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MYELOPROLIFERATIVE SYNDROMES &LEUKEMIA

Doç. Dr. Işın Doğan Ekici

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Myeloproliferative syndromesMyeloproliferative syndromes ( (MPSMPS; ; blast crisisblast crisis))

Excess proliferation of marrow cells (myelopoiesis) with dysplasia

Progress to Leukemia Ineffective Myelopoiesis

marrow hyperplasia with pancytopenia.

Primary or Secondary

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Bone Marrow Cellularity

Normal Hypercellular Hypocellular

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Primary MPS

Agnogenic myeloid metaplasia

Polycythemia rubra veraChronic myeloid leukemiaEssential hemorrhagic

thrombocythemia Myelofibrosis

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The following "myeloproliferative diseases" are all "tumors of the multipotent myeloid stem cell", and can transform into one another (usually from a mild one to a bad one): polycythemia rubra vera (PV) essential (hemorrhagic) thrombocythemia

(ET) agnogenic myeloid metaplasia (AMM) idiopathic "aplastic anemia" (AA) chronic myeloid leukemia. (CML)

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Myeloproliferative syndromesMyeloproliferative syndromes:: PathogenesisPathogenesis

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AAgnogenicgnogenic (idiopathic) (idiopathic) myeloid myeloid metaplasiametaplasia

• Proliferation of neoplastic stem cells in the – bone marrow (becomes hypercellular) – red pulp of the spleen (enlarges greatly;

splenomegaly).

• the cells that enter the blood are fully functional

• neutrophilia/neutropenia/normal neutrophil counts

• no tendency to over-produce red cells.• Peripheral smear shows a

leukoerythroblastic pattern:– red cells made in the spleen tend to be

teardrop-shaped (poikilocyte), – nucleated red-cell precursors from the spleen.

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• Bone marrow dense fibrosis (several years) Cytopenia or transformation to acute leukemia.

• Differential diagnosis (if there is an unexplained myelofibrosis without splenomegaly) : – Chronic myeloid leukemia, – Polycythemia vera, – Metastatic carcinoma.

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Polycythemia rubra vera (PV)Polycythemia rubra vera (PV)

• Syn.:Osler's polycythemia; erythrocytosis.

• An abnormally high hemoglobin.

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Classification• Relative

polycythemia – Dehydration

• Absolute polycythemia (increased circulating

red cell mass): – Primary

polycythemia• Polycythemia vera

rubra

– Secondary polycythemia• Effective renal arterial

hypoxia – Emphysema – Tetralogy of Fallot – Hemoglobins with too

much oxygen affinity

• Erythropoietin-producing tumors

– Renal cell carcinoma – Hepatocellular carcinoma – Cerebellar

hemangioblastoma (?!)

• Anabolic steroid users • Sleep apnea • After kidney transplant • Altitude

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• Polycythemia vera is a proliferation of stem cells:– they are very

erythropoietin-sensitive – mostly mature into red

cells– in addition to a high red

cell count, white cells and platelets are likely to be high.

• Older middle-age. • Increased volume of

hyperviscous blood.

On biopsy:• a very hypercellular

marrow, • with all cell

lineages increased. • In the late stages:

– marrow fibrosis – replacement by

blasts– transformation to

acute myelogenous leukemia.

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Complications:• Congestion (widespread; red

face)

• Venous stasis• Rupture of dilated veins

– hemorrhage

• GI bleedings• Hemorrhagic stroke.

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MyelofibrosisMyelofibrosis The marrow is replaced by fibrous (scar) tissue. Causes blood formation to take place in sites

other than the bone marrow, such as the liver and spleen, causing enlargement of these organs. Primary

Idiopathic myeloid metaplasia Secondary

Autoimmune SLE Polycytemia vera Carcinoma infiltration Leukemias

Complications: Sever anemia with low platelet & splenomegaly Hepatomegaly & Liver failure Acute myelogenous leukemia.

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Myelofibrosis

teardrop cells

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(P(Preleukemias ; releukemias ; Carl Sagan's disease)Carl Sagan's disease) Ineffective Myelopoiesis

marrow hyperplasia with pancytopenia.

Excess proliferation with dysplasia. This is a family of disorders in which

there are problems in producing red cells, granulocytes, platelets.

MyeloMyelodysplasticdysplastic syndromes syndromes

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FAB classificationFAB classification

• 1. Refractory anemia (poor hemoglobinization, too few red cells): (Blasts <1%)

• 2. Refractory anemia with ringed sideroblasts (>15% of nucleated red cells)

• 3. Refractory anemia with excess blasts (5-20% myeloblasts)

• 4. Refractory anemia with excess blasts in transformation (20-30% myeloblasts)

• 5. Chronic myelocytic leukemia.

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WHO 2008 MDS CLASSIFICATION ● Refractory anemia (RA): <5% blasts, <15% ringed

sideroblasts; variable marrow cellularity, unicytopenia or bicytopenia, unilineage dysplasia >10% in one myeloid lineage● RA with Ringed Sideroblasts (RARS): 15% or more sideroblasts, less than 5% blasts, erythroid dysplasia only● Refractory cytopenia with multilineage dysplasia (RCMD): cytopenia, <5% blasts, dysplasia in >10% of cells in two or more lineages, no Auer rods● RA with Excess Blasts (RAEB): type 1 has 5-9% blasts in blood/marrow, peripheral cytopenia, unilineage or multilineage dysplasia, no Auer rods; type 2 has 10-19% blasts in blood/marrow, unilineage or multilineage dysplasia, Auer rods may be present, peripheral cytopenia ● MDS with isolated 5q- syndrome: anemia, <5% blasts, del(5q), no Auer rods, normal/increased hypolobated megakarycoytes ● MDS, unclassified: cytopenia(s), dysplasia in <10% of cells in one or more myeloid cell lines, accompanied by cytogenetic abnormalities with presumptive evidence of MDS, <5% blasts ● Therapy related MDS

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Dysplastic ErythroblastsDysplastic Erythroblasts

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Clinical findings

• Most patients are older adults,• often asymptomatic (detected on

routine screening) • in the more aggressive forms,

death follows in a few years. • Propensity to transform into acute

myeloid leukemia.

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LEUKEMIAS

ACUTE & CHRONIC

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WBC Neoplastic disorders

Leukemias Bone marrow, blood, blast cells Acute/Chronic & Myeloid/Lymphoid AML / ALL & CML / CLL

Lymphomas – Lymph nodes, tumor Hodgkins - Non-Hodgkins. Myeloma

Premalignant conditions: Myeloproliferative syndromes (MPS) Myelodysplastic syndromes (MDS)

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Introduction:

No Benign Neoplasms – All are considered malignant or premalignant.

Neoplastic Cells flood blood stream – Leukemia.

Commonly arise in marrow (myelo/ly) or Lymph node (lymphoid),

Spread to blood & other RES tissues rarely to other organs

Symptoms are due to deficient normal hemopoiesis. RBC, WBC & Plt.

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Leukemia - Clinical Features

Anemia (low RBC) Fever - Infections (low WBC) Bleeding tendency (low PLT) Tender bones, lymphadenopathy,

spleenomegaly etc. (Leukemic infiltration)

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Leukemia Classification

Acute Leukemias: Acute Myeloid Leukemia - AML

AML M0, M1, M2, M3, M4, M5, M6 & M7

Acute Lymphoid Leukemia - ALL ALL - L1, L2 & L3 - maturity

Chronic Leukemias: Chronic Myeloid Leukemia- CML Chronic Lymphoid Leukemia - CLL

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ACUTE LEUKEMIA

Genetic disorder characterized by uncontrolled clonal proliferation of expansion of hematopoietic cells that do not retain the capacity to differentiate normally to mature cells

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Triggers of Differentiation Mishap Not really known

Virus Clusters of leukemia

Ionizing radiation Survivors of Hiroshima and Nagasaki

Genetics Higher incidence in siblings and twins of affected

pt Higher incidence in children with fragile

chromosomes and impaired DNA repair mechanisms

Down syndrome, Fanconi syndrome, Bloom Syndrome Ataxia-telangiectasia, congenital

hypogammaglobulinemia

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ACUTE LEUKEMIASystemic Findings Cytopenias

anemia, neutropenia, thrombocytopenia.

Bone pain expansion of the marrow infiltration of the periosteum.

Involvement of all other organs brain involvement is especially troublesome. T-cell leukemias often produce a mass in the anterior

mediastinum. Death

hemorrhage (cerebral, GI, other), infection (neutropenia, chemotherapy), complications of bone marrow transplantation.

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ALL-Acute Lymphocytic Leukemia

Common in Children. FAB classification L1, L2 & L3 CD10 + and, Pre B cell type

common. Growth failure, Fever, Anemia

Lymphadenopathy, bleeding. Moderate Hepatosplenomegaly

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The Cause

Clonal expansion of lymphoid progenitor cells is altered

Progenitor cells get stuck at a particular stage of differentiation and do not progress

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Acute Lymphocytic Leukemia (ALL)

Acute lymphoid / lymphocytic leukemia “Childhood leukemia", with peak age in

four year old kids. Risk Factors:

Radiation exposure Down's syndrome kids are at 15x the

normal risk, Viruses (as-yet-unidentified) an unusual

response to.

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Subclassification of Acute lymphoblastic leukemia by blast morphology “FAB classification”

L1 (85%): Cells <= 2x the diameter of a normal lymphocyte; smooth nuclei; common in kids.

L2 (14%): Bigger cells, lots of clefts, often nucleoli; more common in adults.

L3 (1%): Even bigger cells; leukemic form of Burkitt's lymphoma.

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ALL-L1

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ALL-L2

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ALL-L3

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The immunologic classification: B-cell (80%) leukemia “pre-B” cell leukemia (Burkitt's) T-cell (15%) leukemia

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ALL:Cervical Lymphadenopathy

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Mediastinal Lymphadenopathy - ALL

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AML-Acute Myeloid Leukemia

Adults common FAB classification - M0 to M7. Anemia, Fever, Bleeding Hepatosplenomegaly moderate No significant lymphadenopathy

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Organomegaly

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Platelet Coagulation

Petechiae, Purpura Hematoma, Joint bl.

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Acute Myeloblastic Leukemia (AML)

“Poorly differentiated granulocytic leukemia", “Acute non-lymphocytic leukemia",

This is the common acute leukemia of adults (seldom over age 40, occasionally children are affected)

Bleeding tendency: DIC Gum bleeding common

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AML-M5 - Gum Hypertrophy:

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Risk factors

Down's syndrome

Fragile chromosome syndromes Bloom's ataxia telangiectasia Fanconi's anemia

Benzene exposure Ethylene oxide exposure Radiation exposure

Previous cancer chemotherapy Myelodysplastic syndromes (preleukemia) Any "chronic myeloproliferative syndrome" ("blast crisis")

agnogenic myeloid metaplasia polycythemia vera rubra "essential" hemorrhagic thrombocythemia chronic myelogenous leukemia idiopathic aplastic anemia.

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The FAB classification of AML

M0: undifferentiated myeloblasts without myeloperoxidase

M1: undifferentiated myeloblasts with myeloperoxidase

M2: some promyelocytic differentiation, maybe a few Auer rods;

M3: very granular promyelocytes, often many Auer rods, DIC (from annexin II on the surfaces which activates plasmin).

M4: myeloid and monocytic differentiation

M5: monocytic differentiation only M6: features of red cell precursors

predominate; "erythroleukemia" M7: platelet markers; acute

marrow fibrosis.

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Promyelocytic M3

Monocytic leukemiaM5

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M0 - AML No maturation (<3% Peroxidase +) M1 - AML Min.Maturation(>3% Peroxidase +) M2 - AML With full maturation M3 - Acute Promyelocytic leukemia M4 - Acute Myelomonocytic leukemia M5 - Acute Monocytic L (Monocytic, Monoblastic) M6 - Acute Erythroleukemia M7 - Acute Megakaryocytic leukemia.

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AML-M0 - Undifferentiated:

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AML-M2 - with maturation

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AML-M3 - Auer Rods

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AML-M4 - Myelomonocytic

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AML-M6 : Erythroleukemia

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AML-M7 : Megakaryocytic

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Chronic Myeloid Leukemia

Middle age 40-60y Philadelphia chromosome, t(9:22) BCR-

ABL Anemia, Fever & Bleeding Marked leucocytosis – >50,000

(abnormal) Marked splenomegaly, Hepatomegaly

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Chronic Myeloid Leukemia:

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Chronic Myeloid Leukemia (CML)

Syn: Chronic myelogenous leukemia, Well-differentiated granulocytic leukemia

This is cancer of the myeloid stem cells in which there is overgrowth of normally-maturing myeloid cells

Middle age Risk Factors:

radiation exposure to chemicals (notably benzene)

Marked leukocytosis 50,000 (abnormal) high counts of neutrophils and their precursors (and

almost always basophils

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Marked splenomegaly with little infarcts White cells plugging important small vessels

("leukostatic ischemia" of the brain, etc.) Hyperuricemia (gout, renal impairment) After a few years, in blast crisis, (50%/50%). The following "myeloproliferative diseases" are

all "tumors of the multipotent myeloid stem cell", and can transform into one another (usually from a mild one to a bad one): polycythemia vera rubra essential hemorrhagic thrombocythemia agnogenic myeloid metaplasia idiopathic "aplastic anemia" chronic myelogenous leukemia.

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Chronic Lymphocytic LeukemiaCLL

Elderly age Anemia, fever & bleeding – slow over

years. Lymphocytosis & Lymphadenopathy Spleen, & liver enlargement Common B cell (CD5 +)

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CLL

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CLL – Blood Film

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Chronic Lymphocytic Leukemia (CLL)

Well-differentiated lymphocytic leukemia The liquid phase of well-differentiated lymphocytic

lymphoma, A clone of B-cells which multiply slowly and do nothing

useful. The lymphocytes:

do somewhat suppress the heathy plasma cells, the patients have troubles with infections.

Risk factor: ataxia-telangiectasia. Elderly age Anemia, fever & bleeding (slow, over years). Lymphocytosis & Lymphadenopathy Hepatosplenomegaly

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Paraneoplastic syndromes are more troublesome in this disease than in most other leukemias.

Autoimmune hemolytic anemia (15%) Richter's syndrome: a few percent of

patients develop a diffuse large-cell lymphoma (rapidly-fatal).

Around 1% of CLL terminates as ALL ("blast crisis of CLL").

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Chronic Lymphocytic Leukemia (CLL)

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Summary

Leukemias – Starts in marrow spread to blood Anemia, infections & Bleeding Enlargement of Liver, Spleen lymph nodes Acute/Chronic & Myeloid & Lymphoid.

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