Chronic Myeloproliferative Neoplasms (MPN) + Overview Flashcards
What are the 4 main categories of myeloid neoplasms?
- Myeloproliferative neoplasms
- Myelodysplastic syndromes
- Myeloproiferative / myelodysplastic neoplsms
- Acute myeloid leukemias
What features are common to all 4 types of myeloid neoplasms?
involve blood, bone marrow
loss of normal control of proliferation
suppression normal hematopoietic cells
may all progress to AML
The clinical disease is related to what variables of the myeloid neoplasms?
stage of development of neoplastic cells
clinical effects of leukocytosis or cytopenias
What are the general features associated with Myeloproliferative neoplasms (MPN)?
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
What are the general features associated with Myelodysplastic syndromes (MDS)?
ineffective hematopoiesis → peripheral blood cytopenias
varying degrees dyspoiesis in one or more cells lines
What are the general features associated with Myeloproliferative/myelodysplastic neoplesms (MPN/MDS)?
neoplasms with overlapping features of MPN & MDS
What are the general features associated with Acute myeloid leukemias (AML)?
accumulation immature myeloid forms in bone marrow
normal hematopoiesis is suppressed → peripheral blood cytopenias
What is the only myeloid neoplasm in which you will not see peripheral blood cytopenia?
Myeloproliferative neoplasm (MPN)
What clinical features would you expect to see in a patient with myeloproliferative neoplasm?
- 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
What is the molecular abnormalities found in myeloproliferative neoplasms? What are the impacts of this mutation?
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
What is the typical clinical outcome associated with chronic myeloproliferative neoplasms?
typically indolent
develop over months to years
most people live for many years
What are the 4 classifications for chronic myeloproliferative neoplasms?
- chronic myelogenous leukemia
- BCR-ABL1 positive
- Polycythemia vera
- Primary myelofibrosis
- Essential thrombocytosis
What genetic abnormality is associated with chronic myelogenous leukemia?
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
What is the molecular result of the chimeric BCR-ABL1 gene?
usually codes for cytoplasmic fusion protein, BCR-ABL, a constitutively activated tyrosine kinase
this alone is sufficient to cause disease
Is BCR-ABL1 specific to chronic myelogenous leukemia?
no- it is required for diagnosis but not entirely specific
it may be seen in some acute leukemias - but fusion transcripts will differ
Chronic myelogenous leukemia is what kind of disorder? It most commonly affects people of what age group?
Pluripotent stem cell disorder
middle age (40-60)
What risk factors are associated with chronic myelogenous leukemia?
radiation exposure
no inherited predisposition known
What are the three phases of CML?
chronic
accelerated
blast
Describe the clinical presentation of chronic phase of CML?
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
What peripheral blood findings would you expect to see in a patient in the chronic phase of CML?
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
What bone marrow findings would you expect to see in a patient in the chronic phase of CML?
- hypercellular marrow with myeloid hyperplasia
- increased eosinophils
- increased megakaryocytes & “dwarf megakaryocytes”
- no significant dyspoiesis (except megakaryocytes)
- no increase blasts
- pseudogaucher cells
- pump, blue histiocytes
This peripheral blood smear is from what phase of CML?
chronic
almost looks like bone marrow, but it is peripheral blood
The provided bone marrow sample is from what phase of CML?
chronic
(can’t see, but will be mostly myeloid precursors)
What cells are shown in the provided smear that are characteristic of the chronic phase of CML?
dwarf megakaryocytes
(small & hypolobated)
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?
pseudo-Gaucher cells
chronic phase of CML
increased hemophagocytic activity associated with high turnover of hematopoietic cells
The provided bone marrow aspirate smear is from what phase of CML?
accelerated
(increase in the percent of blasts - still <20%)
may see some dyspoiesis
The provided bone marrow biopsy is from what phase of CML?
accelerated
(increase in the percent of blasts - still <20%)
may see some dyspoiesis
increased # megakaryocytes
The provided bone marrow biopsy is from what phase of CML?
blast phase
will have >20% blasts
The provided peripheral blood smear is from what phase of CML?
blast phase
What features are indicative of the accelerated phase of CML?
- 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
What does a “granulocytic left shift” mean?
increase in immature myeloid cells in peripheral blood
What features are indicative of the blast phase of CML?
-
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”
What is the prognosis of CML?
usually fatal within in weeks-months
due to infection or bleeding
What is the treatment for CML?
-
Tyrosine kinase inhibitors (imatinib)
- highly effective - 5yr survival is 85-90%
- hematopoietic stem cell transplant is curative (but w/ many risks)
What is polycythemia vera?
MPN with peripheral blood polycythemia & proliferation of erythroid, granulocytic, and megakaryocytic lineages in marrow
What genetic mutation is associated with Polycythemia Vera?
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)
What clinical features are seen in patients with polycythemia vera?
- 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
The clinical features seen in polycythemia vera are mainly due to what physiologic cause?
- increased blood volume
- stagnation of blood flow
- plethora (red face) and cyanosis
What are the three phases of polycythemia vera?
pre-polycythemic phase
polycythemic phase (usually diagnosed in this phase)
post-polycythemic phase
The provided histologic slide is from what phase of polycythemia vera?
polycythemic phase
megakaryocytes are more normally sized than with CML
red cell morphology is usually normal, but will see an increase Hb & Hct
What are the features seen in the pre-polycythemic phase of polycythemic vera?
borderline/mild erythrocytosis
difficult to diagnosis - usually asymptomatic
What are the features seen in the peripheral blood smear & bone marrow in the polycythemic phase of polycythemia vera?
- 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
What does panmyelosis mean?
hyperplasia of all 3 cell lines
What are the features seen in the peripheral blood smear & bone marrow in the post-polycythemic phase of polycythemia vera?
- peripheral blood
- cytopenia and/or leukoerythroblastosis
- many teardrop cells
- bone marrow
- prominent reticulin and collagen fibrosis
- decreased hematopoiesis
What are the clinical features seen in the post-polycythemic “spent” phase of polycythemia vera?
extramedullary hematopoiesis (EMH)
and splenomegaly
What is the prognosis of polycythemia vera & what is the goal of treatment?
incurable with present therapy - may progress to MDS/MPN or AML
reduce risk of thrombosis
The provided stains are characteristic of what phase of polycythemia vera?
post-polycythemic
increased fibrosis
(notice cells look like they are all headed in the same direction, this is because of the increased fibrosis)
What disease is characterized by MPN defined by a sustained thrombocytosis (>450,000) in peripheral blood & overproduction of megakaryocytes in marrow with normal hematocrit.
essential thrombocytosis
What are the main sites that are involved with essential thrombocytosis?
blood and bone marrow
What genetic mutation is associated with essential thrombocytosis?
NONE are specific for ET
JAK2 V617F (60%)
constitutively active tyrosine kinase → uncontrolled cell expansion
Negative BCR-ABL1
Describe the typical clinical presentation of a patient with essential thrombocytosis.
- abnormal CBC (w/ thrombocytosis)
- normal RBC/Hb/Hct
- thombi & bleeding
- No spleno/hepatomegaly
Why do you not typically see splenomegaly in patients with essential thrombocytosis?
spleen in not a major site of extramedullary hematopoiesis b/c don’t see much fibrosis in the BM
What peripheral blood morphology would you expect to see in a patient with essential thrombocytosis?
thrombocytosis
large & giant platelets (may be larger than red cells)
nucleated megakaryocytic fragments
Normal RBC & WBC
The provided peripheral blood smear is from what Myeloid Neoplasm?
Essential Thrombocytosis
increased # platelets & nucleated megakaryocytic fragments
What bone marrow findings would you expect to see in a patient with essential thrombocytosis?
normal to slightly hypercellular (blast<5%)
striking megakaryocytic proliferation with large, hyperlobulated megakaryocytes
other cells have normal morphology
absent/minimal reticulin fibrosis
The provided bone marrow slide is from a patient with what myeloid neoplasm?
Essential Thrombocytosis
striking megakaryocytic proliferation with large, hyperlobulated megakaryocytes
What is the prognosis & treatment of essential thrombocytosis (ET)?
small risk of transformation to myelofibrosis or AML
low-dose aspirin
What are the other names for primary meylofibrosis?
chronic myelofibrosis
agnogenic myeloid metaplasia
idiopathic myelofibrosis
What are the general characteristics associated with primary myelofibrosis?
proliferation marrow megakaryocytes
bone marrow fibrosis
extramedullary hematopoiesis
NO erythrocytosis
What is the typical clinical presentation of a patient with primary myelofibrosis?
- massive splenomegaly (b/c extramedullary hematopoiesis)
- older adults (>60)
- late stage anemia
- nonspecific symptoms (fatigue, weight loss, night sweats)
- hyperuricemia (gout & stones)
What are the molecular/cytogenic abnormalities associated with primary myelofibrosis?
none that are specific
JAK2 V617F (60%)
CALR (35%)
Negative BCR-ABL1
What are the phases of primary myelofibrosis?
pre-fibrotic and fibrotic
What is the peripheral blood morphology in the pre-fibrotic phase of primary myelofibrosis?
initially normal progressing to variable thrombocytosis, variable granulocytic leukocytosis
no dyspoiesis or left shift
anemia w/ normal RBC morphology
What is the peripheral blood morphology in the fibrotic phase of primary myelofibrosis?
- moderate normochormatic normocytic anemia with leukoerythroblastosis
- marked anisopoikilocytosis (dif size & shape) with teardrop cells
- thrombocytopenia with large, bizarre platelets & megakaryocyte fragments
What is the bone marrow morphology in the pre-fibrotic phase of primary myelofibrosis?
- hypercellular for age (granulocytic & megakaryocytic hyperplasia)
- no dysgranulopoiesis or dyserythropoiesis
- megakaryocytes are atypical
- absent/minimal fibrosis
What is the bone marrow morphology in the fibrotic phase of primary myelofibrosis?
- 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
What is the major defining feature of CML?
many neutrophils & their precursors
What is the major defining feature of polycythemia vera?
many of everything
especially erythrocytes & their precursors
What is the major defining feature of essential thrombocytosis?
many platelets and megakaryocytes
What is the major defining feature of primary myelofibrosis?
pre-fibrotic: thrombocytosis & mild granulocytosis but NO erythrocytosis
fibrotic: fibrosis, osteomyelosclerosis & marrow hypoplasia → splenomegaly
What steps would you take to work up chronic myeloproliferative neoplasms?
- CBC & peripheral blood smear
- bone marry biopsy & aspirate
- flow cytometry in fibrotic phase
- staining for CD34, CD117 and/or TdT
- conventional cytogenetic analysis, FISH, molecular methods
- looking for specific translocations / markers
*not tested in this class, but probably good reminder for MEDI
