakaryocytes /// dward megak

33

Polycythemia vera-PV:
Definition:
Characteristics:

1) MPN with increase RBC production
2) characteristics:
**a) INCREASED RBC MASS ( RBC, HGB, HCT)
b) may affect all cell lines
**c) MEDIAN AGE 60 YEARS AT DIAGNOSIS
d) 5% younger than 40 yrs
e) a little bit more males than females affected
f) rarely develop into AML

34

defining feature of PV?

INCREASED RBC MASS ( RBC, HGB, HCT)

35

PV- Clinical features:

**1) HYPERVISCOSITY and related symptoms
**2) PRURITUS AFTER WARM H20 (aquagenic pruritus) - ITCHY AFTER SHOWER DUE TO WARM INCREASED HISTAMINE FROM MAST CELLS
3) impaired CNS circlation (HA, blurry vision, TIA)
4) thrombosis (arterial and venous)
5) hemorrhage
6) splenomgaly
7) gout
8) erythromelalgia (red painful joint swelling)
9) two phases (polycythemic and spent)

36

ithcy after a warm shower - what condition?

polycythemia vera PV

37

PV diagnostic criteria: (DONT WORRY ABOUT THIS SO MUCH

*1) elevated HBG
*2) JAK2 mutation
3) hypercellular marrow with panmyelosis
4) low serum EPO (inc in RBC is NOT due to EPO)
5) endogenous erythroid colony formation in vitro

38

PV- Periperal blood findings:

erythrocytosis - on smear there are many RBC and they are on top of each other a lot bc so many

39

PV - bone marrow biopsy and aspirate findings:

1) hypercellular with panmyelosis
2) erythroid predominance
3) variably enlarged megakaryocytes

40

PV - pathological features of SPENT PHASE:
-PB?
-BM?

1) leukoerythroblastosis (non-specific):
a)nRBC & left-shifted neutropils
b) tear drop shaped RBC (dacrocytes)
2) bone marrow aspirate and biopsy
a) often a dry-tap - so much fibrosis that you dont really get a good sample-dry tap
b) increasing fibrosis

41

other name for spend phase?

post-polycythemic myeloid metaplasia

42

Tear drop shaped RBC - condition is?

Polycythemia vera
(and primary myelofibrosis?)

43

What is the stain for BM in PV? what does this stain show?

reticulin stain - shows fibrosis

44

Pathophysiology of PV? How to detect this cause? Problem with detection?

1) point mutation in JAK2 tyrosine kinase (OVER 95% have this mutation other 3-4% have JAK2 exon12 mutation)
2) use PCR
3) problem is that PCR is not specific for PV -- also could be ET and PMF

45

PV- treatment:

-phlebotomy to reduce hyperviscosity
-myelosuppresive drugs (hydroxyurea, interferon)

46

PV - prognosis:

-15year survival is 65%
-worse prognosis with history of thrombosis

47

PV - differential diagnosis:

1) Secondary polycythemia
2) smoking (CO)
3) living at high altitude
4) respiratory compromise (obesity, emphysema)
5) EPO-secreting tumors
6) RCC, HCC, Pheo, Hemangioblastoma
7) OTHER MPNs

48

**Secondary polycythemia vs PV

secondary polycythemia /// PV
1) nml response to hypoxia /// clonal MPN
2) increase EPO /// dec EPO
3) no splenomegaly /// splenomegaly
4) normocellular marrow /// panmyelosis
5) nml megakaryos /// enlarges megakaryos
6) explained clinically /// unexplained

49

Essential thrombocytosis (ET)
Etiology:

-MPN with increased platelets
-medain age 60 years at diagnosis
-more females than males
-rare progression to fibrosis and AML

50

ET- clinical features:

*-MANY ARE ASYMPTOMATIC
-thrombosis (periph, CNL, large vessel)
-splenomegaly
-hemorrhage
-erythromelalgia (red, painful joint swelling)
-HA, blurry vision, palpitations
-spontaneous abortions

51

ET - diagnostic criteria: (DONT WORRY ABOUT THIS SO MUCH)

-sustained platelet > 450K
-BM=megakaryocytic hyperplasia
-JAK2 mutation
-not meeting criterial for other MPN, MDS, myeloid neoplasms

NEED ALL 4

52

ET- pathologic features of PB smear?

thrombocytosis

53

ET-pathologic feature of BM aspirate and biopsy

-megakaryocytic hyperplasia
-enlarged megakaryocytes, clustered , and prominent hyperlobations

54

staghorn like megakaryoblasts is what disorder?

Essential thrombocytopenia

55

Pathophys of ET? How is issue detected?

1)tyrosine kinase JAK2 mutation
2) detected by PCR but not specific for ET (also finds PV and PMF)

56

ET - treatment:

-asymptomatic = observe
-symptomatic = cytoreduction -aphoresis (ASA)

57

ET- prognosis

very good!
ET does not usually reduce life expectancy
-progression to AML is rare

58

ET - differential diagnosis:

***1) secondary thrombocytosis
2) infection
3) iron def
4) acute blood loss
5) hemolytic anemia
6) vasculitis
7) IBD
8) splenectomy surgery
9) malignancy
10) drug effect
11) tissue injury

59

secondary Thrombocytosis vs essential thrombocytosis

secondary /// essential
1) nml resposne /// clonal MPN
2) no splenomegaly /// splenomegaly
3) normal megakaryos /// hyperlobated megakaryos
4) platelet count 1 mil
5) nml BT (bleeding time) & PFT (platelet fucntion test) /// abn BT & PFT
6) explained clinically /// unexplained

60

Primary myelofibrosis (PMF) - characteristics/etiology:

**-MPN with megakaryocyte, granulocyte proliferation and progressive fibrosis
**-progressive fibrosis
**- transformation to AML in 5-30%
-affected male = female
-median age 54-62 years at Dx

61

key feature of primary myelofibrosis:

errr DUH PRIMARY FIBROSIS.

62

PMF - clinical features:

**1) Often asymptomatic
**2) two phases (prefibrotic and fibrotic)
3) weight loss
4) nonspecific constitutional symptoms
5) anemia gout renal stones
6) splenomegaly

63

PMF - PB and BM pathological features - PREFIBROTIC PHASE:

PB- thrombocytosis; mild anemia; mild leukocytosis

BM-mildly hypercellular; minimal megakaryo abnormalities; minimal fibrosis

64

PMF- PB and BM pathological features - FIBROTIC PHASE:

PB- *LEUKOERYTHROMBLASTOSIS; thrombocytosis; mild anemia; mild leukocytosis; rare blasts

BM- *PROGRESSIVE FIBROSIS; * ATYPICAL MEGAKARYOS (BIZARRE AND HYPERCHROMIC); blasts< 20%

65

bizarre hyperchromic atypical megakaryocytes are seen in which disorder?

PMF

66

Pathophysiology of PMF-

**JAK2 point mutation
detected by PCR but not specific bc also finds PV and ET

67

PMF - treatment:

-progressive disease with no effective treatment
-supportive (transfusions, antibiotics)

68

PMF - prognosis

-mean survival 3-5 years from dignosis
-worse prognosis = 70 or older, worsening anemia, abnormal karyotype

69

myelodysplastic syndromes definition:

-heterogenous group of monoclonal myeloid neoplasms characterized by peripheral blood *cytopenias*, *ineffective hematopoesis* and variable progression to acute myeloid leukemia

70

myelodysplastic syndromes features:

-chronic bone marrow disorders
-*Abnormal (dysplastic) cell growth* in myeloid cell line (WBC, RBC platelets)
-similar signs and symptoms with some overlap

EVERYTHING IS LOW

71

myelodysplastic syndromes common features:

-insidious onset
-initial chronic and relatively indolent phase
-variable progression
****-peripheral cytopenias and hypercellular marrow
-transformation to acute blastic phase

72

identification of dysplasia:

1) must be present in at least 10% of cells in a given lineage to call the lineage dysplastic
2) requires well-prepared aspirate smears
3) megakaryo morphology best assessed in biopsy material
4) review peripheral smear for neutrophil dysplasia

73

dysplasia morphological features - erythroid lyneage:
---> PB
---> BM

PB: dimorphic RBC -PALE CELLS

BM:
-nuclear budding or lobulation;
-asymetric bi or tri nucleation
-karyorrhexis
-megaloblasic changes (N:C asynchrony)
-iron stain - ring sideroblasts (Not specific)

74

dysplasia morphological features - granulocyte lyneage:
---> PB

PB:
-pale hypolobated neutrophils
-nuclear hyperlobation (Rare)
-hypergranular (rare)

75

dysplasia morphological features - megakaryocytes:
---> BM

BM:
-small or large
-hypolobated nuclei
-multinucleated forms
-present in clusters

76

ringed sideroblasts are:

RBC precursors with iron depsits (seen with stain) in mitochondria

NOT SPECIFIC FOR DYSPLASIA

77

Best prognosis

-RA- refractory anemia
-RARS: refractory anemia with ringed sideroblasts

78

So you have a cytogenic abnormality ...

Doesnt mean you have MDS!

79

Most common MDS cytogenic abnormalities are chromosomes:

5,7,8,20

80

MDS treatment:

-supportive (transfusions, antibiots, G-CSF
-chemotherapy (azacytidine, decitabine, lenalidomide)
-allogenic stem cell transplant (only potentiailly curative)

81

MDS- prognosis:

-primary cause of death is BM failure
-40% transform to acute leukemia

82

myeloproliferative v myelodysplastic features:

myeloproliferative/myelodysplastic
-High periph count / low periph cnt
-organomegaly/ no organomegaly
-normal cell morphology / dysplastic cell morphology
-effective hemopoiesis / ineffective

THERE ARE SOME OVERLAP SYNDROMES

83

MDS and MDN overlap syndromes:

-chronic myelomonocytic leukemia (CMML)
-atypical chronic myelogenous leukemia (aCML)
-juvenile myelomonocytic leukemia (JMML)
-myelodysplastic/myeloproliferative neoplasms, unclassifiable (MDS/MPN,U)