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Myelodysplastic Syndromes ppt
1. 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
2. • 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 )
3. • 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
4. 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
5. • 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
6. • 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.
.
7. • 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
8. 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
9. • ETIOLOGY
a) PRIMARY OR DE-NOVO
Benzene exposure
Cigarette smoking
Agricultural chemicals
Family h/o haematopoietic neoplasms
Fanconi anemia, Shwachmann diamond, Diamond-Blackfan
10. • 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
13. FAB CLASSIFICATION OF MDS
SUBTYPE BLOOD BONE MARROW
• 1%BLAST
REFRACTORY <1%BLASTS DYSPLASIA;
ANEMIA(RA) <5%BLASTS
REFRACTORY <1%BLASTS DYSPLASIA;
ANEMIA WITH <5%BLASTS;
RINGED >15%RINGED
SIDEROBLASTS( SIDEROBLASTS
RARS)
REFRACTORY <5%BLASTS DYSPLASIA;
ANEMIA WITH 5-19%BLASTS
EXCESS
BLASTS(RAEB)
14. contd
SUBTYPE BLOOD BONE MARROW
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)
15. WHO CLASSIFICATION OF MDS (2008)
SUBTYPE BLOOD BONE MARROW
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;
16. SUBTYPE BLOOD BONE MARROW
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
17. SUBTYPE BLOOD BONE MARROW
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
18. SUBTYPE BLOOD BONE MARROW
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
19. 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
20. 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.
21. 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
22. 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.
23. • 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
24. 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.
25. 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
26. 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
27. ENVIRON
MENTAL
MOLECUL
AR GAIN
EPIGENET
OF
IC
FUNCTIO
N
IMMUNOL
OGICAL MDS APOPTOSI
S
STEM
ANGIOGE
CELL
NESIS
DEFECT
GENETIC
LOSS OF
SIGNAL
28. 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.
29. • Autoimmune abnormalities (uncommon) - Seen in 14 %
of the patients. Most common is cutaneous vasculitis.
• Cutaneous manifestations of MDS
Sweet syndrome
Granulocytic sarcoma
30. 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.
31. TYPE I
• Finely dispersed nuclear
chromatin
• Prominent nucleoli
• Variable N:C ratio , agranular
cytoplasm
55. • OTHER ERYTHROCYTE CHANGES
• Increase in fetal hemoglobin
• Altered A,B, antigens on the surface.
56.
57. • 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
58.
59. • 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.
60. 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.
61.
62. 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
63. 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
64. 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
65. • Thrombopoiesis
• Usually normal or megakaryocytic hyperplasia
• Micromegakaryocytes, multinucleated megakaryocytes , &
hypolobated megakaryocytes
• Presence of > 10 % Micromegakaryocytes in a population
suggests MDS
• CD 61 staining
66. 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
67. 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
68. 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.
69. • 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.
70. 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
71. • 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
72. 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
73. • 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
74. • 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
75. • 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
76.
77.
78. • 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
79. 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
81. 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
82. • 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
83. • 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
84. 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
85.
86.
87.
88. 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
89. • 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
90. • 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
91. • C/F – due to BM failure with cytopenia
• Morphology
BM is hypercellular
Neutrophil dysplasia characterised by
Hypogranulation
nuclear hyposegmentation
Pseudo pelger huet nuclei
92. • Erythroid precursors shows marked nuclear irregularity
including
internuclear bridging
nuclear budding
Multilobation
Megaloblastoid nuclei
• Cytoplasmic vacoules are poorly defined, PAS positive
94. 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
95.
96.
97.
98. 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 % .
99. • Approx 40 % of all MDS
• Affects individuals over 50 yrs of age
• Risk factors
Environmental toxins eg pesticides
Petroleum products
Cigarette smoking
Heavy metals
100. • 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
101. • 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
102. • 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 +
103. • 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
104. • 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
105.
106.
107.
108.
109.
110.
111.
112. 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
113. • 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
114. • 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
115. • 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
116. • 10% progress to AML
• lenalidomide, a thalidomide analogue and immunomodulating
drug, has high response rate
123. 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
124. 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
125. 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
126.
127.
128.
129.
130.
131. 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
132. • 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
133.
134. • 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
135. 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
136. • 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%
137. • 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
139. • Cytoplasm- nucleus maturation asynchrony
Megakaryocytic changes
• Detection of micromegakaryocytes is a strong indicator of
RCC
140.
141.
142. 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%
143. 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
144. 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
145. 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
146. 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
147. 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
148. • 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
149.
150. 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
151. 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
152. 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
153. 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
154. • 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
155. 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
156. REFERENCES
• Swedlow SH,Campo E , Haris NL WHO classification of
Tumours of Hematopoietic and Lymphoid tissue, IARC
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• 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
157. • John M Benett ,The MDS/MPD disorders , the interface
Hematol Oncol Clinic N Am 17(2006) 1095- 1100
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cytogenetics,immunoproliferative & other prognostic
parameters in MDS, IJPM 51(1) Jan 2008 97-101
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sideroblasts and thrombocytosis (RARS-T) a necessary or
useful diagnostic category? Br J Haematol. 2009;144:809–817
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1971- 1985