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Flashcards in Myeloid Neoplasm Deck (78):

What are the three main categories of myeloid neoplasia?

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.


What are the 5 terminally differentiated myeloid cells?

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


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

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


What age group is typically affected by AML?
How do cases of AML arise?

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.


How do most AML cases arise?
What are two situations when this is not the case?

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)


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

undifferentiated or show only early signs of differentiation


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

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


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

the cytogenetic aberration detected at the time of diagnosis


How does AML present clinically?

Bone marrow infiltration causes:
1. anemia- fatigue, pallor
2. thrombocytopenia- bruising, petechial rash, mucousal bleeding
3. Leukocytosis


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

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


What can complicate AML, particularly in cases of APML?



How is AML diagnoses?

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

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


What are the general morphological features of AML blasts?
Describe nuclear features and cytoplasmic features.

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


Describe the morphology of a monoblast.

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


What type of blast would be positive for MPO?
What type of blast would be positive for "nonspecific esterase"?

MPO = myelobast
non-specific esterase = monoblast


Describe the morphological appearance of megakaryoblasts.

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


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

1. immunohistochemical staining
2. flow cytometry


What are the lineage associated markers of myeloblasts?



What are the lineage associated markers of monoblasts?



What are the lineage associated markers of erythroids?



What are the markers of megakaryoblasts?

CD41 and CD61


What is CD34?

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


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

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


AML with ___________ tend to respond well to therapy.

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


What two forms of AML have a poor prognosis?

MDS-related AML or therapy-related AML

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


What therapies are associated with increased risk of AML?

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


AML with t(8,21) generally presents in what age patients?
The patient presents usually with __________ in addition to ______________________.

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


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

-large myeloblasts that have granules and Auer rods
- spectrum of maturation of neutrophils with abnormal nuclear segmentation and cytoplasm staining


What are the four stages of neutrophilic maturation?

mature neutrophil


AML with inv(16) presents in what age patients?
What is the physical presentation at the hospital?

Younger adults.
There may be myeloid sarcoma at presentation


What is the morphology of inv(16) AML?

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


What age patient does t(15,17) AML occur in?
What is the other name for this AML?

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


What is APML frequently associated with?
What is the treatment for it?

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


Describe the morphology of APML.

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


Why is ATRA able to treat APML?

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


In what age patient would you see AML with myelodysplasia?
What two AMLs does this encompass?

Older patients

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


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

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


What is myelodysplastic syndrome?

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


What are the cytogenetic abnormalities associated with MDS?

deletions on chromosomes 5 or 7


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

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


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

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


How do you grade MDS?

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


What is the prognosis for MDS?

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.


What is chronic myeloproliferative neoplasm?

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


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

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


How are CMPNs classified?

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


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

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


What translocation is associated with CML?

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


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

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


ALL CMPN share in common an increased risk of ___________________________.

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


What is the "spent phase" associated with CMPN?

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


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

Mostly they affect adults except CML can affect children


How do patients with CMPN present?

Fatigue, malaise, weight loss
They commonly have hepatosplenomegaly due to the extramedullary hematopoiesis


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

Chronic myeloproliferative neoplasm


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

granulocytic proliferation leading to a high WBC count


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

The phases are determined by the blast count at the time of evaluation.
1. chronic phase
2. accelerated phase
3. blast phase


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

1. prominent leukocytosis with left-shifted granulocytes, specifically:
- neutrophils
- myelocytes (myelocyte bulge)

2. Absolute basophilia
3. thrombocytosis


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

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


What indicates progression to the accelerated phase of CML?

more than 10% blasts in the marrow or blood


What indicates blast phase of CML?

more than 20% blasts in peripheral blood or marrow


What does BCR-ABL do?

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


What is the treatment for CML?

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


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

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


What three cell types are normally increased in PV?

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


What are the clinical features associated with PV?

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


In PV, the hematocrit is _____% or higher.



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

Histamine released from neoplastic basophils


What are the epo levels in PV?

Low because there are already too many RBC


How do you treat PV?

with repeated phlebotomy.
Indolent- patients survive 10-15 years unless it progresses to spent stage or AML


What is the preferred initial diagnostic test for PV?

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


What is primary myelofibrosis?

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


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

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

Fibrotic stage: pancytopenia, massive splenomegaly due to extramedullary hematopoiesis


Describe the peripheral blood in a patient with PM.

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


What is a leukoerythroblastic reaction?
What disease is it associated with?

Primary myelofibrosis and it is the combination of:
1. dacrocytes (tear drop cells)
2. nucleated RBC
3. left-shifted granulocytes


What is essential thrombocythemia?

The proliferation of megakaryocyte lineage that results in sustained thrombocytosis


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

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


How is essential thrombocythemia diagnosed?

1. Exclude all other CMPN
2. platelet count >450x10^9


What are the morphological findings of ET?

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