Myelodysplastic Syndromes Between FAB and WHO

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Myelodysplastic SyndromesBetween FAB and WHO

• Mona F. Melhem, MD
• Professor, Department of Pathology
• University of Pittsburgh School of Medicine
• Chief Hematology
• VA Medical Center of Pittsburgh
• Pittsburgh, Pennsylvania

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Myelodysplastic Syndromes (MDS)

• Clonal hematopoietic Stem Cell Disease
• Dysplasia
• Ineffective Hematopoiesis (1 or more lines)
• Myeloblasts lt 20 of all marrow cells
• Synonyms
• Dysmyelopoietic syndromes
• Preleukemic syndromes
• Oligoblastic leukemia

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MDS Epidemiology

• Older adults (median age 70 years)
• Primary vs. Secondary MDS (S/P chemotherapy)
• Incidence 3/100,000 non-age corrected
• 20/100,000 over age 70

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MDS Clinical

• Symptoms of Cytopenia
• Anemia gt Neutropenia /- Thrombocytopenia
• Organomegaly (infrequent)

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MDS Etiology

• Primary
• No known history of toxic exposure
• Possible etiologies Virus, Benzene, cigarette (2
  fold risk), Fanconi anemia.
• Therapy-related
• Chemotherapy (alkylating agents)
• Radiation Therapy

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MDS Morphology

• blasts in marrow and blood
• Type and degree of dysplasia
• /- ringed sideroblasts
• Cytogenetic abnormalities del (5q)
• 500 cell diff in marrow
• 200 cell diff in PB

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MDS Differential Diagnosis

• B12/folate deficiency
• Heavy metals (Arsenic)
• Congenital dyserythropoietic anemia
• Parvovirus B19
• GCSF therapy (increased blasts)

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Myelodysplastic Syndromes

• FAB Classification
• RA
• RARS
• RAEB
• RAEB-T
• CMML

• WHO classification
• Myelodysplastic Syndromes
• RA
• RARS
• RCMD RCMD-RS
• RAEB-1 RAEB-2
• MDS Unclassified
• MDS del(5q)
• Myelodysplastic/Myeloproliferative Diseases
• CMML
• Atypical CML
• Juvenile CMML
• MDS/MPD, unclassified

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MDS Genetics

• 5q- syndrome (women, megakaryocyte anomalies
• Del 17p (pseudo Pelger-Huet anomaly, therapy
  related)
• Complex cytogenetic (chromosomes 5 7)
  unfavorable prognosis
• Del(20q) (erythroid and megakaryocytes)
• Abnormal Ch 3 (abnormal megas)

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MDS Prognosis

• Low Risk group
• RA and RARS
• Normal cytogenetics, del(5q), del(20q) and -Y
• High Risk
• RAEB and RCMD
• Complex abnormalities
• Abnormal Ch 7

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MDS Score predicts survival

• Low 0
• INT-1 0.5-1.0
• INT-2 1.5-2.0
• High gt 2.5

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Myelodysplastic Syndromes

• WHO classification
• Myelodysplastic Syndromes
• RA
• RARS
• RCMD RCMD-RS
• RAEB-1 RAEB-2
• MDS Unclassified
• MDS del(5q)
• Myelodysplastic/Myeloproliferative Diseases
• CMML
• Atypical CML
• Juvenile CMML
• MDS/MPD, unclassified

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Myelodysplastic Syndromes

• Refractory Anemia
• Blood Anemia, no or rare blasts
• BM Erythroid Dysplasia only
• lt 5 blasts
• lt 15 ringed sideroblasts

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Refractory Anemia (RA)

• Unilineage Dysplasia (Erythroid)
• Anemia refractory to therapy
• Unequivocal dyserythropoiesis
• Exclude all other possibilities i.e
• Drugs, toxins, virus, immunologic, congenital and
  vitamin deficiencies

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Refractory Anemia (RA)

• Observe for 6 months and re-evaluate
• Myeloblasts lt1 PB and lt5 BM
• DD Other MDS with multilineage dysplasia or
  Ringed Sideroblasts

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Refractory Anemia (RA)

• PB Normochromic, Normocytic RBCs
• Anisocytosis
• Poikilocytosis
• Blasts lt1
• Normal neutrophils and platelets

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Refractory Anemia (RA)

• BM Hypercellular, normocellular or hypocellular
• Dyserythropoiesis
• Nuclear budding, internuclear bridging,
  karyorrhexis, multinuclearity, megaloblastoid
  features
• Cytoplasmic vacuolization, PAS positivity
• Ringed Sideroblasts lt15 erythroid precursors
• Myeloblasts lt 5 all marrow cells
• Aur rods absent

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Refractory Anemia (RA)

• Genetics (useful, not specific)
• 25 of cases
• Del (20q), 8, abnormal 5 and/or 7

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Refractory Anemia (RA)

• Prognosis
• 66 months survival
• 6 progress to leukemia

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Refractory Anemia with Ringed Sideroblasts (RARS)

• 15 erythroid precursors are ringed sideroblasts
• 1/3 or more of the nucleus encircled by
  sideroblastic granules (Fe stain)
• Myeloblasts lt5
• R/O other causes of sideroblasts (anti-TB drugs,
  alcohol)

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Refractory Anemia with Ringed Sideroblasts (RARS)

• 10-12 of MDS cases
• Older patients
• Males gt females
• Moderate anemia (Normo or Macro)
• Dysplasia restricted to erythroid lineage
• Genetic abnormalities in lt10 of cases
• 1-2 evolve to AML
• Median survival 6 years

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Refractory Cytopenia with Multilineage Dysplasia
(RCMD)

• Bi-cytopenia or pancytopenia
• Dysplasia 10 of cells, 2 or more lineages
• lt1 blasts (PB)
• lt5 blasts (BM)
• Absent Aur Rods
• Monocytes lt 1x109/L

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Refractory Cytopenia with Multilineage Dysplasia
(RCMD)

• RCMD 24 cases of MDS
• RCMD-RS 15 cases of MDS
• Older patients
• BM failure, cytopenia 2 or more myeloid lineage
• Dysplasia gt10 of marrow cells
• Trisomy 8, monosomy 7, del(7q), monosomy 5, del
  (5q), del (20q)
• 11 progress to AML, Mean survival 33 mo

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Refractory Anemia with Excess blasts (RAEB)

• 5-19 myeloblasts in BM
• RAEB-1 5-9 blasts (BM)
• lt5 blasts (PB)
• RAEB-2 10-19 blasts (BM)
• or 5-19 blasts (PB) lt10 blasts (BM)
• or Presence of Aur Rods

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Refractory Anemia with Excess Blasts (RAEB)

• 40 of all patients with MDS
• 50 yrs and older
• Anemia, thrombocytopenia or neutropenia
• Abnormalities in all three lines (PB)
• Anisopoikilocytosis
• Atypical plts
• Pseudo Pelger Huet anomaly
• Blasts (0-19)

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Refractory Anemia with Excess Blasts (RAEB)

• BM Mostly Hypercellular ALIPs
• Neutrophil Hyperplasia with dysplasia
• Small, nuclear hypolobation, hypersegmentation,
  hypogranularity
• Erythroid dyserythropoiesis
• Megakaryocytes hypolobated, micromegas, widely
  separated nucleii

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Refractory Anemia with Excess Blasts (RAEB)

• 30-50 clonal cytogenetic abnormalities
• 8, -5, del(5q), -7, del(7q) and del(20q)
• Immunophemotype
• Blasts express CD13, CD33, CD117
• 25 RAEB-1 and 33 RAEB-2 progress to AML
• Median survival 18 mo (RAEB-1), 10 mo (RAEB-2)

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MDS, unclassified

• No specific morphologic findings
• Neutropenia and thrombocytopenia
• Dysplasia restricted to myeloid or megas
• Hyper/normo or hypocellular marrow
• No specific cytogenetic findings
• Older or younger patients, even children
• No increase in blasts

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5q- syndrome

• Myelodysplastic syndrome associated with isolated
  del (5q) chromosome
• lt 5 Blasts in marrow and blood
• Predominantly middle-aged to older women
• Severe Refractory Anemia (Macrocytic)
• Hypercellular marrow with abnormal megas

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Myelodysplastic Syndromes

• FAB Classification
• RA
• RARS
• RAEB
• RAEB-T
• CMML

• WHO classification
• Myelodysplastic Syndromes
• RA
• RARS
• RCMD RCMD-RS
• RAEB-1 RAEB-2
• MDS Unclassified
• MDS del(5q)
• Myelodysplastic/Myeloproliferative Diseases
• CMML
• Atypical CML
• Juvenile CMML
• MDS/MPD, unclassified

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Myelodysplastic/Myeloproliferative Diseases
(MDS/MPD)

• Chronic Myelomonocytic Leukemia (CMML)
• Atypical Chronic Myeloid Leukemia (CML)
• Juvenile CMML
• MDS/MPD, unclassified

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Myelodysplastic/Myeloproliferative Diseases
(MDS/MPD)

• Clonal hematopoietic neoplasms
• Clinical/lab/morph supporting MDS
• finding c/w Chronic myeloproliferative
  diseases, No Phchromosome
• Hypercellular marrow, spleno hepatomegaly
• Dysplasia
• Blasts lt20

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Myelodysplastic/Myeloproliferative Diseases
(MDS/MPD)

• t(512) (q31p12) and t(510)(q33q22), enhances
  the tyrosine kinase of PDGF-R, leading to
  abnormal RAS activation.
• JMML associated with neurofibromatosis type-1
  (NF-1)
• Survival ranges from months to years
• Complications of cytopenias, leukemia

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Chronic Myelomonocytic Leukemia (CMML)

• Clonal disorder of marrow stem cell
• Persistent Monocytosis gt1x109/L (PB), 3mo
• (-) Philadelphia and BCR/ABL fusion gene
• lt20 blasts (PB BM), including myeloblasts,
  monoblasts and promonocytes
• /- Dysplasia in 1 or more BM lineages.

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Chronic Myelomonocytic Leukemia (CMML)

• Differntial diagnosis
• Tumors (leukemoid reaction)
• Infection
• Inflammation
• CML
• Other myeloproliferative disorders

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Chronic Myelomonocytic Leukemia (CMML)

• 31 of cases of MDS
• Median age at Dx 65-75 yrs
• Male predominance 1.5-3.11
• Blood BM involvement /- spleen, liver, skin,
  LN extramedullary leukemic infiltrate

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Chronic Myelomonocytic Leukemia (CMML)

• WBC normal (50 of cases), or increased
• Monocytosis with neutropenia
• Fatigue, wt loss, fever, night sweat, infection,
  bleeding
• Hepatomegaly splenomegaly if WBC hi
• Unknown etiology (carcinogens, radiation,
  cytotoxic agents.)

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NSE
NSE/fluoride
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Chronic Myelomonocytic Leukemia (CMML)

• CMML-1 blastslt5 PB
• blastslt10 BM
• CMML-2 blasts 5-19 PB
• blasts 10-19 BM
• Blasts gt20 is AML

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CMML with eosinophilia

• CMML PB Eos gt1.5 x 10 9/L
• Complication with tissue damage due to
  degranulation of eos
• Should be classified as CMML-1 or CMML-2 with
  eosinophilia

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CMML

• CD33, CD13
• Variable CD14, CD68 and CD64
• Increased CD 34 may indicate transformation to
  AML
• Genetics
• 8, -7/del (7q), abnormal 12p
• Survival 1-100 months
• Progression to acute leukemia 15-30

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Atypical Chronic Myeloid Leukemia (aCML)

• MDS and MPD changes
• NO Philadelphia Chromosome or BCR-ABL fusion gene
• Elderly patient (60-70s)
• MF ratio 11-2.51
• Blood, BM, spleen and liver
• Neutrophil precursors gt10 PB

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aCML

• Hypercellular marrow
• ME ratio 101
• lt20 blasts
• Dysmyelopoiesis (trilineage)
• Poor prognosis
• 8, 13, del(20q), i(17q), del (12p)

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Juvenile Myelomonocytic leukemia (JMML)

• Childhood disorder
• Clonal hematopoietic disorder
• Proliferation of granulocytes and monocytes
• /- erythroid and megakaryocytic abnormalities
• 1.3/million children 0-14 yrs of age (75 of
  cases less than 3 yrs of age)
• 2-3 of all leukemias

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JMML

• Malaise, palor, fever, bronchitis, tonsilitis,
  skin rash, café-au-lait spots, bleeding,
  hepatosplenomegaly
• PB Monocytosis gt1x109/L (PB), 3mo
• (-) Philadelphia ch or BCR/ABL fusion gene
• lt20 blasts (PB BM), including myeloblasts,
  monoblasts and promonocytes
• two or more of the following
• Hb F (high for age)
• Immature granulocytes in PB
• Clonal chromosomal abnormality (CH 7)
• GM-CSF hypersensitivity of myeloid precursors (in
  vitro)

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JMML (etiology)

• ? Genetic predisposition
• Cases reported in twins
• JMML Neurofibromatosis (NF-1)
• Children with NF-1 have 200-500 x risk to develop
  JMML

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JMML (prognosis)

• Variable
• Poor with death within 1 year (30 of cases)
• Median survival 5 mo-4 yrs
• Better prognosis in children lt 1yr of age
• Poor prognosis if pltslt 33 k or HbFgt15

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MDS/MPD, unclassified

• Lab and Morphologic features of MDS
• AND
• Prominent myeloprolifetarive features
• No hx of underlying CMPD or MDS, no toxins, no Ph
  ch, no del (5q), no t(33)(q21q26), no inv
  (3)(q21q26)
• Mixed MPD and MDS cannot be assigned any other
  category