Myeloproliferative Neoplasms (MPNs) & Myelodysplastic Syndromes (MDS) Flashcards
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
myeloproliferative neoplasms features:
- chronic bone marrow disorders
- excess growth in myeloid cell line (RBC, WBC, PLTS)
- similar signs and symptoms with some overlap
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
Chronic myelogenous leukemia (CML) -
1) what gene associated?
t(9,22) - philadelphia (Ph) chromosome - BCR/ABL1 fusion gene
most common MPN?
chronic myelogenous leukemia
1st leukemia described?
Chronic myelogenous leukemia
1st leukemia associated with chromosomal abnormality?
Chronic myelogenous leukemia
Disease for which “leukemia” (white blood) is coined?
Chronic myelogenous leukemia
Chronic myelogenous leukemia
-mediam age of diagnosis?
-median age 46-53 years at Dx but can occur at any age*
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
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
myelocyte bulge- think which sample and disease?
- Chronic myelogenous leukemia - CHRONIC PHASE = neutrophilia
- blood smear
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
dwarf megakaryocytes - which sample and which disease?
- Chronic myelogenous leukemia - CHRONIC PHASE
- bone marrow aspirate and biopsy
How are pseudo-gaucher cells seen on bone marrow aspirate? what does this mean?
sea-blue histiocytes
-really high cell turnover
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
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
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
***Which BCR gene region is most common in CML?
p210 breakpoint***
p210 breapoint disease associations?
conventional CML with usual pathologic characteristcs
p190 breakpoint diease associations?
Ph chromosome ALL and CML with monocytosis
p230 breakpoint disease associations?
CML with thrombocytosis
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
Acute leukemia definition? related to CML accelerated phase?
-acute leukemia has >20% blasts while CML-accelerated has 10-19% increase
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)
How to distinguish lymphoid and myeloid lineage CMLs? which phase?
- immunophenotyping via flow cytometry
- blast phase CML
CML Treatment:
- tyrosine kinase inhibitors (Imatanib/Gleevac)
- stem cell transplantation for younger patients
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)
imatanib is treatment for?
CML
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
What is a leukemoid reaction?
reactive benign neutrophilia due to infection or inflammatory state
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
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
defining feature of PV?
INCREASED RBC MASS ( RBC, HGB, HCT)
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)
ithcy after a warm shower - what condition?
polycythemia vera PV
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
PV- Periperal blood findings:
erythrocytosis - on smear there are many RBC and they are on top of each other a lot bc so many
PV - bone marrow biopsy and aspirate findings:
1) hypercellular with panmyelosis
2) erythroid predominance
3) variably enlarged megakaryocytes
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
other name for spend phase?
post-polycythemic myeloid metaplasia
Tear drop shaped RBC - condition is?
Polycythemia vera
and primary myelofibrosis?
What is the stain for BM in PV? what does this stain show?
reticulin stain - shows fibrosis
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
PV- treatment:
- phlebotomy to reduce hyperviscosity
- myelosuppresive drugs (hydroxyurea, interferon)
PV - prognosis:
- 15year survival is 65%
- worse prognosis with history of thrombosis
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
**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
Essential thrombocytosis (ET) Etiology:
- MPN with increased platelets
- medain age 60 years at diagnosis
- more females than males
- rare progression to fibrosis and AML
ET- clinical features:
- -MANY ARE ASYMPTOMATIC
- thrombosis (periph, CNL, large vessel)
- splenomegaly
- hemorrhage
- erythromelalgia (red, painful joint swelling)
- HA, blurry vision, palpitations
- spontaneous abortions
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
ET- pathologic features of PB smear?
thrombocytosis
ET-pathologic feature of BM aspirate and biopsy
- megakaryocytic hyperplasia
- enlarged megakaryocytes, clustered , and prominent hyperlobations
staghorn like megakaryoblasts is what disorder?
Essential thrombocytopenia
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)
ET - treatment:
- asymptomatic = observe
- symptomatic = cytoreduction -aphoresis (ASA)
ET- prognosis
very good!
ET does not usually reduce life expectancy
-progression to AML is rare
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
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
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
key feature of primary myelofibrosis:
errr DUH PRIMARY FIBROSIS.
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
PMF - PB and BM pathological features - PREFIBROTIC PHASE:
PB- thrombocytosis; mild anemia; mild leukocytosis
BM-mildly hypercellular; minimal megakaryo abnormalities; minimal fibrosis
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%
bizarre hyperchromic atypical megakaryocytes are seen in which disorder?
PMF
Pathophysiology of PMF-
**JAK2 point mutation
detected by PCR but not specific bc also finds PV and ET
PMF - treatment:
- progressive disease with no effective treatment
- supportive (transfusions, antibiotics)
PMF - prognosis
- mean survival 3-5 years from dignosis
- worse prognosis = 70 or older, worsening anemia, abnormal karyotype
myelodysplastic syndromes definition:
-heterogenous group of monoclonal myeloid neoplasms characterized by peripheral blood cytopenias, ineffective hematopoesis and variable progression to acute myeloid leukemia
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
myelodysplastic syndromes common features:
- insidious onset
- initial chronic and relatively indolent phase
- variable progression
- ***-peripheral cytopenias and hypercellular marrow
- transformation to acute blastic phase
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
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)
dysplasia morphological features - granulocyte lyneage:
—> PB
PB:
- pale hypolobated neutrophils
- nuclear hyperlobation (Rare)
- hypergranular (rare)
dysplasia morphological features - megakaryocytes:
—> BM
BM:
- small or large
- hypolobated nuclei
- multinucleated forms
- present in clusters
ringed sideroblasts are:
RBC precursors with iron depsits (seen with stain) in mitochondria
NOT SPECIFIC FOR DYSPLASIA
Best prognosis
- RA- refractory anemia
- RARS: refractory anemia with ringed sideroblasts
So you have a cytogenic abnormality …
Doesnt mean you have MDS!
Most common MDS cytogenic abnormalities are chromosomes:
5,7,8,20
MDS treatment:
- supportive (transfusions, antibiots, G-CSF
- chemotherapy (azacytidine, decitabine, lenalidomide)
- allogenic stem cell transplant (only potentiailly curative)
MDS- prognosis:
- primary cause of death is BM failure
- 40% transform to acute leukemia
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
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)
