myeloproliferative
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MYELOPROLIFERATIVE MYELOPROLIFERATIVE DISORDERSDISORDERS
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Hematopoietic NeoplasmsHematopoietic Neoplasmsoverviewoverview
The majority of hematopoietic neoplasms can be classified and characterized according to three characteristics:
1. Lineage: Lymphoid vs. Myelogenous
2. Survival: Acute vs. Chronic
3. Blood/Bone Marrow vs. Tissue
Virtually any combination of these characteristics can occur.
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Lymphoid vs MyelogenousLymphoid vs Myelogenous
Lymphoid neoplasms:• derived from the CFU-L or one of its more
differentiated derivatives• can exhibit B-cell lineage or T-cell lineage
Myelogenous neoplasms:• derived from the CFU-GEMM or one of the
differentiated derivatives of the CFU-GEMM• can exhibit features of multiple lineages
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Acute vs ChronicAcute vs Chronic
Acute:• primarily of immature cells, with little of no differentiation• aggressive course with survival of only weeks to few
months if untreated• primarily involving blood and bone marrow• examples:
• acute lymphoblastic leukemia/lymphoma (ALL)• acute myelogenous leukemia (AML)
various subtypes of ALL and AML exist, depending on the specific lineage or differentiation exhibited by the neoplastic cells
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Acute vs ChronicAcute vs Chronic
Chronic:• primarily of mature cells• tends to be indolent, with survival in years• examples:
• chronic lymphocytic leukemia (CLL)• chronic myeloproliferative disorders
» chronic myelogenous leukemia (CML)» polycythemia rubra vera» essential thrombocythemia» agnogenic myeloid metaplasia
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Blood/BM vs TissueBlood/BM vs Tissue
Blood/BM leukemia
Tissue “lymphoma”
myeloid : granulocytic sarcoma
lymphoid : lymphoma (non-Hodgkin’s)
Hodgkin’s disease
plasma cell : multiple myeloma
plasmacytoma
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““leukoproliferative disorders”leukoproliferative disorders”
lymphoid lymphoid neoplasms acute
chronic
myeloidmyeloid neoplasms acute
chronic
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““leukoproliferative disorders”leukoproliferative disorders”
lymphoid lymphoid neoplasms acute
chronic
myeloidmyeloid neoplasms acute
chronic
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myeloid neoplasmsmyeloid neoplasms
acute myeloid leukemia >30% blasts in BM (1985 FAB classification)
trilineage morphologic dysplasia
myelodysplastic syndrome +
chronic myeloproliferative disorders - www.freelivedoctor.com
““leukoproliferative disorders”leukoproliferative disorders”
lymphoid lymphoid neoplasms acute
chronic
myeloidmyeloid neoplasms acute
chronic
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Myeloproliferative DisordersMyeloproliferative Disorders(old classification)(old classification)
a group of disease characterized by overgrowth of one or more hematologic cell lines in BM
1. chronic myelogenous leukemia (CML)
2. polycythemia vera (PV)
3. essential thrombocythemia
4. agnogenic myeloid metaplasia/myelofibrosis
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Chronic Myeloproliferative DisordersChronic Myeloproliferative Disorders(new WHO classification)(new WHO classification)
1. polycythemia vera
2. chronic idiopathic myelofibrosis
3. essential thrombocytosis
4. chronic myeloid leukemia (CML)
5. [chronic neutrophilic leukemia]
6. [chronic eosinophilic leukemia]
7. [hypereosinophilic syndrome]
“myelodysplastic/myeloproliferative diseases”
juvenile myelomonocytic leukemia
atypical chronic myeloid leukemia (lacking t(9;22))
chronic myelomocytic leukemia
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Chronic Myelogenous Leukemia (CML)Chronic Myelogenous Leukemia (CML)
• second most common leukemia• middle aged • excess number of “mature” and immature granulocytes• all stages of maturation in bone marrow• chromosomal abnormality
Philadelphia chromosome t(9;22)Philadelphia chromosome t(9;22)
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Chronic Myelogenous Leukemia (CML) Chronic Myelogenous Leukemia (CML) laboratorylaboratory
• WBC : >100,000• thrombocytosis• numerically increased, but functionally impaired granulocytes
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Chronic Myelogenous Leukemia (CML) Chronic Myelogenous Leukemia (CML) clinicalclinical
• non-specific constitutional symptoms• weakness• wt. Loss• fatigue
• excessive bleeding or bruising• two-phase disease
• slowly progressive disease (chronic phase)• terminal “blast crisis” (acute/blast phase)
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Polycythemia Vera (PV)Polycythemia Vera (PV)• increased red blood mass• increased blood volume and viscosity (hyperviscosity syndrome)• BM: hypercellular
erythroid, megakaryocytic & granulocytic hyperplasia may eventually become fibrotic
• Tx: repeated phlebotomy
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Polycythemia Vera (PV)Polycythemia Vera (PV)
Incidence: 0.5 to 3.5 per 100,000Age at Dx: ~60 y/oF to M ratio: male dominance (1:1.6 to 2.2)Social risk factor: participants in nuclear weapons testClinical features: hyperviscosity, thrombosis
headachedizzinessvisual symptoms
Median survival: 12 to 13 years
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Polycythemia Vera (PV)Polycythemia Vera (PV)diagnostic criteriadiagnostic criteria
by polycythemia vera study group (1975)Major Criteria
1. increased RBC male >= 36 mL/kgfemale >= 32 mL/kg
2. normal arterial oxygen saturation >= 92%3. splenomegaly
Minor Criteria1. platelet > 400,000/L2. leukocytes >13,000/L3. leukocyte alkaline phosphatase >100
or vit B12 >900 pg/mL
or unbound B12 binding capacity >2200 pg/mL
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Essential ThrombocythemiaEssential Thrombocythemia
• Rare disorder (1.5 per 100,000)• proliferation of megakaryocytes causing marked increase in
circulating platelets (>1 million)• morphologically abnormal platelets• splenomegaly, mucosal hemorrhage, thromboses
arrow: macrothrombocyte
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Essential ThrombocythemiaEssential Thrombocythemia
Incidence: 1.5 per 100,000Age at Dx: 60 y/o (~20% <40 y/o)F to M ratio: 1.6 : 1Social risk factor: 1. long-term use of dark hair dyes
2. living in tuff house3. electrician
Clinical features: - near normal life expectancy- frequent vasomotor and thrombo- hemorrhagic episodes
Treatment: low-dose acetylsalicylic acidwww.freelivedoctor.com
MyelofibrosisMyelofibrosis
• bone marrow fibrosis• fibroblasts may be “innocent bystanders”• fibrosis probably driven by neoplastic megakaryocytes
• middle aged adults (50-60 y/o)• extramedullary hematopoiesis (spleen, liver)• may occur as an extension of CML or PV• abnormal peripheral RBCs (“tear-drop” & nucleated RBCs)• immature WBC and abnormal platelets• infection, thrombosis and hemorrhage as a major
complication
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MyelofibrosisMyelofibrosis
Aniso-poikilocytosis
leukemoid reaction
“naked” nuclear fragments
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Acute Myelogenous Leukemia (AML)Acute Myelogenous Leukemia (AML)
• 60% of acute leukemias• arises from myeloid stem cell line• young to middle aged adults• pallor & petechiae may be initial presentation• lymphadenopathy/splenomegaly may or may not be present• no fever unless secondary infection
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Acute Myelogenous LeukemiaAcute Myelogenous Leukemia
• Incidence: ~3.6 per 100,000 people per year• M:F = 4.4:3.0 (M>F)• incidence increases with age
1.7 in <65 yrs age group16.2 in >65 yrs age group
• Etiology: heredity, radiation, chemical and other occupational exposures and drugs have been implicated
• increased incidence in trisomy 21, XXY, trisomy 13, Fanconi anemia, Bloom syndrome, ataxia telangiectasia, Kostmann syndrome
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AMLAMLclinical symptomsclinical symptoms
• non-specific symptoms that are consequence ofanemialeukocytosisleukopenia or leukocyte dysfunctionthrombocytopenia
• fatigue (most common)• anorexia and wt. loss• fever with or without infection (~10%)• bleeding, easy bruising (~5%)
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AMLAMLphysical findingsphysical findings
• hepatosplenomegaly, lymphadenopathy, sternal tenderness, evidence of infection and hemorrhage
acute promyelocytic leukemia (APL)
gastrointestinal bleeding
intrapulmonary hemorrhage
intracranial hemorrhage
monocytic AML
coagulopathy
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Acute Myelogenous Leukemia (AML) Acute Myelogenous Leukemia (AML) peripheral blood smearperipheral blood smear
• normocytic, normochromic anemia• decreased reticulocyte count• normal or depressed WBC count• myeloblast (may be with Auer rods)• low platelet
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AMLAMLhematologic findingshematologic findings
• anemia: can be severeusually normocytic normochromic
• reduced reticulocyte count low erythropoiesis• short erythrocyte survival accelerated destruction• median WBC count: 15,000/μL• platelet count: <100,000/μL (~75% of patients)
<25,000/μL (~25% of patients)• morphologic and functional platelet abnormalities
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Acute Myelogenous Leukemia (AML) Acute Myelogenous Leukemia (AML) special stainsspecial stains
• myeloperoxidase (MP)• Sudan black B (SBB)• nonspecific esterase (NSE)• chloroacetate esterase (CLE)• periodic acid Schiff (PAS)
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AML classificationAML classification
Until 2000, the diagnosis of AML was established by the presence of ≥30% myeloblasts in the marrow and further classified based on morphology and cytochemistry according to the French-American-British (FAB) schema, which includes eight major subtypes, M0 to M7.
The 2001 WHO classification modified the FAB schema by reducing the number of blasts required for a diagnosis and incorporating molecular (including cytogenetic), morphologic (multilineage dysplasia), and clinical features (such as prior hematologic disorder) in defining disease entities.
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Acute Myelogenous Leukemia (AML) Acute Myelogenous Leukemia (AML) WHO classification (2001)WHO classification (2001)
I. AML with rucurrent genetic abnormalities AML with t(8;21)(q22;q22);AML1(CBFα)/ETO AML with abnormal bone marrow eosinophils [inv(16)(p13q22) or t(16;16)(p13;q22);CBFβ/MYH11] Acute promyelocytic leukemia [AML with t(15;17)(q22;q12) (PML/RARα and variants] AML with 11q23 (MLL) abnormalities
II. AML with multilineage dysplasia Following a myelodysplastic syndrome or myelodysplastic syndrome/myeloproliferative disorder Without antecedent myelodysplastic syndrome
III. AML and myelodysplastic syndromes, therapy-related Alkylating agent-related Topoisomerase type II inhibitor-related Other types
IV. AML not otherwise categorized AML minimally differentiated AML without maturation AML with maturation Acute myelomonocytic leukemia Acute monoblastic and monocytic leukemia Acute erythroid leukemia Acute megakaryoblastic leukemia Acute basophilic leukemia Acute panmyelosis with myelofibrosis Myeloid sarcoma
≥20% myeloblasts in blood and/or bone marrow = AML
positive myeloperoxidase reaction in >3% of blasts = AML (↔ ALL)www.freelivedoctor.com
Acute Myelogenous Leukemia (AML) Acute Myelogenous Leukemia (AML) FAB classification (1985)FAB classification (1985)
M0 : minimally differentiated acute myeloblastic leukemia
M1 : acute myeloblastic leukemia without maturation
M2 : acute myeloblastic leukemia with maturation
M3 : acute promyelocytic leukemia
M4 : acute myelomonocytic leukemia
M5 : acute monocytic leukemia
M6 : erythroleukemia
M7 : acute megakaryoblastic leukemia
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M0 : Minimally Differentiated Acute M0 : Minimally Differentiated Acute Myelogenous LeukemiaMyelogenous Leukemia
• no conclusive morphologic evidence of cellular differentiation
peroxidase negative
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M1 : Acute Myeloblastic Leukemia M1 : Acute Myeloblastic Leukemia without Maturationwithout Maturation
• MP (+), SBB (+), NSE (neg), CLE (+)• 90% or more of BM non-erythroid cells are blasts
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M2 : Acute Myeloblastic Leukemia with M2 : Acute Myeloblastic Leukemia with MaturationMaturation
• MP (+), SBB (+), NSE (neg), CLE (neg)• blasts in 30-9% of BM non-erythroid cells• t(8;21) --- seen in 40-50% of case
favorable prognosis
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M3 : Acute Promyelocytic LeukemiaM3 : Acute Promyelocytic Leukemia
• MP (+), SBB (+), NSE (neg), CLE (+)• abnormal promyelocytes• heavy primary granulation• frequently associated with DIC• t(15;17) --- favorable prognosis
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M4 : Acute Myelomonocytic LeukemiaM4 : Acute Myelomonocytic Leukemia
• MP (+), SBB (+), NSE (+), CLE (+)• monocytic lineage cells in 20-80% of BM non-erythroid cells• abnormal 11q
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M5 : Acute Monocytic LeukemiaM5 : Acute Monocytic Leukemia• MP (+), SBB (+), NSE (+), CLE (neg)• monocytic lineage cells in 80% or more of BM non-erythroid cells• erythrophagocytosis may be present• hypertrophied gum, oral and anorectal ulcers• “chloroma” (green tumor)• lymphadenopathy and splenomegaly• t(9;11) --- unfavorable prognosis
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M6 : ErythroleukemiaM6 : Erythroleukemia
• >50% of all nucleated cells in BM are erythroblasts• >30% of non-erythroid cells are blasts• dyserythropoiesis• unfavorable prognosis
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M7 : Acute Megakaryoblastic LeukemiaM7 : Acute Megakaryoblastic Leukemia
• MP (neg), SBB (neg)• associated with trisomy 21• unfavorable prognosis
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Acute Myelogenous Leukemia (AML) Acute Myelogenous Leukemia (AML) prognostic factorsprognostic factors
good bad
age <40 y/o >60 y/o
WBC <10,000 >100,000
DIC absent present
LDH normal high
type M3, M4Eo M0, M5, M6, M7
cytogenetics t(15;17) complex karyotypet(8;21) -7inv(16) inv(3)
molecular markers PTD of MLLITD of FLT3
history primary lesion post-therapywww.freelivedoctor.com
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