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Fundamentals 3- Heme > Myeloid Neoplasm > Flashcards

Myeloid Neoplasm Flashcards

1
Q

What are the three main categories of myeloid neoplasia?

A
  1. Acute myeloid leukemia (AML)
  2. Chronic myeloproliferative neoplasms (CMPN)
  3. myelodysplastic syndrome (MDS)

There is overlap between the categories. Ex. a myeloid neoplasm can have MDS and CMPN properties. In some cases CMPN and MDS can “transform” to AML.

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2
Q

What are the 5 terminally differentiated myeloid cells?

A
  1. neutrophils
  2. eosinophils
  3. basophils
  4. RBC
  5. platelets (even though they are not actual cells)
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3
Q

What is acute myeloid leukemia (AML)?
What is the proliferating cell?
What are the three things that occur as a result of the neoplasm?

A

It is the proliferation of immature cell forms (blasts) of the myeloid series resulting in:

  1. the replacement of normal bone marrow elements
  2. suppression of normal hematopoiesis
  3. circulation of neoplastic cells
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4
Q

What age group is typically affected by AML?

How do cases of AML arise?

A

AML affects adults (but can affect any age).

Most cases of AML are sporadic, but constitutional disorders with increased DNA fragility are at an increased risk.

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5
Q

How do most AML cases arise?

What are two situations when this is not the case?

A

Most AML cases are sporadic.

  1. Disorders that increase DNA fragility increase the risk
  2. DNA damaging agents (radiation, chemo alkylating agents and topoII inhibitors , smoking)
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6
Q

AML occurs due to genetic lesions that cause blasts that are ________ or show only _______________.

A

undifferentiated or show only early signs of differentiation

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7
Q

What are the two hits for the sporadic development of AML?

A
  1. first hit is a mutation in a gene encoding transcription factors necessary for normal maturation
  2. second hit is a new mutation in FLT3 tyr kinase receptor mutation that allows for increased cell proliferation
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8
Q

At present, what is the most valuable piece of information for predicting clinical outcome of AML?

A

the cytogenetic aberration detected at the time of diagnosis

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9
Q

How does AML present clinically?

A

Bone marrow infiltration causes:

  1. anemia- fatigue, pallor
  2. thrombocytopenia- bruising, petechial rash, mucousal bleeding
  3. Leukocytosis
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10
Q

What is crucial to obtain when working up patients with unexplained pancytopenia?

A

a bone marrow biopsy because sometimes blasts don’t make it to the peripheral smear.

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11
Q

What can complicate AML, particularly in cases of APML?

A

DIC

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12
Q

How is AML diagnoses?

A

Greater than or equal to 20% blasts in the blood or bone marrow.

Exceptions:
Recurrent translocations can have less than 20% but have
1. t(8,21)
2. t(15,17)
3. inv(16)
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13
Q

What are the general morphological features of AML blasts?

Describe nuclear features and cytoplasmic features.

A

Myeloblasts have granulocytic differentiation.
Nuclear:
1. high N/C
2. dispersed chromatin
3. one–>multiple nucleoli
Cytoplasmic:
1. fine granules or crystalized granular material
2. Auer rods (specific for myeloid neoplasms)
3.Myeloperoxidase positive (MPO+)

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14
Q

Describe the morphology of a monoblast.

A

Monoblasts have more cytoplasm than myeloblasts and have greyer cytoplasm.
The nucleus is folded or round with lacy chromatin

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15
Q

What type of blast would be positive for MPO?

What type of blast would be positive for “nonspecific esterase”?

A

MPO = myelobast

non-specific esterase = monoblast

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16
Q

Describe the morphological appearance of megakaryoblasts.

A

They have round nuclei with one to three nucleoli and characteristic cytoplasmic blebs.

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17
Q

Immunophenotyping for myeloid lukemias can be done by what two techniques?

A
  1. immunohistochemical staining

2. flow cytometry

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18
Q

What are the lineage associated markers of myeloblasts?

A

CD117
CD13
CD33
MPO

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19
Q

What are the lineage associated markers of monoblasts?

A

CD14

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20
Q

What are the lineage associated markers of erythroids?

A

CD71

glycophorin-A

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21
Q

What are the markers of megakaryoblasts?

A

CD41 and CD61

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22
Q

What is CD34?

A

It is present on pluripotent hematopoietic stem cells and is considered a marker of immaturity
BLASTS

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23
Q

What is the difference between FAB classification of AML and WHO classification of AML?

A

FAB diagnosed AML on morphological appearance of the leukemic blasts.
WHO incorporates morphology with clinical and genetic information

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24
Q

AML with ___________ tend to respond well to therapy.

A

Balanced translocations (15,17) (8,21)

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25
Q

What two forms of AML have a poor prognosis?

A

MDS-related AML or therapy-related AML

These AMLs usually involve deletions or monosomies of chromosomes 5 or 7

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26
Q

What therapies are associated with increased risk of AML?

A

Alkylating agents or TopoII inhibitors

TopoII inhibitors are associated with translocations of MLL gene on chromosome 11

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27
Q

AML with t(8,21) generally presents in what age patients?

The patient presents usually with __________ in addition to ______________________.

A

Younger adults and they present with myeloid sarcoma (soft tissue masses) with bone marrow and blood involvement

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28
Q

What are the morphological features of t(8,21) AML?

A
  • large myeloblasts that have granules and Auer rods

- spectrum of maturation of neutrophils with abnormal nuclear segmentation and cytoplasm staining

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29
Q

What are the four stages of neutrophilic maturation?

A

Promyelocyte
Myelocyte
Metamyelocyte
mature neutrophil

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30
Q

AML with inv(16) presents in what age patients?

What is the physical presentation at the hospital?

A

Younger adults.

There may be myeloid sarcoma at presentation

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31
Q

What is the morphology of inv(16) AML?

A
  1. myeloblasts
  2. monocytic precursors
  3. maturing eosinophils with purple granules
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32
Q

What age patient does t(15,17) AML occur in?

What is the other name for this AML?

A

Middle age adults and is called APL (acute promyelocytic leukemia)

33
Q

What is APML frequently associated with?

What is the treatment for it?

A

IT is associated with DIC and it is treated with ATRA (all-trans retinoic acid).

34
Q

Describe the morphology of APML.

A
  1. Abnormal promyelocytes with bilobed nuclei and densely packed cytoplasmic granules
  2. cells with MULTIPLE Auer rods
35
Q

Why is ATRA able to treat APML?

A

retinoic acid receptor a (RARA) plays a role in promoting granulocytic differentiation.
PML fuses with RARA in the t(15,17) which blocks differentiation and stops the cells in promyelocytic stage.
High concentrations of ATRA can inhibit the PML-RARA fusion protein and allow differentiation to occur again

36
Q

In what age patient would you see AML with myelodysplasia?

What two AMLs does this encompass?

A

Older patients

  1. AML that arises from MDS
  2. AML that demonstrates cytogenetic or morphological abnormalities associated with myelodysplasia (deleted 5 or 7)
37
Q

What are the four commonly implicated drugs in the emergence of AML?

A
  1. Alkylating agents (cyclophosphamide, cisplatin, dacarbazine, mitomycin)
  2. Topo II inhibitors (etoposide, doxorubicin)
  3. Antimetabolites (thiopurines)
  4. Antitubulin (vincristine)
38
Q

What is myelodysplastic syndrome?

A

Clonal stem cell disorder characterized by ineffective hematopoiesis which results in hyperplasia of myeloid precursors in the bone marrow and peripheral cytopenia.
The cells are able to differentiate, they just have abnormal hematopoiesis so there is :
1. abnormalities in neutrophils and their precursors
2. RBCs and their precursors
3. platelets
4. megakaryocytes

39
Q

What are the cytogenetic abnormalities associated with MDS?

A

deletions on chromosomes 5 or 7

40
Q

What age patient does MDS usually affect? How does MDS arise?
How do patients present?

A

Older patients
In many cases it arises sporadically but it can also arise years after radiation or chemotherapy
Patients present with cytopenia without organomegaly

41
Q

What is the morphological presentation of peripheral blood or bone marrow aspirate for MDS?
Neutrophils, RBC, platelets, megakaryocytes

A

Dysplasia
Neutrophils: hypogranular and hypolobated
RBC: anisopoikilocytosis and basophilic stippling

You may see cells that have abnormal nuclear budding, multinucleation, and megaloblastoid changes

Platelets: large and hypogranular
Megakaryocytes: small and hypolobated

42
Q

How do you grade MDS?

A

based on the number of blasts in the peripheral blood and bone marrow.

43
Q

What is the prognosis for MDS?

A

It depends on the subtype and grade of the MDS.
Lower grade: 5 or more years but a mean around 2 years
Higher grade are more likely to progress to AML so the prognosis is poorer.

44
Q

What is chronic myeloproliferative neoplasm?

A

CMPN are clonal stem cells characterized by unregulated sustained myeloid cell proliferation in the marrow with little disturbance in maturation, leading to accumulation of neoplastic cells in the periphery

45
Q

What is notable about the marrow and the peripheral blood for CMPN?

A

Marrow is hyperplastic and the peripheral blood has elevated numbers in one or more cell lineage (WBC, Hb, platelets)

46
Q

How are CMPNs classified?

A

by the predominant cell type in the peripheral blood and the genetic characteristics of the neoplasm

47
Q

What are the 4 types of chronic myeloproliferative neoplasms?
What are the genetic changes associated with each?

A
  1. CML - neutrophils are elevated (t(9.22))
  2. Polycythemia vera - RBC elevated
  3. Primary myelofibrosis- all cells
  4. Essential thrombocythemia - platelets

2,3,4 all JAK2 mutations

48
Q

What translocation is associated with CML?

A

t(9,22) BCR-ABL fusion gene from the Philadelphia chromosome

49
Q

What point mutation is associated with PV, ET, and PM?

A

JAK2 mutation of the tyrosine kinase which results in constitutive signaling similar to those that induce hemotopoietic growth factors

50
Q

ALL CMPN share in common an increased risk of ___________________________.

A

Progression to bone marrow failure that coincides with on-going accumulation of mutations (clonal evolution)

51
Q

What is the “spent phase” associated with CMPN?

A

the terminal stage where bone marrow elements are replaced with fibrosis (myelofibrosis) and there is a transformation to AML/

52
Q

What age group do CMPN affect? What is the exception?

A

Mostly they affect adults except CML can affect children

53
Q

How do patients with CMPN present?

A

Fatigue, malaise, weight loss

They commonly have hepatosplenomegaly due to the extramedullary hematopoiesis

54
Q

If someone has unexplained increases in peripheral blood elements, what should be suspected?

A

Chronic myeloproliferative neoplasm

55
Q

CML is characterized by a predominantly __________ proliferation that leads to a high _______.

A

granulocytic proliferation leading to a high WBC count

56
Q

What are the 3 phases of CML? How are the phases determined?

A

The phases are determined by the blast count at the time of evaluation.

  1. chronic phase
  2. accelerated phase
  3. blast phase
57
Q

What are the morphological findings in the chronic phase of CML?

A
  1. prominent leukocytosis with left-shifted granulocytes, specifically:
    - neutrophils
    - myelocytes (myelocyte bulge)
  2. Absolute basophilia
  3. thrombocytosis
58
Q

What does the bone marrow biopsy of chronic phase CML show?

A

hypercellularity with increased granulocytes with a spectrum of maturation similar to the periphery

59
Q

What indicates progression to the accelerated phase of CML?

A

more than 10% blasts in the marrow or blood

60
Q

What indicates blast phase of CML?

A

more than 20% blasts in peripheral blood or marrow

61
Q

What does BCR-ABL do?

A

IT encodes a messenger RNA for a tyrosine kinase that drives the processes resulting in CML

62
Q

What is the treatment for CML?

A

Imatinib (Gleevec) which inhibits tyrosine kinase that interferes with bcr/abl induction

63
Q

Polycythemia vera is characterized by increased _________________production that is independent of ___________________.

A

Increased RBC production that is independent of mechanisms that normally regulate erythropoiesis (hypoxia signaling kindey to release epo, etc)

64
Q

What three cell types are normally increased in PV?

A
  1. RBC
  2. megakaryocytes
  3. myeloid elements- specifically basophils, WBC and platelets
65
Q

What are the clinical features associated with PV?

A
  1. Hypertension - due to increased RBC and sluggish blood flow
  2. thrombotic episodes due to increased megakaryocytes (that make platelets)
66
Q

In PV, the hematocrit is _____% or higher.

A

60%

67
Q

Why is pruritus (itch), erythromelalgia (burning sensation, redness) associated with PV?

A

Histamine released from neoplastic basophils

68
Q

What are the epo levels in PV?

A

Low because there are already too many RBC

69
Q

How do you treat PV?

A

with repeated phlebotomy.

Indolent- patients survive 10-15 years unless it progresses to spent stage or AML

70
Q

What is the preferred initial diagnostic test for PV?

A

mutation screening for the JAK2 mutation in conjunction with Epo level serum testing

71
Q

What is primary myelofibrosis?

A

Increase in all myeloid cells including granulocytes, erythroids, megakaryocytes (which drive reactive proliferation of fibroblasts) that lead to bone marrow fibrosis

72
Q

What are the clinical features of early/pre-fibrotic stage PM?
What are the clinical features of the fibrotic stage?

A

Elderly patients will be asymptomatic or with fever, weight loss, night sweats

Fibrotic stage: pancytopenia, massive splenomegaly due to extramedullary hematopoiesis

73
Q

Describe the peripheral blood in a patient with PM.

A

Pre-fibrotic- leukocytosis, left-shifted myeloid elements, basophils
Fibrotic phase- cytopenia with tear-drop cells from squeezing out past the fibrosis, nucleated RBC

74
Q

What is a leukoerythroblastic reaction?

What disease is it associated with?

A

Primary myelofibrosis and it is the combination of:

  1. dacrocytes (tear drop cells)
  2. nucleated RBC
  3. left-shifted granulocytes
75
Q

What is essential thrombocythemia?

A

The proliferation of megakaryocyte lineage that results in sustained thrombocytosis

76
Q

What age does essential thrombocythemia (ET) usually affect?
What is the presentation?

A 
It affects adults and they present with:
1. transient cerebral ischemia
2. paresthesia 
3. digital ischemia
 due to microvascular occlusion
77
Q

How is essential thrombocythemia diagnosed?

A
  1. Exclude all other CMPN

2. platelet count >450x10^9

78
Q

What are the morphological findings of ET?

A

Bone marrow biopsy is normocellular with proliferation of enlarged megakaryocytes but there is thrombocytosis in the blood

Fundamentals 3- Heme (19 decks)

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