Chapter 1: CHRONIC
MYELOPROLIFERATIVE DISEASE
A. Chronic Myelogenous Leukemia
General
·
Clonal
·
Abnormal pluripotent bone marrow (BM) stem cell
·
Ph and/or BCR/ABL fusion gene (all myeloid lineages and some
lymphocytes)
·
Chronic phase, accelerated phase, blast phase
Epidemiology
·
Most common MPD
·
15-20% of all leukemia
·
1-1.5/100,000 annually world wide
·
Any age, 5th-6th decades
·
Slight male predominance
Site of Involvement
·
Chronic phase: limited to hematopoietic sites (primarily blood,
BM, spleen, and liver)
·
Blast phase: can infiltrate extrahematopoietic sites (including
LNs, skin, soft tissue, and CNS)
Clinical Features
·
20-40% pts asx at diagnosis, incidental findings
·
Non-specific symptoms (fatigue, wgt loss, anemia, night sweats,
and splenomegaly)
·
Blast phase can be initial presentation (severe anemia,
thrombocytopenia, marked splenomegaly)
Morphology-Chronic Phase
Peripheral blood:
·
Leukocytosis (median 170k), due mainly to neutrophils (peak in
myelocytes and PMNs); no significant dysplasia; blasts <2%
·
Absolute basophilia: invariably present; eosinophilia
·
Monocytes: can be increased in absolute numbers, but usually
<3%
·
Thrombocytosis common, thrombocytopenia rare
BM:
- hypercellular
- increased immature neutrophils @ paratrabecular cuff 5-10
cells thick
- megakaryocytes are small and hypolobated nuclei
- pseudo-Gaucher cells in aspirate (seen as foamy cells in
biopsy), 30%
Spleen: infiltration of red pulp by granulocytic precursors
Morphology-Accelerated Phase
·
Blasts 10-19% in PB or BM
·
Basophils ³20% in PB
·
Plt <100k, unrelated to therapy
·
Plt >1,000k, despite therapy
·
Increasing WBC count and spleen size, unresponsive to therapy
·
Evidence of clonal evolution
Morphology- Blast Phase
·
≥20% blasts in PB or BM
·
Extramedullary proliferation of blasts
·
Large aggregates and clusters of blasts in BM bx
Myeloid: 70%; lymphoid: 20-30%
Cytochemistry/Immunophenotype
·
Chronic phase: decreased LAP
·
Blast phase: myeloid, lymphoid (precursor B)
Genetics/Molecular
·
Ph: 90-95%
·
Cryptic t(9:22)-> PCR, RT-PCR, FISH
·
BCR/ABL
·
M-bcr, p210, CML (almost always)
·
m-bcr, p230, CML (rare),
prominent neutrophilic maturation
·
m-bcr, p190, ALL, CML (rare)
·
p190, small amount in >90% of CML, alternative splicing
·
AP or BP, additional cytogenetic changes in 80%: extra Ph, +8, or
i(17q)
Prognosis and Predictive Features
·
Natural history: chronic phase to AP and/or BP
·
Median survival: 5-7 yrs
·
Prognostic parameters: age, spleen, blasts, basophils, fibrosis
·
STI517 (Gleevec): tyrosine kinase inhibitor
B. CHRONIC NEUTROPHILIC LEUKEMIA
Definition
Sustained PB neutrophilia
BM hypercellularity
Hepatosplenomegaly
Should exclude
all causes
of reactive neutrophilia
all other
myeloproliferative diseases
Epidemiology
True incidence is unknown
<100 cases reported
Generally affects older adults
No gender predilection
Sites of involvement
PB and BM: always involved
Spleen, liver: usually show leukemic infiltrates
Clinical features
Most constant feature: splenomegaly
Hepatomegaly usually present
Up to 30% of cases: h/o bleeding from mucocutaneous
surfaces or GI tract
Gout
Pruritis
Etiology
Unknown
a/w multiple myeloma (up to 20% of cases)
PB Morphology
Neutrophilia (≥25 x 109/L)
Mostly segs (+/- toxic granules)
and bands (>80% of WBC)
Immature granulocytes (<10% of
WBC)
Blasts almost never seen (<1%
of WBC)
No dysplasia
BM morphology
Hypercellular (neutrophilic
proliferation)
M:E may reach 20:1
No increase in myeloblasts (<5%
of nucleated marrow cells) and promyelocytes
Myelocytes and mature granulocytes
increased
No dysplasia (if present, consider
atypical CML)
Look for plasma cell dyscrasia
Cytochemistry/immunophenotype
Increased Leukocyte Alkaline Phosphatase (LAP)
Genetics
Normal in 90% of
cases
+8, +9, del (20q), del (11q)
Beware of CML with P230 (PB neutrophilia)
Prognosis
Slowly progressive disorder
Variable survival (6 mo to >20 y)
Development of myelodysplastic features may signal
transformation to acute leukemia
C. CHRONIC EOSINOPHILIC LEUKEMIA /
HYPEREOSINOPHILIC SYNDROME
(CEL / HES)
Definition
Persistently increased numbers of
eosinophils in the blood (≥1.5 x 109/L), bone marrow, and
peripheral tissues.
Organ damage occurs as result of leukemic
infiltration or the release of cytokines, enzymes, or other proteins by the
eosinophils.
To make the dx of HES
Exclude all causes of reactive
eosinophilia
Exclude all neoplastic disorders in which
eosinophils are part of the neoplastic clone
Exclude T cell population with aberrant
phenotype and abnormal cytokine production
To make the dx of CEL
Same
as HES, and
Evidence of
eosinophilic clonality
Or > 2%
but < 20% myeloblasts in PB
Or > 5%
but < 20% myeloblasts in BM
Epidemiology
Rare
True incidence is unknown
HES
M:F = 9:1
Peak in 4th decade
CEL
Marked male predominance
Site of involvement
PB and BM always involved
Spleen and liver involved in 30-50% of cases
Heart, lungs, CNS, skin, GI tract
Clinical features
Asymptomatic (10%)
Constitutional sxs (fever, fatigue, cough, angioedema,
muscle pains, pruritis, diarrhea)
Most serious findings are cardiac
Endomyocardial fibrosis with restrictive cardiomyopathy
Mitral/tricuspid valve scarring with regurgitation and
embolization
Other frequent findings
Peripheral neuropathy, CNS dysfunction, pulmonary sxs,
rheumatologic sxs
Etiology
Unknown
PB Morphology
Striking eosinophilia (mainly mature eos.)
Possible eosinophil abnormalities
Sparse
granulation with clear areas of cytoplasm
Cytoplasmic
vacuolization
Nuclear hypersegmentation
or hyposegmentation
Enlarged
size
Neutrophilia
Monocytosis
If blasts >2%, consider CEL
BM Morphology
Hypercellular (due to proliferation of eos.)
Orderly eosinophilic proliferation
Charcot-Leyden crystals in macrophages
Normal erythropoiesis and megakaryopoiesis
If blasts 5%-19%, consider CEL
Possible fibrosis
Cytochemistry / immunophenotype
MPO positive (cyanide-resistant)
Genetics
No single abnormality identified
+8, i(17q) in occasional patients
Genetic abnormalities a/w
eosinophilia
inv16(p13;q22)
t(5;12)(q33;p13)
8p11 translocations
t(8;13)(p11;q12)
t(8;9)(p11;q32-34)
t(6;8)(q27;p11)
Prognosis
Variable 5 yr. survival rates (up to 80%)
Unfavorable prognostic factors
Marked
splenomegaly
Blasts in
PB or BM
Cytogenetic
abnormalities
Dysplasia
in other myeloid lineages
D. Polycythemia Vera
General
Increased red cells
Clonal
Myeloid lineages also increased
2-13 cases per million
Mean age 60 years
Slight male predominance, M:F = 1-2:1
Sites
of Involvement
Bone marrow
Peripheral blood
Liver (extramedullary hematopoiesis)
Spleen (extramedullary hematopoiesis)
WHO
Criteria
A1: RBCs >25% above
normal, or Hb >18.5g/dL in men and 16.5g/dL in women
A2: No cause of
secondary erythrocytosis (Hypoxia, abnormal Hb, familial conditions)
A3: Splenomegaly
A4: Clonal genetic
abnormalities (but not Ph+)
A5: Endogenous
erythroid colony formation in vitro
B1: Thrombocytosis >400 x 109/L
B2: WBCs >12 x 109/L
B3: BM Bx with panmyelosis, erythroid and
megakaryocytic hyperplasia
B4: Low serum erythropoietin levels
Diagnosis
of Polycythemia Vera
A1 + A2 and any other category
A, or
A1 + A2 and any two of category
B
Clinical
Features
Thrombosis (25%)
Hemorrhage
Stroke
Plethora (70%)
Splenomegaly (70%)
Hepatomegaly (40%)
Leukocyte Alkaline Phosphatase (LAP): normal
Polycythemic
Stage
Erythroid proliferation in BM
Normochromic, normocytic RBCs in PB
If bleeding, RBCs hypochromic and microcytic
Neutrophilia
Basophilia
Thrombocytosis (>50%)
BM cellularity 35-100% (median 80%)
Panmyelosis (Erythroid, granulocytic, and megakaryocytic
proliferation)
Blasts not increased
Megakaryocytes: increased, clustered (parasinusoidal
and paratrabecular); sinusoids dilated, pleomorphic, nuclear hyperlobulation, but
not dysplastic
No stainable iron in 95% of cases
Only 30% with fibrosis (reticulin increased)
Spleen and liver congested
Extramedullary hematopoiesis: minimal
10-50% progress to fibrotic stage
Spent
Phase - Post-Polycythemic Myelofibrosis and Myeloid Metaplasia
Red cell mass decreases
BM cellularity decreases
BM fibrosis (reticulin and collagen increased)
Splenomegaly - Extramedullary hematopoiesis
Leukoerythroblastic blood smear: RBC poikilocytosis
with tear-drop cells, NRBCs, immature granulocytes
Megakaryocytes still prominent and clustered
Genetics
Specific defects in only 20%
+8, +9, del (20q),
del (13q), del (1p)
No Philadelphia chromosome or BCR/ABL fusion gene
Genetic defects increase during progression to MDS or
AML
Prognosis
Without therapy: survival few months
With therapy: survival >10 years
Death due to thrombosis or hemorrhage
MDS or AML in only 2% treated without cytotoxic agents
MDS or AML in 10-20% treated with cytotoxic agents
E. Chronic Idiopathic Myelofibrosis
(CIMF)
General
Megakaryocytic proliferation
Granulocytic proliferation
Bone marrow fibrosis
Extramedullary hematopoiesis
Initial prefibrotic stage -
hypercellular bone marrow
Fibrotic stage with leukoerythroblastic
peripheral blood
Hepato- and splenomegaly with
extramedullary hematopoiesis
Epidemiology
0.5-1.5 per 100,000 per year
Seventh decade
Men and women equally
Anatomic
Sites
Blood and bone marrow
Spleen and liver with
extramedullay hematopoiesis
Lymph nodes (and other sites)
Clinical
Features
30% asymptomatic, discovered by
chance
Splenomegaly (90%) (fibrotic
stage)
Hepatomegaly (20%) (fibrotic
stage)
Mild anemia
Leukocytosis
Thrombocytosis
Prefibrotic
(Cellular) Stage
20-30% detected in this stage
Peripheral blood with
leukocytosis, thrombocytosis, anemia
Bone marrow hypercellular
Granulocytic hyperplasia
Megakaryocytic hyperplasia with naked
megakaryocytic nuclei
Erythroid lineage variable
Megakaryocytes large and bizarre
form
Cloud-like or balloon-like
lobulation of megakaryocytic nuclei
Reticulin minimal or variable
Blasts not increased
Fibrotic
Stage
Most diagnosed in this stage
(70-80%)
Splenomegaly and hepatomegaly
Extramedullary hematopoiesis
Leukoerythroblastic peripheral
blood smear with tear-drop RBCs (dacrocytes) and nucleated RBCs
Leukocytosis, leucopenia, or
normal
Bone marrow fibrosis (reticulin
increased)
Dilated marrow sinuses with
intrasinusoidal hematopoiesis
Marrow cellularity decreases
Osteosclerosis
Blasts <10%; if more, then
accelerated phase
If blasts >20%, then acute
leukemia (DDX with acute panmyelosis with myelofibrosis if organomegaly is not
prominent)
Extramedullary hematopoiesis in
splenic red pulp and hepatic sinusoids
Fibrosis and cirrhosis
Genetics
Cytogenetic abnormalities in 60%
None specific for CIMF
No Philadelphia chromosome or
BCR/ABL fusion gene
Del 13q, del(20q), partial trisomy 1q most common
Prognosis
Survival range: months to decades
Median survival: 3 to 5 years from
Dx
Adverse factors: >70 years, Hb
<10g/dL, platelets <100 x 106/L, granulocytic immaturity,
abnormal karyotype
Morbidity and mortality: bone
marrow failure, infection, thromboembolic events, portal hypertension, cardiac
failure, and acute leukemia
Acute leukemia: 5-30%
Some, but not all, may be
cytotoxic therapy related
F. Essential Thrombocythemia
General
Incidence 1-2.5 per 100,000 annually
50-60 years of age, equally in men and women
Minor peak at 30 years, mostly women
Rarely in children
Sites of involvement
Bone marrow
Peripheral blood
Spleen (platelet sequestration site -
minimal extramedullary hematopoiesis)
Clinical
Features
More than one-half asymptomatic - discovered
fortuitously
The rest with thrombosis or hemorrhage
Modest splenomegaly in 50%
Significant hepatomegaly in 15-20%
Diagnostic
criteria
Positive criteria
Platelets >600 x 109/L
BM Bx proliferation of enlarged, mature megakaryocytes
Exclusion criteria
1. No
evidence of Polycythemia vera
·
Hb <18.5 g/dL in men and
<16.5 g/dL in women
·
Stainable iron in BM
·
Normal ferritin levels
2. No CML (Ph negative)
3. No chronic idiopathic myelofibrosis
4. No MDS
5. No reactive thrombocytosis (tumor,
infection, splenectomy)
Peripheral
Blood Morphology
Thrombocytosis
Anisocytosis - platelets small to giant
WBCs normal
Basophilia absent
RBCs normal
Bone
Marrow Morphology
Normocellular or mildly hypercellular
Giant megakaryocytes: clustered or scattered, abundant
mature cytoplasm, hyperlobulated nuclei
Reticulin not increased
Genetics
Only 5-10% with abnormal karyotype
del (13q22), +8, +9
Prognosis
and Predictive Factors
10-15 year survival common
Splenectomy worsens survival (elimination of
sequestration reservoir increases PLTs)
Transformation to MDS and AML in <5% and usually
therapy-related
Fibrosis may increase (DDX: CIMF)
G. Chronic Myeloproliferative Disease,
Unclassifiable (CMPD, U)
General
Fail to meet criteria of any one
disease
Overlap with several specific
diseases
No Philadelphia chromosome or
BCR/ABL fusion gene
Initial stages of polycythemia
vera, essential thrombocythemia, chronic idiopathic myelofibrosis
Late stages of above diseases
after myelosclerosis, osteosclerosis, or acute transformation
Term used after exclusion of
specific diseases
Must exclude other non-CMPD
diseases
Proper sampling must be performed
with adequate follow-up
Rule out non-myeloproliferative
processes: infection, chemotherapy, toxins, growth factors, immunosuppressive agents,
lymphomas and metastatic tumors
CMPDs do have overlapping
characteristics
Variations occur
10-20% of all CMPDs
Clinical and morphologic features
similar to other CMPDs, but without clear-cut categorization
Many cases in early stages are
categorized after adequate follow-up
If blasts between 10-19%, then
accelerated stage of CMPD, U
If blasts >20%, then AML
suggestive of transformation of previous CMPD, U
If dysplasia present, then
MDS/CMPD, U
Genetics
and Immunophenotype
Similar to other CMPDs
Philadelphia chromosome or BCR/ABL fusion product gene must be
excluded
Prognosis
Patients with marrow fibrosis have
advanced disease and poor outcome
Patients in early stages have
outcome similar to those of the group into which their disease evolves
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