Myelodysplastic syndrome and acute myeloid leukaemia

Dr. Edmond S. K. Ma

Division of Haematology

Department of Pathology

The University of Hong Kong

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

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

Myelodysplastic syndrome

• A group of clonal haemopoietic stem cell disorder characterized by dysplasia and ineffective haemopoiesis in one or more major myeloid cell line

• < 20% blasts in blood and bone marrow

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. Fanconi’s anaemia)

Dyserythropoiesis

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

Dyserythropoiesis

Dyserythropoiesis

Dysgranulopoiesis

• Small size

• Nuclear hypolobulation (pseudo-Pelger Heut)

• Hypersegmentation

• Hypogranularity

• Pseudo-Chediak Higashi granules

Dysgranulopoiesis

Dysgranulopoiesis

Dysmegakaryocytopoiesis

• Hypolobulated micro-megakaryocyte

• Non-lobulated nuclei in megakaryocyte of all sizes

• Multiple, widely separated nuclei

Megakaryocyte dysplasia

Megakaryocyte dysplasia

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

Abnormal localization of immature precursors

Genetics

• 5q- syndrome• del (17p), small hypolobulated or

vacuolated neutrophils, p53 mutations, poor prognosis

• -5/5q-• -7/7q-• del(20q) • 3q21q26 abnormality

Cytogenetics and prognosis

• Good risk– Normal, isoloted 5q-, isolated 20q-, -Y

• Poor risk– Complex changes (> 3 abnormalities)– Chromosome 7 abnormalities

• Intermediate risk– All other changes

International Prognostic Scoring System

Score 0 0.5 1 1.5

• % blasts <5 5-10 - 11-20

• Karyotype Good Intermediate Poor

• Cytopenia 0-1 2-3

• Cytopenia: Hb < 10 g/dL; neutrophils < 1.5 X 109/L; plt < 100 X 109/L

• Risk groups

Low = 0; Intermediate-1 = 0.5-1; Intermediate-2 = 1.5-2; High = 2.5

Refractory anaemia

• PB

anaemia,

no or rare (<1%)

blasts

• MB

Unilineage dysplasia, restricted to erythroid lineage,

< 5% blasts,

< 15% ringed sideroblasts

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%

Giant pronormoblast is parvovirus infection

Refractory anaemia with ringed sideroblasts

• PB

Anaemia

No blast

• MB

15% ringed sideroblasts

Erythroid dysplasia only

<5% blasts

Ringed sideroblast

• Erythroid precursor• One third or more of

the nucleus • Encircled by 10 or

more siderotic granules

Refractory anaemia with ringed sideroblasts

• Indolent clinical course

• Median survival = 6 years

• Leukaemic transformation 1 – 2 %

Refractory cytopenia with multilineage dysplasia

• PB

Bicytopenia or pancytopenia

No or rare blasts

No Auer rod

< 1 X 109/L monocytes

• MB

Dysplasia in 10% of cells in two or more myeloid cell lines

< 5% blasts

No Auer rod

< 15% ringed sideroblasts

Refractory cytopenia with multilineage dysplasia

Refractory cytopenia with multilineage dysplasia

Refractory cytopenia with multilineage dysplasia

Refractory cytopenia with multilineage dysplasia and ringed sideroblasts

• PB

Bicytopenia or pancytopenia

No or rare blasts

No Auer rod

< 1 X 109/L monocytes

• MB

Dysplasia in 10% of cells in two or more myeloid cell lines

< 5% blasts

No Auer rod

15% ringed sideroblasts

Refractory cytopenia with multilineage dysplasia

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

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

Refractory anaemia with excess blasts-1

• PB

Cytopenia

<5% blasts

No Auer rod

<1% monocytes

• MB

Unilineage or multilineage dysplasia

5-9% blasts

No Auer rod

Refractory anaemia with excess blasts-2

• PB

Cytopenia

5-19 % blasts

Auer rod ±

<1% monocytes

• MB

Unilineage or multilineage dysplasia

10-19% blasts

Auer rod ±

Refractory anaemia with excess blasts-2

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

Myelodysplastic syndrome, unclassifiable

• PB

Cytopenias

No or rare blasts

No Auer rods

• MB

Unilineage dysplasia, one myeloid cell line

(non-erythroid)

<5% blasts

No Auer rod

5q- syndrome

• PB

Anaemia

Usually normal or increased platelet count

<5% blasts

• MB

Normal or increased megakaryocytes with hypolobulated nuclei

<5% blasts

Isolated 5q- abnormality

No Auer rod

5q- syndrome

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

Acute myeloid leukaemia

Acute myeloid leukaemia

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

Myeloblasts versus lymphoblasts

Acute myeloid leukaemia

Acute lymphoblastic leukaemia

Acute myeloid leukaemia: cytochemistry

Myeloperoxidase

Sudan Black B

Non-specific esterase-naphthyl butyrate

-naphthyl acetate

Cytochemistry: MPO

Cytochemistry: NSE

Cytochemistry

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

CD56+ve 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

Acute myeloid leukaemia: role of immunophenotyping

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

Acute myeloid leukaemia with recurrent genetic abnormalities

• Acute myeloid leukaemia with t(8;21)(q22;q22); AML1/ETO

• Acute myeloid leukaemia with abnormal bone marrow eosinophils and inv(16)(p13q22) or t(16;16)(p13;q22); CBF/MYH11

• Acute promyelocytic leukaemia (AML with t(15;17)(q22;q12); PML/RAR and variants

• Acute myeloid leukaemia with 11q23 (MLL) abnormalities

Acute myeloid leukaemia with t(8;21)(q22;q22); AML1/ETO

• t(8;21) is the commonest translocation in AML

• Associated with AML-M2 morphology

• Tumour masses (granulocytic sarcoma)

Acute myeloid leukaemia with t(8;21)(q22;q22); AML1/ETO

• Morphology– Large blasts, heavily granulated– Frequent Auer rods– Variable dysplasia in granulocytic series– Rare cases with blast count < 20%

• Immunophenotype– CD13+ CD33+ anti-MPO+– CD19+ CD34+ CD56±

Acute myeloid leukaemia with t(8;21)(q22;q22); AML1/ETO

Acute myeloid leukaemia with t(8;21)(q22;q22); AML1/ETO

Acute myeloid leukaemia with t(8;21)(q22;q22); AML1/ETO

Acute myeloid leukaemia with t(8;21)(q22;q22); AML1/ETO

Detection of fusion genes by FISH

Detection of fusion genes by FISH

Acute myeloid leukaemia with t(8;21)(q22;q22); 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

Acute myeloid leukaemia with inv(16)(p13q22) or t(16;16)(p13;q22); CBF/MYH11

• Granuolocytic and monocytic features

• AML-M4 (acute myelomonocytic leukaemia) morphology

• Abnormal eosinophils with coarse basophilic granules

Acute myeloid leukaemia with inv(16)(p13q22) or t(16;16)(p13;q22); CBF/MYH11

Acute myeloid leukaemia with inv(16)(p13q22) or t(16;16)(p13;q22); CBF/MYH11

• Cytochemistry– Abnormal eosinophils are CAE +ve

• Immunophenotype– Granulocytic and monocytic markers– Co-expression of CD2 in blast population

• Prognosis– Favourable

Acute myeloid leukaemia with inv(16)(p13q22) or t(16;16)(p13;q22); CBF/MYH11

Acute promyelocytic leukaemia

• AML with t(15;17)(q22;q12); PML/RAR and variants

• Characteristic morphology

• Associated with disseminated intravascular coagulation

Acute promyelocytic leukaemia

Acute promyelocytic leukaemia

Acute promyelocytic leukaemia• Immunophenotype

– CD33+ CD13+– HLA-DR and CD34 negative– Co-expression of CD2 and CD9

• Genetics– t(15;17)(q22;q12)– Variants: t(11;17)(q23;q12) PLZF/RAR; t(5;17)

(q32;q12) NPM/RAR; t(11;17)(q13;q12) NuMA/RAR

Acute promyelocytic leukaemia

Acute promyelocytic leukaemia

• Treatment– All-trans retinoic acid (ATRA)– Arsenic for relapse cases– RAR variants: resistant to ATRA

• Prognosis– Favourable when treated optimally with ATRA

followed by anthracyclines

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

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

AML and MDS, therapy related

• Alkylating agent related

• Topoisomerase type II inhibitor related

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

AML without maturation

Acute myeloid leukaemia with maturation

Acute monocytic leukaemia

Erythroleukaemia

Acute leukaemia of ambiguous lineage

• Mixed myeloid and lymphoid characteristics

• Biclonal (two clones)

• Biphenotypic (two characteristics on same blast cell)