12.mds 22.4.2019

Myelodysplastic syndrome
Moderator : Dr Arathi.C.A
Presenter: Dr Santhi priya G
9/15/2020 SEMINAR-PESIMSR-MDS 1

Contents
• Introduction
• History
• Incidence
• Aetiology
• Classification
• Pathogenesis
• Cytogenetic abnormalities
in MDS
• Molecular basis of MDS
• Diagnosis
• Differential diagnosis
• Prognostic scoring
systems
• Management and
treatment
• Case discussion
• References

Introduction
• The myelodysplastic syndromes (MDS) are a group of
clonal haematopoietic stem cell diseases
• Characterized by
– cytopenia,
– dysplasia in one or more of the major myeloid
lineages,
– ineffective haematopoiesis,
– recurrent genetic abnormalities and
– increased risk of developing acute myeloid leukaemia
(AML)

History
• 1900 by Von Leube, leukanamie -a patient with severe
megaloblastic anaemia that progressed to acute leukaemia
• 1930s, the term ‘refractory anaemia- macrocytic anaemia
that was unresponsive to iron or other dietary haematinics
• 1980s, the term ‘myelodysplasia’, or ‘myelodysplastic
syndromes’ gained widespread acceptance and reflects the
heterogeneity of the disease

Incidence
• Disease of elderly with median age of presentation being
65 years
• 3.5-4.5 per 1,00,000 in US
• Increases to >20 per 1,00,000 at >70 years
• India, median age of presentation being 45 years

Aetiology
HEREDITARY ACQUIRED
Constitutional genetic factors (Down’s
syndrome, Monosomy 7)
Senescence
Neurofibromatosis Radiation
Congenital neutropenia Mutagen/ Genotoxic
DNA repair defects ( Fanconi’s anemia,
ataxia telengiectasia etc.)
Alkylating agents, P 32, DNA topoisomerase
II inhibitors
Mutagen detoxification(GST q1- null) Benzene, tobacco
Dyskeratosis congenita Aplastic anemia, PNH
Shwachman diamond syndrome Agricultural chemical solvents
Diamond Blackfan syndrome

Pathogenesis

Classification- FAB(1982)

Classification- WHO(2016)
• MDS with single lineage dysplasia(MDS-SLD)
• MDS with multilineage dysplasia(MDS-MLD)
• MDS with ring sideroblasts(MDS-RS)
– MDS with single lineage dysplasia(MDS-RS-SLD)
– MDS with multilineage dysplasia(MDS-RS-MLD)
• MDS with isolated del(5q)

Classification – WHO(2016) contd..
• MDS with excess blasts(MDS-EB)
– MDS with excess blasts-1(MDS-EB-1)
– MDS with excess blasts-2(MDS-EB-2)
• MDS, unclassifiable(MDS-U)
– MDS-U with 1% blood blasts
– MDS-U with single lineage dysplasia and
pancytopenia
– MDS-U based on defining cytogenetic abnormality
• Refractory cytopenia of chilhood

Cytogenetic abnormalities

Molecular basis of MDS
Genes with mutations in MDS
SF3B1 DNMT3A
TET2 RUNX1
SRSF2 U2AF1
ASXL1 TP53
EZH2

Diagnosis
• Clinical features
• Blood counts
• Peripheral smear morphology
• Bone marrow morphology
• Bone marrow histology
• Immunophenotyping
• Cytogenetic abnormalities
• Molecular abnormalities
• Biochemical tests
₋ Conventional karyotyping
₋ Multicolour FISH
₋ Gene sequencing
₋ SNP array

Clinical features
• Anemia dominates the early course
• Gradual onset of fatigue and weakness, dyspnea, and
pallor
• One-half the patients are asymptomatic-incidentally on
routine blood counts
• 20% of patients have splenomegaly.

Blood counts(WHO-2016)
• Anemia: Hb<10g/dl
• Leucopenia: absolute neutrophil count <1.8x109/L
• Thrombocytopenia: platelet count<100x109/l
• Monocytes<1x109/L

PB and BM Morphology
‘Pince- nez’ nuclei
Or Doughnut
:Pawn –ball

BM histology
• Hypercellular marrows
• 10% hypocellular marrow
• Dysplasia
• Abnormal localization of immature precursors (ALIP)
• Reticulin fibrosis

ALIP

Morphological features of subtypes of MDS(WHO)
Entity name No of
dyspl
astic
linea
ges
No
of
cyto
peni
as
Ring
sideroblasts
as % of
marrow
erythroid
elements
BM and
PB blasts
Cytogenetics
MDS-SLD 1 1-2 < 15 %/<5% BM 5%,
PB<1%, no
Auer rods
Any, unless fullfills all
criteria for MDS with
isolated del (5q)
MDS-MLD 2-3 1-3 <15%/<5% BM 5%,
PB<1%, no
Auer rods
isolated del (5q)
MDS-RS
MDS-RS-SLD 1 1-2 ≥15%/≥5%
BM 5%,
PB<1%, no
Auer rods
isolated del (5q)
MDS-RS-MLD 2-3 1-3 ≥15%/≥5% BM 5%,
PB<1%, no
Auer rods
isolated del (5q)
MDS with isolated
del(5q)
1-3 1-2 None or any BM 5%,
PB<1%, no
Auer rods
del(5q) alone or with 1
additional abnormality,
except loss of chromosome
7 or del (7q)9/15/2020 SEMINAR-PESIMSR-MDS 20

MDS-SLD

Entity name No of
dyspl
astic
linea
ges
No
of
cyto
peni
as
Ring
sideroblasts
as % of
marrow
erythroid
elements
BM and
PB blasts
Cytogenetics
MDS-SLD 1 1-2 < 15 %/<5% BM 5%,
PB<1%, no
Auer rods
isolated del (5q)
MDS-MLD 2-3 1-3 <15%/<5% BM 5%,
PB<1%, no
Auer rods
isolated del (5q)
MDS-RS
MDS-RS-SLD 1 1-2 ≥15%/≥5%
BM 5%,
PB<1%, no
Auer rods
isolated del (5q)
MDS-RS-MLD 2-3 1-3 ≥15%/≥5% BM 5%,
PB<1%, no
Auer rods
isolated del (5q)
MDS with isolated
del(5q)
PB<1%, no
Auer rods

MDS-RS-SLD

Entity name No of
dyspl
astic
linea
ges
No
of
cyto
peni
as
Ring
sideroblasts
as % of
marrow
erythroid
elements
BM and
PB blasts
Cytogenetics
MDS-SLD 1 1-2 < 15 %/<5% BM 5%,
PB<1%, no
Auer rods
isolated del (5q)
MDS-MLD 2-3 1-3 <15%/<5% BM 5%,
PB<1%, no
Auer rods
isolated del (5q)
MDS-RS
MDS-RS-SLD 1 1-2 ≥15%/≥5%
BM 5%,
PB<1%, no
Auer rods
isolated del (5q)
MDS-RS-MLD 2-3 1-3 ≥15%/≥5% BM 5%,
PB<1%, no
Auer rods
isolated del (5q)
MDS with isolated
del(5q)
PB<1%, no
Auer rods

MDS-MLD

Entity name No of
dyspl
astic
linea
ges
No
of
cyto
peni
as
Ring
sideroblasts
as % of
marrow
erythroid
elements
BM and
PB blasts
Cytogenetics
MDS-SLD 1 1-2 < 15 %/<5% BM 5%,
PB<1%, no
Auer rods
isolated del (5q)
MDS-MLD 2-3 1-3 <15%/<5% BM 5%,
PB<1%, no
Auer rods
isolated del (5q)
MDS-RS
MDS-RS-SLD 1 1-2 ≥15%/≥5%
BM 5%,
PB<1%, no
Auer rods
isolated del (5q)
MDS-RS-MLD 2-3 1-3 ≥15%/≥5% BM 5%,
PB<1%, no
Auer rods
isolated del (5q)
MDS with isolated
del(5q)
PB<1%, no
Auer rods

MDS with isolated del(5q)

Entity name No of
dyspl
astic
linea
ges
No
of
cyto
peni
as
Ring
sideroblasts
as % of
marrow
erythroid
elements
BM and PB blasts Cytoge
netics
MDS-EB
MDS-EB-1 1-3 1-3 None or any
BM 5-9% or PB 2-4%,BM<10%
and PB<5%, no Auer rods
Any
MDS-EB-2 1-3 1-3 None or any BM 10-19% or PB 5-19 % or
Auer rods, BM and PB <20%
Any
MDS-U
With 1%
blood blasts
1-3 1-3 None or any
BM-5%,PB=1%, no Auer rods Any
With SLD and
pancytopenia
1 3 None or any BM-5%,PB<1%, no Auer rods Any
Based on
defining
cytogenetic
abnormality
0 1-3 <15% BM-5%,PB<1%, no Auer rods MDS-
defining
abnorm
ality9/15/2020 SEMINAR-PESIMSR-MDS 33

MDS-EB-1

Entity name No of
dyspl
astic
linea
ges
No
of
cyto
peni
as
Ring
sideroblasts
as % of
marrow
erythroid
elements
netics
MDS-EB
BM 5-9% or PB 2-4%,BM<10%
Any
Any
MDS-U
With 1%
blood blasts
1-3 1-3 None or any
With SLD and
pancytopenia
Based on
defining
cytogenetic
abnormality
defining
abnorm

MDS-EB-2

Entity name No of
dyspl
astic
linea
ges
No
of
cyto
peni
as
Ring
sideroblasts
as % of
marrow
erythroid
elements
netics
MDS-EB
BM 5-9% or PB 2-4%,BM<10%
Any
Any
MDS-U
With 1%
blood blasts
1-3 1-3 None or any
With SLD and
pancytopenia
Based on
defining
cytogenetic
abnormality
defining
abnorm

Childhood MDS
• Aggressive clinical course
• More often associated with preexisting marrow failure or
congenital abnormalities
• Monosomy 7 is most common cytogenetic abnormality
for primary MDS
• Bone marrow transplantation is the treatment

Minimal diagnostic criteria for MDS in children
• At least two of the following:
– Sustained unexplained cytopenia (neutropenia,
thrombocytopenia or anemia)
– At least bilineage morphologic myelodysplasia
– Acquired clonal cytogenetic abnormality in
hematopoietic cells
– Increased blasts (> 5%)

Types of childhood MDS
• Refractory cytopenia of childhood
• Conventional MDS in children
– MDS-EB
– t- MDS
– MDS-RS

Bone marrow findings in refractory cytopenia of
childhood(WHO-2016)
Bone marrow biopsy Bone marrow aspirate cytology
Erythropoiesis Patchy distribition
Left shift
Increased
Nuclear lobulation
Multinuclearity
Megaloblastoid changes
Granulopoiesis Marked decrease
Left shift
Pseudo – pelger- huet anomaly
Agranulation of cytoplasm
Hypogranulation of cytoplasm
Nuclear- cytoplasmic maturation
defects
Megakaryopoiesis Marked decrease
Dysplastic changes
Micromegakaryocytes
Micromegakaryocytes
Multiple separated nuclei
Small round nuclei
Lymphocytes May be increased focally or
dispersed
May be increased
CD 34+ cells No increase9/15/2020 SEMINAR-PESIMSR-MDS 43

Hypocellular MDS(h-MDS)

• Differential diagnosis of this group includes
– Toxic myelopathy
– Autoimmune disorders
– Hypoplastic AML

Secondary / therapy related MDS(s- MDS and t-
MDS)
• Stromal changes like increased reticulin (grade 2-3)
• Stromal edema
• Gelatinous marrow transformation are observed
• Necrosis of bone and marrows
• Plasma cells
• Reactive lymphoid nodules
• Granulomas

• Therapy related MDS (t-MDS) is of 2 types
– MDS occurring after many years of alkylating drug
intake and are associated with -7/ del 7q and /or -5/del
5q abnormalities
– MDS resulting after > 2 yrs of use of topoisomerase II
inhibitor drugs like epipodophyllotoxins e. g.
etoposide and teniposide.

MDS-Eo
• This rare form of MDS demonstrates clonal eosinophilia
showing hyposegmented and dysplastic eosinophils

MDS with marrow fibrosis (MDS-f)

Familial MDS(myeloid neoplasms with
germline predisposition)
• Families with > 2 cases of MDS/acute leukemia/
unexplained cytopenias/cases with organ manifestations
fitting into the category of hereditary myeloid malignancy
syndrome (HMMS) should be screened for familial MDS.

Differential diagnosis for MDS
• Vit B12 and folic acid deficiency
• Exposure to arsenic and other heavy metals
• Congenital dyserythropoietic anemias
• PNH
• HIV
• G-CSF therapy
• Parvo virus B 19 therapy

Prognostic scoring systems and risk stratification
• International prognostic scoring system
• WHO prognostic scoring system

International prognostic scoring system

WHO prognostic scoring system

Management and treatment
• Supportive care
• Haematopoietic growth factors
• Immunosuppresion
• Chelation therapy
• Intensive chemotherapy
• Allogeneic stemcell transplantation
• Hypomethylating drugs
• Lenalidomide

Case
65-year-old male, complaints of fatigue, malaise, anorexia
• RBC 1.60x1012/L
• Hb 5.8 g/dL (58 g/L)
• Hct 0.17 L/L (17%)
• WBC 10.5 x109/L
• Platelets 39x109/L
• Reticulocyte Count
0.8%
• WBC Differential
– 44% segmented
neutrophils
– 7% band neutrophils
– 6% lymphocytes
– 28% eosinophils
– 1% metamyelocytes
– 1% myelocytes
– 9% promyelocytes
– 4% blasts

Peripheral smear
• The neutrophilic cells show marked hyposegmentation
and hypogranulation.
• Red blood cell (RBC) morphology includes anisocytosis
and poikilocytosis, teardrop cells, ovalocytes, and
schistocytes.

Bone marrow
• Cellularity of about 75%
• Myeloid hyperplasia with
• 9% blasts
• 26% promyelocytes
• 18% myelocytes
• 6% metamyelocytes
• 4% bands
• 37% eosinophils
• M:E was 12:1
• The myelocytes were hypogranular, and some had two nuclei and
blasts
• The erythroid precursors showed megaloblastoid changes.
• Megakaryocytes were adequate in number but showed abnormal
forms with nuclear separation and single nucleated forms.9/15/2020 SEMINAR-PESIMSR-MDS 62

• ?Subtype of MDS

• karyotype showed multiple complex
abnormalities.
• what is the prognosis?

WHO prognostic scoring system

References
• Raj K, Mufti G J. The myelodysplastic syndromes.In
Hoffbrand A V, Higgs D R, Keeling D M, Mehta A B:
Postgraduates haematology. 7th ed.Wiley Blackwell: 2016.
P.438-73
• Young N S. Myelodysplasia.In Bone Marrow Failure
Syndromes Including Aplastic Anemia and Myelodysplasia.In
Kasper et al. Harrison’s principles of internal medicine. 19th
ed. McGraw-Hill Edu: 2015. P. 669-72
• World Health Organization Classification of Tumours . Steven
H. Swerdlow .Elias Campo.Nancy Lee Harris .Elaine S. Jaffe
.Stefano A. Pileri .Harald Stein .Jorgen Thiele. International
Agency for Research on Cancer. 4th edition. Lyon, 2017
• Tejinder Singh. Atlas and text of hematology. 4th edition.
Volume 2. pg315-345. 2018

• Thank you!!

12.mds 22.4.2019

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