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  1. 1. Myeloproliferative/Myeloproliferative/MyelodysplasticMyelodysplasticDr. Rafi Ahmed GhoriDr. Rafi Ahmed GhoriProfessor MedicineProfessor MedicineLiaquat University of Medical &Liaquat University of Medical &Health Sciences, JamshoroHealth Sciences, Jamshoro
  2. 2. BIKHABIKHAMyeloproliferative DisordersMyeloproliferative DisordersChronic Myelocytic LeukemiaChronic Myelocytic LeukemiaAcute Non-Lymphoblastic LeukemiaAcute Non-Lymphoblastic LeukemiaPolycythemia VeraPolycythemia VeraEssential ThrombocythemiaEssential ThrombocythemiaMyelofibrosisMyelofibrosisRafi
  3. 3. BIKHABIKHARafi
  4. 4. BIKHABIKHAEssential ThrombocythemiaEssential Thrombocythemiaclonal myeloproliferative disorderclonal myeloproliferative disorderinvolving increased megakaryopoiesisinvolving increased megakaryopoiesisDiagnostic criteriaDiagnostic criteria– platelet count over 600,000platelet count over 600,000– hemoglobin less than 13.0 g/dL or a normalhemoglobin less than 13.0 g/dL or a normalredcell 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 orsplenomegaly, leukoerythroblastic reaction orcause for reactive thrombocytosiscause for reactive thrombocytosisRafi
  5. 5. BIKHABIKHAEssential ThrombocythemiaEssential ThrombocythemiaPeripheral bloodPeripheral blood• thrombocytosis - variation in size andthrombocytosis - variation in size andshapeshape• increased segmented neutrophils withoutincreased segmented neutrophils withoutbasophiliabasophilia• RBC normocytic/normochromic unlessRBC normocytic/normochromic unlesscomplicated by iron deficiencycomplicated by iron deficiencyRafi
  6. 6. BIKHABIKHAEssential ThrombocythemiaEssential ThrombocythemiaBone marrowBone marrow• Hypercellularity with increasedHypercellularity with increasedmegakaryocytic elements showingmegakaryocytic elements showingclustering and increased sizeclustering and increased sizeTherapy and prognosisTherapy and prognosis• relative long survivalrelative long survival• thromboemboic or hemorrhagicthromboemboic or hemorrhagiccomplicationscomplicationsRafi
  7. 7. BIKHABIKHAAgnogenic Myeloid MetaplasiaAgnogenic Myeloid Metaplasia(Myelofibrosis)(Myelofibrosis)Clonal ineffective hematopoiesisClonal ineffective hematopoiesismanifesting marrow hypercellularity andmanifesting marrow hypercellularity andfibrosis with myeloerythroblastosis infibrosis with myeloerythroblastosis inthe peripheral blood - Causes pg 378the peripheral blood - Causes pg 378Fibrosis is secondary to increasedFibrosis is secondary to increasedrelease of fibroblastic growth factorsrelease of fibroblastic growth factorsProduction of extramedullaryProduction of extramedullaryhematopoiesishematopoiesisRafi
  8. 8. BIKHABIKHAAgnogenic Myeloid MetaplasiaAgnogenic Myeloid Metaplasia(Myelofibrosis)(Myelofibrosis)Age 50 - 70Age 50 - 70Clinical featuresClinical features• splenomegaly - hepatomegalysplenomegaly - hepatomegaly• anemiaanemia• bleedingbleeding• bone painbone pain• night sweatsnight sweatsRafi
  9. 9. BIKHABIKHAAgnogenic 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 increasedplatelets decreased, normal or increasedand may have abnormal functionand may have abnormal functionBone marrowBone marrow• hypercellularhypercellular• dyspoiesisdyspoiesisRafi
  10. 10. BIKHABIKHAAgnogenic Myeloid MetaplasiaAgnogenic Myeloid Metaplasia(Myelofibrosis)(Myelofibrosis)Radiologic osteosclerosisRadiologic osteosclerosisImmunological abnormalitiesImmunological abnormalitiesPrognosisPrognosis• mean survival is 5 yearsmean survival is 5 years• mortality associated with infection,mortality associated with infection,hemorrhage, and transformation to acutehemorrhage, and transformation to acuteleukemialeukemiaRafi
  11. 11. BIKHABIKHAPolycythemiaPolycythemiaIncrease in absolute red cell massIncrease in absolute red cell massmeasure with Crmeasure with Cr5151Relative polycythemiaRelative polycythemia• decreased plasma volumedecreased plasma volume• spurious, stress, Gaisbocks diseasespurious, stress, Gaisbocks diseasePrimary polycythemiaPrimary polycythemiaSecondary polycythemiaSecondary polycythemia• physiologically appropriatephysiologically appropriate• physiologically inappropriatephysiologically inappropriate Rafi
  12. 12. BIKHABIKHAPolycythemiaPolycythemiaImportance of erythropoietinImportance of erythropoietin• produced in kidney in response to tissueproduced in kidney in response to tissuehypoxiahypoxiaerythropoietinBMRBCTissuehypoxiakidneyRafi
  13. 13. BIKHABIKHAPolycythemiaPolycythemiaPolycythemiaerythropoietin(P. vera)erythropoietin(Secondarypolycythemia)Rafi
  14. 14. BIKHABIKHAPolycythemia veraPolycythemia veraOne of the group of myeloproliferativeOne of the group of myeloproliferativediseases - group of diseases of bonediseases - group of diseases of bonemarrow proliferationmarrow proliferationMyeloproliferative DisordersMyeloproliferative Disorders• RBC - P. vera - DiGuglielmo’sRBC - P. vera - DiGuglielmo’s• fibrotic - myelofibrosis ( agnogenic myeloidfibrotic - myelofibrosis ( agnogenic myeloidmetaplasiametaplasia• WBC - chronic myelocytic - acuteWBC - chronic myelocytic - acutemyeloblasticmyeloblastic• Platelets - Primary thrombocythemiaPlatelets - Primary thrombocythemia Rafi
  15. 15. BIKHABIKHAPolycythemia veraPolycythemia veraDiagnosis 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 BAll 3 A criteria or A1 and A2 plus 2 Bcriteriacriteria– A1. Increased red cell massA1. Increased red cell mass– A2. OA2. O22 saturation normalsaturation normal– A3. SpenomegalyA3. SpenomegalyRafi
  16. 16. BIKHABIKHAPolycythemia veraPolycythemia veraDiagnosis of P. veraDiagnosis of P. vera• B1. Leukocytosis - left shift - increasedB1. Leukocytosis - left shift - increasedbasophilsbasophils• B2. Thrombocytosis (abnormal)B2. Thrombocytosis (abnormal)• B3. Increased LAPB3. Increased LAP• B4. Increased vit BB4. Increased vit B1212 or unbond Bor unbond B1212 bindingbindingcapacitycapacityRafi
  17. 17. BIKHABIKHAPolycythemia veraPolycythemia veraDiagnosis 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 - thentreatment - phlebotomy - thenchemotherapy - radiation for high platelets.chemotherapy - radiation for high platelets. Rafi
  18. 18. BIKHABIKHASecondary PolycythemiaSecondary PolycythemiaPhysiologically appropriatePhysiologically appropriate• decreased Odecreased O22 saturationsaturation• high altitude, chronic obstructivehigh altitude, chronic obstructivepulmonary disease, heart shunt disorders,pulmonary disease, heart shunt disorders,hemoglobinopathies, smokers,hemoglobinopathies, smokers,emphasema, carboxyhemoglobinemphasema, carboxyhemoglobinRafi
  19. 19. BIKHABIKHASecondary PolycythemiaSecondary PolycythemiaPhysiologically inappropriatePhysiologically inappropriate• normal or increased Onormal or increased O22 saturationsaturation• tumors producing erythropoietin (renal,tumors producing erythropoietin (renal,liver, adrenal, uterine fibroid) renal causesliver, adrenal, uterine fibroid) renal causes(cysts, hydronephrosis, transplantation,(cysts, hydronephrosis, transplantation,nephrotic syndrome pheochromocytoma)nephrotic syndrome pheochromocytoma)familialfamilialRafi
  20. 20. BIKHABIKHAMyelodysplastic syndromesMyelodysplastic syndromesDefect in “colony forming unit” whichDefect in “colony forming unit” whichresults in abnormal production andresults in abnormal production andmaturation of all three marrow cell linesmaturation of all three marrow cell linesMorphologically falls short of acuteMorphologically falls short of acutenonlymphoblastic leukemianonlymphoblastic leukemia5 subgroups5 subgroupsRafi
  21. 21. BIKHABIKHAMyelodysplastic syndromesMyelodysplastic syndromes5 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 LeukemiaRafi
  22. 22. BIKHABIKHAMyelodysplastic syndromesMyelodysplastic syndromesClinical FeaturesClinical Features• RA and RAEB are the most commonRA 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 tobleeding or infections related topancytopeniapancytopenia• CMMoL - 50% have mild splenomegalyCMMoL - 50% have mild splenomegalyand/or cervical adenopathyand/or cervical adenopathyRafi
  23. 23. BIKHABIKHAMyelodysplastic syndromesMyelodysplastic syndromesHematologic features Peripheral smearHematologic features Peripheral smear• typically cytopenias of 2 or all 3 cell linestypically cytopenias of 2 or all 3 cell linesexcept in RA and RA-S which commonlyexcept in RA and RA-S which commonlypresent as isolated refractory anemiapresent as isolated refractory anemia• RBC - macrocytosis - some aniso -RBC - macrocytosis - some aniso -poikilocytosis with microangiopathicpoikilocytosis with microangiopathicchanges - few teardrops - poly and coarsechanges - few teardrops - poly and coarsebasophilic 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%Rafi
  24. 24. BIKHABIKHAMyelodysplastic syndromesMyelodysplastic syndromesPeripheral smearPeripheral smear• Platelets - increased numbers of giantPlatelets - increased numbers of giantand/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 allthrombocytosis in 10-30% of RA-S and allcases with chromosome abnormalitiescases with chromosome abnormalities• Granulocytes - few type I and II blasts -Granulocytes - few type I and II blasts -Pelgeroid cells - hypermature chromatinPelgeroid cells - hypermature chromatinclumping and hypogranulation - may haveclumping and hypogranulation - may havefine vacuolization and Dohle bodiesfine vacuolization and Dohle bodiesRafi
  25. 25. BIKHABIKHAMyelodysplastic syndromesMyelodysplastic syndromesPeripheral smearPeripheral smear• In CMMoL the monocytes may beIn CMMoL the monocytes may bemorphologically normal or atypical andmorphologically normal or atypical anddifficult to distinguish from myelocytes anddifficult to distinguish from myelocytes andmetas - abnormal monocytes may havemetas - abnormal monocytes may havehypersegmented and/or horseshoe shapedhypersegmented and/or horseshoe shapednuclei - recognized as monocytes bynuclei - recognized as monocytes bynuclear characteristics, abundantnuclear characteristics, abundantcytoplasm and vacuolescytoplasm and vacuoles• Hypersegmented neutrophils NOT seenHypersegmented neutrophils NOT seenRafi
  26. 26. BIKHABIKHAMyelodysplastic syndromesMyelodysplastic syndromesBone MarrowBone Marrow• At least normocellular and usuallyAt least normocellular and usuallyhypercellularhypercellular• Erythroid series - megaloblastoidErythroid series - megaloblastoidmaturation with early nuclear chromatinmaturation with early nuclear chromatinclumping - nuclear budding andclumping - nuclear budding andcytoplasmic vacuoles (PAS positive) - incytoplasmic vacuoles (PAS positive) - inRA-S greater than 15% ringed sideroblastsRA-S greater than 15% ringed sideroblastsRafi
  27. 27. BIKHABIKHAMyelodysplastic syndromesMyelodysplastic syndromesBone MarrowBone Marrow• Myeloid - less than 20% myeloblasts (I/II)Myeloid - less than 20% myeloblasts (I/II)except in RAEB-T (20-30%) - may haveexcept in RAEB-T (20-30%) - may haveAuer rods - minimal abnormalities in RAAuer rods - minimal abnormalities in RAand RA-S - RAEB and CMMoL haveand RA-S - RAEB and CMMoL havemyeloid hyperplasia with bulge atmyeloid hyperplasia with bulge atmyelocyte stage - myelocytes appearmyelocyte stage - myelocytes appearimmature with poor cytoplasmicimmature with poor cytoplasmicgranulation - often show monocytoidgranulation - often show monocytoidfeaturesfeaturesRafi
  28. 28. BIKHABIKHAMyelodysplastic syndromesMyelodysplastic syndromesBone MarrowBone Marrow• Megakarycytes - often occur in clusters -Megakarycytes - often occur in clusters -many are small and uninucleatedmany are small and uninucleated(micromegakarycytes)(micromegakarycytes)Other features - usually haveOther features - usually havesignificantly increased amounts ofsignificantly increased amounts ofreticuloendothelial storage iron -reticuloendothelial storage iron -mild/moderate reactive plasmocytosismild/moderate reactive plasmocytosiswithout significant myelofibrosiswithout significant myelofibrosisRafi
  29. 29. BIKHABIKHAMyelodysplastic syndromesMyelodysplastic syndromesLaboratory FindingsLaboratory Findings• LAP often lowLAP often low• PNH-like alteration with positive sucrosePNH-like alteration with positive sucroseand 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 lysozymeIncreased serum and/or urine lysozymelevels in CMMoLlevels in CMMoLRafi
  30. 30. BIKHABIKHAMyelodysplastic syndromesMyelodysplastic syndromesLaboratory FindingsLaboratory Findings• May have acquired thrombopathy evenMay have acquired thrombopathy evenwith normal platelet numberswith normal platelet numbers• Moderate increased LDH is commonModerate increased LDH is commonPrognosisPrognosis• Survival relates to % blastsSurvival relates to % blasts• RA/RA-S --- RAEB/CMMoL -- RAEB-TRA/RA-S --- RAEB/CMMoL -- RAEB-T• Decreased with thrombocytopenia and/orDecreased with thrombocytopenia and/oranemia and/or chromosomal abnormalitiesanemia and/or chromosomal abnormalitiesRafi
  31. 31. BIKHABIKHAMyelodysplastic syndromesMyelodysplastic syndromesDifferential DiagnosisDifferential Diagnosis• Aplastic anemia - lacks morphologicAplastic anemia - lacks morphologicatypias characteristic of MDS - boneatypias characteristic of MDS - bonemarrow hypocellularmarrow hypocellular• PNH - laboratory evidence of intravascularPNH - laboratory evidence of intravascularhemolysis - decreased or absent marrowhemolysis - decreased or absent marrowiron storesiron stores• Megaloblastic anemia - hypersegmentationMegaloblastic anemia - hypersegmentationof PMN - marrow megaloblastic -of PMN - marrow megaloblastic -decreased Bdecreased B1212 or folateor folateRafi
  32. 32. BIKHABIKHAMyelodysplastic syndromesMyelodysplastic syndromesDifferential DiagnosisDifferential Diagnosis• CML - peripheral count usually muchCML - peripheral count usually muchhigher with eosinophilia and basophilia -higher with eosinophilia and basophilia -splenomegaly - presence of Ph’ - bonesplenomegaly - presence of Ph’ - bonemarrow in CMMoL may closely resemblemarrow in CMMoL may closely resembleCMLCML• Agnogenic myeloid metaplasia - teardropsAgnogenic myeloid metaplasia - teardropsand poik - more prominent NRB’s andand poik - more prominent NRB’s andsplenomegaly - bone marrow myelofibrosissplenomegaly - bone marrow myelofibrosis• ANLL - marrow contains over 30% blastsANLL - marrow contains over 30% blastsRafi