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MYELOPROLIFERATIVEMYELOPROLIFERATIVEDISORDERSDISORDERSDr sapna mDr sapna m
The myeloproliferative diseases (MPDs) areThe myeloproliferative diseases (MPDs) areclonal stem cell disorders characteris...
Myeloproliferative DisordersMyeloproliferative Disorders(old classification)(old classification)a group of disease charact...
Myeloproliferative DisordersMyeloproliferative Disorders(2008 WHO classification)(2008 WHO classification)1. polycythemia ...
Chronic myeloid leukemia (CML)Chronic myeloid leukemia (CML)
CML results from a somatic mutation in aCML results from a somatic mutation in apluripotential hematopoietic cellpluripote...
EtiologyEtiologyExposure to high- dose ionizing radiationExposure to high- dose ionizing radiationChemical agents have not...
EpidemiologyEpidemiologyCML accounts for approximately 15 percent ofCML accounts for approximately 15 percent ofall cases ...
PathogenesisPathogenesisHematopoietic abnormalityHematopoietic abnormalityExpansion of granulocytic progenitors and aExpan...
PathogenesisPathogenesisGenetic abnormalityGenetic abnormalityCML is the result of an acquired geneticCML is the result of...
Translocation t(9;22)Translocation t(9;22)(q34;q11)(q34;q11)
Philadelphia ChromosomePhiladelphia Chromosome• More than 95% of patients with CML haMore than 95% of patients with CML ha...
The bcr/abl fusion proteinThe bcr/abl fusion proteinUncontrolled kinase activityUncontrolled kinase activity1.1. Deregulat...
Clinical featuresClinical features30 -50% of patients are asymptomatic at the time of30 -50% of patients are asymptomatic ...
Laboratory featuresLaboratory featuresThe hemoglobin concentration is decreased or normalThe hemoglobin concentration is d...
Laboratory features (2)Laboratory features (2)The marrow is hypercellular (granulocytic hyperplasia)-The marrow is hyperce...
DiagnosisDiagnosisDiagnosis is based on blood counts (leukocytosis andDiagnosis is based on blood counts (leukocytosis and...
Accelerated phase of CMLAccelerated phase of CMLMost patients eventually became resistant to therapyMost patients eventual...
BlastBlast phasephase (blast crisis)(blast crisis) of CMLof CML• Criteria of blast phaseCriteria of blast phase1.1. Blasts...
CML in Blast CrisisCML in Blast Crisis
Differential diagnosisDifferential diagnosisPolycythemia veraPolycythemia veraMMyelofibrosisyelofibrosisEssentialEssential...
TreatmentTreatmentAlgorithm for treating CMLAlgorithm for treating CMLDIAGNOSISImatinib for allResponse to imatinib‘Failed...
LeukemoidreactionCMLWBC High HighAnemia (-) (+)PBS Shift to the LeftToxic granulationDohle bodiesShift to the left (blast)...
Polycythemia VeraPolycythemia Vera(lots of red cells - for real)(lots of red cells - for real)An uncommon disorder - disti...
Definition of ErythrocytosisDefinition of ErythrocytosisNormal hematocrit :Normal hematocrit :Male 47Male 47 ±± 5 percent...
Absolute vs. RelativeAbsolute vs. RelativeErythrocytosisErythrocytosisNormal Spurious PolycythemiaPlasma VolRBC
Pathophysiology ofPathophysiology ofPolycythemiaPolycythemia
Secondary PolycythemiaSecondary PolycythemiaAppropriate EPO (tissue/kidney hypoxia)Appropriate EPO (tissue/kidney hypoxia)...
Secondary PolycythemiaSecondary PolycythemiaInappropriate EPO (ectopic production)Inappropriate EPO (ectopic production)T...
Polycythemia VeraPolycythemia VeraP. vera is a rare diseaseP. vera is a rare diseaseMedian age 60 - 65 yearsMedian age 60 ...
P. Vera - Symptoms & SignsP. Vera - Symptoms & SignsSymptomsSymptomsHeadacheHeadacheWeaknessWeaknessPruritis (aquagenic...
P. Vera - DiagnosisP. Vera - Diagnosis(PVSG criteria)(PVSG criteria)CriteriaCriteriaRBC mass elevatedRBC mass elevated S...
P. vera - Bone Marrow BiopsyP. vera - Bone Marrow Biopsy
Treatment Options - SummaryTreatment Options - SummaryA g e > 7 0H y d r o x y u r e a3 2 P ?A g e 5 0 - 7 0H y d r o x y ...
Essential ThrombocythemiaEssential ThrombocythemiaRare disorder (1.5 per 100,000)Rare disorder (1.5 per 100,000)proliferat...
Essential ThrombocythemiaEssential ThrombocythemiaIncidence:Incidence: 1.5 per 100,0001.5 per 100,000Age at Dx:Age at Dx: ...
MyelofibrosisMyelofibrosisbone marrow fibrosisbone marrow fibrosis•fibroblasts may be “innocent bystanders”fibroblasts may...
MyelofibrosisMyelofibrosisAniso-poikilocytosisleukemoid reaction“naked” nuclear fragmentswww.freelivedoctor.comwww.freeliv...
Myelofibrosis
HypereosinophilicHypereosinophilicSyndromesSyndromes
Produced in the bone marrowProduced in the bone marrowFunction to combat parasiticFunction to combat parasiticinfections, ...
These granules are full of:These granules are full of:Major Basic Protein = toxic toMajor Basic Protein = toxic tohelmint...
Represents a heterogenous group of uncommonRepresents a heterogenous group of uncommondisorders marked by blood or tissue ...
SecondarySecondary(reactive)(reactive)causes ofcauses ofeosinophiliaeosinophiliaHypereosinophilic SyndromesHypereosinophi...
Morbidity and mortalityMorbidity and mortalityassociated with theseassociated with thesesyndromes = usuallysyndromes = usu...
Primary cardiac complications includePrimary cardiac complications includecardiogenic shock or heart failure due tocardiog...
Clinical ApproachClinical Approach CBC with diff, serumCBC with diff, serumtryptase, strongyloidestryptase, strongyloides...
Chronic eosinophilic leukemia (CEL)Chronic eosinophilic leukemia (CEL)Diagnostic criteria:Diagnostic criteria:● ≥1.5 x 10●...
Mast cell diseaseMast cell diseaseMastocytosisMastocytosis is a group of rare disordersis a group of rare disordersof both...
Mast cells are located in connective tissue,Mast cells are located in connective tissue,including the skin, the linings of...
Urticaria pigmentosaUrticaria pigmentosa
Mast cell leukemiaMast cell leukemia
Myeloproliferative disorders
Myeloproliferative disorders
Myeloproliferative disorders
Myeloproliferative disorders
Myeloproliferative disorders
Myeloproliferative disorders
Myeloproliferative disorders
Myeloproliferative disorders
Myeloproliferative disorders
Myeloproliferative disorders
Myeloproliferative disorders
Myeloproliferative disorders
Myeloproliferative disorders
Myeloproliferative disorders
Myeloproliferative disorders
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Myeloproliferative disorders

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Myeloproliferative disorders

  1. 1. MYELOPROLIFERATIVEMYELOPROLIFERATIVEDISORDERSDISORDERSDr sapna mDr sapna m
  2. 2. The myeloproliferative diseases (MPDs) areThe myeloproliferative diseases (MPDs) areclonal stem cell disorders characterised byclonal stem cell disorders characterised byleukocytosis, thrombocytosis, erythrocytosis,leukocytosis, thrombocytosis, erythrocytosis,splenomegaly, and bone marrowsplenomegaly, and bone marrowhypercelularityhypercelularity
  3. 3. Myeloproliferative DisordersMyeloproliferative Disorders(old classification)(old classification)a group of disease characterized by overgrowth of one or morea group of disease characterized by overgrowth of one or morehematologic cell lines in BMhematologic cell lines in BM1. chronic myelogenous leukemia (CML)1. chronic myelogenous leukemia (CML)2. polycythemia vera (PV)2. polycythemia vera (PV)3. essential thrombocythemia3. essential thrombocythemia4. agnogenic myeloid metaplasia/myelofibrosis4. agnogenic myeloid metaplasia/myelofibrosiswww.freelivedoctor.comwww.freelivedoctor.com
  4. 4. Myeloproliferative DisordersMyeloproliferative Disorders(2008 WHO classification)(2008 WHO classification)1. polycythemia vera1. polycythemia vera2. chronic idiopathic myelofibrosis2. chronic idiopathic myelofibrosis3. essential thrombocytosis3. essential thrombocytosis4. chronic myeloid leukemia (CML)4. chronic myeloid leukemia (CML)5. [chronic neutrophilic leukemia]5. [chronic neutrophilic leukemia]6. [chronic eosinophilic leukemia]6. [chronic eosinophilic leukemia]7. [hypereosinophilic syndrome]7. [hypereosinophilic syndrome]8.Mast cell disease8.Mast cell disease““myelodysplastic/myeloproliferative diseases”myelodysplastic/myeloproliferative diseases”juvenile myelomonocytic leukemiajuvenile myelomonocytic leukemiaatypical chronic myeloid leukemia (lacking t(9;22))atypical chronic myeloid leukemia (lacking t(9;22))chronic myelomocytic leukemiachronic myelomocytic leukemiawww.freelivedoctor.comwww.freelivedoctor.com
  5. 5. Chronic myeloid leukemia (CML)Chronic myeloid leukemia (CML)
  6. 6. CML results from a somatic mutation in aCML results from a somatic mutation in apluripotential hematopoietic cellpluripotential hematopoietic cellCML is a MPD characterized by increasedCML is a MPD characterized by increasedgranulocytic cell line, associatedgranulocytic cell line, associated often withoften withplatelet hyperplasiaplatelet hyperplasiaThe disease usually envolves into anThe disease usually envolves into anaccelerated phase that often terminates inaccelerated phase that often terminates inacute phaseacute phase--chronic phasechronic phase 3-5 years3-5 years--accelerated phaseaccelerated phase 6-9 months6-9 months--blastic phaseblastic phase 3-6 months3-6 months
  7. 7. EtiologyEtiologyExposure to high- dose ionizing radiationExposure to high- dose ionizing radiationChemical agents have not been established asChemical agents have not been established asa ca caauseuse
  8. 8. EpidemiologyEpidemiologyCML accounts for approximately 15 percent ofCML accounts for approximately 15 percent ofall cases of leukemia and approximately 3all cases of leukemia and approximately 3percent of childhood leukemiaspercent of childhood leukemiasThe median age of onset is 53 yearsThe median age of onset is 53 years
  9. 9. PathogenesisPathogenesisHematopoietic abnormalityHematopoietic abnormalityExpansion of granulocytic progenitors and aExpansion of granulocytic progenitors and adecreased sensitivity of the progenitors todecreased sensitivity of the progenitors toregulation – increased white cell countregulation – increased white cell countMegakaryocytopoiesis is often expandedMegakaryocytopoiesis is often expandedErythropoiesis is usually deficientErythropoiesis is usually deficientFunction of the neutrophils and platelets isFunction of the neutrophils and platelets isnearly normalnearly normal
  10. 10. PathogenesisPathogenesisGenetic abnormalityGenetic abnormalityCML is the result of an acquired geneticCML is the result of an acquired geneticabnormalityabnormalityA translocation between chromosome 9 andA translocation between chromosome 9 and2222 [t(9;22)] – the[t(9;22)] – the Philadelphia chromosomePhiladelphia chromosomeThe oncogene BCThe oncogene BCRR-ABL encodes an-ABL encodes anenzyme – tyrosine phosphokinase (usuallyenzyme – tyrosine phosphokinase (usuallyp210)p210)
  11. 11. Translocation t(9;22)Translocation t(9;22)(q34;q11)(q34;q11)
  12. 12. Philadelphia ChromosomePhiladelphia Chromosome• More than 95% of patients with CML haMore than 95% of patients with CML havevePhiladelphia (Ph) chromosomePhiladelphia (Ph) chromosome A subset of patients with CML lack aA subset of patients with CML lack adetectable Ph chromosome but have thedetectable Ph chromosome but have thefusion product for the bcr/abl translocationfusion product for the bcr/abl translocationdetectable by reverse transcriptase-detectable by reverse transcriptase-polymerase chain reaction (RT-PCR)polymerase chain reaction (RT-PCR)
  13. 13. The bcr/abl fusion proteinThe bcr/abl fusion proteinUncontrolled kinase activityUncontrolled kinase activity1.1. Deregulated cellular proliferationDeregulated cellular proliferation2.2. Decreased adherence of leukemia cells toDecreased adherence of leukemia cells tothe bone marrow stromathe bone marrow stroma3.3. Leukemic cells are protected from normalLeukemic cells are protected from normalprogrammed cell death (apoptosis)programmed cell death (apoptosis)
  14. 14. Clinical featuresClinical features30 -50% of patients are asymptomatic at the time of30 -50% of patients are asymptomatic at the time ofdiagnosis (90% are diagnosed in chronic phase)diagnosis (90% are diagnosed in chronic phase)Symptoms are gradual in onset:Symptoms are gradual in onset:fatigue, malaise, anorexia, abdominal discomfort,fatigue, malaise, anorexia, abdominal discomfort,weight loss, excessive sweatingweight loss, excessive sweating●Less frequent symptomsLess frequent symptoms::Night sweats, heat intolerance- mimickingNight sweats, heat intolerance- mimickinghyperthyroidism, symptoms of leukostasishyperthyroidism, symptoms of leukostasis(tinnitus, stupor), splenic infarction (left upper-(tinnitus, stupor), splenic infarction (left upper-quadrant and left shoulder pain), urticaria (resultquadrant and left shoulder pain), urticaria (resultof histamine release)of histamine release)●Physical signsPhysical signs::Pallor, splenomegaly, sternal painPallor, splenomegaly, sternal pain
  15. 15. Laboratory featuresLaboratory featuresThe hemoglobin concentration is decreased or normalThe hemoglobin concentration is decreased or normalNucleated red cells in blood film can be seenNucleated red cells in blood film can be seenThe leukocyte count above 25000/The leukocyte count above 25000/μl (often aboveμl (often above100000/μ100000/μll), granulocytes are at all stages of), granulocytes are at all stages ofdevelopmentdevelopmentHypersegmentated neutrophilsHypersegmentated neutrophilsThe basophiles count is increasedThe basophiles count is increasedThe platelet count is normal or increasedThe platelet count is normal or increasedNeutrophils alkaline phosphatase (GAF) activity is lowNeutrophils alkaline phosphatase (GAF) activity is lowor absent (90%)or absent (90%)
  16. 16. Laboratory features (2)Laboratory features (2)The marrow is hypercellular (granulocytic hyperplasia)-The marrow is hypercellular (granulocytic hyperplasia)-proportion >10:1 (blasts <10% in chronic phase)proportion >10:1 (blasts <10% in chronic phase)Reticulin fibrosisReticulin fibrosisHyperuricemia and hyperuricosuriaHyperuricemia and hyperuricosuriaSerum vitamin B12-binding proteine and serum vitaminSerum vitamin B12-binding proteine and serum vitaminB12 levels are increasedB12 levels are increasedPseudohyperkalemia, and spurious hypoxemia andPseudohyperkalemia, and spurious hypoxemia andhypoglycemiahypoglycemiaCytogenetic test-Cytogenetic test- presence of the Ph chromosomepresence of the Ph chromosomeMolecular testMolecular test – presence of the BCR-ABL fusion gene– presence of the BCR-ABL fusion gene
  17. 17. DiagnosisDiagnosisDiagnosis is based on blood counts (leukocytosis andDiagnosis is based on blood counts (leukocytosis andfrequently also thrombocytosis) and differentialfrequently also thrombocytosis) and differential(immature granulocytes, from the metamyelocyte to(immature granulocytes, from the metamyelocyte tothe myeloblast, and basophilia). Splenomegaly isthe myeloblast, and basophilia). Splenomegaly ispresent in >50% of cases of CML in the initial chronicpresent in >50% of cases of CML in the initial chronicphase, but 50% of patients are asymptomatic.₃phase, but 50% of patients are asymptomatic.₃Proof of diagnosis is attained by demonstration of theProof of diagnosis is attained by demonstration of thePhiladelphia (Ph) chromosome (22q–) resulting fromPhiladelphia (Ph) chromosome (22q–) resulting fromthe balanced translocation t(9; 22) (q34;q11), and/orthe balanced translocation t(9; 22) (q34;q11), and/orthe BCR–ABL rearrangement in peripheral blood orthe BCR–ABL rearrangement in peripheral blood orbone marrow cells.bone marrow cells.
  18. 18. Accelerated phase of CMLAccelerated phase of CMLMost patients eventually became resistant to therapyMost patients eventually became resistant to therapyand the disease enters a more agressive phaseand the disease enters a more agressive phaseCriteria of accelerated phaseCriteria of accelerated phase1.1. Blasts in blood or bone marrow-10-Blasts in blood or bone marrow-10-229%9%2.2. BasophiliaBasophilia ≥≥ 20%20%3.3. Thrombocytopenia <100G/lThrombocytopenia <100G/l4.4. Thrombocytaemia >1000G/lThrombocytaemia >1000G/l5.5. Additional chromosomal aberrationsAdditional chromosomal aberrations6.6. RRefractory splenomegalyefractory splenomegaly or refractory leucocytosisor refractory leucocytosis
  19. 19. BlastBlast phasephase (blast crisis)(blast crisis) of CMLof CML• Criteria of blast phaseCriteria of blast phase1.1. BlastsBlasts ≥≥330%0% in PB or BMin PB or BM2.2. extramedullary tumorsextramedullary tumors• Phenotype of blastsPhenotype of blasts1.1. Mieloblasts - 50%Mieloblasts - 50%2.2. Limphoblasts - 30%Limphoblasts - 30%3.3. Megakarioblasts – 10%Megakarioblasts – 10%4.4. Acute myelofibrosisAcute myelofibrosis
  20. 20. CML in Blast CrisisCML in Blast Crisis
  21. 21. Differential diagnosisDifferential diagnosisPolycythemia veraPolycythemia veraMMyelofibrosisyelofibrosisEssentialEssential thrombocytemiathrombocytemiaChronic myelomonocytic leukemia (Mo>1000/µl)Chronic myelomonocytic leukemia (Mo>1000/µl)Extreme reactive leukocytosis (GAF is increased)Extreme reactive leukocytosis (GAF is increased)
  22. 22. TreatmentTreatmentAlgorithm for treating CMLAlgorithm for treating CMLDIAGNOSISImatinib for allResponse to imatinib‘Failed” responseto imatinibContinueConsider for other TKIor SCT
  23. 23. LeukemoidreactionCMLWBC High HighAnemia (-) (+)PBS Shift to the LeftToxic granulationDohle bodiesShift to the left (blast)Eosinophilia,basophiliaLAP score High LowPhiladelphiachromosome(-) (+)
  24. 24. Polycythemia VeraPolycythemia Vera(lots of red cells - for real)(lots of red cells - for real)An uncommon disorder - distinguish fromAn uncommon disorder - distinguish fromother causes of erythrocytosisother causes of erythrocytosisDiagnosis depends on knowledge ofDiagnosis depends on knowledge oferythropoeisiserythropoeisisComplications most commonly fromComplications most commonly fromthrombosis and vascular incidentsthrombosis and vascular incidentsLong natural history with treatmentLong natural history with treatment
  25. 25. Definition of ErythrocytosisDefinition of ErythrocytosisNormal hematocrit :Normal hematocrit :Male 47Male 47 ±± 5 percent5 percentFemale 42Female 42 ±± 5 percent5 percentNormal hemoglobin :Normal hemoglobin :Male 15Male 15 ±± 2 gm/dl2 gm/dlFemale 13.5Female 13.5 ±± 1.5 gm/dl1.5 gm/dl
  26. 26. Absolute vs. RelativeAbsolute vs. RelativeErythrocytosisErythrocytosisNormal Spurious PolycythemiaPlasma VolRBC
  27. 27. Pathophysiology ofPathophysiology ofPolycythemiaPolycythemia
  28. 28. Secondary PolycythemiaSecondary PolycythemiaAppropriate EPO (tissue/kidney hypoxia)Appropriate EPO (tissue/kidney hypoxia)pulmonary diseasepulmonary diseasehigh altitudehigh altitudecongenital heart diseasecongenital heart diseaseabnormal hemoglobinabnormal hemoglobinhigh affinityhigh affinitycarboxyhemoglobincarboxyhemoglobin
  29. 29. Secondary PolycythemiaSecondary PolycythemiaInappropriate EPO (ectopic production)Inappropriate EPO (ectopic production)Tumors (hepatoma, renal carcinoma,Tumors (hepatoma, renal carcinoma,leiomyoma, hamartoma)leiomyoma, hamartoma)Renal disorders (transplantation, cysts)Renal disorders (transplantation, cysts)hemangiomashemangiomasAndrogen abuseAndrogen abuseEPO abuseEPO abuseFamilial polycythemiaFamilial polycythemia
  30. 30. Polycythemia VeraPolycythemia VeraP. vera is a rare diseaseP. vera is a rare diseaseMedian age 60 - 65 yearsMedian age 60 - 65 yearsClinical featuresClinical featuresAttributed to increased blood viscosity andAttributed to increased blood viscosity andpoor oxygen delivery to organs (brain)poor oxygen delivery to organs (brain) Poor OPoor O22 delivery leads to ischemia anddelivery leads to ischemia andthrombosisthrombosisExpanded blood volume and viscosityExpanded blood volume and viscosityleads to increased cardiac work loadleads to increased cardiac work load
  31. 31. P. Vera - Symptoms & SignsP. Vera - Symptoms & SignsSymptomsSymptomsHeadacheHeadacheWeaknessWeaknessPruritis (aquagenic)Pruritis (aquagenic)DizzinessDizzinessDiaphoresisDiaphoresisVisual disturbanceVisual disturbanceWeight lossWeight lossSignsSignsSplenomegalySplenomegaly 70%70%Skin plethoraSkin plethora 67%67%HepatomegalyHepatomegaly 40%40%Conjunctival plethoraConjunctival plethora59%59%Systolic HypertensionSystolic Hypertension72%72%
  32. 32. P. Vera - DiagnosisP. Vera - Diagnosis(PVSG criteria)(PVSG criteria)CriteriaCriteriaRBC mass elevatedRBC mass elevated SaOSaO22 > 92%> 92%Splenomegaly (or)Splenomegaly (or)thrombocytosisthrombocytosisLeukocytosisLeukocytosishigh LAPhigh LAPhigh Bhigh B1212SignificanceSignificanceTrue vs. spuriousTrue vs. spuriousR/O most 2R/O most 2°° causescausesEvidence for MPDEvidence for MPDFalse Positive 0.5%False Positive 0.5%smokers, drinkerssmokers, drinkers
  33. 33. P. vera - Bone Marrow BiopsyP. vera - Bone Marrow Biopsy
  34. 34. Treatment Options - SummaryTreatment Options - SummaryA g e > 7 0H y d r o x y u r e a3 2 P ?A g e 5 0 - 7 0H y d r o x y u r e aP h le b o to m yA g e < 5 0P h le b o to m yH y d r o x y u r e aP . V e r aP h le b o to m iz e to H C T < 4 5
  35. 35. Essential ThrombocythemiaEssential ThrombocythemiaRare disorder (1.5 per 100,000)Rare disorder (1.5 per 100,000)proliferation of megakaryocytes causing marked increase inproliferation of megakaryocytes causing marked increase incirculating platelets (>1 million)circulating platelets (>1 million)morphologically abnormal plateletsmorphologically abnormal plateletssplenomegaly, mucosal hemorrhage, thrombosessplenomegaly, mucosal hemorrhage, thrombosesarrow: macrothrombocytewww.freelivedoctor.comwww.freelivedoctor.com
  36. 36. Essential ThrombocythemiaEssential ThrombocythemiaIncidence:Incidence: 1.5 per 100,0001.5 per 100,000Age at Dx:Age at Dx: 60 y/o60 y/o (~20% <40 y/o)(~20% <40 y/o)F to M ratio:F to M ratio: 1.6 : 11.6 : 1Social risk factor:Social risk factor: 1. long-term use of dark hair dyes1. long-term use of dark hair dyes2. living in tuff house2. living in tuff house3. electrician3. electricianClinical features:Clinical features: - near normal life expectancy- near normal life expectancy- frequent vasomotor and thrombo-- frequent vasomotor and thrombo-hemorrhagic episodeshemorrhagic episodesTreatment:Treatment: low-dose acetylsalicylic acidlow-dose acetylsalicylic acidwww.freelivedoctor.comwww.freelivedoctor.com
  37. 37. MyelofibrosisMyelofibrosisbone marrow fibrosisbone marrow fibrosis•fibroblasts may be “innocent bystanders”fibroblasts may be “innocent bystanders”•fibrosis probably driven by neoplastic megakaryocytesfibrosis probably driven by neoplastic megakaryocytesmiddle aged adults (50-60 y/o)middle aged adults (50-60 y/o)extramedullary hematopoiesis (spleen, liver)extramedullary hematopoiesis (spleen, liver)may occur as an extension of CML or PVmay occur as an extension of CML or PVabnormal peripheral RBCs (“tear-drop” & nucleated RBCs)abnormal peripheral RBCs (“tear-drop” & nucleated RBCs)immature WBC and abnormal plateletsimmature WBC and abnormal plateletsinfection, thrombosis and hemorrhage as a major complicationinfection, thrombosis and hemorrhage as a major complicationwww.freelivedoctor.comwww.freelivedoctor.com
  38. 38. MyelofibrosisMyelofibrosisAniso-poikilocytosisleukemoid reaction“naked” nuclear fragmentswww.freelivedoctor.comwww.freelivedoctor.com
  39. 39. Myelofibrosis
  40. 40. HypereosinophilicHypereosinophilicSyndromesSyndromes
  41. 41. Produced in the bone marrowProduced in the bone marrowFunction to combat parasiticFunction to combat parasiticinfections, ectoparasites, certain viralinfections, ectoparasites, certain viralinfections, and amplify responses ofinfections, and amplify responses ofmast cells in atopymast cells in atopyThis is largely accomplished byThis is largely accomplished bygenerating ribonucleases, oxidativegenerating ribonucleases, oxidativespecies = apoptosis, and inducingspecies = apoptosis, and inducingdegranulation of basophils and mastdegranulation of basophils and mastcellscellsEosinophils are attracted to tissues byEosinophils are attracted to tissues bycertain chemokines (RANTES,certain chemokines (RANTES,CCL11/24) and leukotrienesCCL11/24) and leukotrienesThey require IL-5 (Eosinophil growthThey require IL-5 (Eosinophil growthfactor, secreted by T-cells) forfactor, secreted by T-cells) forproliferation and to prevent apoptosisproliferation and to prevent apoptosisThey are VERY sensitive to steroidsThey are VERY sensitive to steroidsEosinophils – The BasicsEosinophils – The Basics
  42. 42. These granules are full of:These granules are full of:Major Basic Protein = toxic toMajor Basic Protein = toxic tohelminths and epithelial cellshelminths and epithelial cellsRibonuclease A (aka EosinophilRibonuclease A (aka EosinophilCationic Protein)Cationic Protein)Eosinophil Peroxidase =Eosinophil Peroxidase =generation of hypobromite used togeneration of hypobromite used tocombat Helminths and TBcombat Helminths and TBProteases that are involved inProteases that are involved intissue remodelingtissue remodelingEosinophils – The BasicsEosinophils – The Basics
  43. 43. Represents a heterogenous group of uncommonRepresents a heterogenous group of uncommondisorders marked by blood or tissue eosinophiliadisorders marked by blood or tissue eosinophilia Known causes of secondary or reactive eosinophilia must beKnown causes of secondary or reactive eosinophilia must beruled outruled out Range from benign idiopathic eosinophilia to eosinophilicRange from benign idiopathic eosinophilia to eosinophilicleukemialeukemiafor secondary etiologies of hypereosinophiliafor secondary etiologies of hypereosinophiliaHypereosinophilic SyndromesHypereosinophilic Syndromes
  44. 44. SecondarySecondary(reactive)(reactive)causes ofcauses ofeosinophiliaeosinophiliaHypereosinophilic SyndromesHypereosinophilic Syndromes
  45. 45. Morbidity and mortalityMorbidity and mortalityassociated with theseassociated with thesesyndromes = usuallysyndromes = usuallydue to cardiac anddue to cardiac andneuropathicneuropathiccomplicationscomplicationsThese representThese representmedical emergenciesmedical emergenciesthat require emergentthat require emergenttreatment withtreatment withcorticosteroidscorticosteroidsHypereosinophilic SyndromesHypereosinophilic Syndromes Main DDx include:Main DDx include:Systemic mastocytosisSystemic mastocytosisOccult malignancy, solidOccult malignancy, solid(adenocarcinoma) or liquid(adenocarcinoma) or liquid(leukemia/lymphoma)(leukemia/lymphoma)Churg StraussChurg StraussAtopyAtopyParasitic infectionsParasitic infectionsChronic TBChronic TBOther granulomatousOther granulomatousdisease such as sarcoid anddisease such as sarcoid andIBDIBDEndocrine causes such asEndocrine causes such ashypoadrenalismhypoadrenalism
  46. 46. Primary cardiac complications includePrimary cardiac complications includecardiogenic shock or heart failure due tocardiogenic shock or heart failure due toLoeffler’s endocarditis = a restrictive cardiomyopathyLoeffler’s endocarditis = a restrictive cardiomyopathyfrom eosinophilic infiltration leading to fibroticfrom eosinophilic infiltration leading to fibroticthickeningthickeningEndomyocardial fibrosis (aka Davies Disease, seen inEndomyocardial fibrosis (aka Davies Disease, seen inthe tropics)the tropics)Other clinical manifestations include:Other clinical manifestations include:Skin and mucosal ulcerationsSkin and mucosal ulcerationsThromboembolic diseaseThromboembolic diseaseSplenomegalySplenomegalyPleural effusions and/or pulmonary fibrosisPleural effusions and/or pulmonary fibrosisHypereosinophilic SyndromesHypereosinophilic Syndromes
  47. 47. Clinical ApproachClinical Approach CBC with diff, serumCBC with diff, serumtryptase, strongyloidestryptase, strongyloidesantibody, peripheralantibody, peripherallymphocyte clonal studieslymphocyte clonal studies Bone marrow biopsy withBone marrow biopsy withFISH/Flow, ANA, SPEPFISH/Flow, ANA, SPEP TTE, CT chest andTTE, CT chest andabdomenabdomen
  48. 48. Chronic eosinophilic leukemia (CEL)Chronic eosinophilic leukemia (CEL)Diagnostic criteria:Diagnostic criteria:● ≥1.5 x 10● ≥1.5 x 1099/L peripheral blood eosinophils (persistent)/L peripheral blood eosinophils (persistent)● Either peripheral blood blasts > 2%, bone marrow blasts >● Either peripheral blood blasts > 2%, bone marrow blasts >5% or abnormal cytogenetics; exclusion of secondary5% or abnormal cytogenetics; exclusion of secondaryeosinophiliaeosinophilia● Exclusion of other acute or chronic myeloid neoplasms● Exclusion of other acute or chronic myeloid neoplasms● No evidence of phenotypically abnormal or clonal T● No evidence of phenotypically abnormal or clonal Tlymphocyteslymphocytes● No evidence of PDFGRA, PDGFRB or FGFR1● No evidence of PDFGRA, PDGFRB or FGFR1rearrangementsrearrangements
  49. 49. Mast cell diseaseMast cell diseaseMastocytosisMastocytosis is a group of rare disordersis a group of rare disordersof both children and adults caused by theof both children and adults caused by thepresence of too many mast cellspresence of too many mast cells((mastocytesmastocytes) and CD34+ mast cell) and CD34+ mast cellprecursors in a persons bodyprecursors in a persons bodyClassificationClassificationCutaneous urticaria pigmentosa ,Cutaneous urticaria pigmentosa ,Telangiectasia macularis eruptiva perstansTelangiectasia macularis eruptiva perstans(TMEP)(TMEP)systemicsystemic
  50. 50. Mast cells are located in connective tissue,Mast cells are located in connective tissue,including the skin, the linings of theincluding the skin, the linings of thestomach and intestine, and other sites.stomach and intestine, and other sites.They play an important role in helpingThey play an important role in helpingdefend these tissues from disease.defend these tissues from disease.By releasing chemical "alarms" such asBy releasing chemical "alarms" such ashistamine, mast cells attract other keyhistamine, mast cells attract other keyplayers of the immune defense system toplayers of the immune defense system toareas of the body where they are needed.areas of the body where they are needed.
  51. 51. Urticaria pigmentosaUrticaria pigmentosa
  52. 52. Mast cell leukemiaMast cell leukemia

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