Myeloproliferative/Myeloproliferative/MyelodysplasticMyelodysplastic

Dr. Rafi Ahmed GhoriDr. Rafi Ahmed Ghori Professor MedicineProfessor MedicineLiaquat University of Medical & Liaquat University of Medical & Health Sciences, JamshoroHealth Sciences, Jamshoro

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Myeloproliferative DisordersMyeloproliferative Disorders

Chronic Myelocytic LeukemiaChronic Myelocytic Leukemia Acute Non-Lymphoblastic LeukemiaAcute Non-Lymphoblastic Leukemia Polycythemia VeraPolycythemia Vera Essential ThrombocythemiaEssential Thrombocythemia MyelofibrosisMyelofibrosis

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Essential ThrombocythemiaEssential Thrombocythemia

clonal myeloproliferative disorder clonal myeloproliferative disorder involving increased megakaryopoiesisinvolving increased megakaryopoiesis

Diagnostic criteriaDiagnostic criteria– platelet count over 600,000platelet count over 600,000– hemoglobin less than 13.0 g/dL or a normal hemoglobin less than 13.0 g/dL or a normal

redcell massredcell mass– stainable iron or failure of iron therapystainable iron or failure of iron therapy– No Ph’ chromosome, no marrow fibrosis, No Ph’ chromosome, no marrow fibrosis,

splenomegaly, leukoerythroblastic reaction or splenomegaly, leukoerythroblastic reaction or cause for reactive thrombocytosiscause for reactive thrombocytosis

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Essential ThrombocythemiaEssential Thrombocythemia

Peripheral bloodPeripheral blood• thrombocytosis - variation in size and thrombocytosis - variation in size and

shapeshape• increased segmented neutrophils without increased segmented neutrophils without

basophiliabasophilia• RBC normocytic/normochromic unless RBC normocytic/normochromic unless

complicated by iron deficiencycomplicated by iron deficiency

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Essential ThrombocythemiaEssential Thrombocythemia

Bone marrowBone marrow• Hypercellularity with increased Hypercellularity with increased

megakaryocytic elements showing megakaryocytic elements showing clustering and increased sizeclustering and increased size

Therapy and prognosisTherapy and prognosis• relative long survival relative long survival • thromboemboic or hemorrhagic thromboemboic or hemorrhagic

complications complications

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Agnogenic Myeloid MetaplasiaAgnogenic Myeloid Metaplasia(Myelofibrosis)(Myelofibrosis)

Clonal ineffective hematopoiesis Clonal ineffective hematopoiesis manifesting marrow hypercellularity and manifesting marrow hypercellularity and fibrosis with myeloerythroblastosis in fibrosis with myeloerythroblastosis in the peripheral blood - Causes pg 378the peripheral blood - Causes pg 378

Fibrosis is secondary to increased Fibrosis is secondary to increased release of fibroblastic growth factorsrelease of fibroblastic growth factors

Production of extramedullary Production of extramedullary hematopoiesis hematopoiesis

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Agnogenic Myeloid MetaplasiaAgnogenic Myeloid Metaplasia(Myelofibrosis)(Myelofibrosis)

Age 50 - 70Age 50 - 70 Clinical featuresClinical features

• splenomegaly - hepatomegalysplenomegaly - hepatomegaly• anemiaanemia• bleedingbleeding• bone painbone pain• night sweatsnight sweats

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Agnogenic Myeloid MetaplasiaAgnogenic Myeloid Metaplasia(Myelofibrosis)(Myelofibrosis)

Peripheral bloodPeripheral blood• leukoerythroblastic blood pictureleukoerythroblastic blood picture• may have abnormal neutrophil functionsmay have abnormal neutrophil functions• RBC poikilocytosis with tear dropsRBC poikilocytosis with tear drops• platelets decreased, normal or increased and platelets decreased, normal or increased and

may have abnormal function may have abnormal function Bone marrowBone marrow

• hypercellularhypercellular• dyspoiesisdyspoiesis

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Agnogenic Myeloid MetaplasiaAgnogenic Myeloid Metaplasia(Myelofibrosis)(Myelofibrosis)

Radiologic osteosclerosisRadiologic osteosclerosis Immunological abnormalitiesImmunological abnormalities PrognosisPrognosis

• mean survival is 5 yearsmean survival is 5 years• mortality associated with infection, mortality associated with infection,

hemorrhage, and transformation to acute hemorrhage, and transformation to acute leukemialeukemia

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PolycythemiaPolycythemia Increase in absolute red cell massIncrease in absolute red cell mass measure with Crmeasure with Cr5151

Relative polycythemiaRelative polycythemia• decreased plasma volumedecreased plasma volume• spurious, stress, Gaisbocks diseasespurious, stress, Gaisbocks disease

Primary polycythemiaPrimary polycythemia Secondary polycythemiaSecondary polycythemia

• physiologically appropriatephysiologically appropriate• physiologically inappropriatephysiologically inappropriate

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PolycythemiaPolycythemia

Importance of erythropoietinImportance of erythropoietin• produced in kidney in response to tissue produced in kidney in response to tissue

hypoxiahypoxia

erythropoietinBM

RBCTissuehypoxia

kidney

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PolycythemiaPolycythemia

Polycythemia

erythropoietin (P. vera)

erythropoietin(Secondary polycythemia)

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Polycythemia veraPolycythemia vera One of the group of myeloproliferative One of the group of myeloproliferative

diseases - group of diseases of bone diseases - group of diseases of bone marrow proliferationmarrow proliferation

Myeloproliferative DisordersMyeloproliferative Disorders• RBC - P. vera - DiGuglielmo’sRBC - P. vera - DiGuglielmo’s• fibrotic - myelofibrosis ( agnogenic myeloid fibrotic - myelofibrosis ( agnogenic myeloid

metaplasiametaplasia• WBC - chronic myelocytic - acute myeloblasticWBC - chronic myelocytic - acute myeloblastic• Platelets - Primary thrombocythemiaPlatelets - Primary thrombocythemia

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Polycythemia veraPolycythemia vera

Diagnosis of P. veraDiagnosis of P. vera• generally over age 50 - ruddy complextiongenerally over age 50 - ruddy complextion• All 3 A criteria or A1 and A2 plus 2 B All 3 A criteria or A1 and A2 plus 2 B

criteriacriteria– A1. Increased red cell massA1. Increased red cell mass

– A2. OA2. O22 saturation normal saturation normal

– A3. SpenomegalyA3. Spenomegaly

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Polycythemia veraPolycythemia vera

Diagnosis of P. veraDiagnosis of P. vera• B1. Leukocytosis - left shift - increased B1. Leukocytosis - left shift - increased

basophilsbasophils• B2. Thrombocytosis (abnormal)B2. Thrombocytosis (abnormal)• B3. Increased LAPB3. Increased LAP

• B4. Increased vit BB4. Increased vit B1212 or unbond B or unbond B1212 binding binding

capacitycapacity

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Polycythemia veraPolycythemia vera Diagnosis of P. veraDiagnosis of P. vera

• May have enlarged liverMay have enlarged liver• 75% have enlarged spleen75% have enlarged spleen• May have itching (basophils)May have itching (basophils)• may have increased uric acid (gout)may have increased uric acid (gout)• 30-40% have bleeding or thrombosis30-40% have bleeding or thrombosis• 15% progress to AML15% progress to AML• life span 11 - 13 years after diagnosislife span 11 - 13 years after diagnosis• treatment - phlebotomy - then treatment - phlebotomy - then

chemotherapy - radiation for high platelets.chemotherapy - radiation for high platelets. Rafi

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Secondary Polycythemia Secondary Polycythemia

Physiologically appropriatePhysiologically appropriate• decreased Odecreased O22 saturation saturation

• high altitude, chronic obstructive high altitude, chronic obstructive pulmonary disease, heart shunt disorders, pulmonary disease, heart shunt disorders, hemoglobinopathies, smokers, hemoglobinopathies, smokers, emphasema, carboxyhemoglobinemphasema, carboxyhemoglobin

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Secondary Polycythemia Secondary Polycythemia

Physiologically inappropriatePhysiologically inappropriate• normal or increased Onormal or increased O2 2 saturationsaturation

• tumors producing erythropoietin (renal, tumors producing erythropoietin (renal, liver, adrenal, uterine fibroid) renal causes liver, adrenal, uterine fibroid) renal causes (cysts, hydronephrosis, transplantation, (cysts, hydronephrosis, transplantation, nephrotic syndrome pheochromocytoma) nephrotic syndrome pheochromocytoma) familialfamilial

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Myelodysplastic syndromesMyelodysplastic syndromes

Defect in “colony forming unit” which Defect in “colony forming unit” which results in abnormal production and results in abnormal production and maturation of all three marrow cell linesmaturation of all three marrow cell lines

Morphologically falls short of acute Morphologically falls short of acute nonlymphoblastic leukemianonlymphoblastic leukemia

5 subgroups5 subgroups

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Myelodysplastic syndromesMyelodysplastic syndromes

5 subgroups5 subgroups• Refractory anemiaRefractory anemia• Refractory anemia with “ringed” Refractory anemia with “ringed”

sideroblastssideroblasts• Refractory anemia with excessive “blasts”Refractory anemia with excessive “blasts”• Refractory anemia with excessive “blasts” Refractory anemia with excessive “blasts”

in transitionin transition• Chronic Myelomonocytic LeukemiaChronic Myelomonocytic Leukemia

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Myelodysplastic syndromesMyelodysplastic syndromes

Clinical FeaturesClinical Features• RA and RAEB are the most common RA and RAEB are the most common • Age 50 - 60Age 50 - 60• Males > femalesMales > females• insidious onset of fatigue and weakness, insidious onset of fatigue and weakness,

bleeding or infections related to bleeding or infections related to pancytopeniapancytopenia

• CMMoL - 50% have mild splenomegaly CMMoL - 50% have mild splenomegaly and/or cervical adenopathyand/or cervical adenopathy

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Myelodysplastic syndromesMyelodysplastic syndromes Hematologic features Peripheral smearHematologic features Peripheral smear

• typically cytopenias of 2 or all 3 cell lines typically cytopenias of 2 or all 3 cell lines except in RA and RA-S which commonly except in RA and RA-S which commonly present as isolated refractory anemiapresent as isolated refractory anemia

• RBC - macrocytosis - some aniso - RBC - macrocytosis - some aniso - poikilocytosis with microangiopathic poikilocytosis with microangiopathic changes - few teardrops - poly and coarse changes - few teardrops - poly and coarse basophilic stippling - dimorphism in RA-S - basophilic stippling - dimorphism in RA-S - Pappenheimer bodies in splenectomized - Pappenheimer bodies in splenectomized - NRBC’s in over 50-70% NRBC’s in over 50-70%

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Myelodysplastic syndromesMyelodysplastic syndromes

Peripheral smearPeripheral smear• Platelets - increased numbers of giant Platelets - increased numbers of giant

and/or bizarre forms - variation in size - and/or bizarre forms - variation in size - poor or clumped granulation - poor or clumped granulation - thrombocytosis in 10-30% of RA-S and all thrombocytosis in 10-30% of RA-S and all cases with chromosome abnormalitiescases with chromosome abnormalities

• Granulocytes - few type I and II blasts - Granulocytes - few type I and II blasts - Pelgeroid cells - hypermature chromatin Pelgeroid cells - hypermature chromatin clumping and hypogranulation - may have clumping and hypogranulation - may have fine vacuolization and Dohle bodiesfine vacuolization and Dohle bodies

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Myelodysplastic syndromesMyelodysplastic syndromes

Peripheral smearPeripheral smear• In CMMoL the monocytes may be In CMMoL the monocytes may be

morphologically normal or atypical and morphologically normal or atypical and difficult to distinguish from myelocytes and difficult to distinguish from myelocytes and metas - abnormal monocytes may have metas - abnormal monocytes may have hypersegmented and/or horseshoe shaped hypersegmented and/or horseshoe shaped nuclei - recognized as monocytes by nuclei - recognized as monocytes by nuclear characteristics, abundant nuclear characteristics, abundant cytoplasm and vacuolescytoplasm and vacuoles

• Hypersegmented neutrophils NOT seenHypersegmented neutrophils NOT seenRafi

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Myelodysplastic syndromesMyelodysplastic syndromes

Bone MarrowBone Marrow• At least normocellular and usually At least normocellular and usually

hypercellularhypercellular• Erythroid series - megaloblastoid Erythroid series - megaloblastoid

maturation with early nuclear chromatin maturation with early nuclear chromatin clumping - nuclear budding and clumping - nuclear budding and cytoplasmic vacuoles (PAS positive) - in cytoplasmic vacuoles (PAS positive) - in RA-S greater than 15% ringed sideroblasts RA-S greater than 15% ringed sideroblasts

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Myelodysplastic syndromesMyelodysplastic syndromes

Bone MarrowBone Marrow• Myeloid - less than 20% myeloblasts (I/II) Myeloid - less than 20% myeloblasts (I/II)

except in RAEB-T (20-30%) - may have except in RAEB-T (20-30%) - may have Auer rods - minimal abnormalities in RA Auer rods - minimal abnormalities in RA and RA-S - RAEB and CMMoL have and RA-S - RAEB and CMMoL have myeloid hyperplasia with bulge at myeloid hyperplasia with bulge at myelocyte stage - myelocytes appear myelocyte stage - myelocytes appear immature with poor cytoplasmic granulation immature with poor cytoplasmic granulation - often show monocytoid features- often show monocytoid features

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Myelodysplastic syndromesMyelodysplastic syndromes

Bone MarrowBone Marrow• Megakarycytes - often occur in clusters - many Megakarycytes - often occur in clusters - many

are small and uninucleated are small and uninucleated (micromegakarycytes) (micromegakarycytes)

Other features - usually have significantly Other features - usually have significantly increased amounts of reticuloendothelial increased amounts of reticuloendothelial storage iron - mild/moderate reactive storage iron - mild/moderate reactive plasmocytosis without significant plasmocytosis without significant myelofibrosismyelofibrosis

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Myelodysplastic syndromesMyelodysplastic syndromes

Laboratory FindingsLaboratory Findings• LAP often lowLAP often low• PNH-like alteration with positive sucrose PNH-like alteration with positive sucrose

and Ham’s hemolysis testand Ham’s hemolysis test• Increased serum iron, decreased TIBC, Increased serum iron, decreased TIBC,

increased saturation, increased ferritinincreased saturation, increased ferritin• May have increased HbF (30% in CMMoL)May have increased HbF (30% in CMMoL)• Increased serum and/or urine lysozyme Increased serum and/or urine lysozyme

levels in CMMoLlevels in CMMoLRafi

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Myelodysplastic syndromesMyelodysplastic syndromes

Laboratory FindingsLaboratory Findings• May have acquired thrombopathy even with May have acquired thrombopathy even with

normal platelet numbersnormal platelet numbers• Moderate increased LDH is commonModerate increased LDH is common

PrognosisPrognosis• Survival relates to % blasts Survival relates to % blasts • RA/RA-S --- RAEB/CMMoL -- RAEB-TRA/RA-S --- RAEB/CMMoL -- RAEB-T• Decreased with thrombocytopenia and/or Decreased with thrombocytopenia and/or

anemia and/or chromosomal abnormalitiesanemia and/or chromosomal abnormalities

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Myelodysplastic syndromesMyelodysplastic syndromes

Differential DiagnosisDifferential Diagnosis• Aplastic anemia - lacks morphologic atypias Aplastic anemia - lacks morphologic atypias

characteristic of MDS - bone marrow characteristic of MDS - bone marrow hypocellularhypocellular

• PNH - laboratory evidence of intravascular PNH - laboratory evidence of intravascular hemolysis - decreased or absent marrow iron hemolysis - decreased or absent marrow iron storesstores

• Megaloblastic anemia - hypersegmentation of Megaloblastic anemia - hypersegmentation of PMN - marrow megaloblastic - decreased BPMN - marrow megaloblastic - decreased B1212

or folateor folate

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Myelodysplastic syndromesMyelodysplastic syndromes Differential DiagnosisDifferential Diagnosis

• CML - peripheral count usually much higher CML - peripheral count usually much higher with eosinophilia and basophilia - with eosinophilia and basophilia - splenomegaly - presence of Ph’ - bone splenomegaly - presence of Ph’ - bone marrow in CMMoL may closely resemble marrow in CMMoL may closely resemble CMLCML

• Agnogenic myeloid metaplasia - teardrops Agnogenic myeloid metaplasia - teardrops and poik - more prominent NRB’s and and poik - more prominent NRB’s and splenomegaly - bone marrow myelofibrosissplenomegaly - bone marrow myelofibrosis

• ANLL - marrow contains over 30% blasts ANLL - marrow contains over 30% blasts

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