Section of Hematology & Oncology
Department of Medicine
Section of Hematology & Oncology
Department of Medicine
Myeloproliferative and Myeloproliferative and Lymphoproliferative DisordersLymphoproliferative Disorders
Myeloproliferative and Myeloproliferative and Lymphoproliferative DisordersLymphoproliferative Disorders
PNHPNHPNHPNH
CMMLCMMLCMMLCMML
MYELODYSPLASTIC MYELODYSPLASTIC SYNDROMESSYNDROMES
MYELODYSPLASTIC MYELODYSPLASTIC SYNDROMESSYNDROMES
RARSRARSRARSRARSRARARARA
AMLAML
RAEB, TRAEB, TRAEB, TRAEB, T
CMLCML
MYELOPROLIFERATIVE MYELOPROLIFERATIVE SYNDROMESSYNDROMES
MYELOPROLIFERATIVE MYELOPROLIFERATIVE SYNDROMESSYNDROMES
MMMMMM
LEUKEMIASLEUKEMIASLEUKEMIASLEUKEMIASCLL
ALL
P.V.P.V.P.V.P.V. E.T.E.T.E.T.E.T.
Clonal Bone Marrow DisordersClonal Bone Marrow DisordersClonal Bone Marrow DisordersClonal Bone Marrow Disorders
Kouides PA and Bennett JM. Kouides PA and Bennett JM. Sem Hematol,Sem Hematol, April 1996 April 1996Kouides PA and Bennett JM. Kouides PA and Bennett JM. Sem Hematol,Sem Hematol, April 1996 April 1996
Case 2-01-01Case 2-01-01Case 2-01-01Case 2-01-01 46 year old Filipino female profuse menstrual flow for the past few months on and off fever, easy bruisability, shortness of breath on exertion for the
past 3 weeks no headache, bone pain, nausea, vomiting, melena, hematochezia,
dysuria, nor hematuria denies any exposure to insecticides or other chemicals FH: diabetes mellitus Physical examination: BP: 100/70, pulse rate of 100/min, regular and
full; RR of 24/min pale, not jaundiced, no palpable cervical lymphadenopathy Cardiovascular and pulmonary examinations are normal Liver and spleen are not palpable Neurologic and musculoskeletal examinations are unremarkable
46 year old Filipino female profuse menstrual flow for the past few months on and off fever, easy bruisability, shortness of breath on exertion for the
past 3 weeks no headache, bone pain, nausea, vomiting, melena, hematochezia,
dysuria, nor hematuria denies any exposure to insecticides or other chemicals FH: diabetes mellitus Physical examination: BP: 100/70, pulse rate of 100/min, regular and
full; RR of 24/min pale, not jaundiced, no palpable cervical lymphadenopathy Cardiovascular and pulmonary examinations are normal Liver and spleen are not palpable Neurologic and musculoskeletal examinations are unremarkable
Case 2-01-01Case 2-01-01Case 2-01-01Case 2-01-01
CBC : hgb : 7.2wbc of 45,000 with blasts of 55%, platelets: 65,000.
CBC : hgb : 7.2wbc of 45,000 with blasts of 55%, platelets: 65,000.
Case 2-01-01Case 2-01-01Case 2-01-01Case 2-01-01
1. What are blast cells? Describe them.
2. What laboratory examinations should be requested? Why?
3. What is/are your clinical impression(s)?
4. What is the appropriate management for this patient?
1. What are blast cells? Describe them.
2. What laboratory examinations should be requested? Why?
3. What is/are your clinical impression(s)?
4. What is the appropriate management for this patient?
Blast cellsBlast cellsBlast cellsBlast cells
Immature cells characterized morphologically as mononuclear cells with large nuclei relative to the cytoplasm, containing one or more nucleoli
May be of lymphoid or myeloid origin
Immature cells characterized morphologically as mononuclear cells with large nuclei relative to the cytoplasm, containing one or more nucleoli
May be of lymphoid or myeloid origin
Back to Questions
ExaminationsExaminationsExaminationsExaminations
Peripheral smear Bone marrow examination:
Aspirate Light microscopic studies Flow cytometry Cytogenetics
Biopsy
Blood chemistries: LFT, Renal function, BUA Others as indicated by clinical situation
Peripheral smear Bone marrow examination:
Aspirate Light microscopic studies Flow cytometry Cytogenetics
Biopsy
Blood chemistries: LFT, Renal function, BUA Others as indicated by clinical situation
AML, peripheral bloodAML, peripheral bloodAML, peripheral bloodAML, peripheral blood
Blast cells
Myelomonocytic leukemia
Acute promyelocytic leukemia
Acute Myelogenous LeukemiaAcute Myelogenous LeukemiaAcute Myelogenous LeukemiaAcute Myelogenous Leukemia
Undifferentiated
Myelomonocytic Monoblastic, bone marrow biopsy
Acute ErythroleukemiaAcute ErythroleukemiaAcute ErythroleukemiaAcute Erythroleukemia
Peripheral blood Bone marrow
ALL, microscopy & cytochemistryALL, microscopy & cytochemistryALL, microscopy & cytochemistryALL, microscopy & cytochemistry
Lymphoblasts, peripheral blood
PAS stain: lymphoblasts positive
Myeloperoxidase stain: lymphoblasts are negative
Alpha naphthyl esterase stain: lymphoblasts are negative
Immunophenotyping: AMLImmunophenotyping: AMLImmunophenotyping: AMLImmunophenotyping: AMLCD GrpCD Grp AntibodiesAntibodies ReactivityReactivity
CFU-GEMM to promyelo-cyte and mature mono-cytes
CFU-GEMM to promyelo-cyte and mature mono-cytes
CD33CD33 MY9, LeuM9, L4F3MY9, LeuM9, L4F3
CFU-GM to mature granulo-cytes and monocytesCFU-GM to mature granulo-cytes and monocytes
CD13CD13 MY7, LeuM7MY7, LeuM7
MonocytesMonocytesCD14CD14 MY4, LeuM3, MO2MY4, LeuM3, MO2
CD15CD15 LeuM1, MY1LeuM1, MY1 Promyelocytes to granulo-cytes, monocytesPromyelocytes to granulo-cytes, monocytes
Immunophenotyping: AMLImmunophenotyping: AMLImmunophenotyping: AMLImmunophenotyping: AMLCD GrpCD Grp AntibodiesAntibodies ReactivityReactivity
Progenitor cells, B- lymphocytes, monocytes, activated T-cells
Progenitor cells, B- lymphocytes, monocytes, activated T-cells
CD34CD34 MY10, HPCA-1, HLA-DR, Ia
MY10, HPCA-1, HLA-DR, Ia
Platelets and megakaryocytesPlatelets and megakaryocytes
CD41CD41 GPIIbIIIa, PL-273GPIIbIIIa, PL-273
MonocytesMonocytesCD42CD42 GP1b, FMC-25, Glycophorin A, 10F7
GP1b, FMC-25, Glycophorin A, 10F7
CD56CD56 Leu19, NKH1Leu19, NKH1 Natural killer cellsNatural killer cells
Cytogenetic Abnormalities: Cytogenetic Abnormalities: SignificanceSignificance
Cytogenetic Abnormalities: Cytogenetic Abnormalities: SignificanceSignificance
Cytogenetic AbnormalityCytogenetic Abnormality
Rearrangements of 16q22Rearrangements of 16q22
t(8;21)(q22;q22)t(8;21)(q22;q22)NormalNormalAbnormal 11qAbnormal 11qAbnormal 5 and/or 7Abnormal 5 and/or 7t(15;17)(q22;q11)t(15;17)(q22;q11)
Median Survival(months)
Median Survival(months)
1818
14141010
883322
(Overall Survival in De Novo AML)(Overall Survival in De Novo AML)
Acute Myelogenous LeukemiaAcute Myelogenous LeukemiaAcute Myelogenous LeukemiaAcute Myelogenous Leukemia
French-American-British (FAB) ClassificationFrench-American-British (FAB) ClassificationAML - M0AML - M0 (Acute undifferentiated leukemia) cells
with undifferentiated morphology, with less than 3% MPO positive blasts
(Acute undifferentiated leukemia) cells with undifferentiated morphology, with less than 3% MPO positive blasts
AML - M1AML - M1 30% blasts with 3% MPO positivity, occasionally containing Auer rods, and showing little maturation beyond the myeloblast stage. The blasts can be NASD-negative
30% blasts with 3% MPO positivity, occasionally containing Auer rods, and showing little maturation beyond the myeloblast stage. The blasts can be NASD-negative
Acute Myelogenous LeukemiaAcute Myelogenous LeukemiaAcute Myelogenous LeukemiaAcute Myelogenous Leukemia
French-American-British (FAB) ClassificationFrench-American-British (FAB) Classification
AML-M2AML-M2 >30% myeloblasts ( 3% MPO positive) with > 10% maturing granulocytic elements (progranulocyte through granulocytes) and <20% monocytic cells. Auer rods are often present, and some blasts show NASD positivity. Some cases are associated with t(8;21)
>30% myeloblasts ( 3% MPO positive) with > 10% maturing granulocytic elements (progranulocyte through granulocytes) and <20% monocytic cells. Auer rods are often present, and some blasts show NASD positivity. Some cases are associated with t(8;21)
AML - M3AML - M3 (Acute promyelocytic leukemia, APL) strong MPO positivity, showing a predominance of abnormal promyelocytes, with abnormally heavy granulation and occasional cells with bundles of Auer rods. A microgranular variant lacks the heavy granulation but maintains the other features. Both forms show strong NASD positivity and are associated with t(15;17).
(Acute promyelocytic leukemia, APL) strong MPO positivity, showing a predominance of abnormal promyelocytes, with abnormally heavy granulation and occasional cells with bundles of Auer rods. A microgranular variant lacks the heavy granulation but maintains the other features. Both forms show strong NASD positivity and are associated with t(15;17).
Acute Myelogenous LeukemiaAcute Myelogenous LeukemiaAcute Myelogenous LeukemiaAcute Myelogenous Leukemia
French-American-British (FAB) ClassificationFrench-American-British (FAB) ClassificationAML - M4AML - M4 (Acute myelomonocytic leukemia) MPO positive,
resembles M2 except that 20% of the cells are promonocytes (NSE-positive). A distinct subtype, associated with inv(16), has increased eosinophils with basophilic granules
(Acute myelomonocytic leukemia) MPO positive, resembles M2 except that 20% of the cells are promonocytes (NSE-positive). A distinct subtype, associated with inv(16), has increased eosinophils with basophilic granules
AML - M5AML - M5 (Acute monocytic leukemia) leukemic cells are either monoblasts or promonocytes with abundant cytoplasm and eccentric nuclei. NSE and NASD positive; MPO staining is rare (<3%)
(Acute monocytic leukemia) leukemic cells are either monoblasts or promonocytes with abundant cytoplasm and eccentric nuclei. NSE and NASD positive; MPO staining is rare (<3%)
Acute Myelogenous LeukemiaAcute Myelogenous LeukemiaAcute Myelogenous LeukemiaAcute Myelogenous Leukemia
French-American-British (FAB) ClassificationFrench-American-British (FAB) ClassificationAML - M6AML - M6 (Erythroleukemia) consisted of M1, M2,
or M4 blasts intermingled with dysplastic erythroid precursors, PAS positive
(Erythroleukemia) consisted of M1, M2, or M4 blasts intermingled with dysplastic erythroid precursors, PAS positive
AML - M7AML - M7 (Acute megakaryoblastic leukemia) cytochemical stains are usually negative(Acute megakaryoblastic leukemia) cytochemical stains are usually negative
Adult Acute Lymphocytic Adult Acute Lymphocytic LeukemiaLeukemia
Adult Acute Lymphocytic Adult Acute Lymphocytic LeukemiaLeukemia
FAB classification:L1: MPO negative , with small cells
predominating
L2: MPO negative, heterogeneous population with larger blasts
L3: Burkitt type, MPO negative, homogeneous population of large blasts
FAB classification:L1: MPO negative , with small cells
predominating
L2: MPO negative, heterogeneous population with larger blasts
L3: Burkitt type, MPO negative, homogeneous population of large blasts
Adult Acute Lymphocytic Adult Acute Lymphocytic LeukemiaLeukemia
Adult Acute Lymphocytic Adult Acute Lymphocytic LeukemiaLeukemia
patients older than 15 to 18 years of age biologically different from childhood ALL
Philadelphia chromosome (Ph)-positive is more frequent (15% to 30% v <5%) in adult ALL
Translocations t(1;19) and t(4;11) are less common.
patients older than 15 to 18 years of age biologically different from childhood ALL
Philadelphia chromosome (Ph)-positive is more frequent (15% to 30% v <5%) in adult ALL
Translocations t(1;19) and t(4;11) are less common.
Back to Questions
Treatment of AMLTreatment of AMLTreatment of AMLTreatment of AML
Remission-induction therapy: combination of daunorubicin (45mg / m2 / d for 3 days) and cytarabine (100 to 200mg / m2 / d as continuous IV infusion for 7 days)
Post-remission therapy as:
maintenance therapy
consolidation therapy
intensification therapy
Remission-induction therapy: combination of daunorubicin (45mg / m2 / d for 3 days) and cytarabine (100 to 200mg / m2 / d as continuous IV infusion for 7 days)
Post-remission therapy as:
maintenance therapy
consolidation therapy
intensification therapy
Prognosis: Acute Myelogenous Prognosis: Acute Myelogenous LeukemiaLeukemia
Prognosis: Acute Myelogenous Prognosis: Acute Myelogenous LeukemiaLeukemia
De novo AML has a complete response (CR) rate of 60-75%
Long-term disease free survival occurs in 25-50% of patients in CR
Secondary AML has remission rates of 30-40%; long-term survivorship is unusual unless bone marrow transplantation is used
De novo AML has a complete response (CR) rate of 60-75%
Long-term disease free survival occurs in 25-50% of patients in CR
Secondary AML has remission rates of 30-40%; long-term survivorship is unusual unless bone marrow transplantation is used
Prognostic Factors in AMLPrognostic Factors in AMLPrognostic Factors in AMLPrognostic Factors in AML
Age Leukemia Leukocytosis CNS disease Cytoreduction
Age Leukemia Leukocytosis CNS disease Cytoreduction
< 45 years De Novo <25,000/mm3
Absent Rapid
< 45 years De Novo <25,000/mm3
Absent Rapid
<2 yrs, >60 yrs Preceding MDS >100,000/mm3
Present Delayed
<2 yrs, >60 yrs Preceding MDS >100,000/mm3
Present Delayed
FactorFactor FavorableFavorable UnfavorableUnfavorable
Greer JP and Kinney MC, Clinical Hematology; 1993Greer JP and Kinney MC, Clinical Hematology; 1993
ClinicalClinical
Prognostic Factors in AMLPrognostic Factors in AMLPrognostic Factors in AMLPrognostic Factors in AML
Auer rods Eosinophils Megaloblastic
erythroids FAB type
Auer rods Eosinophils Megaloblastic
erythroids FAB type
Present Present Absent
M3, M4
Present Present Absent
M3, M4
Absent Absent Present
M5, 6, 7
Absent Absent Present
M5, 6, 7
FactorFactor FavorableFavorable UnfavorableUnfavorable
Greer JP and Kinney MC, Clinical Hematology; 1993Greer JP and Kinney MC, Clinical Hematology; 1993
MorphologyMorphology
Prognostic Factors in AMLPrognostic Factors in AMLPrognostic Factors in AMLPrognostic Factors in AML
Myeloid
HLA-DR TdT Lymphoid
Myeloid
HLA-DR TdT Lymphoid
MY4-, MY7-
Negative Absent OKT11 (CD2),
B4 (CD19)
MY4-, MY7-
Negative Absent OKT11 (CD2),
B4 (CD19)
MY4+(CD14), MY7+(CD13), MY10+(CD34)
Positive Present Biphenotypic ( 2
lymphoid markers)
MY4+(CD14), MY7+(CD13), MY10+(CD34)
Positive Present Biphenotypic ( 2
lymphoid markers)
FactorFactor FavorableFavorable UnfavorableUnfavorable
Greer JP and Kinney MC, Clinical Hematology; 1993Greer JP and Kinney MC, Clinical Hematology; 1993
Surface/Enzyme MarkersSurface/Enzyme Markers
Prognostic Factors in AMLPrognostic Factors in AMLPrognostic Factors in AMLPrognostic Factors in AML
t(15; 17), t(8; 21), inv(16)/del(16q)
t(15; 17), t(8; 21), inv(16)/del(16q)
-7, del(7q); -5, del(5q); 11q23 abnormalities; 3q21 and 3q26 abnormalities
-7, del(7q); -5, del(5q); 11q23 abnormalities; 3q21 and 3q26 abnormalities
FavorableFavorable UnfavorableUnfavorable
Greer JP and Kinney MC, Clinical Hematology; 1993Greer JP and Kinney MC, Clinical Hematology; 1993
CytogeneticsCytogenetics
Adult Acute Lymphocytic Adult Acute Lymphocytic LeukemiaLeukemia
Adult Acute Lymphocytic Adult Acute Lymphocytic LeukemiaLeukemia
Complete response rates (CR) range from 65% to 85%, and cure rates from 20% to 35%
Adults with ALL do not tolerate intensive chemotherapy as well as children.
Complete response rates (CR) range from 65% to 85%, and cure rates from 20% to 35%
Adults with ALL do not tolerate intensive chemotherapy as well as children.
Poor Prognostic Factors: ALLPoor Prognostic Factors: ALLPoor Prognostic Factors: ALLPoor Prognostic Factors: ALL
Presence of Ph-positive disease and Burkitt leukemia before the intensive regimen
Older age Leucocytosis
Presence of Ph-positive disease and Burkitt leukemia before the intensive regimen
Older age Leucocytosis
Poor Prognostic FactorsPoor Prognostic FactorsPoor Prognostic FactorsPoor Prognostic Factors
Longer time to achieve complete remission
Non-T-cell immunophenotype Karyotypes: t(9;22) or t(4;11)
Longer time to achieve complete remission
Non-T-cell immunophenotype Karyotypes: t(9;22) or t(4;11)
Treatment of Adult ALLTreatment of Adult ALLTreatment of Adult ALLTreatment of Adult ALL
Induction therapy with vincristine-corticosteroids-anthracyclines is the current standard of care.CR rate of 64% to 87%Combining cyclophosphamide, asparaginase, or
cytarabine does not improve the results except in a subset of patients.
Induction therapy with vincristine-corticosteroids-anthracyclines is the current standard of care.CR rate of 64% to 87%Combining cyclophosphamide, asparaginase, or
cytarabine does not improve the results except in a subset of patients.
Treatment of Adult ALLTreatment of Adult ALLTreatment of Adult ALLTreatment of Adult ALL
Consolidation-intensification with higher doses of asparaginase, 6 mercaptopurine (6MP) plus methotrexate, and cyclophosphamide plus cytarabine improve overall outcome in specific adult ALL subsets (B-cell ALL, T-cell ALL)
Consolidation-intensification with higher doses of asparaginase, 6 mercaptopurine (6MP) plus methotrexate, and cyclophosphamide plus cytarabine improve overall outcome in specific adult ALL subsets (B-cell ALL, T-cell ALL)
Treatment of Adult ALLTreatment of Adult ALLTreatment of Adult ALLTreatment of Adult ALL
Maintenance therapy with 6MP and methotrexate is beneficial except in Burkitt’s and other mature B-cell ALL, and in Ph-positive ALL
Maintenance therapy with 6MP and methotrexate is beneficial except in Burkitt’s and other mature B-cell ALL, and in Ph-positive ALL
Central Nervous System Central Nervous System ProphylaxisProphylaxis
Central Nervous System Central Nervous System ProphylaxisProphylaxis
CNS relapse rate in patients without prophylaxis: 21% to 50%
CNS prophylaxis with intrathecal chemotherapy and high dose systemic therapy using agents with good CNS penetration ( cytarabine, methotrexate, dexamethasone) is sufficient.
Radiation therapy limits the application of high dose chemotherapy and compromises TBI for BMT.
CNS relapse rate in patients without prophylaxis: 21% to 50%
CNS prophylaxis with intrathecal chemotherapy and high dose systemic therapy using agents with good CNS penetration ( cytarabine, methotrexate, dexamethasone) is sufficient.
Radiation therapy limits the application of high dose chemotherapy and compromises TBI for BMT.
Myelodysplastic Syndromes (MDS)Myelodysplastic Syndromes (MDS)Myelodysplastic Syndromes (MDS)Myelodysplastic Syndromes (MDS)
Clonal refractory cytopenias whose marrows show characteristic dysplastic changes in at least 2 of 3 hemopoietic cell lines.
Propensity to transform to acute leukemiaPrimary or secondary (therapy-related)
Clonal refractory cytopenias whose marrows show characteristic dysplastic changes in at least 2 of 3 hemopoietic cell lines.
Propensity to transform to acute leukemiaPrimary or secondary (therapy-related)
Myelodysplastic syndromeMyelodysplastic syndromeMyelodysplastic syndromeMyelodysplastic syndrome
Disease of the elderly More common above 50 years
Relatively common Therapy related MDS not age-related
Late toxicity of cancer treatment: radiation, alkylating agents: busulfan, nitrosourea, procarbazine, DNA topoisomerase inhibitors
Disease of the elderly More common above 50 years
Relatively common Therapy related MDS not age-related
Late toxicity of cancer treatment: radiation, alkylating agents: busulfan, nitrosourea, procarbazine, DNA topoisomerase inhibitors
Clinical presentationClinical presentationClinical presentationClinical presentation
Asymptomatic Symptoms of
Anemia: gradual onset of fatigue, weakness, dyspnea, pallor Some bleeding manifestations
Physical examination Signs of anemia Spenomegaly (20%) commonly in CMML lymphadenopathy is uncommon Unusual skin manifestations (Sweet’s syndrome: febrile neutrophilic
dermatosis) Autoimmune syndromes not infrequent
Asymptomatic Symptoms of
Anemia: gradual onset of fatigue, weakness, dyspnea, pallor Some bleeding manifestations
Physical examination Signs of anemia Spenomegaly (20%) commonly in CMML lymphadenopathy is uncommon Unusual skin manifestations (Sweet’s syndrome: febrile neutrophilic
dermatosis) Autoimmune syndromes not infrequent
Diagnosis of MDSDiagnosis of MDSDiagnosis of MDSDiagnosis of MDS
No single morphologic finding is No single morphologic finding is diagnosticdiagnostic
Combination of dysplastic features in Combination of dysplastic features in the peripheral blood and bone marrow the peripheral blood and bone marrow is necessary.is necessary.
The diagnosis of MDS is a diagnosis The diagnosis of MDS is a diagnosis of exclusion.of exclusion.
No single morphologic finding is No single morphologic finding is diagnosticdiagnostic
Combination of dysplastic features in Combination of dysplastic features in the peripheral blood and bone marrow the peripheral blood and bone marrow is necessary.is necessary.
The diagnosis of MDS is a diagnosis The diagnosis of MDS is a diagnosis of exclusion.of exclusion.
Diagnosis of MDSDiagnosis of MDSDiagnosis of MDSDiagnosis of MDS
The following must always be excluded The following must always be excluded Absolute exclusionsAbsolute exclusions
Vitamin B12 and / or folate deficiencyVitamin B12 and / or folate deficiency Proven exposure to heavy metalsProven exposure to heavy metals Recent cytotoxic therapyRecent cytotoxic therapy
Relative exclusionsRelative exclusions Ongoing inflammation including HIV and Ongoing inflammation including HIV and
cancercancer Chronic liver disease / alcohol useChronic liver disease / alcohol use
The following must always be excluded The following must always be excluded Absolute exclusionsAbsolute exclusions
Vitamin B12 and / or folate deficiencyVitamin B12 and / or folate deficiency Proven exposure to heavy metalsProven exposure to heavy metals Recent cytotoxic therapyRecent cytotoxic therapy
Relative exclusionsRelative exclusions Ongoing inflammation including HIV and Ongoing inflammation including HIV and
cancercancer Chronic liver disease / alcohol useChronic liver disease / alcohol use
Laboratory Studies in MDSLaboratory Studies in MDSLaboratory Studies in MDSLaboratory Studies in MDS
Serum B12 and folate Serum iron and ferritin Iron and reticulin stain of
the marrow Chromosomal studies Flow cytometry
Serum B12 and folate Serum iron and ferritin Iron and reticulin stain of
the marrow Chromosomal studies Flow cytometry
Peripheral Blood and Bone Marrow Peripheral Blood and Bone Marrow FindingsFindings
DyserythropoiesisDyserythropoiesis
Peripheral Blood and Bone Marrow Peripheral Blood and Bone Marrow FindingsFindings
DyserythropoiesisDyserythropoiesis Peripheral blood
Macrocytes Hypochromic microcytes,
poikilocytosis Bone marrow
Megaloblastoid Nuclear-cytoplasmic
asynchrony Cytoplasmic tears or rents Pathologic ringed
sideroblasts
Peripheral blood Macrocytes Hypochromic microcytes,
poikilocytosis Bone marrow
Megaloblastoid Nuclear-cytoplasmic
asynchrony Cytoplasmic tears or rents Pathologic ringed
sideroblasts
Nucleo-cytoplasmic maturation dissociation
Hyposegmentation / hypersegmentation of nucleus
Increase in myeloblasts Abnormal localization of
immature precursors
Nucleo-cytoplasmic maturation dissociation
Hyposegmentation / hypersegmentation of nucleus
Increase in myeloblasts Abnormal localization of
immature precursors
Peripheral Blood and Bone Marrow Findings
Dyserythropoiesis
Peripheral Blood and Bone Marrow Findings
Dyserythropoiesis
Peripheral Blood and Bone Marrow Findings
Dysmegakaryocytopoiesis
Peripheral Blood and Bone Marrow Findings
Dysmegakaryocytopoiesis Peripheral Blood
Thrombocytopenia Giant forms Lack of aggregation
Bone Marrow Mononuclear or bilobed forms Hypersegmented forms Cytoplasmic vacuolization Increase in
micromegakaryocytes
Peripheral Blood Thrombocytopenia Giant forms Lack of aggregation
Bone Marrow Mononuclear or bilobed forms Hypersegmented forms Cytoplasmic vacuolization Increase in
micromegakaryocytes
FISH, MDS FISH, MDS
French - American and British Morphologic French - American and British Morphologic Classification (FAB)Classification (FAB)
French - American and British Morphologic French - American and British Morphologic Classification (FAB)Classification (FAB)
Refractory anemia (RA Refractory anemia (RA) with ringed
sideroblasts (RARS) Chronic myelomonocytic leukemia
(CMML) Refractory anemia with excess of blasts
(RAEB) Refractory anemia with excess of blasts
in transformation (RAEB-T)
Refractory anemia (RA Refractory anemia (RA) with ringed
sideroblasts (RARS) Chronic myelomonocytic leukemia
(CMML) Refractory anemia with excess of blasts
(RAEB) Refractory anemia with excess of blasts
in transformation (RAEB-T)
WHO Classification of MDSWHO Classification of MDSWHO Classification of MDSWHO Classification of MDS
Refractory Anemia (RA) Refractory Anemia with Ringed Sideroblasts(RARS) Refractory Cytopenia with Multilineage Dysplasia(RCMD) Refractory Cytopenia with Multilineage Dysplasia and
Ringed Sideroblasts (RCMD-RS) Refractory Anemia with Excess Blasts-1(RAEB-1) Refractory Anemia with Excess Blasts-2(RAEB-2) Myelodysplastic Syndrome, Unclassified (MDS-U) Myelodysplastic Syndrome Associated with del (5q)
Refractory Anemia (RA) Refractory Anemia with Ringed Sideroblasts(RARS) Refractory Cytopenia with Multilineage Dysplasia(RCMD) Refractory Cytopenia with Multilineage Dysplasia and
Ringed Sideroblasts (RCMD-RS) Refractory Anemia with Excess Blasts-1(RAEB-1) Refractory Anemia with Excess Blasts-2(RAEB-2) Myelodysplastic Syndrome, Unclassified (MDS-U) Myelodysplastic Syndrome Associated with del (5q)
Follow-up Observations of MDSFollow-up Observations of MDSFollow-up Observations of MDSFollow-up Observations of MDS
Those with stable clinical course with no life threatening cytopenias, follow-up examinations.
Cytogenetic studies may show change in karyotype; clonal evolution suggestive of imminent leukemic transformation.
Those with stable clinical course with no life threatening cytopenias, follow-up examinations.
Cytogenetic studies may show change in karyotype; clonal evolution suggestive of imminent leukemic transformation.
Immunological Abnormalities in Immunological Abnormalities in MDSMDS
Immunological Abnormalities in Immunological Abnormalities in MDSMDS
ImmunoglobulinsPolyclonal
hypergammaglobulinemiaHypogammaglobulinemiaMonoclonal gammopathyAnti-red cell antibodies
B cellsNormal in numberFunctionally immature
ImmunoglobulinsPolyclonal
hypergammaglobulinemiaHypogammaglobulinemiaMonoclonal gammopathyAnti-red cell antibodies
B cellsNormal in numberFunctionally immature
International Prognostic Scoring International Prognostic Scoring System: MDSSystem: MDS
International Prognostic Scoring International Prognostic Scoring System: MDSSystem: MDS
Prognostic variable
Score Value
0 0.5 1.0 1.5 2.0
Bone marrow blasts
<5% 5-10%
11-20 21-30
Karyotype good intermediate
poor
Cytopenia 0 or 1
2 or 3
Risk group scores
Score
Low 0
Intermediate-1 0.5-1.0
Intermediate-2 1.5-2.0
High >2.5
Therapy of MDSTherapy of MDSTherapy of MDSTherapy of MDS
Standard therapy: supportive careAnemia may be treated with transfusionJudicious use of red cell and platelet
transfusions to minimize the risk of alloimmunization
Erythropoietin may be successful in low erythropoietin states
Antibiotics when indicated
Standard therapy: supportive careAnemia may be treated with transfusionJudicious use of red cell and platelet
transfusions to minimize the risk of alloimmunization
Erythropoietin may be successful in low erythropoietin states
Antibiotics when indicated
Treatment of MDSTreatment of MDSTreatment of MDSTreatment of MDS
Factors to be considered: clinical severity and patient age
Stable process: no treatment
Factors to be considered: clinical severity and patient age
Stable process: no treatment
Treatment of MDSTreatment of MDSTreatment of MDSTreatment of MDS
Treatment with hematopoietic growth factors (G-CSF, GM-CSF, IL-3)
Low-dose Ara-C, retinoids Bone marrow transplantation Aggressive anti-leukemic therapy
Treatment with hematopoietic growth factors (G-CSF, GM-CSF, IL-3)
Low-dose Ara-C, retinoids Bone marrow transplantation Aggressive anti-leukemic therapy
Novel TreatmentsNovel TreatmentsNovel TreatmentsNovel Treatments
Anti-angiogenic : Thalidomide, lenalidomide, bevacizumab, arsenic trioxide
Tyrosine kinase inhibitors: Glivec Farnesyl transferase inhibitors: tipifarnib DNA methylation inhibitors: azacytidine,
deoxycytidine
Anti-angiogenic : Thalidomide, lenalidomide, bevacizumab, arsenic trioxide
Tyrosine kinase inhibitors: Glivec Farnesyl transferase inhibitors: tipifarnib DNA methylation inhibitors: azacytidine,
deoxycytidine
Case 2-02-01Case 2-02-01Case 2-02-01Case 2-02-01 55 year old female was referred because of hemoglobin of 19 mg/dL and
hematocrit of 56 cv% admitted because of right sided extremity weakness, dizziness and
headache and was diagnosed to have left cerebral infarction ROS: occasional pruritus no prior history of hypertension or diabetes mellitus did not take contraceptive pills postmenopausic, G3P3 family history of hypertension, no cancer Physical examination
facial plethora splenomegaly neurologic deficits as described
55 year old female was referred because of hemoglobin of 19 mg/dL and hematocrit of 56 cv%
admitted because of right sided extremity weakness, dizziness and headache and was diagnosed to have left cerebral infarction
ROS: occasional pruritus no prior history of hypertension or diabetes mellitus did not take contraceptive pills postmenopausic, G3P3 family history of hypertension, no cancer Physical examination
facial plethora splenomegaly neurologic deficits as described
Case 2-02-01Case 2-02-01Case 2-02-01Case 2-02-01
What are the signs and symptoms of erythrocytosis? What are the causes of secondary erythrocytosis? What is polycythemia rubra vera? What are the laboratory abnormalities in polycythemia
vera? W hat are the diagnostic criteria for polycythemia vera? How do you How do you manage this patient?this patient? What are the What are the complications associated with this condition? associated with this condition?
What are the signs and symptoms of erythrocytosis? What are the causes of secondary erythrocytosis? What is polycythemia rubra vera? What are the laboratory abnormalities in polycythemia
vera? W hat are the diagnostic criteria for polycythemia vera? How do you How do you manage this patient?this patient? What are the What are the complications associated with this condition? associated with this condition?
Polycythemia Rubra VeraPolycythemia Rubra VeraPolycythemia Rubra VeraPolycythemia Rubra Vera
Myeloproliferative disorder affecting mainly red blood cells
Incidence varies considerably in different parts of the world
Age incidence: 6th and 7th decades of life No obvious causative agent identifiable in
majority of patients
Myeloproliferative disorder affecting mainly red blood cells
Incidence varies considerably in different parts of the world
Age incidence: 6th and 7th decades of life No obvious causative agent identifiable in
majority of patients
Polycythemia Rubra VeraPolycythemia Rubra VeraPathophysiologyPathophysiology
Polycythemia Rubra VeraPolycythemia Rubra VeraPathophysiologyPathophysiology
primary defect involves a pluripotent stem cell capable of differentiating into both myeloid and lymphoid cells.
Increased sensitivity to EPO, interleukin-3 (IL-3), GM-CSF Alteration or activation of the EPO receptor Alteration or activation of the EPO receptor
gives rise to autonomous erythropoiesisgives rise to autonomous erythropoiesis Lack of negative feedback mechanisms
primary defect involves a pluripotent stem cell capable of differentiating into both myeloid and lymphoid cells.
Increased sensitivity to EPO, interleukin-3 (IL-3), GM-CSF Alteration or activation of the EPO receptor Alteration or activation of the EPO receptor
gives rise to autonomous erythropoiesisgives rise to autonomous erythropoiesis Lack of negative feedback mechanisms
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Polycythemia Rubra VeraPolycythemia Rubra VeraClinical FeaturesClinical Features
Polycythemia Rubra VeraPolycythemia Rubra VeraClinical FeaturesClinical Features
Headache Dyspnea Weakness Sweating Weight loss Plethora Dizziness Visual changes
Headache Dyspnea Weakness Sweating Weight loss Plethora Dizziness Visual changes
Epistaxis Angina Pruritus Paresthesia Gout Splenomegaly Hypertension Leg ulcers
Epistaxis Angina Pruritus Paresthesia Gout Splenomegaly Hypertension Leg ulcers
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Polycythemia Rubra VeraPolycythemia Rubra VeraLaboratory AbnormalitiesLaboratory Abnormalities
Polycythemia Rubra VeraPolycythemia Rubra VeraLaboratory AbnormalitiesLaboratory Abnormalities
Erythrocytosis, leucocytosis, thrombocytosis Hyperuricemia Elevated leucocyte alkaline phosphatase pO2 > 92% Elevated LDH Elevated B12, unbound B12 binding
capacity
Erythrocytosis, leucocytosis, thrombocytosis Hyperuricemia Elevated leucocyte alkaline phosphatase pO2 > 92% Elevated LDH Elevated B12, unbound B12 binding
capacity
PRVPRVPRVPRV
Peripheral blood Bone marrow biopsy
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Polycythemia Rubra VeraPolycythemia Rubra VeraDiagnostic CriteriaDiagnostic Criteria
Polycythemia Rubra VeraPolycythemia Rubra VeraDiagnostic CriteriaDiagnostic Criteria
Major Criteria A1 Hematocrit > 60% or rbc
mass (ml/kg) > 36 in males and >32 in females
A 2 Arterial O2 saturation of >95%
A 3 Splenomegaly
Major Criteria A1 Hematocrit > 60% or rbc
mass (ml/kg) > 36 in males and >32 in females
A 2 Arterial O2 saturation of >95%
A 3 Splenomegaly
Polycythemia Rubra VeraDiagnostic Criteria
Polycythemia Rubra VeraDiagnostic Criteria
Minor CriteriaMinor Criteria B1 B1 Platelet count >400,000/uLPlatelet count >400,000/uL B2 B2 WBC >12,000/uLWBC >12,000/uL B3 B3 Leucocyte alkaline Leucocyte alkaline
phosphatase >100phosphatase >100 B4 B4 Unbound vit B12 binding Unbound vit B12 binding
capacity >2,200pg/mLcapacity >2,200pg/mL
Minor CriteriaMinor Criteria B1 B1 Platelet count >400,000/uLPlatelet count >400,000/uL B2 B2 WBC >12,000/uLWBC >12,000/uL B3 B3 Leucocyte alkaline Leucocyte alkaline
phosphatase >100phosphatase >100 B4 B4 Unbound vit B12 binding Unbound vit B12 binding
capacity >2,200pg/mLcapacity >2,200pg/mL
Polycythemia Rubra VeraDiagnostic Criteria
Polycythemia Rubra VeraDiagnostic Criteria
Diagnosis is acceptable if:Diagnosis is acceptable if: A1 + A2 + A3 orA1 + A2 + A3 or A1 + A2 + any two from A1 + A2 + any two from
category Bcategory B
Diagnosis is acceptable if:Diagnosis is acceptable if: A1 + A2 + A3 orA1 + A2 + A3 or A1 + A2 + any two from A1 + A2 + any two from
category Bcategory B
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Differential Diagnosis of Differential Diagnosis of PolycythemiaPolycythemia
Differential Diagnosis of Differential Diagnosis of PolycythemiaPolycythemia
Spurious polycythemia Secondary polycythemia Polycythemia Vera
Spurious polycythemia Secondary polycythemia Polycythemia Vera
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Secondary PolycythemiaSecondary PolycythemiaSecondary PolycythemiaSecondary PolycythemiaInappropriate Renal cysts, hydronephrosis Tumors
Renal Uterine myoma Hepatoma Cerebellar hemangioma
Inappropriate Renal cysts, hydronephrosis Tumors
Renal Uterine myoma Hepatoma Cerebellar hemangioma
Secondary PolycythemiaSecondary PolycythemiaAppropriateAppropriate Arterial hypoxemiaArterial hypoxemia
High altitudeHigh altitude Right-to-left shuntRight-to-left shunt Lung diseaseLung disease Liver cirrhosisLiver cirrhosis
Defective oxygen deliveryDefective oxygen delivery Congenital abnormal hemoglobinCongenital abnormal hemoglobin CarboxyhemoglobinCarboxyhemoglobin
AppropriateAppropriate Arterial hypoxemiaArterial hypoxemia
High altitudeHigh altitude Right-to-left shuntRight-to-left shunt Lung diseaseLung disease Liver cirrhosisLiver cirrhosis
Defective oxygen deliveryDefective oxygen delivery Congenital abnormal hemoglobinCongenital abnormal hemoglobin CarboxyhemoglobinCarboxyhemoglobin
Back to Polycythemia vera
Polycythemia VeraPolycythemia VeraTreatmentTreatment
Polycythemia VeraPolycythemia VeraTreatmentTreatment
Removal of red cells through phlebotomy until the hematocrit is in the normal range.
Myelosuppressive drugs: hydroxyurea, busulfan, interferons
Anti-thrombotic therapy
Removal of red cells through phlebotomy until the hematocrit is in the normal range.
Myelosuppressive drugs: hydroxyurea, busulfan, interferons
Anti-thrombotic therapy
Polycythemia Rubra VeraPolycythemia Rubra VeraCourseCourse
Polycythemia Rubra VeraPolycythemia Rubra VeraCourseCourse
15% will develop postpolycythemia myeloid metaplasia (PPMM), also termed the spent phase due to the waning of bone marrow proliferative activity.Appears at an average interval of 10 yearsNo effective therapy for this phase
Transformation to acute leukemia is a frequent cause of death
15% will develop postpolycythemia myeloid metaplasia (PPMM), also termed the spent phase due to the waning of bone marrow proliferative activity.Appears at an average interval of 10 yearsNo effective therapy for this phase
Transformation to acute leukemia is a frequent cause of death
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Polycythemia Rubra VeraPolycythemia Rubra VeraThrombo-Hemorrhagic ComplicationsThrombo-Hemorrhagic Complications
Polycythemia Rubra VeraPolycythemia Rubra VeraThrombo-Hemorrhagic ComplicationsThrombo-Hemorrhagic Complications
Cerebral thrombosisCerebral thrombosis Coronary thrombosisCoronary thrombosis Peripheral vascular Peripheral vascular
diseasedisease Budd-Chiari Budd-Chiari
syndromesyndrome ErythromelalgiaErythromelalgia Mesenteric vein Mesenteric vein
thrombosisthrombosis
Cerebral thrombosisCerebral thrombosis Coronary thrombosisCoronary thrombosis Peripheral vascular Peripheral vascular
diseasedisease Budd-Chiari Budd-Chiari
syndromesyndrome ErythromelalgiaErythromelalgia Mesenteric vein Mesenteric vein
thrombosisthrombosis
Raynaud’s Raynaud’s phenomenonphenomenon
Monocular blindnessMonocular blindness Spontaneous abortionSpontaneous abortion Cardiac valve Cardiac valve
abnormalitiesabnormalities Cerebral hemorrhageCerebral hemorrhage GI bleedingGI bleeding
Raynaud’s Raynaud’s phenomenonphenomenon
Monocular blindnessMonocular blindness Spontaneous abortionSpontaneous abortion Cardiac valve Cardiac valve
abnormalitiesabnormalities Cerebral hemorrhageCerebral hemorrhage GI bleedingGI bleeding
Myeloproliferative Myeloproliferative Disorders Disorders
Myeloproliferative Myeloproliferative Disorders Disorders
Polycythemia Rubra Vera Primary (Essential)
Thrombocythemia Chronic Myelogenous Leukemia Agnogenic Myeloid Metaplasia
Polycythemia Rubra Vera Primary (Essential)
Thrombocythemia Chronic Myelogenous Leukemia Agnogenic Myeloid Metaplasia
Essential (Primary) ThrombocythemiaEssential (Primary) ThrombocythemiaEssential (Primary) ThrombocythemiaEssential (Primary) Thrombocythemia
Clonal myeloid disorder characterized primarily by thrombocytosis
Median age at diagnosis is 60 years
Clonal myeloid disorder characterized primarily by thrombocytosis
Median age at diagnosis is 60 years
Essential (Primary) ThrombocythemiaEssential (Primary) ThrombocythemiaNatural HistoryNatural History
Essential (Primary) ThrombocythemiaEssential (Primary) ThrombocythemiaNatural HistoryNatural History
Morbidity results from thrombohemorrhagic complications
5% transforms to acute leukemia 5 - 10% develop rises in hemoglobin
and hematocrit in to the PV range
Morbidity results from thrombohemorrhagic complications
5% transforms to acute leukemia 5 - 10% develop rises in hemoglobin
and hematocrit in to the PV range
Essential (Primary) ThrombocythemiaDiagnostic Criteria
Essential (Primary) ThrombocythemiaDiagnostic Criteria
Platelet count > 600,000/uLPlatelet count > 600,000/uL No cause for reactive thrombocytosisNo cause for reactive thrombocytosis Hematocrit < 40% or red cell mass < 36 Hematocrit < 40% or red cell mass < 36
for males and < 32 for femalesfor males and < 32 for females Normal red cell MCV or serum ferritin or Normal red cell MCV or serum ferritin or
marrow iron storesmarrow iron stores
Platelet count > 600,000/uLPlatelet count > 600,000/uL No cause for reactive thrombocytosisNo cause for reactive thrombocytosis Hematocrit < 40% or red cell mass < 36 Hematocrit < 40% or red cell mass < 36
for males and < 32 for femalesfor males and < 32 for females Normal red cell MCV or serum ferritin or Normal red cell MCV or serum ferritin or
marrow iron storesmarrow iron stores
Essential (Primary) ThrombocythemiaDiagnostic Criteria
Essential (Primary) ThrombocythemiaDiagnostic Criteria
Collagen fibrosis of marrow absent or < Collagen fibrosis of marrow absent or < 1/3 of biopsy area without both 1/3 of biopsy area without both splenomegaly and leucoerythroblastic splenomegaly and leucoerythroblastic reactionreaction
No myelodysplastic changes on marrow No myelodysplastic changes on marrow smearsmear
No Philadelphia chromosome or bcr/abl No Philadelphia chromosome or bcr/abl gene rearrangement gene rearrangement
Collagen fibrosis of marrow absent or < Collagen fibrosis of marrow absent or < 1/3 of biopsy area without both 1/3 of biopsy area without both splenomegaly and leucoerythroblastic splenomegaly and leucoerythroblastic reactionreaction
No myelodysplastic changes on marrow No myelodysplastic changes on marrow smearsmear
No Philadelphia chromosome or bcr/abl No Philadelphia chromosome or bcr/abl gene rearrangement gene rearrangement
Essential ThrombocytosisEssential ThrombocytosisEssential ThrombocytosisEssential Thrombocytosis
Reactive (secondary) Reactive (secondary) ThrombocytosisThrombocytosis
Reactive (secondary) Reactive (secondary) ThrombocytosisThrombocytosis
Infectious or inflammatory statesInfectious or inflammatory states Surgical procedure and tissue damageSurgical procedure and tissue damage MalignancyMalignancy Iron deficiency anemia, hemolytic anemia, Iron deficiency anemia, hemolytic anemia,
acute blood lossacute blood loss
Infectious or inflammatory statesInfectious or inflammatory states Surgical procedure and tissue damageSurgical procedure and tissue damage MalignancyMalignancy Iron deficiency anemia, hemolytic anemia, Iron deficiency anemia, hemolytic anemia,
acute blood lossacute blood loss
Postsplenectomy statePostsplenectomy state Rebound effect after chemotherapy or Rebound effect after chemotherapy or
immune thrombocytopeniaimmune thrombocytopenia Renal disorders (renal failure, nephrotic Renal disorders (renal failure, nephrotic
syndrome) syndrome)
Postsplenectomy statePostsplenectomy state Rebound effect after chemotherapy or Rebound effect after chemotherapy or
immune thrombocytopeniaimmune thrombocytopenia Renal disorders (renal failure, nephrotic Renal disorders (renal failure, nephrotic
syndrome) syndrome)
Reactive (secondary) Reactive (secondary) ThrombocytosisThrombocytosis
Reactive (secondary) Reactive (secondary) ThrombocytosisThrombocytosis
Essential (Primary) ThrombocythemiaPathophysiology
Essential (Primary) ThrombocythemiaPathophysiology
Primary platelet overproduction from clonally Primary platelet overproduction from clonally proliferating megakaryocytesproliferating megakaryocytes
In contrast, reactive thrombocytosis is In contrast, reactive thrombocytosis is related to overproduction of interleukin-6 related to overproduction of interleukin-6 ( IL-6) ( IL-6)
during the acute phase responseduring the acute phase response chronic conditions associated with infection, chronic conditions associated with infection,
inflammation, malignancyinflammation, malignancy
Primary platelet overproduction from clonally Primary platelet overproduction from clonally proliferating megakaryocytesproliferating megakaryocytes
In contrast, reactive thrombocytosis is In contrast, reactive thrombocytosis is related to overproduction of interleukin-6 related to overproduction of interleukin-6 ( IL-6) ( IL-6)
during the acute phase responseduring the acute phase response chronic conditions associated with infection, chronic conditions associated with infection,
inflammation, malignancyinflammation, malignancy
Essential (Primary) ThrombocythemiaTherapy
Essential (Primary) ThrombocythemiaTherapy
Platelet-lowering therapyPlatelet-lowering therapy HydroxyureaHydroxyurea AnagrelideAnagrelide InterferonsInterferons
Platelet pheresisPlatelet pheresis Anti-thrombotic therapy Anti-thrombotic therapy
Platelet-lowering therapyPlatelet-lowering therapy HydroxyureaHydroxyurea AnagrelideAnagrelide InterferonsInterferons
Platelet pheresisPlatelet pheresis Anti-thrombotic therapy Anti-thrombotic therapy
Agnogenic Myeloid MetaplasiaAgnogenic Myeloid MetaplasiaPathogenesisPathogenesis
Agnogenic Myeloid MetaplasiaAgnogenic Myeloid MetaplasiaPathogenesisPathogenesis
Primary process: neoplasia of the hematopoietic stem cell
Second aspect of the disease is bone marrow fibrosis, consisting primarily of type I and type III collagen
Primary process: neoplasia of the hematopoietic stem cell
Second aspect of the disease is bone marrow fibrosis, consisting primarily of type I and type III collagen
Agnogenic Myeloid MetaplasiaPathogenesis
Agnogenic Myeloid MetaplasiaPathogenesis
Bone marrow fibrosis Bone marrow fibrosis reactive process that is the result of reactive process that is the result of
functional and kinetic stimulation of functional and kinetic stimulation of nonclonal fibroblasts by growth factors nonclonal fibroblasts by growth factors shed from clonal megakaryocytesshed from clonal megakaryocytes
mediated predominantly by transforming mediated predominantly by transforming growth factor-growth factor-ßß (TGF- (TGF-ßß))
Others: platelet-derived growth factor Others: platelet-derived growth factor (PDGF) and epidermal growth factor (EGF)(PDGF) and epidermal growth factor (EGF)
Bone marrow fibrosis Bone marrow fibrosis reactive process that is the result of reactive process that is the result of
functional and kinetic stimulation of functional and kinetic stimulation of nonclonal fibroblasts by growth factors nonclonal fibroblasts by growth factors shed from clonal megakaryocytesshed from clonal megakaryocytes
mediated predominantly by transforming mediated predominantly by transforming growth factor-growth factor-ßß (TGF- (TGF-ßß))
Others: platelet-derived growth factor Others: platelet-derived growth factor (PDGF) and epidermal growth factor (EGF)(PDGF) and epidermal growth factor (EGF)
Agnogenic Myeloid MetaplasiaAgnogenic Myeloid MetaplasiaClinical FeaturesClinical Features
Agnogenic Myeloid MetaplasiaAgnogenic Myeloid MetaplasiaClinical FeaturesClinical Features
Symptoms secondary to anemia and Symptoms secondary to anemia and marked splenomegalymarked splenomegaly
Leucoerythroblastosis and Leucoerythroblastosis and dacryocytosisdacryocytosis
Hypermetabolism: weight loss, night Hypermetabolism: weight loss, night sweats and feversweats and fever
Symptoms secondary to anemia and Symptoms secondary to anemia and marked splenomegalymarked splenomegaly
Leucoerythroblastosis and Leucoerythroblastosis and dacryocytosisdacryocytosis
Hypermetabolism: weight loss, night Hypermetabolism: weight loss, night sweats and feversweats and fever
Agnogenic Myeloid MetaplasiaClinical Features
Agnogenic Myeloid MetaplasiaClinical Features
Hepatomegaly in 50%Hepatomegaly in 50% Bleeding tendencies secondary to Bleeding tendencies secondary to
intrinsic platelet dysfunction, acquired intrinsic platelet dysfunction, acquired Factor V deficiency, DICFactor V deficiency, DIC
Extramedullary hematopoiesisExtramedullary hematopoiesis Accelerated bone turnover Accelerated bone turnover
demonstrated as increased bone density demonstrated as increased bone density
Hepatomegaly in 50%Hepatomegaly in 50% Bleeding tendencies secondary to Bleeding tendencies secondary to
intrinsic platelet dysfunction, acquired intrinsic platelet dysfunction, acquired Factor V deficiency, DICFactor V deficiency, DIC
Extramedullary hematopoiesisExtramedullary hematopoiesis Accelerated bone turnover Accelerated bone turnover
demonstrated as increased bone density demonstrated as increased bone density
Agnogenic Myeloid MetaplasiaAgnogenic Myeloid MetaplasiaAgnogenic Myeloid MetaplasiaAgnogenic Myeloid Metaplasia
Peripheral blood Bone marrow biopsy Bone marrow biopsy, Reticulin stain
Agnogenic Myeloid MetaplasiaPrognosis
Agnogenic Myeloid MetaplasiaPrognosis
Median survival: 5 yearsMedian survival: 5 years No curative therapy currently availableNo curative therapy currently available PalliationPalliation
Androgen therapyAndrogen therapyDanazolDanazolHydroxyureaHydroxyureaSplenectomySplenectomyRadiation treatment Radiation treatment
Median survival: 5 yearsMedian survival: 5 years No curative therapy currently availableNo curative therapy currently available PalliationPalliation
Androgen therapyAndrogen therapyDanazolDanazolHydroxyureaHydroxyureaSplenectomySplenectomyRadiation treatment Radiation treatment
Chronic Myelogenous LeukemiaChronic Myelogenous LeukemiaChronic Myelogenous LeukemiaChronic Myelogenous Leukemia
Clonal MPD of a pluripotent stem cell with a specific cytogenetic abnormality: the Philadelphia chromosome
A causative factor can not be identified
The first phase of the disease, the chronic phase, terminates in a second, more acute course, the blastic phase. There may be an intervening accelerated phase in between.
Clonal MPD of a pluripotent stem cell with a specific cytogenetic abnormality: the Philadelphia chromosome
A causative factor can not be identified
The first phase of the disease, the chronic phase, terminates in a second, more acute course, the blastic phase. There may be an intervening accelerated phase in between.
Chronic Myelogenous LeukemiaClinical and Hematologic Features
Chronic Myelogenous LeukemiaClinical and Hematologic Features
Fatigue, anemia, progressive splenomegaly, Fatigue, anemia, progressive splenomegaly, leucocytosisleucocytosis
Myeloid cells in the peripheral blood show all Myeloid cells in the peripheral blood show all stages of differentiationstages of differentiation
Basophils and eosinophils are increasedBasophils and eosinophils are increased Reduction in leucocyte alkaline phosphatase Reduction in leucocyte alkaline phosphatase
(LAP)(LAP) Hypercellular bone marrow Hypercellular bone marrow
Fatigue, anemia, progressive splenomegaly, Fatigue, anemia, progressive splenomegaly, leucocytosisleucocytosis
Myeloid cells in the peripheral blood show all Myeloid cells in the peripheral blood show all stages of differentiationstages of differentiation
Basophils and eosinophils are increasedBasophils and eosinophils are increased Reduction in leucocyte alkaline phosphatase Reduction in leucocyte alkaline phosphatase
(LAP)(LAP) Hypercellular bone marrow Hypercellular bone marrow
CML, peripheral bloodCML, peripheral bloodCML, peripheral bloodCML, peripheral bloodA: myeloblasts
B: Neutrophilic myelocyte
C:Neutrophilic metamyelocyte
D: Band
E: Basophil
CML, cytogeneticsCML, cytogeneticsCML, cytogeneticsCML, cytogenetics
CML, cytogenetic abnormalityCML, cytogenetic abnormalityCML, cytogenetic abnormalityCML, cytogenetic abnormality
Chronic Myelogenous LeukemiaTreatment
Chronic Myelogenous LeukemiaTreatment
Allogeneic stem cell transplantation Imatinib: tyrosine kinase inhibitor Interferon Hydroxyurea Busulfan
Allogeneic stem cell transplantation Imatinib: tyrosine kinase inhibitor Interferon Hydroxyurea Busulfan
Case 2-03-01Case 2-03-01Case 2-03-01Case 2-03-01 70 year old male presented with masses in both sides of his neck of one
year duration gradual weight loss, low grade fever, anorexia and body weakness no cough, shortness of breath, abdominal pain and leg swelling PE: BP: 120/80 PR: 87/min, RR: 20/min, Temp: 38’C.
not pale, no jaundice bilateral cervical lymph nodes, the largest measuring 3 x 2 cm, discrete,
nontender and movable mass in the right axilla of the same character no inguinal lymph nodes heart and lung examination were normal spleen was palpable 3 cm below the left subcostal margin at the
midclavicular line no pedal edema
70 year old male presented with masses in both sides of his neck of one year duration
gradual weight loss, low grade fever, anorexia and body weakness no cough, shortness of breath, abdominal pain and leg swelling PE: BP: 120/80 PR: 87/min, RR: 20/min, Temp: 38’C.
not pale, no jaundice bilateral cervical lymph nodes, the largest measuring 3 x 2 cm, discrete,
nontender and movable mass in the right axilla of the same character no inguinal lymph nodes heart and lung examination were normal spleen was palpable 3 cm below the left subcostal margin at the
midclavicular line no pedal edema
Case 2-03-01Case 2-03-01Case 2-03-01Case 2-03-01
What are the possible causes of lymphadenopathy in this patient?
How would you establish the diagnosis? What are the examinations necessary for
diagnosis and staging? What are the What are the types of lymphoma?of lymphoma? What is the What is the treatments available for patients s available for patients
with lymphoma?with lymphoma?
What are the possible causes of lymphadenopathy in this patient?
How would you establish the diagnosis? What are the examinations necessary for
diagnosis and staging? What are the What are the types of lymphoma?of lymphoma? What is the What is the treatments available for patients s available for patients
with lymphoma?with lymphoma?
Lymphoproliferative DisordersLymphoproliferative DisordersLymphoproliferative DisordersLymphoproliferative Disorders
Heterogenous group of diseases with protean manifestations Lymph node enlargement Bone marrow involvement
Anemia, lymphocytosis, thrombocytopenia
Involvement of secondary lymphoid organs Constitutional “B” symptoms: fever, weight loss,
night sweats, pruritus
Heterogenous group of diseases with protean manifestations Lymph node enlargement Bone marrow involvement
Anemia, lymphocytosis, thrombocytopenia
Involvement of secondary lymphoid organs Constitutional “B” symptoms: fever, weight loss,
night sweats, pruritus
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Diseases/ Exposures Associated with Diseases/ Exposures Associated with Increased Risk of LymphomaIncreased Risk of Lymphoma
Inherited immunodeficiency disease Klinefelter’s syndrome Chediak Hegashi syndrome Ataxia telagiectasia syndrome Wiskott-Aldrich syndrome Common variable
immunodefiency disease Acquired immunodeficiency
Iatrogenic immunosuppression HIV-1 infection Acquired
hypogammaglobulinemia
Autoimmune disease Sjogren’s syndrome Celiac sprue Rheumatoid arthritis Systemic lupus
erythematosus Chemical or Drug exposures
Phenytoin Dioxin, phenoherbicides Radiation Prior chemotherapy &
radiation therapy
Agent Lymphoid Malignancy
Epstein Barr virus Burkitt’s lymphoma
Post-transplant lymphoma
Primary CNS Diffuse large B cell lymphoma
Hodgkin’s disease
Extranodal NK/T cell lymphoma, nasal type
HTLV-1 Adult T-cell leukemia/lymphoma
Human Herpes Virus-8 multicentric Castleman's disease
Primary effusion lymphoma
Hepatitis C virus (HCV) essential mixed cryoglobulinemia
monocytoid B-cell lymphoma lymphoplasmacytoid lymphoma
Helicobacter pylori gastric MALT lymphoma
Infectious AgentsInfectious Agents
A properly done biopsy is extremely A properly done biopsy is extremely important in the diagnosis of lymphomaimportant in the diagnosis of lymphoma
A properly done biopsy is extremely A properly done biopsy is extremely important in the diagnosis of lymphomaimportant in the diagnosis of lymphoma
Benign reactive lymph node Follicular, small cleaved cell (NHL)
Diffuse small lymphocytic (NHL) Diffuse large cell (NHL)
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Diagnosis of Hodgkin’s Diagnosis of Hodgkin’s DiseaseDisease
Diagnosis of Hodgkin’s Diagnosis of Hodgkin’s DiseaseDisease
The presence of the Reed-Sternberg cell is a sine qua non for the diagnosis of Hodgkin’s disease
Evaluation for Diagnosis & Evaluation for Diagnosis & StagingStaging
Evaluation for Diagnosis & Evaluation for Diagnosis & StagingStaging
Complete blood count ESR Biochemical studies of major
organ function For NHL
SLDH B2 microglobulin Serum protein electrophoresis
Excision biopsy of lymph node Flow cytometry IHC Cytogenetics
Complete blood count ESR Biochemical studies of major
organ function For NHL
SLDH B2 microglobulin Serum protein electrophoresis
Excision biopsy of lymph node Flow cytometry IHC Cytogenetics
Imaging studies Contrast-enhanced CT scan
of the chest and whole abdomen
MRI if indicated Gallium scan not necessary
for primary staging PET scan
Bone marrow aspiration and biopsy
Imaging studies Contrast-enhanced CT scan
of the chest and whole abdomen
MRI if indicated Gallium scan not necessary
for primary staging PET scan
Bone marrow aspiration and biopsy
Back
Revised European-American Lymphoma Revised European-American Lymphoma (REAL)/WHO Classification(REAL)/WHO Classification
Revised European-American Lymphoma Revised European-American Lymphoma (REAL)/WHO Classification(REAL)/WHO Classification
B cell neoplasms Precursor B-cell neoplasm
Precursor B-lymphoblastic leukemia/lymphoma (precursor B-cell acute lymphoblastic leukemia)
Mature (peripheral) B-cell neoplasms Chronic lymphocytic leukemia/B-cell small
lymphocytic lymphoma B-cell prolymphocytic leukemia Lymphoplasmacytic lymphoma Splenic marginal zone B-cell lymphoma
(splenic lymphoma with villous lymphocytes) Hairy cell leukemia Plasma cell myeloma/plasmacytoma Extranodal marginal zone B-cell lymphoma
(MALT lymphoma) Nodal marginal zone B-cell lymphomaFollicular lymphoma Mantle cell lymphoma Diffuse large B-cell lymphomas Burkitt's lymphoma/leukemia
B cell neoplasms Precursor B-cell neoplasm
Precursor B-lymphoblastic leukemia/lymphoma (precursor B-cell acute lymphoblastic leukemia)
Mature (peripheral) B-cell neoplasms Chronic lymphocytic leukemia/B-cell small
lymphocytic lymphoma B-cell prolymphocytic leukemia Lymphoplasmacytic lymphoma Splenic marginal zone B-cell lymphoma
(splenic lymphoma with villous lymphocytes) Hairy cell leukemia Plasma cell myeloma/plasmacytoma Extranodal marginal zone B-cell lymphoma
(MALT lymphoma) Nodal marginal zone B-cell lymphomaFollicular lymphoma Mantle cell lymphoma Diffuse large B-cell lymphomas Burkitt's lymphoma/leukemia
T- and NK-cell neoplasms Precursor T-cell neoplasm
Precursor T-lymphoblastic leukemia/lymphoma (precursor T-cell acute lymphoblastic leukemia)
Blastoid NK cell lymphoma Mature (peripheral) T-cell neoplasms
T-cell prolymphocytic leukemia T-cell large granular lymphocytic leukemia Aggressive NK cell leukemia Adult T-cell lymphoma/leukemia (HTLV-1+) Extranodal NK/T-cell lymphoma, nasal type nteropathy-type T-cell lymphomaHepato splenic T-cell lymphoma Subcutaneous panniculitis-like T-cell lymphoma Mycosis fungoides/Sézary syndrome Primary cutaneous anaplastic large cell
lymphoma Peripheral T-cell lymphoma, not otherwise
specified Angioimmunoblastic T-cell lymphoma Primary systemic anaplastic large cell
lymphoma
T- and NK-cell neoplasms Precursor T-cell neoplasm
Precursor T-lymphoblastic leukemia/lymphoma (precursor T-cell acute lymphoblastic leukemia)
Blastoid NK cell lymphoma Mature (peripheral) T-cell neoplasms
T-cell prolymphocytic leukemia T-cell large granular lymphocytic leukemia Aggressive NK cell leukemia Adult T-cell lymphoma/leukemia (HTLV-1+) Extranodal NK/T-cell lymphoma, nasal type nteropathy-type T-cell lymphomaHepato splenic T-cell lymphoma Subcutaneous panniculitis-like T-cell lymphoma Mycosis fungoides/Sézary syndrome Primary cutaneous anaplastic large cell
lymphoma Peripheral T-cell lymphoma, not otherwise
specified Angioimmunoblastic T-cell lymphoma Primary systemic anaplastic large cell
lymphoma
Table 41.5-2: Classifications of Hodgkin's Lymphoma (HL)
Jackson and Parkera
Lukes and Butlerb Rye Conferencec REAL Classificationd WHO Classificatione
Paragranuloma Lymphocytic and/or histiocytic, nodular
Lymphocyte predominant
Nodular lymphocyte predominant
Lymphocyte predominant, nodular
Lymphocytic and/or histiocytic, diffuse
Classic HL Classic HL
Lymphocyte-rich classic HLf
Lymphocyte-rich classic HL
Granuloma Nodular sclerosis Nodular sclerosis Nodular sclerosis Nodular sclerosis
Mixed cellularityg Mixed cellularityg Mixed cellularity Mixed cellularity
Sarcoma Diffuse fibrosis Lymphocytic depleted
Lymphocyte depleted Lymphocyte depleted
Reticular Unclassifiable classic HL
Classification of Hodgkin’s Classification of Hodgkin’s LymphomaLymphoma
Classification of Hodgkin’s Classification of Hodgkin’s LymphomaLymphoma
Histologic subtypes of Hodgkin’s Histologic subtypes of Hodgkin’s DiseaseDisease
Histologic subtypes of Hodgkin’s Histologic subtypes of Hodgkin’s DiseaseDisease
Lymphocytic predominance
Mixed Cellularity
Nodular sclerosis
Lymphocyte depletion
Disease Cytogenetic abnormality
Oncogene
CLL/ Small lymphocytic lymphoma
t(14;15)(q32;q13)
MALT lymphoma t(11;18)(q21;q21)
Precursor B cell acute lymphoid leukemia
t(9;22)(q34;q11)
t(12;21)(p12;q22)
11q23/MLL
BCR/ABL
ETV6
ETV6-CBFA2 TEL-AML1
Molecular MarkersMolecular Markers
Disease Cytogenetic abnormality
Oncogene
Mantle cell lymphoma
t(11;14)(q13;q32) BCL-1
Follicular lymphoma t(14;18)(q32;q21) BCL-2
Diffuse large cell lymphoma
t(3;-)(q27;-)
t(17;-)(p13;-)
BCL-6
p53
Burkitt’s lymphoma t(8;-)(q24;-) C-MYC
Anaplastic large cell lymphoma
t(2;5)(q23;q35) ALK
Lymphoplasmacytoid lymphoma
t(9:14)(p13;q32)
Molecular MarkersMolecular Markers
Back to Questions
Histologic subtype of lymphoma Indolent vs. Aggressive
Stage Early vs. advanced disease
Age Performance status Co-morbid conditions
Heart disease, liver disease, renal disease
Management: NHLManagement: NHL
Treatment: Intermediate to High Treatment: Intermediate to High Risk NHLRisk NHL
Treatment: Intermediate to High Treatment: Intermediate to High Risk NHLRisk NHL
Chemotherapy Targeted Agents
Rituximab: Anti-CD20 antibody
Chemotherapy Targeted Agents
Rituximab: Anti-CD20 antibody
Watchful waiting Single agent chemotherapy
Chlorambucil Fludarabine
Combination chemotherapy CVP CHOP
Treatment of Indolent Treatment of Indolent LymphomasLymphomas
International Prognostic Index for International Prognostic Index for NHLNHL
International Prognostic Index for International Prognostic Index for NHLNHL
Early stages, favorable: radiation alone (extended field)
Early stages, unfavorable: moderate amount of chemotherapy (typically four cycles) plus radiation
Advanced stages: extensive chemotherapy (typically eight cycles) with or without consolidating (usually local) radiation
Treatment Strategies: HDTreatment Strategies: HD
Case 2-01-02Case 2-01-02Case 2-01-02Case 2-01-02 92 year old male has no complaints but has been noted to have chronic anemia
for the past 3 years consulted several physicians, given oral iron therapy with apparently some
improvement in hemoglobin levels the maximum reached was 97 gm/L requiring blood transfusions for the past year no changes in his bowel movements, including changes in color no changes in the urine volume or color frequent episodes of cough but no fever weight loss, which was not quantified Physical examination: alert elderly male, wheelchair borne, with VS: BP:
110/70, PR: 100/min, regular, RR: 18/min, regular, Temp: 36.5’C. pale, no jaundice, no lymphadenopathy soft blowing systolic murmur in the left parasternal area, clear breath
sounds no hepatoslenomegaly No pedal edema.
92 year old male has no complaints but has been noted to have chronic anemia for the past 3 years
consulted several physicians, given oral iron therapy with apparently some improvement in hemoglobin levels the maximum reached was 97 gm/L
requiring blood transfusions for the past year no changes in his bowel movements, including changes in color no changes in the urine volume or color frequent episodes of cough but no fever weight loss, which was not quantified Physical examination: alert elderly male, wheelchair borne, with VS: BP:
110/70, PR: 100/min, regular, RR: 18/min, regular, Temp: 36.5’C. pale, no jaundice, no lymphadenopathy soft blowing systolic murmur in the left parasternal area, clear breath
sounds no hepatoslenomegaly No pedal edema.
CBC: HB: 89 gm/L, Hct: 0.26,
WBC: 2.6 x 109/L
segmenters: 39%, lymphocytes: 61%, platelets: 200 x 109/L
CBC: HB: 89 gm/L, Hct: 0.26,
WBC: 2.6 x 109/L
segmenters: 39%, lymphocytes: 61%, platelets: 200 x 109/L
Case 2-01-02Case 2-01-02Case 2-01-02Case 2-01-02
Case 2-02-02Case 2-02-02Case 2-02-02Case 2-02-02
63 year old female had recent onset of dizziness 4 days ago accompanied by headache, palpitations, shortness of breath,
and easy fatigability no fever, cough, orthopnea, PND , nor pedal edema Family history is negative for cancer or blood disease past history of asthma PE: VS: BP: 120/70, PR: 90/min, RR: 20/min, Temp:
37.5’C, pale, no jaundice, no palpable lymph nodes no murmurs, clear breath sounds, no crackles liver not palpable but spleen palpable 3 fingerbreadths
below LSCM.
63 year old female had recent onset of dizziness 4 days ago accompanied by headache, palpitations, shortness of breath,
and easy fatigability no fever, cough, orthopnea, PND , nor pedal edema Family history is negative for cancer or blood disease past history of asthma PE: VS: BP: 120/70, PR: 90/min, RR: 20/min, Temp:
37.5’C, pale, no jaundice, no palpable lymph nodes no murmurs, clear breath sounds, no crackles liver not palpable but spleen palpable 3 fingerbreadths
below LSCM.
CBC: Hb: 71 gm/L Hct: 0.31 WBC : 389 x 109/L
metamyelocytes: 24% bands 21%
segmenters 36% lymphocytes 4%
eosinophils 3 %Platelets: 1689 x 109/L
CBC: Hb: 71 gm/L Hct: 0.31 WBC : 389 x 109/L
metamyelocytes: 24% bands 21%
segmenters 36% lymphocytes 4%
eosinophils 3 %Platelets: 1689 x 109/L
Case 2-02-02Case 2-02-02Case 2-02-02Case 2-02-02
Case 2-02-04Case 2-02-04Case 2-02-04Case 2-02-04 55 year old female noted to have gradual abdominal enlargement
for the past three years with significant increase during the past three months
nonproductive cough for the past three weeks good appetite, no early satiety, weight loss or easy fatigability Physical examination showed VS: BP: 120/70, PR: 84/min, RR:
20/min, Temp: 36.7’C. pink palpebral conjunctivae, no jaundice, no lymphadenopathies no murmurs Lung examination: rhonchi on both lung fields liver was palpable 5 cm below the RSCM, the spleen was palpable
21 cm below the LSCM at MCL no pedal edema
55 year old female noted to have gradual abdominal enlargement for the past three years with significant increase during the past three months
nonproductive cough for the past three weeks good appetite, no early satiety, weight loss or easy fatigability Physical examination showed VS: BP: 120/70, PR: 84/min, RR:
20/min, Temp: 36.7’C. pink palpebral conjunctivae, no jaundice, no lymphadenopathies no murmurs Lung examination: rhonchi on both lung fields liver was palpable 5 cm below the RSCM, the spleen was palpable
21 cm below the LSCM at MCL no pedal edema
CBC showed HB: 158 gm/L, Hct: 0.50, WBC: 23 x 109/L Segmenters 87%, Lymphocytes 11%, Monocytes 2%, Platelets: 474 x 109/L
CBC showed HB: 158 gm/L, Hct: 0.50, WBC: 23 x 109/L Segmenters 87%, Lymphocytes 11%, Monocytes 2%, Platelets: 474 x 109/L
Case 2-02-04Case 2-02-04Case 2-02-04Case 2-02-04