Myelodysplastic Syndromes ppt

MYELODYSPLASTIC SYNDROME

MODERATOR-DR SURESH HANAGAVADI
PRESENTER- DR ARIJIT ROY

“We are put off by the fact that MDS is a
heterogenous vaguely defined group of
conditions with seemingly ever changing names
Cole.P, Sateren W - Epimediological perspective
on MDS &Leukemia
Leuk Res 1995 19 361-365

• First described in 1900 by Leube who used the term
―Leukanamie‖
• Subsequently it had undergone a trial of jargon
30’s - Refractory anemia
40’s- Preleukemic anemia
50’s- Preleukemia/RARS/ Refractory normoblastic anemia
60’s-Smoldering acute leukemia
70’s –CMML/Refractory anemia with excess myeloblasts
• 1982- Myelodysplastic syndrome (Benett et al )

• WHO definition 2008
• A group of clonal hematopoietic stem cell diseases
characterized by
Cytopenia
Dysplasia in one or more major myeloid cell lines
Ineffective hematopoiesis
Increased risk of development of AML

The threshold for cytopenia as recommended by the IPSS for
risk stratification are
• Hb < 10 g/dl
• Absolute neutrophil count< 1.8x 109 /L
• Platelets < 100 x 10 9/L

• PREDISPOSING FACTORS
HEREDITARY
A) Constitutional genetic disorders
Downs Syndrome: 10-30 times more risk
Trisomy 8 : Seen in 50% cases of MDS
Monosomy 7 : Seen in 50% cases of MDS.

B) Neurofibromatosis
C) Congenital neutropenia syndrome
Kostmann Agranulocytosis
Shwachman Diamond syndrome

• D) DNA repair defects
Fanconi anemia,
Ataxia telangiectasia
Bloom syndrome

• E) Mutagen detoxification(GSTq1-null)
Glutathione-S-Transferase. Studies show that GST- q1null
genotype increases risk by 4 times.

.

• ACQUIRED
These factors play a major role in secondary MDS/ t-MDS
a)Mutagen exposure
1.Genotoxic therapy- alkylating agents
2. Beta-emitter phosphorus; Used in the treatment of
Polycythemia Vera- 10-15% increased risk.
3. Topoisomerase(Topo-II) interactive agents like
anthracycline, etoposide.
4. Autologous stem cell transplantation- long term survivors

b) Environmental /occupational exposures
Exposure to benzene-5-20 fold increase in risk.
Other agents like solvents, petrochemicals,Insectide

c) Tobacco
Tobacco smoke contains a number of leukemogens like
nitrosamines, benzene and polonium-210

d) Senescence
e) Aplastic anemia

• ETIOLOGY
a) PRIMARY OR DE-NOVO
 Benzene exposure
 Cigarette smoking
 Agricultural chemicals
 Family h/o haematopoietic neoplasms
 Fanconi anemia, Shwachmann diamond, Diamond-Blackfan

• SECONDARY

 Prior exposure to cytotoxic chemotherapy/radiation
 Alkylating agents cyclophosphamide,
 Topoisomerase II inhibitors Etoposide
 Risk increases with age & prolonged exposure to low - dose
chemotherapy
 Autologous transplantation for lymphoma-MDS seen in 12 %
Most cases develop within 5 years—poor outcome

Why Classify?
• Unravel disease biology
• Design accurate diagnostic tests
• Predict prognosis
• Develop novel therapies

FAB CLASSIFICATION OF MDS
SUBTYPE BLOOD BONE MARROW
• 1%BLAST
REFRACTORY <1%BLASTS DYSPLASIA;
ANEMIA(RA) <5%BLASTS

ANEMIA WITH <5%BLASTS;
RINGED >15%RINGED
SIDEROBLASTS( SIDEROBLASTS
RARS)

ANEMIA WITH 5-19%BLASTS
EXCESS
BLASTS(RAEB)

contd


REFRACTORY ANEMIA > 5%BLASTS DYSPLASIA;
WITH EXCESS BLASTS 20-29%BLASTS OR AUER
IN TRANSFORMATION RODS
(RAEBt)

CHRONIC >1X109/L MONOCYTES DYSPLASIA;
MYELOMONOCYTIC <30%BLASTS
LEUKEMIA(CMML)

WHO CLASSIFICATION OF MDS (2008)

REFRACTORY ANEMIA; UNILINEAGE
CYTOPENIA WITH NO OR RARE BLASTS DYSPLASIA > 10%
UNILINEAGE UNICYTOPENIA CELLS IN ONE
DYSPLASIA (RCUD) BICYTOPENIA MYELOID LINE WITH
REFRACTORY < 5% BLASTS
ANEMIA (RA), <15%RINGED
REFRACTORY SIDEROBLASTS
NEUTROPENIA(RN) ,
(REFRACTORY
THROMBOCYTOPENIA
(RT)

REFRACTORY ANEMIA; >15%RINGED
ANEMIA WITH NO OR RARE BLASTS SIDEROBLASTS;
RINGED ERYTHROID
SIDEROBLASTS DYSPLASIA;
<5%BLASTS;

REFRACTORY BI / PAN CYTOPENIAS; DYSPLASIA IN >10% OF
CYTOPENIA WITH NO OR RARE BLASTS; THE CELLS >2
MULTILINEAGE NO AUER RODS; MYELOID LINES
DYSPLASIA (RCMD) <1X109/L MONOCYTES <5%BLASTS IN BM
>15%RINGED
SIDEROBLAST
NO AUER RODS

REFRACTORY ANEMIA BI / PAN CYTOPENIAS; UNI OR MULTILINEAGE
WITH EXCESS BLASTS < 5%BLASTS; DYSPLASIA;
1 NO AUER RODS; 5-9%BLASTS;
<1X109/L MONOCYTES NO AUER RODS

REFRACTORY ANEMIA CYTOPENIAS; UNI OR MULTILINEAGE
WITH EXCESS BLASTS 5-19%BLASTS; DYSPLASIA;
2 AUER RODS PRESENT; 10-19%BLASTS;
<1X109/L MONOCYTES AUER RODS PRESENT


MYELODYSPLASTIC CYTOPENIAS; UNILINEAGE DYSPLASIA;
SYNDROME, NO OR RARE BLASTS; <5% BLASTS;
UNCLASSIFIED(MDS-u) NO AUER RODS; NO AUER RODS

5q-SYNDROME ANEMIA; NORMAL/INCREASED
NORMAL/INCREASED MEGAKARYOCYTES;
PLATELET COUNT; <5%BLASTS;
<5%BLASTS NO AUER RODS

CHILDHOOD MDS < 2 % BLASTS DYSPLASTIC CHANGES IN >
DYSPLASTIC CHANGES IN 10 % ERYTHROID
>10 % NEUTROPHILS PRECURSORS
DYSPLASTIC CHANGES IN >
10 % GRANULOCYTE
PRECURSORS
MICROMEGAKARYOCYTES,
DYSPLASTIC CHANGES IN
MGKS


MYELODYSPLASTIC CYTOPENIAS; UNILINEAGE
SYNDROME, NO OR RARE BLASTS; DYSPLASIA;
UNCLASSIFIED(MDS-u) NO AUER RODS; <5% BLASTS;
NO AUER RODS

5q-SYNDROME ANEMIA; NORMAL/INCREASED
NORMAL/INCREASED MEGAKARYOCYTES;
PLATELET COUNT; <5%BLASTS;
<5%BLASTS NO AUER RODS

CHILDHOOD MDS < 2 % BLASTS DYSPLASTIC CHANGES
DYSPLASTIC CHANGES IN > 10 % ERYTHROID
IN >10 % NEUTROPHILS PRECURSORS
DYSPLASTIC CHANGES
IN > 10 %
GRANULOCYTE
PRECURSORS
MICROMEGAKARYOCY
TES,DYSPLASTIC
CHANGES IN MGKS

DIFFERENCES BETWEEN WHO AND FAB

The WHO system
• Makes use of cytogenetic findings.
• The category of RAEB-t was eliminated as it got included
within AML(>20%blasts).
• CMML was removed and put in a new category of
myelodysplastic/myeloproliferative diseases.
• Adds the subtypes 5q syndrome and unclassifiable MDS.
• Recognizes the prognostic importance of % of bone marrow
blasts

INCIDENCE

• The mean age of presentation in the western population is 65
yrs, whereas in India it is 45 yrs.
• The incidence as reported by Aul et al in United States is 4.1
per 1,00,000.
• Rare in childhood, the median age of onset is 6yrs.

PATHOGENESIS
MDS : a stem cell disorder
• It represents manifestation of the malignant transformation of
myeloid stem cell
• The abnormal cells in MDS are clones derived from an
abnormal stem cell

Apoptosis in MDS
• Mechanism appears to be one of increased apoptosis of
haemopoietic precursors in the marrow,
• Presence of cytopenias despite a typically hypercellular bone
marrow.
• For those patients undergoing leukaemic transformation,the
cytopenias arise due to maturation block of the malignant cells
• Apoptosis is more prominent in early MDS, such as RA and
RARS, than in advanced MDS with excess myeloblasts

Ineffective Hematopoiesis
• Colony forming capacities of pleuripotent stem cells and their
progeny are low or absent
• Lower level of GM-CSF, M-CSF,IL 6 .IL 3,
• CFU- GM less responsive to both G-CSF & GM-CSF
• More dramatic in pts with RAEB or RAEB –t

Immunological abnormalities in MDS
• Commonly encountered in MDS, suggesting that they may
play a role in the aetiology and pathogenesis of the disease.

• Particularly apparent in cases of hypoplastic MDS that share a
number of features in common with aplastic anaemia, notably
clinical presentation with macrocytosis and varying levels of
dyserythropoiesis
• Acquired mutations in the PIG-A gene characteristic of
paroxysmal nocturnal haemoglobinuria (PNH) are also
encountered
Angiogenesis
• Autocrine production of angiogenic molecules promotes
expansion of leukemic clone
• Vascular endothelial growth factor(VEGF) and its receptor
VEGFR-1 And VEGFR-2 is overexpressed

Molecular basis of MDS
• MDS is a preleukaemic disorder characterized by impaired
cellular differentiation that has the potential to transform to
AML if this abnormality is coupled to enhanced survival and
proliferation.
• The common chromosomal abnormalities found in MDS
include loss of Y, monosomy 5, monosomy 7,trisomy 8, 20q – ,
abnormalities of 11q23, and deletions of 17p, 12p, 13q and 11q
among others.

Genetic abnormalities in MDS
• Mutations of the AML1 gene (also known as RUNX1 ) have
recently been recognized to occur in MDS, particularly where
it is treatment - related or radiation - induced.
• Activating mutations of RAS , usually involving NRAS , are
found in up to 20% of cases of MDS
• Class 1 mutation-mutation involving Tyrosine kinase GATA1 ,
PU.1 ( SPI1 ), CEBPA , MLL and TP53 .
• Class 2 mutation –mutation involving Transcription factors
FMS (now called CSF1R ), KIT , FLT3 , PDGFRB and
GCSFR
• Association of both Class 1 &2 – highly predisposed to MDS
& AML

Epigenetic abnormalities
• refers to alteration of gene expression without altering the
DNA sequence
• Two important epigenetic modifications relevant to MDS, are
DNA methylation and histone modification.
• Promoter methylation of p15INK4B – t-MDS
• methylation of p15INK4B also seen in loss of Chr 7 and in pts
who progresses from RA to RAEB

ENVIRON
MENTAL
MOLECUL
AR GAIN
EPIGENET
OF
IC
FUNCTIO
N

IMMUNOL
OGICAL MDS APOPTOSI
S

STEM
ANGIOGE
CELL
NESIS
DEFECT
GENETIC
LOSS OF
SIGNAL

Clinical features

• Asymptomatic - Many patients are diagnosed on routine
laboratory screening

• Fatigue, weakness, angina - as a result of anemia.

• Infections most commonly bacterial, predominate with skin
being the most common site. This is the most common cause
of mortality and morbidity in MDS.

• Autoimmune abnormalities (uncommon) - Seen in 14 %
of the patients. Most common is cutaneous vasculitis.
• Cutaneous manifestations of MDS
Sweet syndrome
Granulocytic sarcoma

MORPHOLOGY OF BLASTS

• The standard criteria for a blast are
 Cell with a central nucleus
 Fine nuclear chromatin
 Prominent nucleoli
 High nucleocytoplasmic ratio
 Deeply basophilic and agranular cytoplasm
3 types of blasts have been found in the blood and bone
marrow of MDS.

TYPE I
• Finely dispersed nuclear
chromatin
• Prominent nucleoli
• Variable N:C ratio , agranular
cytoplasm

TYPE II
They resemble
type I blasts but
have primary
granules in the
cytoplasm(<20)

TYPE III
These are similar to type
II blasts but have more
than 20 granules in their
cytoplasm

CYTOCHEMICAL IDENTIFICATION OF BLASTS

MYELOPEROXIDASE POSITIVE

Morphological manifestations of dysplasia

• Dyserythropoiesis
Nuclear changes
 Nuclear budding
 Internuclear bridging
 Karyorrhexis
 Nuclear hyperlobation
 Megaloblastic changes

• Cytoplasmic changes
 Ring sideroblasts
 Vacuolization
 PAS positivity

Granular PAS positivity in
proerythroblasts and Giant multinucleate late
homogeneous positivity in the normoblasts
later normoblasts

• Dysgranulopoiesis
Small or unusually large size
Nuclear hypolobation(pseudo Pelger Huet)
Irregular hypersegmentation
Decreased granules, agranularity
Pseudo Chediak Higashi granules
Auer rods

• Dysmegakaryopoiesis
Micromegakaryocytes
Nuclear hypolobation
Multinucleation - normal megakaryocytes are
uninucleate with lobulated nuclei

LABORATORY FINDINGS

• PERIPHERAL BLOOD PICTURE
• ERYTHROCYTES
 Anemia-variable
 RBC’s are macrocytic, macro ovalocytes seen.
 Reticulopenia
 Elliptocytosis, tear drop cells, stomatocytes seen.
 Basophilic stippling,Howell-Jolly bodies, normoblasts.

• OTHER ERYTHROCYTE CHANGES
• Increase in fetal hemoglobin

• Altered A,B, antigens on the surface.

• LEUKOCYTES
Neutropenia - 2nd most common cytopenia
Dysgranulopoiesis is seen by agranular or hypogranular
neutrophils
Persistent basophilia of cytoplasm
Hyposegmentation (pseudo Pelger-Huet) of the nucleus
Hypersegmentation of the nucleus is seen sometimes

• OTHER DEFECTS
Enzyme defects such as
 Decreased myeloperoxidase,
 Decreased leukocyte alkaline phosphatase .
Causes functional impairment of the neutrophils like defective
bactericidal, phagocytic and chemotactic properties.

PLATELETS
• Varying degree of thrombocytopenia

• Platelets may show agranular/hypogranular cytoplasm

• Giant platelets are seen

• Micromegakarocytes are seen. They have a single lobe nucleus
with cytoplasmic tags. Nucleus shows densely clumped
chromatin.

BONE MARROW ASPIRATE

• Well stained BM aspirate smears
• At least 500 cells are to be counted
• At least 30 megakaryocyte to be evaluated
• Dysplastic features should be present in > 10 % cells

CELLULARITY
In most cases it is hypercellular
But is hypocellular in Hypoplastic MDS

Erythropoeisis
• Usually megaloblastic erythropoeisis
• Feature of dyserthropoiesis
• Some precursors may show Howell Jolly bodies
• Vacoulization , basophilia and poor hemoglobinisation
• Ring sideroblasts
• PAS stain – may show granular positivity of normoblasts
• Advanced cases – erythroid hypoplasia seen

Granulopoiesis
• Usually myeloid hyperplasia
• Hypogranulrity and hyposegmentation
• Maturation arrest in myelocyte stage may be seen
• Abnormal staining of primary granules seen in myelocyte &
promyelocytes. Granules may be larger than normal or
completely absent.
• Irregular cytoplasmic basophilia seen
• Diminished staining to MPO and SBB

• Thrombopoiesis
• Usually normal or megakaryocytic hyperplasia
• Micromegakaryocytes, multinucleated megakaryocytes , &
hypolobated megakaryocytes
• Presence of > 10 % Micromegakaryocytes in a population
suggests MDS
• CD 61 staining

TREPHINE BIOPSY IN MDS

Useful for determining
• Cellularity of marrow
• Abnormal localization of immature precursors (ALIP)
• Reticulin fibrosis, Megakaryocytic dysplasia, Lymphoid
aggregate
• Hypoplastic MDS
• Increases the diagnostic accuracy & helps in refining the
IPSS score

Flowcytometry

• Erythroid abnormalities detected by
H- ferritin , CD71 ,CD105 in Glycophorin A
• Abnormal maturation pattern in Granulocytes
• For borderline dysplasia ,FC is highly suggestive for MDS
only if aberrant features are present in all three lineages

OTHER INVESTIGATIONS

• A) Immunophenotyping- do not play a major role in the
diagnosis of MDS and need not be routinely performed
• However, various abnormalities are sometimes discernible,
 Low side scatter, reduced expression of normal myeloid
markers,
 Aberrant patterns of expression of markers like CD34 and to
a lesser degree CD117, often correlates with the blast
percentage,
 Coexpression of CD7 is significant for conferring a worse
prognosis.

• B) Ferrokinetics- to assess erythropoiesis.
• C) Haemoglobin electrophoresis or HPLC, to detect HbH and
HbF
• D) Granulocyte function tests to demonstrate defective
phagocytosis
• E) Platelet function tests to demonstrate reduced aggregation
and prolonged bleeding time.
• F) Serum protein electrophoresis to assess immunoglobulins
and detect paraprotein.

EVALUATION OF SUSPECTED MDS

• HISTORY
Prior exposure to CT/RT
Recurrent infections, bleeding gums
• EXAMINATION
Pallor/ bruising
Splenomegaly
• BLOOD COUNTS
Hb, TLC, platelet count reticulocyte count
• BLOOD FILM
Macrocytosis, cytopenia, neytrophilia, monocytosis pseudo
pelger huet anomaly,hypogranular neutrophils

• BONE MARROW ASPIRATE
• BONE MARROW TREPHINE BIOPSY
• BONE MARROW CYTOGENETICS ANALYSIS
• EXCLUSION OF REACTIVE CAUSES OF DYSPLASIA
Megaloblastic anaemia
HIV infection
Recent cytotoxic therapy
Alcoholism
Recurrent intercurrent infection

REFRACTORY CYTOPENIA WITH UNILINEAGE
DYSPLASIA

• Includes
 Refractory Anaemia (RA),
 Refractory neutropenia (RN)
 Refractory Thrombocytopenia (RT)

• Majority of RCUD cases are RA. RN and RT are rare

• 10-20 % of all cases of MDS

• Older age 65-70 yrs
• M:F equal prediliction
• C/F due to type of cytopenia
• Cytopenia refractory to hematinics , but respond to growth
factors

• Refractory Anaemia
 RBC are normochromic ,normocytic or normochromic
microcytic
 Anisopoilkilocytosis- none / marked
 Normal neutrophils and platelets
 BM in RA
Erythroid precursors- decreased / markedly increased
Dyserythropoiesis – slight/ moderate

• Myeloblasts ≤ 5% of nucleated BM cells
• Neutrophils & megakaryocytes – normal or minimal dysplasia
• BM- hypercellular due to increased rbc precursors
• Ring sideroblasts if present are ≤ 15 % of erythroid precursors

• Genetics
RA includes del 20q , +8 , abnormality of 5 and / or 7

• Median survival is 66 months and risk for AML
transformation at 5 yrs is 2 %

• 90-95% of pts with RA have low to intermediate IPSS score

RCUD: Refractory Neutropenia

• Most important to exclude secondary causes eg drugs ,toxins
• Characteristics of Dysgranulopoiesis
• Nuclear: hypolobation (pseudo-Pelger Huet), irregular
hypersegmentation
• Cytoplasmic: hypogranularity, pseudo-Chediak Higashi
granules, Auer rods, small or abnormally large size

RCUD: Refractory Thrombocytopenia
• Evaluate >30 mgk’cytes
• D/D from chronic autoimmune thrombocytopenia is critical
• Features: Micromegakaryocytes, hypolobation, multiple
widely separated nuclei

REFRACTORY ANAEMIA WITH RING
SIDEROBLASTS

• RARS is the MDS chacterized by anemia, morphological
dysplasia in erythroid lineage and ring sideroblast ≥ 15 % of
BM with no significant dysplasia in non erythrod lineage
• 3-11 % of MDS cases
• Median age 60-73 yrs
• Male : female - equal

• Ring sideroblasts – erythroid precursor with abnormal
accumulation of iron within mitochondria
• RARS represents a clonal stem cell defects that manifests as
abnormal iron metabolism in the erythroid lineage and results
in ineffective erythropoiesis
• C/F
anaemia – usually moderate degree
thrombocytopenia or neutropenia

• Symptoms due to iron overload
MORPHOLOGY
PBS-
 Normochromic macrocytic/ Normochromic normocytic
anaemia
 Dimorphic pattern with majority normochromic rbc’s and
minor population of hypochromic cells
BM
 BM normocellular to markedly hypercellular

 increase in erythroid precursors with lineage dysplasia
eg nuclear lobation & megaloblastoid features
 Hemosiderin laden macrophages - often abundant
 Myeloblasts ≤ 10%
 On iron stain ≥ 15 % of rbc precursors are ring sideroblasts
• Prognosis
 1-2% cases of RARS evolve to AML
 Median survival 69-108 months

REFRACTORY CYTOPENIA WITH
MULTILINEAGE DYSPLASIA

• MDS with one or more cytopenias and dysplastic changes in
two or more of the myeloid lineage

• ≤ 1% blasts in PBS and ≤ 5% in the BM

• 30 % of cases of MDS

• Slight predominance in males

• Age 70- 79

• More aggressive than refractory anemia, more likely to
progress to AML
• Some consider it an intermediate disorder between refractory
anemia and refractory anemia with excess blasts
• Poor prognosis if even 1% blasts in peripheral blood
• Proposed modified criteria are refractory anemia, >10%
pseudo-Pelger-Huet anomalies, dysmegakaryopoiesis in ≥40%
or micromegakaryocytes in ≥10%, and no 5q- syndrome
• Termed RCMD with ringed sideroblasts if ≥15% ringed
sideroblasts

• Cytogenetic abnormalities include Trisomy 8,Monosomy 7
del 7q , del 20q as well as complex karyotype
• Frequency of AML development at 2 yrs – 10 %
• Overall survival – 30 months
• Pts with complex karyotype have survival rate similar to
RAEB

• C/F – due to BM failure with cytopenia
• Morphology
BM is hypercellular
Neutrophil dysplasia characterised by
 Hypogranulation
 nuclear hyposegmentation
 Pseudo pelger huet nuclei

• Erythroid precursors shows marked nuclear irregularity
including
 internuclear bridging
 nuclear budding
 Multilobation
 Megaloblastoid nuclei
• Cytoplasmic vacoules are poorly defined, PAS positive

• Megakaryocyte abnormalities
 Non lobated nuclei
 Hypolobated nuclei/ binucleate/multinucleated
 Micromegakaryocyte

Bone marrow aspirate showing erythroid population with marked megaloblastic
change and dyserythropoiesis. Blast cells with round and opened up chromatin
and scant to moderate amount of pale blue cytoplasm. Most of these cells
showed cytoplasmic vacuolation and had fine granules. (Inset) PAS staining on
peripheral blood showing globular as well as diffuse PAS positivity in blasts as
well as the nucleated RBCs

REFRACTORY ANAEMIA WITH EXCESS BLASTS

• MDS with 5-19 % myeloblasts in the BM or 2-19 % blasts in
PB
• Because of difference in survival and evolution to AML,2
categories of RAEB are recognized
 RAEB 1 – 5-9 % blasts in BM or 2-4 % in PB
 RAEB 2 - 10-19% blasts in BM or 5-19 % in PB
Presence of Auer rods in blasts qualifies as RAEB 2
irrespective of blast % .

• Approx 40 % of all MDS
• Affects individuals over 50 yrs of age
• Risk factors
 Environmental toxins eg pesticides
 Petroleum products
 Cigarette smoking
 Heavy metals

• PB smear shows abnormality in all three lines
• Red cell anisopoikilocytosis
• Large , giant or hypogranular platelets
• Abnormal cytoplasmic granularity & nuclear segmentation of
neutrophils . Blasts are commonly present
• BM is hypercellular
• Degree of dysplasia varies
• Erythropoiesis may be increased with macrocytic/
megaloblastoid changes

• Dyserythropoiesis includes internuclear bridging and
lobulated nuclei
• Granulopoiesis characterized by small size with nuclei
hypolobation (Pseudo pelger huet nuclei)/ nuclear
hypersegmentation, cytoplasmic hypogranularity and /or
pseudo Chediak- Higashi granules
• Megakaryopoiesis is normal to increased, shows tendency of
cluster formation
• Dysmegakaryopoietic features include micromegakaryocytes
but all forms and sizes can be seen

• Both erythropoiesis and megakaryopoiesis appears frequently
towards the paratrabecular areas that are normally occupied by
granulopoietic cells
• In minority of cases BM is hypocellular or normocellular.
RAEB with hypocellular BM represents only a small
proportion of hypoplastic MDS
• Blasts in RAEB form clusters and are located away from bony
trabeculae and vascular structures – ALIP
• ALIP – CD 34 +

• Flow cytometry in RAEB – Precursor antigens like CD 34 and
/or CD 117 .These cells are also positive for CD 38, HLA –
DR and myeloid associated antigens CD13 and /or CD 33

• Asynchronous expression of Granulocytic maturation antigens
CD15 ,CD 11b, and /or CD 65 in blast cells

• Antibody to CD 61 or CD 42b – idenification of
micromegakaryocyte and other dysplastic forms

• Cytogenetic abnormalities – in 30-50 % of RAEB +8, del 5q ,
,del 7q , del 20 q
• RAEB is characterized by progressive BM failure and
increasing cytopenia
• RAEB 1 – 25 %
• RAEB 2- 33 %
• Median survival of 16 months for RAEB-1 and 9 months for
RAEB-2
• CD7 expression associated with poor prognosis

MYELODYSPLASTIC SYNDROME WITH
ISOLATED del 5q

• Anaemia with or without other cytopenia and/or
thrombocytosis in which the sole genetic abnormality is del 5q
• Myeloblasts ≤ 5% of nucleated BM cells and ≤ 1% of PB
leucocytes
• Auer rods are absent
• More in women
• Median age 67 yrs

• Etiology
 Presumes loss of a tumour suppressor gene in deleted region
 Early growth phase response (EGR 1) and α – catenin
(CTNNA1), and as yet unidentified gene in 5q32
 The RPS 14 gene that encodes a ribosomal protein has been
proposed as a candidate in the 5q syndrome

• Anaemia is often severe and usually macrocytic
• Thrombocytosis is seen in majority of cases while
thrombocytopenia is uncommon
• BM is usually hypercellular or normocellular and frequently
exhibits erythroid hyperplasia
• Megakaryocytes are increased in no and are normal to slightly
decreased in size with conspicuously hypolobated and
nonlobated nuclei

• Genetic abnormality
 Sole cytogenetic abnormality interstitial deletion of Chr 5

 Recent report a small subset of patients with isolated del 5q
may show a concomitant JAK2 V617F mutation but it is
prudent to report them as del 5q and to note the presence of
JAK2 V617F

• Subtype of refractory anemia with good prognosis

• Stable clinical course but often transfusion dependent causing
frequent hemochromatosis

• 10% progress to AML
• lenalidomide, a thalidomide analogue and immunomodulating
drug, has high response rate

Blasts with numerous platelets

Increased megakaryocytes withoverall PAS +ve
cytoplasm,nuclear hypolobulation

MDS UNCLASSIFIABLE

• Subtype of MDS which lacks findings appropiate for
classification into any other MDS category
• 3 possible instances for MDS-U
1. Patients with findings of refractory cytopenia with unilineage
dysplasia (RCUD) or refractory cytopenia with multilineage
dysplasia (RCMD) but with 1% blasts in PB
2. Cases of MDS with unilineage dysplasia which are associated
with pancytopenia

3. Patients with persistent cytopenia with 1 % or fewer blasts in
the blood and fewer than 5% in BM , unequivocal dysplasia in
less than 10% of cells in one or more of the myeloid lineage and
who have cytogenetic abnormalities considered as presumptive
evidence of MDS

Findings
• Often Auer rods but less than 5% blasts,
• isolated neutropenia without anemia, isolated
thrombocytopenia without anemia,
• significant thrombocytosis, significant leukocytosis,
hypocellular bone marrow (<30% in younger individuals,
<20% if age 60 or more) or myelofibrosis

• Some cases associated with prior aplastic anemia and
monosomy 7

• Myelofibrosis: when present, often is difficult to obtain
bone marrow aspirate; patients often have pancytopenia
with dysplasia in 3 lineages

CHILDHOOD MYELODYSPLASTIC SYNDROME

• MDS in children is very uncommon ,accounting less than 5%
of all hematopoietic neoplasms in patients less than 14 yrs
• This entity should be distinguished from ― secondary MDS”
that follow congenital or acquired BM failure syndromes and
from MDS that follows cytotoxic therapy for a previous
neoplastic or non neoplastic condition
• This entity should be distinguished from MDS with Down
Syndrome

• Most of childhood MDS become symptomatic rather early and
transform to AML in a very short span
• Has an aggressive clinical couse irrespective of WHO subtype
• Often associated with preexisting BM failure syndromes or
congenital abnormalities like Kostmann Syndrome
Schwachmann Diamond syndrome, Fanconi anaemia NF 1
down syndrome, juvenile xanthogranuloma
• JMML is the commonest
• Cytogenetic abnormalities- occurs in 60-70% of primary MDS
in children. Monosomy 7 is the most common

• DIFFERENCE BETWEEN ADULT AND CHILDHOOD
MDS
 Pts may not have increased blasts in their PB or BM
 RARS and MDS with del 5q are exceedingly rare in children
 Neutropenia or Thrombocytopenia is more likely seen
 Hypocellular bone marrow is more commonly observed in
childhood MDS

REFRACTORY CYTOPENIA OF CHILDHOOD (RCC)
• It’s a type of MDS characterized by persistent cytopenia with
<5% blasts in BM and < 2% blasts in PB
• BM trephine biopsy specimen is indispensable
• 75% of children with RCC shows BM hypocellularity
• Down syndrome related myeloid neoplasms are excluded
• RCC is the most common MDS in childhood accounting for
50% of the cases
• Equal incidence in both sexes

• Clinical features
 Malaise, bleeding , fever, infection
 Lymphadenopathy – secondary to local infection
 Hepatosplenomegaly is absent
 Platelet count < 150 x 10 9/L seen in 75% cases
 Hb <10g/dL seen in 50% cases
 WBC decreased with severe neutropenia seen in 25%

• PB
 Anisopoikilocytosis with macrocytosis, anisochromasia
 Platelets show anisocytosis and occasionally giant platelets
 Neutropenia with pseudo-Pelger Huet nuclei/ hypogranular
cytoplasm
• BM
 Dysplastic changes in two different myeloid cell lineages or
exceed 10% in one single cell line

Erythroid changes
• Nuclear budding
• Internuclear bridging
• Karyorrhexis
• Nuclear hyperlobation
• Megaloblastic changes
Granulocytic changes
• Hyposegmentation with pseudo pelger huet
• Hypo/agranular cytoplasm
• Giant bands

• Cytoplasm- nucleus maturation asynchrony
Megakaryocytic changes
• Detection of micromegakaryocytes is a strong indicator of
RCC

MINIMAL DIAGNOSTIC CRITERIA FOR MDS IN
CHILDREN

• At least two of the following
 Sustained unexplained cytopenia( neutropenia,
thrombocytopenia , anemia)
 At least bilineage morphological myelodysplasia
 Acquired clonal cytogenetic abmormality in hematopoietic
cells
 Increased blasts > 5%

DIFFERENTIAL DIAGNOSIS

1. Vitamin B 12 and folic acid deficiency
2. AML M6
3. HIV infection
4. Parvo virus B 19 infection
5. Exposure to arsenic and other heavy metals
6. Congenital Dyserythropoietic anemia
7. Paroxysmal nocturnal hemoglobinemia
8. G- CSF Therapy

DIFFERENCE BETWEEN AML M6 AND MDS
COUNT 500 BM CELLS
All nucleated cells counted

Erythroblast > 50% Erythroblast <50%

< 20% total blasts and AML M0-M5
EP >50 % of all cells
Count non
erythroid cells

>20 % <20 %
NEC NEC
AML MDS
M6

HYPOPLASTIC MDS

• 10-15% of MDS are of hypocellular type
• Higher prevalence in women
• Severe cytopenia and cellularity of the marrow <30% in those
who are <60 yrs of age OR < 20% in those > 60 yrs age
• Majoriy of pt present with refractory anaemia
• BM is hypocellular
• No independent prognostic significance per se
• D/D- Aplastic anaemia and hypocellular AML

MDS-F (MDS with Myelofibrosis)

• Significant marrow fibrosis in 10-15% MDS
• Most cases: excess blasts, aggressive course
• Unclear whether fibrosis has independent prognostic value
• Blast % from aspirate smears alone may understage the disease
• CD34 on BMB may help
• Cytogenetic abnormalities+
• JAK2 - negative

SECONDARY/THERAPY RELATED MDS
• Occur post-chemotherapy or post-radiation therapy, benzene
toxins
• Mean age of presentation is 10 yrs earlier than primary
• PS – Anisopoikilocytosis & nucleated rbc
• BM – normal or increased cellularity,trilineage dysplasia
• Most cases are or RAEB type
• t- MDS are of 2 types
a) MDS occuring many years after alkylating drugs use and
associated with

• t- MDS are of 2 types
a) MDS occuring many years after alkylating drugs use &
associated with del 7q and del 5q
b) MDS occuring 2 yrs after Topoisomerase II inhibitors
• Both subtypes frequently evolve into AML

IPSS risk-based classification system

Marrow blast percentage:
<5 0
5-10 0.5
11-20 1.5
21-30 2.0
Cytogentic features
Good prognosis 0
(–Y, 5q- , 20q-)
Intermediate prognosis 0.5
(+8, miscellaneous single abnormality,
double abnormalities)
Poor prognosis 1.0
(abnor. 7, complex- >3 abnor.)
Cytopenias
None or one type 0
2 or 3 type 0.5

INTERNATIONAL PROGNOSTIC SCORING SYSTEM(IPSS)

RISK SCORE AML MEDIAN
TRANSFOR SURVIVAL
MATION % (YEARS)
LOW 0 19 5.7
INTERMEDIATE -1 0.5- 1.0 30 3.5
INTERMEDIATE -2 1.5 -2.0 33 1.2
HIGH 2.5 45 0.4

Applying WHO to Indian settings

• Indian MDS differs from MDS of West
 Younger age at presentation
 Cytopenias more severe at presentation
 Patients opted for less aggressive treatment
 Poorer treatment outcomes
 Infections, nutritional disorders: commoner
 Follow-up: Not always available
 Majority of pts had MDS-RA, MDS RAEB 1 & 2

PRINCIPLE OF MANAGEMENT OF MDS

• Management is individualized and guided by pt age, prognosis
and toxicity of treatment
 Low risk MDS (low and intermediate 1 risk grp of IPSS) is
associated with longer survival
 High risk MDS (high and intermediate 2 risk grp of IPSS)
have high risk of transformation and shorter survival
• Low risk MDS –
 Erythropoietin , G-CSF, GM-CSF
 Immunosupressive therapy – ATG/ALG
 Antiangiogenic agents – Thalidomide
 For treatment of neutropenia – G- CSF, GM CSF

• HIGH RISK MDS
 Allogenic stem cell transplantation (SCT)
 Chemotherapy
 Newer therapy including 5-Azacytidine- methyl tranferase
inhibitor is the most promising therapy for improving the
quality of life in MDS

CONCLUSION

• MDS can be effectively diagnosed and classified as per WHO
2008 classification
• MDS diagnosis and classification is currently in a transitional
phase from reliance almost entirely on cell morphology
supplemented by cytochemistry and G-banded karyotyping,
towards a new era in which molecular and perhaps
immunophenotypic findings will be fully incorporated
• But in developing countries it is essential to rule out
infections/ nutritional deficiencies especially among the
elderly before considering MDS

REFERENCES
• Swedlow SH,Campo E , Haris NL WHO classification of
Tumours of Hematopoietic and Lymphoid tissue, IARC
press,Lyon 2008 , 94-107
• A F List, A.A Sandberg, Wintrobe Clinical Hematology ,11th Ed
1956-1977
• Barbara J Bain ,David M , Bone Marrow Pathology ,4th
edition,208-225
• A.Victor Hoffbrand ,D, Catovsky ,Postgraduate Hematology 6th
Ed ,503-512
• H D Deeg, DT Brown ,Hematological Malignancies –MDS, 4 th
Ed , 18-132
• Tejinder Singh,Atlas and text of Hematology 1st Ed, 167-181
• www.pathologyoutlines. com

• John M Benett ,The MDS/MPD disorders , the interface
Hematol Oncol Clinic N Am 17(2006) 1095- 1100
• Neelam Verma, S Verma ,Proliferative indices ,
cytogenetics,immunoproliferative & other prognostic
parameters in MDS, IJPM 51(1) Jan 2008 97-101
• Wardrop D, Steensma DP. Is refractory anaemia with ring
sideroblasts and thrombocytosis (RARS-T) a necessary or
useful diagnostic category? Br J Haematol. 2009;144:809–817
• www.ashimages.org , American Society of Hematology
• R. Hoffmann, Hematology: Basic Principles & Practice 4th Ed
1971- 1985

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