Myelodysplastic syndrome and acute myeloid leukaemia Dr. Edmond S. K. Ma Division of Haematology...

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)