Myeloproliferative

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.


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


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


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


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


““leukoproliferative disorders”leukoproliferative disorders”

lymphoid lymphoid neoplasms acute

chronic

myeloidmyeloid neoplasms acute

chronic


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


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


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


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)


Chronic Myelogenous Leukemia (CML) Chronic Myelogenous Leukemia (CML) laboratorylaboratory

• WBC : >100,000• thrombocytosis• numerically increased, but functionally impaired granulocytes


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)


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


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


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


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


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


MyelofibrosisMyelofibrosis

Aniso-poikilocytosis

leukemoid reaction

“naked” nuclear fragments


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


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


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%)


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


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


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


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)


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.


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


M0 : Minimally Differentiated Acute M0 : Minimally Differentiated Acute Myelogenous LeukemiaMyelogenous Leukemia

• no conclusive morphologic evidence of cellular differentiation

peroxidase negative


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


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


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


M4 : Acute Myelomonocytic LeukemiaM4 : Acute Myelomonocytic Leukemia

• MP (+), SBB (+), NSE (+), CLE (+)• monocytic lineage cells in 20-80% of BM non-erythroid cells• abnormal 11q


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


M6 : ErythroleukemiaM6 : Erythroleukemia

• >50% of all nucleated cells in BM are erythroblasts• >30% of non-erythroid cells are blasts• dyserythropoiesis• unfavorable prognosis


M7 : Acute Megakaryoblastic LeukemiaM7 : Acute Megakaryoblastic Leukemia

• MP (neg), SBB (neg)• associated with trisomy 21• unfavorable prognosis


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

Myeloproliferative

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