Myelodysplastic syndrome and acute myeloid leukaemia

1
Myelodysplastic syndrome and acute myeloid
leukaemia

• Dr. Edmond S. K. Ma
• Division of Haematology
• Department of Pathology
• The University of Hong Kong

2
Leukaemia classification

• FAB
• MIC 1987
• EGIL 1996
• REAL
• Proposed by ILSG in 1994
• Lymphoma classification, but principles extended
  to other haemic neoplasms
• Encompasses all available information
• Consensus approach

3
WHO Classification

• Collaborative project of
• European Association for Haematopathology
• Society for Haematopathology
• Started in 1995
• Steering Committee
• Working Group Meeting in Lyon, France, November 8
  11, 2000
• Clinical Advisory Committee

4
Myelodysplastic syndrome

• A group of clonal haemopoietic stem cell disorder
  characterized by dysplasia and ineffective
  haemopoiesis in one or more major myeloid cell
  line
• lt 20 blasts in blood and bone marrow

5
Myelodysplastic syndrome

• A disease of the elderly
• Incidence 3 20 /100,000
• Increasing number of therapy related MDS
• Clinical features related to cytopenia
• Etiology prior chemoradiotherapy, benzene
  exposure, cigarette smoking, inherited syndromal
  disorders (e.g. Fanconis anaemia)

6
Dyserythropoiesis

• Nuclear budding
• Inter-nuclear bridging
• Karyorrhexis
• Multinuclearity
• Megaloblastoid maturation
• Ringed sideroblast
• Vacuolation
• PAS ve

7
Dyserythropoiesis
8
Dyserythropoiesis
9
Dysgranulopoiesis

• Small size
• Nuclear hypolobulation (pseudo-Pelger Heut)
• Hypersegmentation
• Hypogranularity
• Pseudo-Chediak Higashi granules

10
Dysgranulopoiesis
11
Dysgranulopoiesis
12
Dysmegakaryocytopoiesis

• Hypolobulated micro-megakaryocyte
• Non-lobulated nuclei in megakaryocyte of all
  sizes
• Multiple, widely separated nuclei

13
Megakaryocyte dysplasia
14
Megakaryocyte dysplasia
15
Abnormal localization of immature precursors

• Presence of 3 or more small clusters of
  myeloblasts and promyelocytes (5 8 cells) in
  marrow trephine biopsy in the central portion of
  the marrow away from the vascular structure and
  the endosteal surface of the bone trabeculae

16
Abnormal localization of immature precursors
17
Genetics

• 5q- syndrome
• del (17p), small hypolobulated or vacuolated
  neutrophils, p53 mutations, poor prognosis
• -5/5q-
• -7/7q-
• del(20q)
• 3q21q26 abnormality

18
Cytogenetics and prognosis

• Good risk
• Normal, isoloted 5q-, isolated 20q-, -Y
• Poor risk
• Complex changes (gt 3 abnormalities)
• Chromosome 7 abnormalities
• Intermediate risk
• All other changes

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International Prognostic Scoring System

• Score 0 0.5 1 1.5
• blasts lt5 5-10 - 11-20
• Karyotype Good Intermediate Poor
• Cytopenia 0-1 2-3
• Cytopenia Hb lt 10 g/dL neutrophils lt 1.5 X
  109/L plt lt 100 X 109/L
• Risk groups
• Low 0 Intermediate-1 0.5-1 Intermediate-2
  1.5-2 High ?2.5

20
Refractory anaemia

• PB
• anaemia,
• no or rare (lt1)
• blasts

• MB
• Unilineage dysplasia, restricted to erythroid
  lineage,
• lt 5 blasts,
• lt 15 ringed sideroblasts

21
Refractory anaemia

• Exclusion of known secondary causes of
  dyserythropoiesis
• If no cytogenetic abnormality present, reassess
  after 6 months
• Protracted clinical course, median survival is 66
  months, leukaemic transformation 6

22
Giant pronormoblast is parvovirus infection
23
Refractory anaemia with ringed sideroblasts

• PB
• Anaemia
• No blast

• MB
• ? 15 ringed sideroblasts
• Erythroid dysplasia only
• lt5 blasts

24
Ringed sideroblast

• Erythroid precursor
• One third or more of the nucleus
• Encircled by 10 or more siderotic granules

25
Refractory anaemia with ringed sideroblasts

• Indolent clinical course
• Median survival 6 years
• Leukaemic transformation 1 2

26
Refractory cytopenia with multilineage dysplasia

• PB
• Bicytopenia or pancytopenia
• No or rare blasts
• No Auer rod
• lt 1 X 109/L monocytes

• MB
• Dysplasia in ? 10 of cells in two or more
  myeloid cell lines
• lt 5 blasts
• No Auer rod
• lt 15 ringed sideroblasts

27
Refractory cytopenia with multilineage dysplasia
28
Refractory cytopenia with multilineage dysplasia
29
Refractory cytopenia with multilineage dysplasia
30
Refractory cytopenia with multilineage dysplasia
and ringed sideroblasts

• PB
• Bicytopenia or pancytopenia
• No or rare blasts
• No Auer rod
• lt 1 X 109/L monocytes

• MB
• Dysplasia in ? 10 of cells in two or more
  myeloid cell lines
• lt 5 blasts
• No Auer rod
• ? 15 ringed sideroblasts

31
Refractory cytopenia with multilineage dysplasia

• Cytogenetic abnormality seen in 50
• 8
• Monosomy 7
• del(7q)
• Monosomy 5
• del (5q)
• del (20q)
• Complex karyotype

32
Refractory cytopenia with multilineage dysplasia

• Leukaemic transformation 11
• Overall median survival 33 months
• RCMD and RCMD-RS are similar in clinical course
• Patients with complex karyotype have similar
  clinical course to RAEB

33
Refractory anaemia with excess blasts-1

• PB
• Cytopenia
• lt5 blasts
• No Auer rod
• lt1 monocytes

• MB
• Unilineage or multilineage dysplasia
• 5-9 blasts
• No Auer rod

34
Refractory anaemia with excess blasts-2

• PB
• Cytopenia
• 5-19 blasts
• Auer rod
• lt1 monocytes

• MB
• Unilineage or multilineage dysplasia
• 10-19 blasts
• Auer rod

35
Refractory anaemia with excess blasts-2
36
Refractory anaemia with excess blasts

• Blast cells show myeloid phenotype
• Leukaemic transformation
• RAEB-1 25
• RAEB-2 33
• Median survival
• RAEB-1 18 months
• RAEB-2 10 months

37
Myelodysplastic syndrome, unclassifiable

• PB
• Cytopenias
• No or rare blasts
• No Auer rods

• MB
• Unilineage dysplasia, one myeloid cell line
• (non-erythroid)
• lt5 blasts
• No Auer rod

38
5q- syndrome

• PB
• Anaemia
• Usually normal or increased platelet count
• lt5 blasts

• MB
• Normal or increased megakaryocytes with
  hypolobulated nuclei
• lt5 blasts
• Isolated 5q- abnormality
• No Auer rod

39
5q- syndrome
40
Acute myeloid leukaemia

• Acute myeloid leukaemia with recurrent genetic
  abnormalities
• Acute myeloid leukaemia with multilineage
  dysplasia
• Acute myeloid leukaemia and myelodysplastic
  syndrome, therapy-related
• Acute myeloid leukaemia not otherwise categorized

41
Acute myeloid leukaemia
42
Acute myeloid leukaemia
43
Acute myeloid leukaemia

• The blast is lowered from 30 (FAB) to 20
  (WHO)
• Median age of onset 60 yrs
• Incidence 4 10 / 100,000
• Etiology

44
Myeloblasts versus lymphoblasts
45
Acute myeloid leukaemia
46
Acute lymphoblastic leukaemia
47
Acute myeloid leukaemia cytochemistry

• Myeloperoxidase
• Sudan Black B
• Non-specific esterase
• a-naphthyl butyrate
• a-naphthyl acetate

48
Cytochemistry MPO
49
Cytochemistry NSE
50
Cytochemistry
51
Acute myeloid leukaemia role of immunophenotyping

• Distinction of minimally differentiated AML from
  acute lymphoblastic leukaemia
• Recognition of AML-M7
• Recognition of specific AML sub-categories (e.g
  CD56ve AML)
• Diagnosis of biphenotypic leukaemia
• However, immunophenotyping is not mandatory in
  typical cases of AML, unlike in ALL where a
  phenotypic diagnosis is needed in every case

52
Acute myeloid leukaemia role of immunophenotyping
53
Panel of monoclonal antibodies in classification
of acute leukaemia

• Haemopoietic precursors CD34, HLA-DR, Tdt, CD45
• B-lineage CD19, CD20, CD22, CD79a
• T-lineage CD2, CD3, CD5, CD7
• Myeloid CD13, CD33, CD117, anti-MPO
• Megakaryocytic CD41, CD61

54
Acute myeloid leukaemia with recurrent genetic
abnormalities

• Acute myeloid leukaemia with t(821)(q22q22)
  AML1/ETO
• Acute myeloid leukaemia with abnormal bone marrow
  eosinophils and inv(16)(p13q22) or
  t(1616)(p13q22) CBFb/MYH11
• Acute promyelocytic leukaemia (AML with
  t(1517)(q22q12) PML/RARa and variants
• Acute myeloid leukaemia with 11q23 (MLL)
  abnormalities

55
Acute myeloid leukaemia with t(821)(q22q22)
AML1/ETO

• t(821) is the commonest translocation in AML
• Associated with AML-M2 morphology
• Tumour masses (granulocytic sarcoma)

56
Acute myeloid leukaemia with t(821)(q22q22)
AML1/ETO

• Morphology
• Large blasts, heavily granulated
• Frequent Auer rods
• Variable dysplasia in granulocytic series
• Rare cases with blast count lt 20
• Immunophenotype
• CD13 CD33 anti-MPO
• CD19 CD34 CD56

57
Acute myeloid leukaemia with t(821)(q22q22)
AML1/ETO
58
Acute myeloid leukaemia with t(821)(q22q22)
AML1/ETO
59
Acute myeloid leukaemia with t(821)(q22q22)
AML1/ETO
60
Acute myeloid leukaemia with t(821)(q22q22)
AML1/ETO
61
Detection of fusion genes by FISH
62
Detection of fusion genes by FISH
63
Acute myeloid leukaemia with t(821)(q22q22)
AML1/ETO

• Prognosis
• Good response to chemotherapy and high complete
  response rate
• Long term disease free survival
• Adverse factors
• additional chromosomal changes e.g. 9q-
• CD56 ve

64
Acute myeloid leukaemia with inv(16)(p13q22) or
t(1616)(p13q22) CBFb/MYH11

• Granuolocytic and monocytic features
• AML-M4 (acute myelomonocytic leukaemia)
  morphology
• Abnormal eosinophils with coarse basophilic
  granules

65
Acute myeloid leukaemia with inv(16)(p13q22) or
t(1616)(p13q22) CBFb/MYH11
66
Acute myeloid leukaemia with inv(16)(p13q22) or
t(1616)(p13q22) CBFb/MYH11

• Cytochemistry
• Abnormal eosinophils are CAE ve
• Immunophenotype
• Granulocytic and monocytic markers
• Co-expression of CD2 in blast population
• Prognosis
• Favourable

67
Acute myeloid leukaemia with inv(16)(p13q22) or
t(1616)(p13q22) CBFb/MYH11
68
Acute promyelocytic leukaemia

• AML with t(1517)(q22q12) PML/RARa and variants
• Characteristic morphology
• Associated with disseminated intravascular
  coagulation

69
Acute promyelocytic leukaemia
70
Acute promyelocytic leukaemia
71
Acute promyelocytic leukaemia

• Immunophenotype
• CD33 CD13
• HLA-DR and CD34 negative
• Co-expression of CD2 and CD9
• Genetics
• t(1517)(q22q12)
• Variants t(1117)(q23q12) PLZF/RARa
  t(517)(q32q12) NPM/RARa t(1117)(q13q12)
  NuMA/RARa

72
Acute promyelocytic leukaemia
73
Acute promyelocytic leukaemia

• Treatment
• All-trans retinoic acid (ATRA)
• Arsenic for relapse cases
• RARa variants resistant to ATRA
• Prognosis
• Favourable when treated optimally with ATRA
  followed by anthracyclines

74
Acute myeloid leukaemia with 11q23 abnormalities

• Infant leukaemia
• Therapy related AML after exposure to DNA
  topoisomerase II inhibitors
• Acute monocytic and myelomonocytic leukaemia
• Associated with MLL rearrangement

75
Acute myeloid leukaemia with multilineage
dysplasia

• Following MDS or MDS/MPD
• Without antecedent MDS
• Dysplasia in ? 50 of cells in at least 2 lines
• Poor prognosis

76
AML and MDS, therapy related

• Alkylating agent related
• Topoisomerase type II inhibitor related

77
Acute myeloid leukaemia not otherwise categorized

• Equivalent to FAB classification
• AML minimally differentiated
• AML without maturation
• AML with maturation
• Acute myelomonocytic leukaemia
• Acute monoblastic and monocytic leukaemia
• Acute erythroid leukaemia
• Acute megakaryoblastic leukaemia
• Acute basophilic leukaemia
• Acute panmyelosis with myelofibrosis
• Myeloid sarcoma

78
AML without maturation
79
Acute myeloid leukaemia with maturation
80
Acute monocytic leukaemia
81
Erythroleukaemia
82
Acute leukaemia of ambiguous lineage

• Mixed myeloid and lymphoid characteristics
• Biclonal (two clones)
• Biphenotypic (two characteristics on same blast
  cell)