Transcript Myelodysplastic Syndrome

Ahmad Sh. Silmi
Msc Haematology, FIBMS
What Is Myelodysplastic Syndrome?
 The myelodysplastic syndromes are a group of disorders
characterized by one or more peripheral blood cytopenias
secondary to bone marrow dysfunction.
 In MDS the bone marrow cannot produce blood cells
effectively, and many of the blood cells formed are
defective.
 These abnormal blood cells are usually destroyed before
they leave the bone marrow or shortly after entering the
bloodstream.
 As a result, patients have shortages of blood cells, which are
reflected in their low blood
Characteristics
 Varying degree of tri-lineage cytopenia ( red blood
cells, white blood cells and platelets).
 Dysplasia
 Normocellular or hypercellular B.M.
 May progress to acute leukaemia
Signs and Symptoms
 Excessive tiredness, shortness of breath, and pale skin can
be caused by anemia (shortage of red blood cells).
 Serious infections with high fevers can be caused by
leukopenia (not having enough normal white blood cells)
and, in particular, by having neutropenia or
granulocytopenia (too few mature granulocytes).
 Excessive bruising and bleeding, for example, frequent or
severe nosebleeds and/or bleeding from the gums, can be
due to thrombocytopenia (not having enough of the blood
platelets needed for plugging holes in damaged blood
vessels).
Incidence
1- Disease of elderly.
2- Median age is 65 years.
3- <10% are younger than 50 years.
4- Incidence rates 1/100,000 pop./ years.
5- Incidence rise to 1/1000 / years in > 60 years old.
6- Male slightly higher than female
MDS Etiology
 Two etiologic categories of MDS:
1.) De Novo:
Associated with:
-benzene exposure (gasoline)
-cigarette smoking
-viruses
-Fanconi’s anemia
2.) Therapy related:
Associated with:
-alkylating agent chemotherapy
-radiation
Aetiology
This shows the tow arms of haemopoiesis
This shows how stem cell is affected
Aetiological Agents
 Tobacco smoke.
 Ionizing radiation.
 Organic chemicals (such as benzene, toluene, xylene, and
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chloramphenicol).
Heavy metals.
Herbicides.
Pesticides.
Fertilizers.
Stone and cereal dusts.
Exhaust gases.
Nitro-organic explosives.
Petroleum and diesel derivatives.
Alkylating agents.
Marrow-damaging agents used in cancer chemotherapy.
Chromosomal abnormalities and MDS
 Chromosomal abnormalities are present in up to
50%of de novo cases of MDS and in virtually all
cases of secondary MDS. The most common are:

Abnormality

Frequency(%)
-7
15
+7
+8
5q-
7q-
11q-
12q-
13q-
20q- inv3
5
19
27
4
7
5
2
5
1
i(17q)
5
t(1;3)
1
t(1;7) t(3;3)
2
1
Deletion of the long arm of chromosome 5
(5q- syndrome )
 Strongly associated with RA.
 5q- accounts for up to 70% of cytogenetic abnormalities in
this subtype.
 The q arm of chromosome 5 is particularly rich in genes,
which encoded haemopoietic growth factors and their
receptors. For example , IL-3 , IL-4 , IL-5 , GM-CSF and the
M-CSF receptor are located in this region.
 The potential for the loss of any or all of these genes
contribute to the disruption of ordered haemopoiesis.
Monosmy 7 and 7q Most strongly associated with secondary MDS.
 Associated with the loss of a major surface glycoprotein
(gp 130) in neutrophile and susceptibility to bacterial
infection secondary to impaired granulocyte monocyte
chemotatic activity.
Deletion of the q arm of chromosome
11 (11q-)
 Account for 20% of the chromosomal abnormalities in
RAS.
 This abnormality is associated with raised iron stores
and high ring sidroblast counts.
 The presence of the gene , which encoded the H-
subunit of ferritin at chromosome 11 , may explain this
Abnormalities of chromosome 17 (i17q)
 It involves the loss or disruption of the Р53 tumor
suppressor gene are seen in CML in association with
transformation to the blastic phase and in up to 5% of
cases of primary MDS.
 This predisposes to certain dysplastic features and
neutrophil vaculation.
Abnormalities of chromosome 3
 Dysmegakaryopiesis and thombocytosis appear to be
associated with Abnormalities of chromosome 3
The importance of indication of chromosomal
abnormalities
 To confirm diagnoses .
 To know the stage of disease.
 To know the direction of progression of disease.
 Multiple genetic abnormalities indicate late events in
MDS.
Patterns of MDS evolution
 A stable group with no increase in B.M blasts and a
normal karyotype .
 Rapid blast transformation with acquisition of new
cytogenetic changes after an initial , stable phase .
 Gradually increasing blast count in the absence of new
cytogenetic changes .
FAB classification scheme in 1985 for MDS
Refractory Anemia
 RA Definition:
 Dyplasia of the erythroid series only.
 Clinically, anemia is refractory to hematinic
therapy
 Myeloblasts < 1% blood and < 5% marrow
 <15% ringed sideroblasts in marrow
 No Auer rods
 Other etiologies of erythroid abnormalities must
be excluded. These include:
 drug/toxin exposure
 viral infection
-vitamin deficiency
-congenital disease
Refractory Anemia
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Epidemiology:
5-10% of MDS cases.
Older patients
Morphology:
Anisopoikilocytosis on peripheral smears
Dyserythropoiesis with nuclear abnormalities
(megaloblastoid change)
 < 15% ringed sideroblasts
Refractory Anemia
 Genetics:
 25% may have genetic abnormalities
 Prognosis:
 Median survival is 66 months
 6% rate of progression to acute leukemia
Peripheral Smear - Anisopoikilocytosis
Dyserythropoeisis on Bone Marrow Aspirate
Megaloblastoid Change on Bone Marrow
Aspirate
Refractory Anemia with Ringed Sideroblasts
 RARS definition:
 Dyplasia of the erythroid series only.
 Clinically, anemia is refractory to hematinic
therapy
 Myeloblasts < 5% in marrow, absent in blood
 >15% ringed sideroblasts in marrow
 No Auer rods
 Other etiologies of ringed sideroblasts must be
excluded. These include:
 Anti- tuberculosis drugs
 Alcoholism
Refractory Anemia with Ringed Sideroblasts
 Epidemiology:
 10-12% of MDS cases.
 Older patients
 Males > females
 Morphology:
 Dimorphic pattern on peripheral smears
 Majority RBC’s normochromic, 2nd population
hypochromic
 Dyserythropoiesis with nuclear abnormalities
(megaloblastoid change)
Refractory Anemia with Ringed Sideroblasts
 Morphology (con’t.)
 < 15% ringed sideroblasts (RS)
 RS = Erythroid precursor with ≥ 10 siderotic granules
encircling 1/3 or more of the nucleus.
 If excess blasts present, this dictates diagnosis, despite
percentage of RS’s.
Refractory Anemia with Ringed Sideroblasts
 Genetics:
 Clonal chromosomal abnormalities in
 <10%; in fact, development of such an
abnormality should prompt reassessment of
diagnosis.
 Prognosis:
 Median survival 6 years (72 months)
 1-2% rate of progression to acute leukemia
Dimorphic Red Cell Population
Ringed Sideroblasts
Ringed Sideroblasts
Megaloblastoid Change
Refractory Anemia with Excess Blasts
 RAEB definition:
 Refractory anemia with 5-19% myeloblasts in the bone
marrow.
 RAEB-1:
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5-9% blasts in bone marrow and <5% blasts in blood.
 RAEB-2:
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10-19% blasts in the bone marrow
Auer rods present
Refractory Anemia with Excess Blasts
 Epidemiology: 40% of MDS cases.
 Older patients (over 50 years)
Morphology:
 Dysplasia of all three cell lines often present
 Neutrophil abnormalities may include:
 Hypogranulation
-hypersegmentation
 Pseudo-Pelger-huet (hyposegmentation/barbells)
 Pseudo Chediak-Higashi granules
 Megkaryocyte abnormalities may include
 Hypolobation
-Micromegakaryocytes
Refractory Anemia with Excess Blasts
 Morphology (con’t.)
 Erythroid precursor abnormalities may include:
 Abnormal lobulation -megaloblastoid change
 Multinucleation
 0-19% myeloblasts in the blood
 5-19% in the marrow
 Bone marrow:
 Usually hypercellular (10-15% hypocellular)
 Abnormal localization of immature precursors (ALIP) may be
present
 Immunophenotype:
 Blasts express CD 13, CD33 or CD117
 The only MDS with a relevant phenotype
Refractory Anemia with Excess Blasts
 Genetics:
 Clonal chromosomal abnormalities found in 30% - 50% of
RAEB cases. The abnormalities include:
 +8
– -7
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– -5
– del(7q)
– del(5q)
– Complex karyotypes
Prognosis:
Median survival, RAEB-1 = 18 months
Median survival, RAEB-2 = 10 months
RAEB-1 = 25% rate of progression to acute leukemia
RAEB-2 = 33% rate of progression to acute leukemia
Hypercellular Bone Marrow
Blasts and Hypogranulation
Myeloblast with Auer Rod
Chediak-Higashi-like Granules
Photograph courtesy of John Scariano, University of New Mexico, Dept. of Pathology 
Refractory Anemia with Excess Blasts in
Transformation (RAEB-t)
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21-30 percent blasts in the marrow; more than
5 percent in the bloodstream
excessive numbers of monocytes (a type of
white blood cell)
normal or
marrow
hypercellular
(filled
with
accounts for about 25 percent of cases
cells)
Chronic Myelomonocytic Leukemia
(CMMOL)
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5-20 percent blasts in the marrow; less than 5
percent in the bloodstream
cytopenia of at least two cell lines
normal or hypercellular (filled with cells)
marrow
accounts for 15 to 20 percent of cases.
CMML
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1.
Splenomegaly (10%)
Maculopapular skin infiltration
Monocytic pleural or pericardial effusion
JMML (MPD/MDS)
Pallor, bleeding, hepatosplenomegaly, skin
involvement
WHO
 Refractory anemia
 Refractory anemia e ringed siderblast
 Refractory cytopenia e multilineage dysplasia
 Refractory cytopenia e multilineage dysplasia &
ringed sideroblasts
 Refractory anemia e excess blast-1
 Refractory anemia e excess blast-2
 Myelodysplastic syndrome unclassified
 MDS associated e isolated del (5q)
WHO
Subtype
RA
RARS
RCMD
RCMD-RS
Blood
Anemia
Bone Marrow
Erythroid
dysplasia only
Erythroid dys
Anemia
>15% ringed
Bi- pancytopenia >10%Dysp in 2
or more cell
lineage
Bi-pancytopenia >10%Dys 2 or
more cell lineage
>15% ringed
WHO
subtype
Blood
Bone Marrow
RAEB-1
Cytopenia
<5% blast
Uni-multilineage
dys, 5-9%blast
RAEB-2
Cytopenia,
5-19%blast or Auer
rods
Uni-multi dys
10-19%blast
Or Auer rods
MDS-U
cytopenia
Myeloid or
megakaryocte dys
MDS with 5q
Anemia,nor or
increased PLT
Mega e hypolobated
nuclei, <5%blast
Relation FAB & WHO
FAB
WHO
RA
RA(unilineage)
RCMD
5q-syndrome
RARS
RARS(unilineage)
RCMD-RS
RAEB
RAEB-1
RAEB-2
RAEBt
AML e multilieage dys
AML & MDS-TR
CMML
Myelodysplastic/
myeloproliferative disease
Prognostic Groups
 Two groups based on survival and evolution to acute
leukemia
 1.) “Good” group
 Refractory anemia (RA)
 Refractory anemia with ringed sideroblasts (RARS)
 5q - syndrome
 2.) “Bad” group
 Refractory anemia with excess blasts (RAEB)
 Refractory anemia with excess blasts in transformation (RAEB-t)
 CMML
 MDS unclassified can be either
International Prognostic Scoring
System (IPSS) Factors
(1) the percentage of blasts in the bone
marrow.
(2)whether chromosome abnormalities are
present and, if so, which ones.
(3)how low the patient's blood counts are. These
are given a score; the lowest scores have the
best outlook for survival.
Prognostic Scoring
 The International Myelodysplastic Syndrome Working
Group developed a scoring system based on 3 variables:
% Blasts
0
0.5
<5
5-10
Karyotype Normal, -Y,
del(5q),
del(20q)
Cytopenia
0-1
Abnormalities
NOS
2-3
1.0
-≥3
abnormalities,
chr 7
abnormalities
1.5
2.0
11-20
20-30
Differential Diagnosis
 Several common diagnostic considerations given these
findings including:
 Causes of bone marrow failure(idiopathic or drug-
induced aplasia)
 Hypersplenism
 Vitamin B12 or folate deficiency
 (PNH)– can have similar BM findings and MDS.
Pathophysiology
 The initial hematopoietic stem cell injury
can be from cytotoxic chemotherapy,
radiation, virus, chemical exposure, or
genetic predisposition.
 A clonal mutation predominates over bone
marrow, suppressing healthy stem cells.
Laboratory Finding
 Peripheral blood :
Red blood cells : ovalmacrocytosis , hypochromia.
WBCs: promyelocyte and hyposegmentation.
Platelet: large , dysplastic forms.
 Bone Marrow:
RBCs : erythroid hyperplasia , megaloblastic appearance
and dyserythropoiesis with excess sidroblasts.
WBCs: abnormal monocyte maturation and granulocyte
maturation bulge.
Platelet: megakaryocytosis and dysthrombopoiesis.
Erythrodysplasia
 Major changes are found in the peripheral blood counts
and morphology, and bone marrow abnormalities also
are present.
 The peripheral blood counts, (CBC) and blood film :
-
Premature red cell death .
Anemia will vary in degree from mild to severe
Macro - ovalocytosis
Basophilic stippling .
Decreased reticulocyte count .
Nucleated RBC,s .
blood indices:
(Increased MCV, decreased MCHC, decreased MCH )
Leucodysplasia
 Number of WBC,s is Variable .
 Neutropenia .
 Monocytosis .
 Increased Promyelocyte .
 Hyposegmented Neutrophil .
 Hypogranular PMNs .
 Circulating metamylocytes .
 Decreased myeloperoxidase and alkaline phosphatase
activity
Thrombodysplasia
 Thrombocytopenia and Large , atypical
platelets
Bone Marrow
 Erythrodysplasia :
- Ringed sideroblast, Hyponucleated RBC,s and
condensed chromatin pattern .
 Leucodysplasia:
- Myeloid hyperplasia .
- Partial maturation arrest at myelocyte stage .
 Thrombodysplasia:
o Increased number of bizarre megakaryocytes
o Micromegakaryocytes
o
Mononucleas
Survival Time
 Refractory anemia : Survival time varies from 2 to 5
years in most series
 Refractory anemia with ringed sideroblasts : The
same like RA.
 Refractory anemia with excess blasts : Median survival
for RAEB-2 is approximately 10 months.
 Refractory anemia with excess blasts in
transformation: median survival time is 6 months or
less.
Median Survival – Myelodysplastic Syndromes
120
# Months
100
80
60
40
20
0
RA
EB-2
RA RCMD RC
EB-1
MDRS
RA
MDS Category
RARS
5q-
Treatment
o Chemotherapy.
o Supportive therapy, such as WBCs, RBCs, Platelets
transfusions.
o B.M transplantation in young patients.