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S3B5 Pathology > Chronic Myeloproliferative Neoplasms (MPN) + Overview > Flashcards

Chronic Myeloproliferative Neoplasms (MPN) + Overview Flashcards

1
Q

What are the 4 main categories of myeloid neoplasms?

A
  1. Myeloproliferative neoplasms
  2. Myelodysplastic syndromes
  3. Myeloproiferative / myelodysplastic neoplsms
  4. Acute myeloid leukemias
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2
Q

What features are common to all 4 types of myeloid neoplasms?

A

involve blood, bone marrow

loss of normal control of proliferation

suppression normal hematopoietic cells

may all progress to AML

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3
Q

The clinical disease is related to what variables of the myeloid neoplasms?

A

stage of development of neoplastic cells

clinical effects of leukocytosis or cytopenias

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4
Q

What are the general features associated with Myeloproliferative neoplasms (MPN)?

A

increased production one or more types of mature/maturing blood cells

effective hematopoiesis with increases in peripheral blood cell count

no dyspoiesis (abnormal formation of blood cells) - except for megakaryocytes

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5
Q

What are the general features associated with Myelodysplastic syndromes (MDS)?

A

ineffective hematopoiesis → peripheral blood cytopenias

varying degrees dyspoiesis in one or more cells lines

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6
Q

What are the general features associated with Myeloproliferative/myelodysplastic neoplesms (MPN/MDS)?

A

neoplasms with overlapping features of MPN & MDS

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7
Q

What are the general features associated with Acute myeloid leukemias (AML)?

A

accumulation immature myeloid forms in bone marrow

normal hematopoiesis is suppressed → peripheral blood cytopenias

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8
Q

What is the only myeloid neoplasm in which you will not see peripheral blood cytopenia?

A

Myeloproliferative neoplasm (MPN)

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9
Q

What clinical features would you expect to see in a patient with myeloproliferative neoplasm?

A
  • hypercellular bone marrow
  • maturation is present
  • increased myeloid cells in peripheral blood
  • abnormal megakaryocytes with relatively normal granulocytes & erythroid precursors
  • organomegaly (splenomegaly/hepatomegaly)
  • variable transformation to a spent phase
    • marrow fibrosis & peripheral blood cytopenias
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10
Q

What is the molecular abnormalities found in myeloproliferative neoplasms? What are the impacts of this mutation?

A

clonal abnormalities involve genes that encode cytoplasmic or receptor protein tyrosine kinases

  • circumvent normal controls on proliferation
  • lead to growth factor-independent cell proliferation & survival of marrow progenitors
  • differentiation is not impaired - cells will continue to mature
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11
Q

What is the typical clinical outcome associated with chronic myeloproliferative neoplasms?

A

typically indolent

develop over months to years

most people live for many years

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12
Q

What are the 4 classifications for chronic myeloproliferative neoplasms?

A
  • chronic myelogenous leukemia
    • BCR-ABL1 positive
  • Polycythemia vera
  • Primary myelofibrosis
  • Essential thrombocytosis
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13
Q

What genetic abnormality is associated with chronic myelogenous leukemia?

A

BCR-ABL1 fusion gene on the Philadelphia (Ph) chromosome

translocation of ABL1 proto-oncogene on chromosome 9q34 to BCR (breakpoint cluster region) on chromosome 22q11

Ph = abnormal chromosome 22

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14
Q

What is the molecular result of the chimeric BCR-ABL1 gene?

A

usually codes for cytoplasmic fusion protein, BCR-ABL, a constitutively activated tyrosine kinase

this alone is sufficient to cause disease

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15
Q

Is BCR-ABL1 specific to chronic myelogenous leukemia?

A

no- it is required for diagnosis but not entirely specific

it may be seen in some acute leukemias - but fusion transcripts will differ

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16
Q

Chronic myelogenous leukemia is what kind of disorder? It most commonly affects people of what age group?

A

Pluripotent stem cell disorder

middle age (40-60)

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17
Q

What risk factors are associated with chronic myelogenous leukemia?

A

radiation exposure

no inherited predisposition known

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18
Q

What are the three phases of CML?

A

chronic

accelerated

blast

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19
Q

Describe the clinical presentation of chronic phase of CML?

A

insidious onset - malaise, fatigue, weight loss, upper GI discomfort

spleno/hepatomegaly

NO lymphadenopathy

anemia & iron deficiency

bruising & bleeding

hypermetabolic

gout / renal disease

(rarely) visual disturbances

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20
Q

What peripheral blood findings would you expect to see in a patient in the chronic phase of CML?

A

leukocytosis with granulocytic left shift (increased immature myeloid cells)

no significant dyspoiesis

basophilia & eosinophilia

blasts < 2% peripheral blood WBC

normal to increased platelet count

large “buffy” coat

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21
Q

What bone marrow findings would you expect to see in a patient in the chronic phase of CML?

A
  • hypercellular marrow with myeloid hyperplasia
  • increased eosinophils
  • increased megakaryocytes & “dwarf megakaryocytes”
  • no significant dyspoiesis (except megakaryocytes)
  • no increase blasts
  • pseudogaucher cells
    • pump, blue histiocytes
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22
Q

This peripheral blood smear is from what phase of CML?

A

chronic

almost looks like bone marrow, but it is peripheral blood

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23
Q

The provided bone marrow sample is from what phase of CML?

A

chronic

(can’t see, but will be mostly myeloid precursors)

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24
Q

What cells are shown in the provided smear that are characteristic of the chronic phase of CML?

A

dwarf megakaryocytes

(small & hypolobated)

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25
Q

What is the large cell shown in the provided slide that are commonly seen in what myeloid neoplasm? How do these types of cells arise in this condition?

A

pseudo-Gaucher cells

chronic phase of CML

increased hemophagocytic activity associated with high turnover of hematopoietic cells

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26
Q

The provided bone marrow aspirate smear is from what phase of CML?

A

accelerated

(increase in the percent of blasts - still <20%)

may see some dyspoiesis

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27
Q

The provided bone marrow biopsy is from what phase of CML?

A

accelerated

(increase in the percent of blasts - still <20%)

may see some dyspoiesis

increased # megakaryocytes

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28
Q

The provided bone marrow biopsy is from what phase of CML?

A

blast phase

will have >20% blasts

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29
Q

The provided peripheral blood smear is from what phase of CML?

A

blast phase

30
Q

What features are indicative of the accelerated phase of CML?

A
  • increasing cell counts
    • (total WBC, basophils & blasts)
  • increased numbers dwarf megakaryocytes
  • reticulin fibrosis of the marrow
    • worsening splenomegaly
  • blasts are increased, but <20% peripheral WBC or bone marrow cells
  • worsening thrombocytopenia or thrombocytosis
31
Q

What does a “granulocytic left shift” mean?

A

increase in immature myeloid cells in peripheral blood

32
Q

What features are indicative of the blast phase of CML?

A
  • blasts >20% of peripheral blood WBC or nucleated cells of marrow
    • blasts may be myeloid (70-80%) or lymphoid (20-30%)
  • collections of malignant blasts in other tissues “granulocytic sarcoma”
33
Q

What is the prognosis of CML?

A

usually fatal within in weeks-months

due to infection or bleeding

34
Q

What is the treatment for CML?

A
  • Tyrosine kinase inhibitors (imatinib)
    • highly effective - 5yr survival is 85-90%
  • hematopoietic stem cell transplant is curative (but w/ many risks)
35
Q

What is polycythemia vera?

A

MPN with peripheral blood polycythemia & proliferation of erythroid, granulocytic, and megakaryocytic lineages in marrow

36
Q

What genetic mutation is associated with Polycythemia Vera?

A

somatic gain-of-function mutation JAK2 V617F - low serum erythropoietin level

cells can proliferate independent of growth factors

ABSENCE of t(9;22) (negative BCR-ABL1)

37
Q

What clinical features are seen in patients with polycythemia vera?

A
  • red face & cyanosis
  • hypertension, headache, dizziness, paresthesia
  • GI issues (bleeding)
  • Gout, weight loss
  • pruritus
  • erythromegalia (paroxysmal severe burning pain & throbbing in skin of extremities)
  • spleno/hepatomegaly
  • platelets functional
    • venous / arterial thrombosis
  • platelets not functional
    • hemorrhage
38
Q

The clinical features seen in polycythemia vera are mainly due to what physiologic cause?

A
  • increased blood volume
    • stagnation of blood flow
    • plethora (red face) and cyanosis
39
Q

What are the three phases of polycythemia vera?

A

pre-polycythemic phase

polycythemic phase (usually diagnosed in this phase)

post-polycythemic phase

40
Q

The provided histologic slide is from what phase of polycythemia vera?

A

polycythemic phase

megakaryocytes are more normally sized than with CML

red cell morphology is usually normal, but will see an increase Hb & Hct

41
Q

What are the features seen in the pre-polycythemic phase of polycythemic vera?

A

borderline/mild erythrocytosis

difficult to diagnosis - usually asymptomatic

42
Q

What are the features seen in the peripheral blood smear & bone marrow in the polycythemic phase of polycythemia vera?

A
  • Peripheral Blood
    • increased RBC (normal morphology)
    • increased hemoglobin
    • increased hematocrit
    • mild granulocytosis and/or thrombocytosis
  • Bone marrow
    • hypercellular with “panmyelosis”
    • megakaryocytes are variably hyperlobulated
    • no dysgranulopoiesis or dyserythropoiesis
43
Q

What does panmyelosis mean?

A

hyperplasia of all 3 cell lines

44
Q

What are the features seen in the peripheral blood smear & bone marrow in the post-polycythemic phase of polycythemia vera?

A
  • peripheral blood
    • cytopenia and/or leukoerythroblastosis
    • many teardrop cells
  • bone marrow
    • prominent reticulin and collagen fibrosis
    • decreased hematopoiesis
45
Q

What are the clinical features seen in the post-polycythemic “spent” phase of polycythemia vera?

A

extramedullary hematopoiesis (EMH)

and splenomegaly

46
Q

What is the prognosis of polycythemia vera & what is the goal of treatment?

A

incurable with present therapy - may progress to MDS/MPN or AML

reduce risk of thrombosis

47
Q

The provided stains are characteristic of what phase of polycythemia vera?

A

post-polycythemic

increased fibrosis

(notice cells look like they are all headed in the same direction, this is because of the increased fibrosis)

48
Q

What disease is characterized by MPN defined by a sustained thrombocytosis (>450,000) in peripheral blood & overproduction of megakaryocytes in marrow with normal hematocrit.

A

essential thrombocytosis

49
Q

What are the main sites that are involved with essential thrombocytosis?

A

blood and bone marrow

50
Q

What genetic mutation is associated with essential thrombocytosis?

A

NONE are specific for ET

JAK2 V617F (60%)

constitutively active tyrosine kinase → uncontrolled cell expansion

Negative BCR-ABL1

51
Q

Describe the typical clinical presentation of a patient with essential thrombocytosis.

A
  • abnormal CBC (w/ thrombocytosis)
  • normal RBC/Hb/Hct
  • thombi & bleeding
  • No spleno/hepatomegaly
52
Q

Why do you not typically see splenomegaly in patients with essential thrombocytosis?

A

spleen in not a major site of extramedullary hematopoiesis b/c don’t see much fibrosis in the BM

53
Q

What peripheral blood morphology would you expect to see in a patient with essential thrombocytosis?

A

thrombocytosis

large & giant platelets (may be larger than red cells)

nucleated megakaryocytic fragments

Normal RBC & WBC

54
Q

The provided peripheral blood smear is from what Myeloid Neoplasm?

A

Essential Thrombocytosis

increased # platelets & nucleated megakaryocytic fragments

55
Q

What bone marrow findings would you expect to see in a patient with essential thrombocytosis?

A

normal to slightly hypercellular (blast<5%)

striking megakaryocytic proliferation with large, hyperlobulated megakaryocytes

other cells have normal morphology

absent/minimal reticulin fibrosis

56
Q

The provided bone marrow slide is from a patient with what myeloid neoplasm?

A

Essential Thrombocytosis

striking megakaryocytic proliferation with large, hyperlobulated megakaryocytes

57
Q

What is the prognosis & treatment of essential thrombocytosis (ET)?

A

small risk of transformation to myelofibrosis or AML

low-dose aspirin

58
Q

What are the other names for primary meylofibrosis?

A

chronic myelofibrosis

agnogenic myeloid metaplasia

idiopathic myelofibrosis

59
Q

What are the general characteristics associated with primary myelofibrosis?

A

proliferation marrow megakaryocytes

bone marrow fibrosis

extramedullary hematopoiesis

NO erythrocytosis

60
Q

What is the typical clinical presentation of a patient with primary myelofibrosis?

A
  • massive splenomegaly (b/c extramedullary hematopoiesis)
  • older adults (>60)
  • late stage anemia
  • nonspecific symptoms (fatigue, weight loss, night sweats)
  • hyperuricemia (gout & stones)
61
Q

What are the molecular/cytogenic abnormalities associated with primary myelofibrosis?

A

none that are specific

JAK2 V617F (60%)

CALR (35%)

Negative BCR-ABL1

62
Q

What are the phases of primary myelofibrosis?

A

pre-fibrotic and fibrotic

63
Q

What is the peripheral blood morphology in the pre-fibrotic phase of primary myelofibrosis?

A

initially normal progressing to variable thrombocytosis, variable granulocytic leukocytosis

no dyspoiesis or left shift

anemia w/ normal RBC morphology

64
Q

What is the peripheral blood morphology in the fibrotic phase of primary myelofibrosis?

A
  • moderate normochormatic normocytic anemia with leukoerythroblastosis
  • marked anisopoikilocytosis (dif size & shape) with teardrop cells
  • thrombocytopenia with large, bizarre platelets & megakaryocyte fragments
65
Q

What is the bone marrow morphology in the pre-fibrotic phase of primary myelofibrosis?

A
  • hypercellular for age (granulocytic & megakaryocytic hyperplasia)
  • no dysgranulopoiesis or dyserythropoiesis
    • megakaryocytes are atypical
  • absent/minimal fibrosis
66
Q

What is the bone marrow morphology in the fibrotic phase of primary myelofibrosis?

A
  • often a “dry tap” - nothing aspirated
  • hypocellular marrow with moderate to severe reticulin/collagen fibrosis & dilated sinuses
  • megakaryocytic atypic
    • clusters, hyperchromatic bizarre nuclei, cloud-like nuclei
67
Q

What is the major defining feature of CML?

A

many neutrophils & their precursors

68
Q

What is the major defining feature of polycythemia vera?

A

many of everything

especially erythrocytes & their precursors

69
Q

What is the major defining feature of essential thrombocytosis?

A

many platelets and megakaryocytes

70
Q

What is the major defining feature of primary myelofibrosis?

A

pre-fibrotic: thrombocytosis & mild granulocytosis but NO erythrocytosis

fibrotic: fibrosis, osteomyelosclerosis & marrow hypoplasia → splenomegaly

71
Q

What steps would you take to work up chronic myeloproliferative neoplasms?

A
  1. CBC & peripheral blood smear
  2. bone marry biopsy & aspirate
    1. flow cytometry in fibrotic phase
    2. staining for CD34, CD117 and/or TdT
  3. conventional cytogenetic analysis, FISH, molecular methods
    1. looking for specific translocations / markers

*not tested in this class, but probably good reminder for MEDI

S3B5 Pathology (13 decks)

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