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130 Cards in this Set

  • Front
  • Back
In CMPD, the proliferation is associated with ___ maturation that is ___, resulting in _____ numbers of granulocytes, RBCs, and/or platelets
1. relatively normal maturation
2. effective hematopoiesis
3. increased
Hepatomegaly and splenomegaly are ___ in CMPD's
All CMPD's have the potential for clonal evolution, with ___ or ___
1. progression terminating in bone marrow failure due to myelofibrosis or INEFFECTIVE hematopoiesis

2. transformation into an acute blast phase
Indications of worsening disease (progression) in CMPDs include:
1. cytogenetic or molecular evidence of clonal evolution

2. increase in the percentage of blast in the blood and/or bone marrow

10-19% blasts in blood or bone marrow indicates disease acceleration

20%+ = blast phase
The various CMPDs can all exhibit an overlapping constellation of findings including leukocytosis, thrombocytosis, excessive megakaryocytic proliferation, myelofibrosis and organomegaly.

If the initial findings do not allow a specific classification, the designation ____ may be preferable until the process becomes more clearly defined.
CMPD, unclassifiable
Only one CMPD has a defining cytogenetic abnormality, and that is ___
CML with the BCR/ABL fusion gene t(9;22)(q34,q11)
Bone marrow cellularity for the follow is usually __
MDS __
CMPD: increased

MDS: increased (occaisonally decreased)

MDS/CMPD: increased

AML: increased (occaisonally decreased)
Typical marrow blast % for each
MDS __
CMPD <10%
MDS <20%
AML >/=20%
CMPD are associated with ___ blood cell counts, while MDS is associated with ___
1. CMPD: increased

2. MDS: cytopenias
In CMPDs, the myelofibrosis is a ___ event, most likely due to ___
Secondary event - the fibroblasts are not clonal

Megakaryocytes and other marrow cells abnormally producing several cytokines (PDGF, TGF-beta) that stimulate fibroblastic proliferation and synthesis of collagen and fibronectin
CML is a CMPD that is consistently associated with the ___ and/or the ___
Philadelphia (Ph) chromosome and/or BCR/ABL gene fusion
In CML, the abnormal fusion gene is found in which myeloid lineage(s)?
All myeloid lineages as well as some lymphoid cells!
CML is biphasic or triphasic, in that the initial __ phase is followed by ___
chronic phase (indolent)

one or both of the aggressive TRANSFORMED phases:
CML-AP (accelerated phase)
CML-BP (blast phase)
The mose common type of CMPD is __
In CML-CP, the leukemic cells are minimally invasive, meaning that they are confined to ____, in the transformed stages (CML-AP or CML-BP), the leukemic cells are found __
1. hematopoietic tissue (BM, PB, spleen, liver)

2. extramedullary tissues (skin, lymph nodes, soft tissues, CNS)
Most patients with CML are diagnosed in the ___ phase

___percent are ____at diagnosis
chronic phase, with an insidious onset

20-40% are asymptomatic at diagnosis, and discovered due to a high WBC count on a routine exam
Common findings seen in CML at the time of diagnosis
weight loss
night sweats
An atypical presentation of CML may include
presentation in the blast phase (CML-BP) without the detection of a chronic phase
(basically AML w/ the Ph chromosome)
The peripheral blood in CML-CP
Median WBC count 170 (mostly neutrophils in different stages of maturation (increased myelocytes and bands)

Blasts usually <2%

Absolute basophilia (invariable!!)

NO! significant dysgranulopoiesis

Usually mild anemia
Normal or increased platelets (rarely thrombocytopenia)
Bone marrow in CML-CP
hypercellular due increased neutrophils and precursors
In the bone marrow in CML-CP, the paratrabecular cuff of myeloid precursors ___
(in some cases) may be thickened to 5-10 cell layers

normal: 2-3 cell layers
In the bone marrow in CML-CP, the blasts usually account for __% of marrow cells, but more than ___ indicates____
usually <5%, but more than 10-19% indicates transformation to CML-AP
In CML-CP bone marrow, the megakaryocytes are characteristically __
Small in size (micromegakaryocytes) and hypolobated

Often increased in number (40-50% cases), othertimes normal or decreased
Up to 40% of CML-CP patients present with ___ reticulin fibrosis in the marrow, this usually correlates with __
Increased reticulin fibrosis

Increased reticulin fibrosis correlates with:
1. Increased numbers of megakaryocytes
2. Larger spleen size
3. More severe anemia
Pseudo-___ cells and sea-blue ___ are seen in about 30% of CML-CP marrows
pseudo-Gaucher cells
sea-blue histiocytes

These are commonly seen in marrow aspirates. They ARE derived from the neoplastic clone, BUT are secondary to increased cell turnover
In CML-CP, megakaryocytes are characteristically __ and often ___ in number
smaller than normal

Accelerated phase CML is characterized by one or more of the following:(5)
1. Blasts 10-19% in BP and/or

2. Peripheral basophilia

3a. Persistent
thromboCYTOPENIA (<100)
UNRELATED to therapy
3b. Persistent thromboCYTOSIS

4. Worsening splenomegaly
with increasing WBC count,
unresponsive to therapy

5. Cytogenetic evidence of
clonal evolution
In the setting of diagnosed CML-CP, the subsequent finding of marked granylocytic dysplasia or prominent proliferation of small, dysplastic megakaryocytes indicates disease __
Progression (CML-AP)

Independent significance of these findings is unknown.
In the setting of CML-CP, the finding of lymphoblasts in the blood or marrow is cause for concern, because ___
May indicate a lymphoblastic transformation
CML-BP resembles __
Acute leukemia! but with the Ph chromosome and/or BCR/ABL gene fusion
CML-BP is diagnosed if one or more of the following is present:
1. Blasts >/= 20% PB or BM
nucleated cells

2. Extramedullary blast

3. Large foci or clusters of
blasts in the bone marrow
BIOPSY (even if the remainder of the marrow shows chronic phase)
In CML-BP, in __ % of cases, the blast lineage is ___, while in ___%, the lineage is____
70% myeloblast
20-30% lymphoblast

rarely both
Extramedullary blast proliferations, in the setting of CML, indicate __. They are found in ____
Progression to CML-BP

Skin, lymph nodes, bone, spleen, CNS, anywhere
How does the degree of myelofibrosis, in the setting of CML, effect the classification
It does not.
In the spleen, involvement by CML is a __ pulp process
red pulp
The neutrophils in CML-CP, have markedly __ neutrophilic alkalline phosphatase (LAP)
Neutrophils in CML-CP may demonstrate __ expression of CD15 and HLA-DR
weak expression of normal neutrophil antigens (dimCD15, dimHLA-DR)
In CML-BP, the myeloblast may or may not express ___,but will express ___ antigens
myeloperoxidase (strong, weak, or absent)
Will express:
Myeloid/Monocytic (CD13, CD14, CD15, CD33, etc.)
Megakaryocytic (CD61)
Erythroid (glycophorin, HbA)

Not uncommonly, lympoid markers too!!
Most cases of CML, with LYMPHOBLASTIC blast phase, are ____ immunophenotype.

Oftentimes, they also __
precursor B (CD10, CD19, CD34, TdT, sIg-negative)

Often coexpress one or more myeloid markers
At the time of diagnosis __% of CML have t(9;22)

The remaining cases:

1. Have either variant translocations involving a THIRD chromosome IN ADDITION to 9 and 22


2. Have cryptic translocations of 9q34 and 22q11 that are not identified by routine cytogenetics
Ph chromosome [der(22q)]
BCR/ABL fusion gene

BCR gene on chromosome 22
ABl gene on chromosome 9
Cryptic t(9;22)(q34,q11) can be detected by __
FISH, RT-PCR, or Southern blot techniques
The site of breakpoint on the BCR gene may influence the ___ in CML
In CML, the breakpoint in the BCR gene is almost always in the ____ breakpoint cluster region, leading to the formation of an abnormal fusion protein ____, with increased __ activity
Major breakpoint cluster region

p210 with increased tyrosine kinase activity
In CML, other fusion proteins, due to alternate breakpoints in the BCR gene, include: ___ and ___
p230: (RARE) patients may demonstrate CML with promient neutrophilic maturation

p190: most often associated with Ph positive ALL, HOWEVER, small amounts of p190 are detected in 90% of CML!!!
CML with p190 BCR/ABL fusion protein
Small amounts of p190 product can be detected in 90% of CML with the typical p210

BUT! p190 can also be associated with RARE CML cases with increased numbers of MONOCYTES, resembling CMML
At the time of diagnosis of CML, chromosomal abnormalities in addition to Ph chromosome signify?
Unknown significance!!

But, evidence of clonal evolution AFTER the diagnositic specimen usually signifies transformation
Median survival times for treated CML range from __
5-7 years
Chronic neutrophilic leukemia is a ___ disease
rare!! (only about 100 cases reported)
CNL is characterized by:
1. Sustained peripheral neutrophilia
2. BM hypercellularity due to neutrophilic granulocytes
3. hepatosplenomegaly
4. NO Ph chromosome or BCR/ABL fusion gene
CNL is a diagnosis of ____!

Rule out reactive neutrophilia and other MPDs
20% of reported CNL cases are associated with ___
an underlying neoplasm, most commonly multiple myeloma

Most of these of these "CNL" cases lack clonal chromosomal abnormalities and are most likely secondary proliferations due to abnormal cytokine production by myeloma cells
The peripheral blood in CNL demonstrates:
1. neutrophilia (>25), with mostly mature segmented forms, maybe increased bands, but few immature forms (<5%)
In CNL, myeloblast are __ seen in the peripheral blood
In CNL, the neutrophils often appear ___, but can appear ___
toxic, but can appear normal

NO! dysplasia
The M:E ratio in the bone marrow in CNL may be up to
20:1 or more with increased mature neutrophils and myelocytes, NO increased blasts or promyelocytes
The variant of Ph+, BCR/ABL+ CML with a peripheral blood neurtophilia similar to that seen in CNL, is associated with a variant ___
BCR/ABL fusion protein (p230)
A clonal proliferation of eosinophilic precursors resulting in persistently increased peripheral eosinophils, bone marrow eosinophils, and peripheral tissue eosinophilia?
Chronic eosinophilic leukemia (CEL)
What percentage of Chronic eosinophilic leukemia (CEL)cases are associated with Ph chromosome?
Neither t(9;22) nor BCR/ABL fusion gene
The blast% in CEL is by definition:
<20% in the blood and bone marrow
To make a diagnosis of CEL, there should be evidence of ___ or ____
- clonality among the eosinophils
- increased blasts in blood or BM
Persistent eosinophilia without identifiable cause, without evidence of clonality, without an abnormal T cell population with an aberrant phenotype, and without increased blasts?
Idiopathic hypereosinophilic syndrome (HES)
When considering a diagnosis of CEL/HES, you should rule out secondary causes of eosinophilia such as:
Reactive eosinophilia:
-infectious disease
-pulmonary diseases (hypesensitivity pneumonitis, Loeffler's syndrome)
-collagen vascular disease

Exclude underlying neoplasia with secondary, reactive eosinophilia:
-T cell lymphomas
Neoplastic disorders that can be associated with eosinophilia as PART of the clonal process include:
1. CML (Ph+, BCR/ABL+)
2. AML, inlcuding AML with inv(16), t(16;16)
3. other CMPDs (PV, ET, CIMF)
4. MDS
Hypereosinophilic syndrome (HES) is more common in __
men 9:1
CEL/HES is a multisystem disease affecting the ___ and ___ always, plus __
blood and bone marrow always

tissue infiltration
Most serious complication of CEL/HES is __
endomyocardial fibrosis with resultant restrictive cardiomegaly

secondary to prolonged eosinophilia
In the peripheral blood of CEL/HES the most strikining finding is __
eosinophilia with mainly mature eos, only small numbers of eosinophilic myelocyts and promyelocytes

eos may show a range of morphologic abnormalities
In considering between CEL and HES, if blasts are >2%, ___ should be considered

However, blasts are typically infrequent to absent in most cases of CEL/HES
ALL cases associated with eosinophilia are often associated with ___
PV is characterized by increased RBC production that is ___
independent of the normal regulatory mechanisms
Two phases of PV are recognized:
1. polycythemic phase - initial proliferative phase associated with increased RBC mass

2. post-polycythemic phase or spent phase - cytopenias (including anemia) due to ineffective hematopoiesis, bone marrow fibrosis, and associated extramedullary hematopoiesis and hyperplenism
WHO criteria for the diagnosis of PV: A1 and A2 must be present
A1: elevated RBC mass (HCT)>25% above the mean normal predicated value OR HB>18.5 g/dl in men and >16.5 g/dl in women

A2: No cause of secondary erythrocytosis (familial erythrocytosis; no elevation of EPO)

Mean age at diagnosis of PV

rare < 20
In PV, splenomegaly and hepatomegaly are due to __
extramedullary hematopoiesis in the later stages
Major symptoms of PV are due to ___ or ___
1. HTN
2. vascular abnormalities due to increased RBC mass
25% of patients with PV present with __
venous or arterial thrombosis (DVT, AMI, stroke)
Mesenteric, splenic, and portal venous thrombosis should lead to a diagnostic consideration of __
In PV (polycythemic stage) the BM exhibits __
1. normoblastic erythroid proliferation
2. typically hyercellular for age
3. panmyelosis (increased erythroid, megakaryocytic, and granulocytic proliferation)
4. increase megakaryocytes even if normocelluar overall
In PV (polycythemic stage) the PB exhibits __
1. excess normochromic, normocytic RBCs (increased HCT, Hb)
2. oftentimes - neutrophilia and basophilia
3. thrombocytosis (50%)
In PV, stainable iron is __ in the marrow aspirate
In PV (post-polycythemic phase), the red cell mass __ and then ___, while the spleen ___
normalizes and then decreases, while the spleen gets larger (EMH)
In PV, the most common pattern of disease progression is ____ and ___
post-polycythemic myelofibrosis and myeloid metaplasia (PPMM)
PPMM is characterized by:
1. leukoerythroblastic blood
smear due to EMH
2. myelofibrosis (hallmark), reticulin and collagen fibrosis
In PPMM bone marrow, clusters of ___ are prominent
hyperchromatic, dysmorphic megakaryocytes
In PV (spent phase), the finding of >10% blasts in the blood or marrow or significant myelodysplasia are both ____,but may signfiy:

transformation to an MDS or acute leukemia
In PV there are ___ unique immunophenotypic findings or specific genetic abnormalites
Chronic idiopathic myelofibrosis (CIMF) is aka ___
agnogenic myeloid metaplasia or myelofibrosis with myeloid metaplasia
CIMF is a clonal stem cell disorder characterized by:
1. dysplastic megakaryocytic hyerplasia
2. relative increase in immature granulocytes
3. ineffective erythropoiesis
4. reactive reticulin or collagen myelofibrosis
5. EMH (myeloid metaplasia)

(use of MDS buzz words: dysplastic, ineffective)
CIMF can have overlapping features with __ or __, therefore, it is a diagnosis made after __
other CMPDs or MDSs

exluding of clonal and non-clonal process that can be associated with myelofibrosis
CIMF has two phases
Prefibrotic stage
Fibrotic stage
Pre-fibrotic CIMF is characterized by a ___ marrow with ___ reticulin or collagen fibrosis

Fibrotic stage CIMF is characterized by __ marrow reticulin or collagen fibrosis and a peripheral blood ___

leukoerythroblastosis due to EMH with splenomegaly and hepatomegaly
CIMF is a __ disorder that occurs most commonly in the ___ decade of life

7th decade (70's)
A significant percentage of patients are ___ at the time of diagnosis of CIMF
asymptomatic (up to 30%)

detection of splenomegaly on routine exam or abnormal CBC
___ % of CIMF paitents are diagnosed in the prefibrotic (cellular) stage
Prefibrotic CIMF, findings include
-mild to moderate anemia
-some evidence of EMH (leukoerythroblastosis), usually minimal
-HYPERCELLULAR bone marrow
-megakaryocytes are markedly abnormal: key to recognizing the prefibrotic stage of CIMF
The key to recognizing prefibrotic stage CIMF in the marrow is ___
the abnormal megakaryocytes

-clusters of variable sizes adjacent to sinuses and trabeculae
-most are enlarged megaks, but some small too
-abnormal chromatin and nuclei
-freqent NAKED megak nuclei

OVERALL, the megaks in CIMF are MORE aytpical than those seen in other CMPDs
Most patients with CIMF are diagnosed in the ___ stage
fibrotic stage (70-80%) with hepatosplenomegaly due to EMH, and anemia with a leukoerythroblastic PB smear
The finding of dysgranulopoiesis or >10% blasts, in the setting of CIMF, suggest _
transformation to a more aggressive phase (accelerated or blast phase)
In fibrotic stage CIMF the bone marrow is often ____
normocellular or hypocelluar, with PATCHES of hematopoiesis separated by regions of loose connective tissue or fat

Note: BM can be hypercellular
In fibrotic stage CIMF, the marrow sinuses are characteristically __
increased in number and dilated with intrasinusoidal hematopoiesis
In fibrotic stage CIMF, the most notable marrow cell type is most often __
the megakaryocytes, which are aytpical and occur in clusters and sheets or within dilated sinuses
Osteoslcerosis can be seen in CIMF marrow, resulting in
broad, irregular trabeculae that can occupy up to 50% of the marrow space
In patients with a previous diagnosis of CIMF, the subsequent finding of 10-19% blasts and >/=20% blasts indicate
10-19% blasts (PB or BM) - accelerated phase

>/=205 blasts - transformation
Occasional patients present initially with accelerated phase CIMF
- MDS w/ fibrosis
- MDS/MPD unclassifiable
- panmyelosis with fibrosis

The clue to the diagnosis of CIMF is the characteristic morphologic findings, plus these DDX lack the characteristic hepatosplenomegaly
CIMF may present in the acute phase (>/= 20% blasts), in this case the diagnosis should be __
AML, with only mention of the possibility that this may have derived from CIMF
There are myeloid, lymphoid and non-hematologic disorders that are associated with myelofibrosis
-Acute myelofibrosis/acute megakaryoblastic leukemia
-Systemic mastocytosis

-metastatic tumor
-connective tissue disease
-renal osteodystrophy
-vitamin D deficiency (rickets)
-grey platelet syndrome
Essential thrombocythemia (ET) is a clonal proliferation primarily of the ___ lineage
ET is characterized by ____ thrombocytosis in teh blood and ___ in the marrow
sustained thrombcytosis in the PB

increased numbers of large, mature megakaryocytes in the BM
The difference between the megakaryocytic proliferations in ET vs. CIMF
ET: increased numbers of large to giant, mature megak's with abundant cytoplasm, deeply lobulated and hyperlobulated nuclei; megak's may aggregate in loose clusters or be dispersed

CIMF: proliferation of dysplastic, bizzare, atypical megak's forming clusters and/or sheets, as well as intrasinusoidal
Clinically ET is characterized by
presentation in middle age with an indolent course, with long asymptomatic periods, with occasional episodes of thrombosis and/or hemorrhage
In ET, the spleen is a site for __, but there is relatively little ___
platelet sequestration

little EMH
At presentation, __% of patients are asymptomatic
about 50% are asymptomatic, and discovered fortuitously

20-50% present some vascular occlusive event (stroke, TIA, AMI, digital ischemia) or mucosal hemorrhage (GI tract, pulmonary)
Diagnositic criteria for ET
include __ positive criteria and __ criteria of exclusion
(2) positive criteria:
1. sustained platelet count
2. marrow shoing proliferation of megak's with many large, mature megak's

(5) criteria of exlusion
1. No evidence of PV
-normal HCT, Hb, stainable
iron, nml serum ferritin
and MCV (or atleast
correctable with iron if
2. No evidence of CML
- no Ph chromosome or
BCR/ABL fusion gene
3. No evidence of CIMF
- no collagen fibrosis
- no significant reticulin
4. No evidence of MDS
5. No evidence of secondary
cause of thrombocytosis
Secondary causes of sustained thrombocytosis include:
1. infection or inflammation
2. underlying neoplasm
3. prior splenectomy
Most striking PB smear finding in ET is
- platelet aniscytosis (tiny to large)
- no significant numbers of bizarre forms

- WBC count normal w/ normal differential
- RBCs normal (unless hemorrhage leading to iron def)
- no leukoerythroblastosis becuase EMH is NOT significant part of ET
In ET the marrow is typically ___ cellular, with the most striking finding being __
normocellular or slightly hypercellular

marked megak proliferation with large to giant forms

no increased blasts or significant dysplasia
The presence of significant reticulin or ANY collagen fibrosis speaks strongly in ___ of a diagnosis of ET
A common finding in megak's in ET is ___(although not specific for ET)
emperipolesis of marrow cells
There is ___ specific cytogenetic or molecular genetic abnormality known for ET, but ___

But cytogenetic and molecular studies should be done to rule out CML as the cause of thrombocytosis

besides, an abnormal karyotype is unusual in ET
Is splenectomy the treatment of choice of ET?

It could lead to a dramatic increase in the platelet count.
Is transformation of ET to an AML or MDS common?
NO! only 5% or less
Given the proliferation of megak's in the marrow of ET patients, what percentage develop marked myelofibrosis
Not many, it is uncommon.

Plus, at the time of diagnosis, myelofibrosis speaks stronly against a diagnosis of ET
CMPD, unclassifiable should be followed up every ___ until a more specific diagnosis can be made
4-6 months will usually provide sufficient information
Before making the diagnosis of CMPD, U ___
rule out secondary causes of myelofibrosis that can mimic a MPD
In late stage disease with marked myelofibrosis and/or osteomyelosclerosis (terminal or burnt-out stage) the distinction between ___ and ___ may be impossible, without previous history
fibrotic stage CIMF and post-polycythemic stage PV
A clue that one is dealing with CML with marked myelofibrosis and not an unclassifiable CMPD would be __
finding micromegak's and Ph chromosome and/or BCR/ABL gene fusion
As with other CMPD's, CMPD, unclassifiable can progress to accelerated stage with ___ and/or ____
10-19% blasts in the PB and/or marrow


acute leukemia (>/= 20% blasts) and the suggestion that this may be a blast transformation of a previous but unclassifiable CMPD
Prognosis for ET, CIMF,PV, and CML
ET: indolent, presents in midlife so may not significantly effect longevity, median survival 1-15 yrs

CIMF: median survival 3-5 years

PV: without therapy only a few months to live, but with therapy 10 years is not uncommon, alsot presents in midlife

CML: median survival is 5-7 years with therapy, also commonly presents in midlife