pool Hema Orientation slide (1)
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Transcript of pool Hema Orientation slide (1)
血液腫瘤科病房注意事項血液腫瘤科病房注意事項
黃炯棠醫師 黃炯棠醫師
高雄醫學大學附設醫院高雄醫學大學附設醫院血液腫瘤內科血液腫瘤內科
來 來 Hema Hema 要學會的東西要學會的東西
Performance Performance status(ECOG)status(ECOG)
scorescore definitiondefinition
00 Fully active, without restrictionFully active, without restriction
11 Slightly impairedSlightly impaired
22 > 50% of waking hours, capable > 50% of waking hours, capable of all self-careof all self-care
33 Confined to bed or chair > 50% of Confined to bed or chair > 50% of waking hours, limited self carewaking hours, limited self care
44 Totally confined to bed or chair, Totally confined to bed or chair, cancan’’t carry on any self caret carry on any self care
Blood smear Blood smear 製作製作 用 用 blood lancet blood lancet 採血採血 (( 採血部位採血部位 :: 手指 手臂 耳垂 腳指 腳手指 手臂 耳垂 腳指 腳
底底 )) 取半滴血置於載玻片一端,以另一推片靠取半滴血置於載玻片一端,以另一推片靠血滴前方接觸,使血液沿玻片擴散後,呈血滴前方接觸,使血液沿玻片擴散後,呈3030 度緩緩定速推向另一端,立即快乾度緩緩定速推向另一端,立即快乾
Staining of blood smear Reagent
Liu’s A solution : Eosin Y, 1.8 g ; Methylene blue, 0.5 g ; Methanol, 1 LLiu’s B solution : KH2PO4, 12.5 g ; Na2HPO4 . 12H2O, 25.2 g ; Methylene blue, 1.4 g ; Azur I,1.4 g ; H2O, 1 L
操作
滴適當份量 Liu’s A 於玻片上染 30”加滴約 2 倍份量 Liu’s B ,輕吹混合,染1’30” (此時液面可見金屬光澤)小心地水洗
MorphologyMorphology Cytochemistry studyCytochemistry study Immunological studyImmunological study Molecular genetic studyMolecular genetic study
Pluripotential stem cell
LymphocyteStem cell
TLymphoblast
BLymphocyte
TLymphocyte
BLymphoblast
Plasmacell
Myeloid stem cell
Pronormoblast
Basophilicnormoblast
Polychromaticnormoblast
Orthochromicnormoblast
PolychomaticErythrocyte
(Reticulocyte)
Erythrocyte
Megakaryoblast
Megakaryocyte
Platelets
Monoblast
Promonocyte
Monocyte
Macrophage
Myeloblast
PolymorphonuclearNeutrophil(Segment)
Band
Metamyelocyte
Myelocyte
Promyelocyte
EosihophilicMyelocyte
BasophilicMyelocyte
Eosihophilicmetayelocyte
BasophilicMetamyelocyte
EosihophilicBand
BasophilicBand
Eosinophil Basophil
PMN SeriesPMN Series
Myeloblast
Segment form
Band form
Metamyelocyte
MyelocytePromyelocyte
Eosinophilic myelocyte
Eosinophilic Metamyelocyte
Eosinophilic Band
Basophilic myelocyteBasophilic Metamyelocyte
Basophilic Band
PronormoblastBasophilic normoblast
Polychromatic normoblast
Orthochromatic normoblast
Polychromatic erythrocyte(Reticulocyte)
Megakaryblast Immature Megakarycyte
Mature MegakarycytePlatelets
Monoblast Promonocyte
MonocyteMacrophage
LymphoblastProlymphocyte
lymphocyte
Plasma cell
Anemia:General Anemia:General ConsiderationsConsiderations
Table 26.3 Methods of Correcting the Reticulocyte Count for the Degree of Anemia
Reticulocyte count = % reticulocytes in RBC populationCorrected reticulocyte count = % reticulocytes × (patient Hct/45)Reticulocyte production index = Corrected reticulocyte count × maturation time in peripheral blood in days (Normal values of all of above 0.5–1.5%)Absolute reticulocyte count = % reticulocytes × RBC count/L3
(Normal values for the absolute reticulocyte count are from 25 to 75 × 109/L; values <100 × 109/L indicate an inappropriately low erythropoietic response to anemia.)a Reticulocyte maturation time = 1 day for Hct ≥40%; 1.5 days for Hct 30–40%; 2.0 days for Hct 20–30%; 2.5 days for Hct <20%.From Hillman RS, Finch CA. Red cell manual, 5th ed. Philadelphia: FA Davis, 1985.
Table 26.4 Pathogenetic Classification of Megaloblastic Anemia
Combined folate and vitamin B12 deficiency Tropical sprue
Gluten-sensitive enteropathyInherited disorders of DNA synthesis
Orotic aciduria Lesch-Nyhan syndrome
Thiamine-responsive megaloblastic anemia Methyl-tetrahydrofolate reductase
Formiminotransferase Dihydrofolate reductase
Transcobalamin II deficiency Homocystinuria and methylmalonic aciduria
Drug- and toxin-induced disorders of DNA synthesis Folate antagonists (e.g., methotrexate)
Purine antagonists (e.g., 6-mercaptopurine) Pyrimidine antagonists (e.g., cytosine arabinoside)
Alkylating agents (e.g., cyclophosphamide) Zidovudine (AZT, Retrovir)
Trimethoprim Oral contraceptives
Nitrous oxide Arsenic
Chlordane Erythroleukemia
Vitamin B12 deficiency Dietary deficiency (rare) Lack of intrinsic factor Pernicious anemia Gastric surgery Ingestion of caustic materials Functionally abnormal intrinsic factor Biologic competition for vitamin B12
Small bowel bacterial overgrowth Fish tapeworm disease Familial selective vitamin B12 malabsorption (Imerslund-Gräsbeck syndrome) Drug-induced vitamin B12 malabsorption Chronic pancreatic disease Zollinger-Ellison syndrome Diseases of the ileum Previous ileum resection Regional enteritisFolate deficiency Dietary deficiency Increased requirements Pregnancy Infancy Chronic hemolytic anemia Alcoholism Congenital folate malabsorption Drug-induced folate deficiency Extensive intestinal resection, jejunal resection
Table 26.6 Pathogenic Classification of Microcytic Anemias
Disorders of iron metabolism Iron deficiency anemia Anemia of chronic disorders Disorders of globin synthesis α- and β-thalassemias Hemoglobin E syndromes (AE, EE, E-β-thalassemia) Hemoglobin C syndromes (AC, CC) Unstable hemoglobin disease Sideroblastic anemias Hereditary sideroblastic anemia X-linked Autosomal Acquired sideroblastic anemia Refractory anemia with ringed sideroblasts Malignancies Myeloproliferative disorders Reversible acquired sideroblastic anemia Alcoholism Drugs (isoniazid, chloramphenicol)Lead intoxication (usually normocytic)
Microcytic anemia
Table 26.9 Classification of the Normocytic Anemias
Anemia associated with appropriately increased erythrocyte production Posthemorrhagic anemia Hemolytic anemiaDecreased erythropoietin secretion Impaired source Renal: Anemia of renal insufficiency Hepatic: Anemia of liver disease Reduced stimulus (decreased tissue oxygen needs) Anemia of endocrine deficiency Protein-calorie malnutrition Anemia of chronic disorders Anemia with impaired marrow response Bone marrow hypoplasia Red blood cell aplasia Acquired pure red cell aplasia in adults Transient erythroblastopenia of childhood Transient aplastic crises associated with hemolysis Aplastic anemia (pancytopenia) Bone marrow infiltrative disorders Leukemia Myeloma Other myelophthisic anemias Myelodysplastic anemias Dyserythropoietic anemias (congenital dyserythropoietic anemia type II) Iron deficiency (early)
Macrocytosis >9 micrometers
in diameter
Schistocytes(fragmented cells)TTP/HUS,DIC,HELLP syndrome
Malignant hypertension
Acanthocytes(speculated cell with irregular
Projection)Liver diseaseMDS,hypothyroidismVitamin E deficiency
Crenated/Burr cellEchinocytes
Renal failure and UremiaPyruvate kinase dificiencyPremature,MA hemolytic
Bite cellHemolytic anemia(G6PD)
Spleen phagocyte removed Heinz body
Sphercytes( dense, 沒有 Central pallor)Immune hemolytic anemia and
Hereditary spherocytosisBurn
Sickle cellBeta chain 上 第六對 amino acid(Glutamic acid)
被 valine 所取代 , 而形成 alpha2/beta S2
Tear-drop cellMyelofibrosis,Myelophthisic states
Thalassemia
Ovalocyte(elliptical cell)Membrances cytoskeleton 不正常
Megaloblastic anemiaThalassemia major,IDA
Howell-Jolly bodies(DNA 殘餘物 nuclear)Small,single purple cytoplasmic inclusions
Splenectomy, Hemolytic anemia, megaloblastic anemia
Basophilic stippling( Dark-purple inclusions,multiple)RNA 殘餘
Lead poisoning, Thalassemia
Pappenheimer bodies(Iron composition)Splenectmy,Hemolytic anemia
Sideroblastic anemia,Hemoglobinopathy
Cabot ring( mitotic spindle 的殘留物 ):MDS,megaloblastic anemia
Heinz bodies(Precipitate RNA)Violet crystal 所染出 inclusions
表示 denatured Hgb氧化後的 G6PD, erythrocyte maturation
Rouleaux formation因為 red cell 上 coating 不正常Paraprotein, 使的 Electrostatic
charge repelling 不正常Ex:Multiple myeloma
Brilliant cresyl blue:染 Reticulocyte
Diagnosis and Diagnosis and Classification of the Classification of the Acute Leukemias Acute Leukemias
Two hit model of Two hit model of leukemogenesisleukemogenesis
Hematopoietic cellsHematopoietic cells
Class I mutation Class II mutationClass I mutation Class II mutation Proliferation/survival Proliferation/survival
Transcription/Differentiation Transcription/Differentiation FLT3/ITD, FLT3/TKD, RAS
KIT, PTPN11, JAK2
AML1/RUNX1, CEBPA, NPM1MLL/PTD, AML1-ETO
CBFb-MYH11, PML-RARa
ChromosomesAngiogenesis
Micro RNA
Epigenetics
WT1, ASXL1TET2,IDH1/IDH2??
MorphologyMorphology Cytochemistry studyCytochemistry study Immunological studyImmunological study Molecular genetic studyMolecular genetic study
Acute Leukemia FAB Acute Leukemia FAB ClassificationClassification
Myeloid (AML)Myeloid (AML) Mo:minimally Mo:minimally
differentiateddifferentiated M1:without maturationM1:without maturation M2:with maturationM2:with maturation M3:hypergranular M3:hypergranular
promyelocyticpromyelocytic M4:myelomonocyticM4:myelomonocytic M5:a).monoblastic M5:a).monoblastic
b).monocyticb).monocytic M6:erythroleukemiaM6:erythroleukemia M7:megakaryoblasticM7:megakaryoblasticRare type,e.g.eosinophilicRare type,e.g.eosinophilic
Lymphoblastic (ALL)Lymphoblastic (ALL) L1:small,monomorphicL1:small,monomorphic L2:largeheterogeneousL2:largeheterogeneous L3:Burkitts cell type L3:Burkitts cell type
Mo M1
M2
M3
M5
M6
M7
L1 L2 L3
M4
Table 79.3 Classification of Acute Myeloid Leukemia
Acute myeloid leukemia with recurrent genetic abnormalitiesAcute myeloid leukemia with t(8;21)(q22;q22), (RUNX1 - RUNX1T1;AML1/ETO)Acute myeloid leukemia 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 variantsAcute myeloid leukemia with t(9;11)(p22;q23), (MLLT3-MLL)Acute myeloid leukemia with t(6;9)(p23;q34), (DEK-NUP214)Acute myeloid leukemia with inv(3)(q21q26.2) or t(3;3)(q21;q26.2), (RPN1-EVI1)Acute myeloid leukemia (megakaryoblastic) with t(1;22)(p13;q13), (RBM15-MKL1)Provisional entity: AML with mutated NPM1Provisional entity: AML with mutated CEBPAAcute myeloid leukemia with multilineage dysplasiaFollowing a myelodysplastic syndrome or myelodysplastic syndrome/ myeloproliferative disorderWithout antecedent myelodysplastic syndromeAcute myeloid leukemia and myelodysplastic syndromes, therapy-relatedAlkylating agent–relatedTopoisomerase type II inhibitor-related (some may be lymphoid)Other typesAcute myeloid leukemia not otherwise categorizedAcute myeloid leukemia minimally differentiatedAcute myeloid leukemia without maturationAcute myeloid leukemia with maturationAcute myelomonocytic leukemiaAcute monoblastic and monocytic leukemiaAcute erythroid leukemiaAcute megakaryoblastic leukemiaAcute basophilic leukemiaAcute panmyelosis with myelofibrosisMyeloid sarcomaAcute leukemia of ambiguous lineage
MPO stain 染酵素染 Myeloid precursor cell
Sudan black B stain 染 Lipid染 Myeloid precursors
α-Naphthyl butyrate stain: 染 Monoblast(Non specific esterase)
Periodic acid-Schiff stain: 染 Lymphoblast染肝醣
M1 M2
Auer rods in faggot cellbilobed grooved nuclei with
granules in some nuclear grooves
Dysplastic eosinophil precursors M5
Erythroblastic leukemia Dysplastic blasts resemble normal erythroblasts with
occasional cytoplasmic vacuoles
Acute megakaryoblastic leukemia
Cytochemical stains of use in the diagnosis and classification of acute leukaemia
Cytochemical stain Specificity
Myeloperoxidase Stains primary and secondary granules of cells of neutrophil lineageEosinophil granules, Monocyte granules,Auer rodsBasophils granules 不會染出來
Sudan black B Neutrophil granules,eosinophil granules,Monocyte granules,Auer rodsBasophils granules 通常是 Negative
α-Naphthyl butyrate stain(Non-specific esterase)
染 Monocyte, macrophage
Periodic acid-Schiff 染 Neutrophil granular,Eosinophil cytoplasm( 不染 Granular),Basephil cytoplasm,T/B lymphocyte
Naphthol AS-D chloroacetate esterase(Specific esterase)
染 neutrophil and mase cell granules, 染不出 Auer rods( 除非 AML的病人 t(15;17),t(8;21) 的話就可以染出來 )
Acid phosphatase Neutrophils,T lymphocyte, macrophage,plasma cells, Megakaryocyte
Toluidine blue Basophil and mast cell granules
Perls’ stain Erythroblasts 的 haemosiderin, Macrophage and plasma cells
Table 77.1 Flow Cytometry Markers for Acute Leukemia Diagnosis
Lineage Antigen
Precursor-B ALL CD19, CD10, CD79a, TdT, cCD22*, HLA-DR, cCD79a*
Precursor-T ALL CD1, CD2, CD3, CD4, CD5, CD7 CD8, TdT, cCD3*
Burkitt leukemia CD19, CD10, CD20, CD22, CD79a, sIg, bright CD45
Acute myeloid leukemia CD33, CD13, CD117, CD4+CD2-, HLA-DR, cMPO*
With monoblastic differentiation CD11b, CD16, CD14, CD64
True erythroleukemia Glycophorin A
Acute megakaryocytic leukemia CD41, CD61, cCD41*, cCD61*
Lineage-independent antigens HLA-DR, CD45, CD34. CD10
*Most antigens are only lineage-associated. Antigens marked with an asterisk are considered lineage-specific
Minimally differentiated Minimally differentiated Acute myeloid Acute myeloid leukemia(M0)leukemia(M0)
<3% MPO and Sudan black B-positive<3% MPO and Sudan black B-positive >20% expressing myeloid antigens >20% expressing myeloid antigens
(CD13,33,117)(CD13,33,117) CD2,CD7 and TdT (+)CD2,CD7 and TdT (+) CD3,CD22,CD79 are negativeCD3,CD22,CD79 are negative Complex karyotype, similar to MDS and Complex karyotype, similar to MDS and
secondary leukemiasecondary leukemia Occur in older patientsOccur in older patients CR rate and survival are poorCR rate and survival are poor
Acute Myeloid leukemia Acute Myeloid leukemia without maturation(M1)without maturation(M1)
Blast>90% of bone marrow non-erythroid Blast>90% of bone marrow non-erythroid cellscells
>3% of blasts positive for Sudan black B >3% of blasts positive for Sudan black B or Myeloperoxidaseor Myeloperoxidase
Bone marrow maturing monocytic Bone marrow maturing monocytic component<10% of Non-erythroid cellscomponent<10% of Non-erythroid cells
Bone marrow maturing granulocytic Bone marrow maturing granulocytic component < 10% of non-erythroid cellscomponent < 10% of non-erythroid cells
Acute Myeloid leukemia Acute Myeloid leukemia with maturation(M2)with maturation(M2)
AML2: 29%~40% has t(8;21)AML2: 29%~40% has t(8;21) First described by Rowley in 1973First described by Rowley in 1973 Morphology: Marrow eosinophilia with salmo-Morphology: Marrow eosinophilia with salmo-
colored granules,cytoplasmic globules and vcuolescolored granules,cytoplasmic globules and vcuoles Two genes involved in t(8;21) are AML1 at 21q22 Two genes involved in t(8;21) are AML1 at 21q22
and ETO at 8q22and ETO at 8q22 t(8;21) occurs in de novo AML t(8;21) occurs in de novo AML
– predicts an excellent response predicts an excellent response – to chemotherapy to chemotherapy – high remission rate and high remission rate and – long survival long survival
Acute Promyelocytic Acute Promyelocytic leukemia(M3)leukemia(M3)
Translocation between chromosomes 15 and 17Translocation between chromosomes 15 and 17 Median age of 30 to 38 years, rarelyoccurs before Median age of 30 to 38 years, rarelyoccurs before
age 10age 10 The disease was recognized in the 1950s and The disease was recognized in the 1950s and
associated with early mortality ,caused by associated with early mortality ,caused by intracranial hemorrhage (DIC)intracranial hemorrhage (DIC)
Leukemia cell characteristically Leukemia cell characteristically – prominent Granules prominent Granules – Bundles of Auer rodsBundles of Auer rods
– Faggot cellsFaggot cells
Acute Promyelocytic Acute Promyelocytic leukemia(M3)leukemia(M3)
t(15;17) of APL are the retinoic acid receptor RAR-a t(15;17) of APL are the retinoic acid receptor RAR-a gene on chromosome 17q12 and the PML gene on gene on chromosome 17q12 and the PML gene on chromosome 15q22chromosome 15q22
There are 3 different genomic breakpoints in the PML There are 3 different genomic breakpoints in the PML genegene– Bcr1 (55% of cases) or long frmBcr1 (55% of cases) or long frm– Bcr2(5%) or variable formBcr2(5%) or variable form– Bcr3(40%) short form: associated with pediatric APL, Bcr3(40%) short form: associated with pediatric APL,
higher leukocyte counts and worse prognosishigher leukocyte counts and worse prognosis Long and short form are responsive to ATRA, variable Long and short form are responsive to ATRA, variable
form reduced sensitivity to ATRAform reduced sensitivity to ATRA APL with t(11;17) is resistant to ATRAAPL with t(11;17) is resistant to ATRA
Acute Promyelocytic Acute Promyelocytic leukemia(M3)leukemia(M3)
Therapy of APL changed dramatically with the introduction of all-Therapy of APL changed dramatically with the introduction of all-trans-retinoic acid (ATRA) into clinical trials in Shanghai in 1986trans-retinoic acid (ATRA) into clinical trials in Shanghai in 1986– in early trials using ATRA, patients with t(15;17) had a 95% in early trials using ATRA, patients with t(15;17) had a 95%
CR rateCR rate– ATRA :oral dose 45mg/m2/day , induces hematologic ATRA :oral dose 45mg/m2/day , induces hematologic
remission with 1~3 months without marrow aplasia, but does remission with 1~3 months without marrow aplasia, but does not induce a molecular remission not induce a molecular remission
– ATRA treatment with retinoic acid syndrome: occurs in up to ATRA treatment with retinoic acid syndrome: occurs in up to one fourth of patients, particularly in those with high one fourth of patients, particularly in those with high leukocyte countsleukocyte counts
Capillary leak syndrome with feverCapillary leak syndrome with fever Respiratory failure, renal impairment ad cardiac failureRespiratory failure, renal impairment ad cardiac failure
– ATRA prevents DIC:ATRA prevents DIC: related to Protection of related to Protection of endothelium from procoagulants such as tissue endothelium from procoagulants such as tissue factorfactor
Acute Promyelocytic leukemia(M3)Acute Promyelocytic leukemia(M3) Chinese investigators also identified arsenic Chinese investigators also identified arsenic
troxide(As2O3) as effective therapy for APLtroxide(As2O3) as effective therapy for APL Western studies have confirmed CR rate of Western studies have confirmed CR rate of
90% in relapsed or refractory APL90% in relapsed or refractory APL
Acute Myelomonocytic Acute Myelomonocytic leukemia(M4)leukemia(M4)
Blast >20% of bone marrow nucleated cellsBlast >20% of bone marrow nucleated cells Bone marrow maturing monocytic component>20% of Bone marrow maturing monocytic component>20% of
Non-erythroid cellsNon-erythroid cells 5~10% AML5~10% AML Median age 40~45Median age 40~45 Organomegaly is commonOrganomegaly is common Hyperleukocytosis(20%)Hyperleukocytosis(20%) Extramedullary 19~30%LymExtramedullary 19~30%Lym Skin, Ovaries,CNS(Extramedu)Skin, Ovaries,CNS(Extramedu)
Acute Myelomonocytic Acute Myelomonocytic leukemia(M4)leukemia(M4)
AML4 with abnormal eosinophils AML4 with abnormal eosinophils and inversion of chromosome 16, and inversion of chromosome 16, the syndrome was first described the syndrome was first described by Arthur and Bloomfield. Five by Arthur and Bloomfield. Five patient with a deletion of the long patient with a deletion of the long arm of chromosome 16arm of chromosome 16
Acute Myelomonocytic Acute Myelomonocytic leukemia(M4)leukemia(M4)
81~93% CR rate of AML with inversion of 81~93% CR rate of AML with inversion of chromosome 16chromosome 16 to chemotherapy has been to chemotherapy has been higher than for most other subtypes of AMLhigher than for most other subtypes of AML
Prognosis is good with DFS of 48~63%.Prognosis is good with DFS of 48~63%. The absence of CBFB may not be required The absence of CBFB may not be required
for prolonged clinical remissionfor prolonged clinical remission Residual disease can be monitored by Residual disease can be monitored by
quantitative RT-PCR to identifyquantitative RT-PCR to identify patients at patients at risk for relapserisk for relapse
Acute Monocytic leukemia and Acute Monocytic leukemia and 11q23 abnormalities(M5)11q23 abnormalities(M5)
AMoL accounts for 2~10% of AML casesAMoL accounts for 2~10% of AML cases M5 subdivided into M5 subdivided into
– M5a, poorly differentiated(>80% monocytic cells M5a, poorly differentiated(>80% monocytic cells including monoblasts)including monoblasts)
– M5b, well differentiated(80% monocytic, M5b, well differentiated(80% monocytic, predominantly promonocytes and monocytes)predominantly promonocytes and monocytes)
M5a tend to be youngerM5a tend to be younger– (75% are<25 years of age)(75% are<25 years of age)
M5 49% normal karyotypeM5 49% normal karyotype 21% 11q23 abnormality21% 11q23 abnormality 21% trisomy 821% trisomy 8 11q23 and Trisomy 8 is higher in M5a11q23 and Trisomy 8 is higher in M5a FLT3 mutation more common in M5bFLT3 mutation more common in M5b
Acute Monocytic Acute Monocytic leukemia(M5)leukemia(M5)
The gene(11q23) involved on The gene(11q23) involved on chromosome 11 is called mixed-chromosome 11 is called mixed-lineage leukemialineage leukemia
Extramedullary disease occurs in Extramedullary disease occurs in >50% of patients with >50% of patients with AMoL( cutaneous lesions, gum AMoL( cutaneous lesions, gum infiltration, testicular infiltration, testicular involvement, CNS disease)involvement, CNS disease)
Erythroleukemia(M6)Erythroleukemia(M6) 2~4% AML and is prominent component of 2~4% AML and is prominent component of
erythroblastserythroblasts Erythroid/myeloid leukemia(M6a) has >50% Erythroid/myeloid leukemia(M6a) has >50%
erythroid precursors in the nucleated erythroid precursors in the nucleated population and >20% myeloidblasts in the population and >20% myeloidblasts in the nonerythroid populationnonerythroid population
Pure erythroid leukemia(M6b):>80% of the Pure erythroid leukemia(M6b):>80% of the marrow cells are immature erythroids without marrow cells are immature erythroids without significant number of myeloblastssignificant number of myeloblasts
M6c: >30% nonerythroid blasts andM6c: >30% nonerythroid blasts and >30% >30% pronormoblastspronormoblasts
Erythroleukemia(M6)Erythroleukemia(M6)
Peripheral blood smear: Peripheral blood smear: – schistocytes, teardrop, pincered red cell and basophilic schistocytes, teardrop, pincered red cell and basophilic
stippling, hypogranulation and hyposegmentation, Giant stippling, hypogranulation and hyposegmentation, Giant plateletsplatelets
Bone marrow usually Bone marrow usually – hypercellular with megaloblastic changes, erythroid hypercellular with megaloblastic changes, erythroid
precursors commonly have multinuclearity, karyorrhexis, precursors commonly have multinuclearity, karyorrhexis, morulae and cytoplasmic vacuolizationmorulae and cytoplasmic vacuolization
Erythroleukemia(M6)Erythroleukemia(M6)
PAS reaction may stain abnormal erythroid PAS reaction may stain abnormal erythroid cells in a coarse globular(16%) or diffuse cells in a coarse globular(16%) or diffuse pattern(57%)pattern(57%)
Immunophenotypic markers are Immunophenotypic markers are – glycophorin 7glycophorin 7– transferrin receptor(CD71)transferrin receptor(CD71)
Hepatomegaly and splenomegaly occur in Hepatomegaly and splenomegaly occur in 20~40%20~40%
Hypergammaglobulinemia and positive Hypergammaglobulinemia and positive rheumatoid factor, antinuclear atibody and rheumatoid factor, antinuclear atibody and coombs test may be found in patients with coombs test may be found in patients with bone painbone pain
Acute Megakaryocytic Acute Megakaryocytic leukemia(M7)leukemia(M7)
0.6~1.2% of adult AML0.6~1.2% of adult AML Myeloid surface marker and expression of Myeloid surface marker and expression of
at least one platelet antigen( CD41, at least one platelet antigen( CD41, CD42b,CD61 or factorVIII-related antigen) CD42b,CD61 or factorVIII-related antigen) on the leukemia cellson the leukemia cells
Bone marrow may be difficult to aspirate Bone marrow may be difficult to aspirate and more than two thirds of patients have and more than two thirds of patients have significant fibrosissignificant fibrosis
Higher incidence of AMgL in Down Higher incidence of AMgL in Down syndrome (good response to therapy)syndrome (good response to therapy)
Acute panmyelosis with Acute panmyelosis with myelofibrosis (APMF)myelofibrosis (APMF)
APMFwas first described in 1963 by Lewis and APMFwas first described in 1963 by Lewis and SzurSzur
Acute myelosclerosis or acute myelofibrosisAcute myelosclerosis or acute myelofibrosis Peripheral : Pancytopenia with <5% blastsPeripheral : Pancytopenia with <5% blasts Marrow is hypercellular with various degrees Marrow is hypercellular with various degrees
of hyperplasia of the three cell lineagesof hyperplasia of the three cell lineages Prognosis is extremely poor with a median Prognosis is extremely poor with a median
survival of<2 months in some seriessurvival of<2 months in some series
True mixed lineage True mixed lineage leukemialeukemia
Leukemic cells co-expressLeukemic cells co-express– MPO and CD79a or cIg uMPO and CD79a or cIg u– Or MPO and CD3Or MPO and CD3– Or CD3 and cIg uOr CD3 and cIg u
AML( expressing aberrant AML( expressing aberrant lymphoid markers)lymphoid markers)
B lineage ALL(Expressing B lineage ALL(Expressing aberrant myeloid antigens)aberrant myeloid antigens)
T Lineage ALL( expressing T Lineage ALL( expressing aberrant myeloid antigens)aberrant myeloid antigens)
李李 X:25868161X:25868161
75 year-old male with a history of 75 year-old male with a history of Diabetes, hypertensionDiabetes, hypertension
Chief complaint: Hematuria for 2 daysChief complaint: Hematuria for 2 days Lab data: WBC:450000/ul, Lab data: WBC:450000/ul,
Hgb:13/dl,PLT:89000/ul, PT:>100/11.5, Hgb:13/dl,PLT:89000/ul, PT:>100/11.5, PTT:>120/28.5, Fibrinogen:18 PTT:>120/28.5, Fibrinogen:18 mg/dl,GOT/GPTmg/dl,GOT/GPT
Differential count revealed Blast cellDifferential count revealed Blast cell WhatWhat’’s the diagnosis for this patient? s the diagnosis for this patient?
(Non-specific esterase)
Myeloperoxidase
Sudan black B
HLA-DR+:98.3%HLA-DR+:98.3% CD10:4.9%CD10:4.9% CD7:0.9%CD7:0.9% CD19:0.2%CD19:0.2% CD11b:78.8%CD11b:78.8% CD33:99.8%CD33:99.8%
CD15:93.7%CD15:93.7% CD13:87.4%CD13:87.4% CD5:1.7%CD5:1.7% TdT:0%TdT:0% CD14:47.5%CD14:47.5% CD64:98.1%CD64:98.1%
王王 XX 榮榮 :25856243:25856243
28 year-old male with a history of 28 year-old male with a history of mental retardmental retard
Chief complaint: Fever up to 38.3C Chief complaint: Fever up to 38.3C for 3 daysfor 3 days
Lab data:WBC:383000/ul, Lab data:WBC:383000/ul, Hgb:13.5/dl,PLT:81000/ul,UA:17.8,Hgb:13.5/dl,PLT:81000/ul,UA:17.8,BUN/Cr:11.6/1.3, NA:135,K:5.4BUN/Cr:11.6/1.3, NA:135,K:5.4
Differential count: Blast cell was Differential count: Blast cell was notednoted
HLA-DR+:2.9%HLA-DR+:2.9% CD10:11.4%CD10:11.4% CD7:79.4%CD7:79.4% CD19:1.6%CD19:1.6% CD11b:1.7%CD11b:1.7% CD33:1.7%CD33:1.7%
CD5:96.4%CD5:96.4% CD3:9.7%CD3:9.7% TdT:87.6%TdT:87.6% CD20:1.8%CD20:1.8%
Newborn with Down Newborn with Down syndromesyndrome
Multiple myelomaMultiple myeloma
Decreased normal immunoglobins, immunodeficiency
Monoclonal protein BM infiltration
Cytokine release
Bone destruction
Infections
Anemia
Hypercalcemia Bone pain
Amyloidosis
Hyperviscosity
Renal failure
Neurologic
Clinical manifestations Clinical manifestations of MMof MM
Pathophysiology of myeloma bone Pathophysiology of myeloma bone diseasedisease
Terpos E et al. Ann Oncol 2009;20:1303-17
Multiple MyelomaMultiple Myeloma
Rouleaux
Flaming cell
Russell body
Russell body
Gaucher-like cell
Myeloproliferative Myeloproliferative DiseasesDiseases
Table 85.1 2008 World Health Organization Classification of Myeloproliferative NEOPlasms (MPN)
Chronic myeloid leukemia
Polycythemia vera
Essential thrombocythemia
Primary myelofibrosis
Chronic neutrophilic leukemia
Chronic eosinophilic leukemia/not otherwise categorized
Hypereosinophilic syndrome
Mast cell disease
MPNs, unclassifiable
Table 85.7 2008 World Health Organization Classification of Myelodysplastic/ Myeloproliferative Disorders
Chronic myelomonocytic leukemia
Atypical chronic myeloid leukemia
Juvenile myelomonocytic leukemia
Myelodysplastic/myeloproliferative diseases, unclassifiable
History backgroundHistory background
1960 Philadelphia chromosome (22q-)
1973 Reciprocal translocation
t(9;22)(q34;q11)
1980 Unique fusion gene BCR-ABL
Hematopoietic disease of malignant expansion of bone marrow stem cells
Hematological picturesHematological pictures Disease statusDisease status
– Chronic phaseChronic phase– Accelerating phaseAccelerating phase– Blast crisisBlast crisis
Ph1 chromosomePh1 chromosome– 95% in CML95% in CML– 5% of children ALL5% of children ALL– 15%-30% of adults 15%-30% of adults
with ALLwith ALL– 2 o/o AML2 o/o AML
Pseudo-Gaucher cell
Sea-Blue histiocyte
Table 85.5 Characteristic Pathologic Findings in the Peripheral Blood and Bone Marrow in Chronic-Phase CML
Peripheral bloodLeukocytosis (white blood cell count usually >50 × 109/L, range 20 to >500 × 109/L)Full spectrum of granulocytes and precursors with rare blasts <(5%)Absolute basophilia
Bone marrowHypercellular (usually 100%)Granulocytic predominance (M:E ratio >10:1) with spectrum similar to bloodCharacteristic small, hypolobated megakaryocytesBlasts <5%
Table 85.3 Diagnosis of Accelerated and Blast Phase in CML
Accelerated phaseBlasts 10–19% in the peripheral blood and/or bone marrowBasophils ≥20% in the peripheral bloodPersistent thrombocytopeniaIncreasing spleen size and white blood cell count despite therapyCytogenetic evidence of clonal evolution
Blast phaseBlasts ≥20%Extramedullary blast proliferationLarge aggregates or clusters of blasts in the bone marrow
CytogeneticsCytogenetics
FISH
G-banding22q- Ph1 chromosome
9q+
CML CML 的病理生理學的病理生理學
CML
ALL
Leukemogenesis of BCR-ABL oncoprotein
Dysregulated tyrosine kinase activity
Physiologic regulation by normal ABL protein and dysregulation by BCR-ABL oncoprotein
N Engl J Med 2003;349:1455
N
C
會何會 Mutation 是因為 loss ABL 的 N-terminal region: 結果導致 tyrosine phsphorylation 增加f-actin binding 增加 , nuclear translocation 減少
Table 84.5 Proposal for Revising WHO Criteria for the Diagnosis of Polycythemia Vera
Major Criteria
•Hemoglobin >18.5 g/dl in men, >16.5 g/dl in women or evidence of increased red cell volume•Presence of JAK2 mutation
Minor Criteria •Hypercellular bone marrow biopsy with panmyelosis with prominent erythroid, granulocytic, and megakaryocytic hyperplasia •Low serum erythropoietin level •Endogenous erythroid colony formation in vitro
2 Major or1 Major+2minor
Structure of JAK2Structure of JAK2
Leukemia and lymphoma, 2006
NEJM 2006; 355: 2452-2466
Table 84.8 Proposed Modification of the WHO Criteria for Essential Thrombocythemia
•Sustained platelet count ≥450 × 109/L •Bone marrow biopsy showing proliferation of enlarged, mature megakaryocytes, without significant increase or left-shift of granulopoiesis or erythropoiesis •Exclusion of WHO criteria for PV, CIMF, CML, MDS, or other myeloid neoplasm •JAK2 mutation or other clonal marker, or if no clonal marker, then exclusion of reactive thrombocytosis
4 Major
Table 55.2 Causes of Thrombocytosis
Clonal Thrombocytosis Reactive Thrombocytosis
Essential thrombocythemiaPolycythemia veraMyelofibrosis with myeloid metaplasia (overtly fibrotic)Myelofibrosis with myeloid metaplasia (cellular phase)Chronic myeloid leukemiaMyelodysplastic syndromeAtypical myeloproliferative disorderAcute leukemia
InfectionTissue damageChronic inflammationMalignancyRebound thrombocytosisRenal disordersHemolytic anemiaPostsplenectomyBlood loss
MyelodysplasticMyelodysplasticSyndromesSyndromes
Table 83.3 World Health Organization Classification of the Myelodysplastic Syndromes
Classification Peripheral Blood Bone Marrow
Refractory anemia Anemia Erythroid dysplasia only
No or rare blasts <5% blasts
<15% ringed sideroblasts
Refractory anemia with ringed sideroblasts
Anemia >15% ringed sideroblasts
No blasts Erythroid dysplasia only
<5% blasts
Refractory cytopenia with multilineage dysplasia
Cytopenias (bicytopenia or pancytopenia)
Dysplasia in >10% of the cells of two or more myeloid lines
No or rare blasts <5% blasts in the marrow
No Auer rods No Auer rods
<1 × 109/L monocytes <15% ringed sideroblasts
Refractory cytopenia with multilineage dysplasia and ringed sideroblasts
Cytopenias (bicytopenia or pancytopenia)
Dysplasia in >10% of the cells of two or more myeloid lines
No or rare blasts <5% blasts in the marrow
No Auer rods >15% ringed sideroblasts
<1 × 109/L monocytes No Auer rods
Table 83.3 World Health Organization Classification of the Myelodysplastic Syndromes
Classification Peripheral Blood Bone Marrow
Refractory anemia with excess blasts 1 Cytopenias Unilineage or multilineage dysplasia
<5% blasts 5–9% blasts
No Auer rods No Auer rods
<1 × 109/L monocytes
Refractory anemia with excess blasts 2 Cytopenias Unilineage or multilineage dysplasia
5–19% blasts 10–19% blasts
Auer rods present Auer rods present
<1 × 109/L monocytes
Myelodysplastic syndrome, unclassified Cytopenias Unilineage dysplasia: one myeloid cell line
No or rare blasts <5% blasts
No Auer rods No Auer rods
Anemia Normal to increased megakaryocytes with hypolobated nuclei
MDS associated with isolated deletion 5q Usually normal or increased platelet count
<5% blasts
<5% blasts Isolated del(5q) cytogenetic abnormality
No Auer rods
LymphomaLymphoma
HodgkinHodgkin’’s lymphomas lymphoma
- Reed-Sternberg cell - Reed-Sternberg cell ““owl-eye cellowl-eye cell”” Non-HodgkinNon-Hodgkin’’s lymphomas lymphoma
- Treatment: rituximab + CHOP- Treatment: rituximab + CHOP
- Prognosis: IPI score- Prognosis: IPI score
(age, ECOG, LDH, stage, extranodal (age, ECOG, LDH, stage, extranodal sites)sites)
B symptoms: weight loss, fever, night B symptoms: weight loss, fever, night sweatssweats
LymphomaLymphoma
t(8;14), Burkitt lymphomat(8;14), Burkitt lymphoma t(14;18), follicular lymphomat(14;18), follicular lymphoma t(11;14) , mantle cell lymphomat(11;14) , mantle cell lymphoma t(4;11), B cell lineage ALLt(4;11), B cell lineage ALL
The Ann Arbor staging system developed in 1971 for Hodgkin The Ann Arbor staging system developed in 1971 for Hodgkin lymphoma (HL) was adapted for staging non-Hodgkin lymphoma (HL) was adapted for staging non-Hodgkin
lymphomas (NHLs)lymphomas (NHLs) This staging system focuses on the number of tumor sites (nodal and extranodal), location, This staging system focuses on the number of tumor sites (nodal and extranodal), location,
and the presence or absence of systemic ("B") symptomsand the presence or absence of systemic ("B") symptoms Stage I refers to NHL involving Stage I refers to NHL involving
– a a single lymph node regionsingle lymph node region (stage I) (stage I) – single extralymphatic organ or site (stage IE)single extralymphatic organ or site (stage IE)
Stage II refers to Stage II refers to – two or more involved lymph nodetwo or more involved lymph node regions on the regions on the same side of the same side of the
diaphragmdiaphragm (stage II) (stage II)– with localized involvement of an extralymphatic organ or site (stage IIE) with localized involvement of an extralymphatic organ or site (stage IIE)
Stage III refers to lymph node involvement on Stage III refers to lymph node involvement on – both sides of the diaphragmboth sides of the diaphragm (stage III) (stage III)– localized involvement of an extralymphatic organ or site (stage IIIE) or localized involvement of an extralymphatic organ or site (stage IIIE) or
spleen (stage IIIS), or both (stage IIIES) spleen (stage IIIS), or both (stage IIIES) Stage IV refers to the presence of Stage IV refers to the presence of
– diffuse or disseminated involvement of one or more extralymphatic diffuse or disseminated involvement of one or more extralymphatic organs (eg, liver, bone marrow, lung), with or without associated lymph organs (eg, liver, bone marrow, lung), with or without associated lymph node involvement node involvement
The presence or absence of systemic symptoms should be noted The presence or absence of systemic symptoms should be noted with each stage designation. (A = asymptomatic. B = presence of with each stage designation. (A = asymptomatic. B = presence of fever, sweats, or weight loss >10 percent of body weight for 6 fever, sweats, or weight loss >10 percent of body weight for 6 months)months)
Groupe d'Etude Lymphomes Folliculaire Groupe d'Etude Lymphomes Folliculaire (GELF). In this system, any one of the (GELF). In this system, any one of the following characteristics qualifies as a following characteristics qualifies as a
high tumor burden:high tumor burden: Systemic symptoms Systemic symptoms Three or more lymph nodes sites >3 cm in Three or more lymph nodes sites >3 cm in
diameter diameter A single lymph node site >7 cm in diameter A single lymph node site >7 cm in diameter Platelets <100,000/microL or absolute Platelets <100,000/microL or absolute
neutrophils <1000/microL neutrophils <1000/microL Circulating lymphoma cells >5000/microL Circulating lymphoma cells >5000/microL Marked splenomegaly, compressive Marked splenomegaly, compressive
symptoms, pleural effusion, or ascites symptoms, pleural effusion, or ascites
International prognostic indexInternational prognostic index — — Institutions in the Institutions in the United States, Canada, and Europe participated in United States, Canada, and Europe participated in an International non-Hodgkin lymphoma an International non-Hodgkin lymphoma
Prognostic Factors ProjectPrognostic Factors Project Age >60 Age >60 Serum lactate dehydrogenase Serum lactate dehydrogenase
(LDH) concentration greater than (LDH) concentration greater than normal normal
ECOG performance status ≥2 ECOG performance status ≥2 Ann Arbor clinical stage III or IV Ann Arbor clinical stage III or IV Number of involved extranodal Number of involved extranodal
disease sites >1 disease sites >1
Follicular lymphoma IPI Follicular lymphoma IPI (FLIPI)(FLIPI)
Age >60 years Age >60 years Ann Arbor stage III or IVAnn Arbor stage III or IV Hemoglobin level <12.0 g/dL Hemoglobin level <12.0 g/dL Number of involved nodal areas >4 Number of involved nodal areas >4 Serum lactate dehydrogenase level Serum lactate dehydrogenase level
greater than the upper limit of greater than the upper limit of normal normal
NeutropeniaNeutropenia
Bodey, GP, Buckley, M, Sathe, YS, et al. Quantitative relationships between circulating leukocytes and infection in patients with acute leukemia. Ann Intern Med 1966; 64:328.
ANC<1000: 733 個病人 , ANC<100:125 個病人
Fever in a neutropenic patient is Fever in a neutropenic patient is usually defined asusually defined as – a single temperature of >38.3a single temperature of >38.3ººC C
(101(101ººF), or a F), or a – sustained temperature >38sustained temperature >38ººC C
(100.4(100.4ººF) for more than one hour F) for more than one hour Neutropenia is defined as a Neutropenia is defined as a
– neutrophil count of <500 cells/mm3, neutrophil count of <500 cells/mm3, or a or a
– count of <1000 cells/mm3 with a count of <1000 cells/mm3 with a predicted decrease to <500 predicted decrease to <500 cells/mm3. cells/mm3.
2002 Guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis 2002; 34:730
age <60 years age <60 years (children not (children not included)included)
absence of chronic absence of chronic pulmonary diseasespulmonary diseases
absence of diabetes absence of diabetes mellitusmellitus
absence of confusion absence of confusion or other signs of or other signs of mental status mental status alterationalteration
absence of blood lossabsence of blood loss absence of absence of
dehydrationdehydration no history of fungal no history of fungal
infectioninfection
Platelet TransfusionPlatelet Transfusion
1U = ~0.3 x 101U = ~0.3 x 101111
2500 2500 –– 5000 /microliter 5000 /microliter CCI (corrected count increment)CCI (corrected count increment)
= = ΔΔPLT x BSA / No. of platelet transfused PLT x BSA / No. of platelet transfused (10(101111))
- normal CCI- normal CCI
at 1 hr: >7500at 1 hr: >7500
at 12 hr: >6000at 12 hr: >6000
at 18-24 hr: >4500at 18-24 hr: >4500
SD-PLT: 1U:3X10 11RD-PLT: 1U:3X10 10
At 1hr :CCI<7500/ulAutoimmune1hr:CCI>7500/ul,24hrs<4500/ul-->Splenomegaly,sepsis,Bleeding,DIC
Adverse reactions to Adverse reactions to blood transfusionblood transfusion
Immune-mediatedreactions
Acute hemolytic transfusion reactios
Delayed hemolytic and serologic transfusion reactions
Febrile Nonhemolytic transfusion reaction
Graft-versus-Host disease
Transfusion-related acute lung injury
Recipient antibody 會 lyse donor erythrocytes
Antibody 對抗 donor leukocyte 和 HLA antigen體溫 >1oC
Donor T lymphocyte 會去辨識 Host HLA antigen當作外來物而產生 immune response
Donor anti-HLA antibodies 會去結合Recipient leukocytes 而之後產生
Pulmonary vasculature,capillary permeability的增加
Thanks for your attentionThanks for your attention