Editors: Tkachuk, Douglas C.; Hirschmann, Jan V.

Title: Wintrobe's Atlas of Clinical Hematology, 1st Edition

Copyright 2007 Lippincott Williams & Wilkins
> Table of Contents > Chapter 3 - Myelodysplastic Syndromes
Chapter 3
Myelodysplastic Syndromes
Douglas C. Tkachuk MD, FRCPC
Kathy Chun PhD, FCCMG
Jan V. Hirschmann MD
The myelodysplastic syndromes (MDSs)
are disorders caused by a clonal expansion of hematopoietic stem cells in which
maturation is abnormal (dysplastic) and production ineffective, resulting in many cells
being destroyed before they reach the systemic circulation. Anemia typically occurs,
often accompanied by thrombocytopenia and/or neutropenia. Some cases develop from
exposure to ionizing radiation or cytotoxic chemotherapy, usually with alkylating agents,
and in these circumstances the bone marrow is characteristically hypocellular and
partially fibrotic. More frequently, these diseases occur as a primary problem in older
adults, with a median age of about 70 when diagnosed. In them, the bone marrow is
usually hypercellular.
Blasts may be increased in the myelodysplastic syndromes, but they do not exceed 20%
of the differential count of at least 200 leukocytes in the peripheral blood and 500 in the
bone marrow. Dysplasia may involve one or more hematopoietic lines; to be significant it
should affect at least 10% of that line's cells in the bone marrow, but evidence for
dysplasia may also be present on the peripheral smear. In erythrocytes the smear may
show macrocytosis, anisocytosis, basophilic stippling, and Pappenheimer bodies.
Poikilocytosis is usual and includes target cells, acanthocytes, elliptocytes, stomatocytes,
red-cell fragments, and teardrop cells. Bone marrow findings in the erythrocyte
precursors comprise nuclear and cytoplasmic abnormalities. The former consist of
budding, internuclear bridging, the presence of more than one nucleus per cell,
karyorrhexis (fragmentation), abnormal chromatin (either fine or dense) and
megaloblastic changes, in which the nucleus is enlarged and less mature than is the
cytoplasm. Cytoplasmic abnormalities include vacuolization and ringed sideroblasts,
which are erythroblasts that, on iron stain, contain 10 ferritin granules encircling at
least one-third of the nucleus.
Evidence of abnormal granulopoiesis on peripheral smear includes neutropenia,
hypersegmented neutrophils, Dhle bodies, decreased or absent cytoplasmic granules,
and the presence of immature cells, including blasts. The nuclei may have dense
chromatin clumping, and many are hypolobulated, with a single lobe or two joined by a
thin band of chromatin, resembling the congenital disorder, Pelger-Het anomaly. The
presence of these pseudo-Pelger-Het cells on a blood smear strongly suggests an
underlying myelodysplastic syndrome. Eosinophils and basophils may have diminished
granules and decreased nuclear lobulation. These abnormalities also are apparent in the
bone marrow, along with the small size of the granulocyte precursors, which may be

present centrally rather than in their accustomed paratrabecular location, a finding labeled
atypical localization of immature precursors (ALIP) when at least three of such foci occur
in a bone marrow section.
Abnormal thrombopoiesis on peripheral smear is manifested by thrombocytopenia, giant
platelets, and those with decreased or absent granules. In bone marrow specimens,
dysplastic megakaryocytes are small (micromegakaryocytes), and possess abnormal
nuclei that are multiple and widely separated or have decreased or absent lobulation.
Cytogenetic abnormalities are common in the myelodysplastic syndromes and all types
are at varying risk for developing acute leukemia, which is almost always myelogenous.
The World Health Organization (WHO) has defined eight types of myelodysplasia based
primarily on bone marrow findings.
Refractory Anemia (RA)
This entity accounts for about 5% to 10% of cases of MDS, the median survival is about
5 years, and acute leukemia eventuates in approximately 5% of patients. Dysplasia occurs
in the erythroid precursors alone, ranges from mild to pronounced, and consists of the
findings described in the first section. On peripheral blood smear the red cells are
normocytic or macrocytic. Nonspecific cytogenetic abnormalities occur in about 25% of
cases.
Refractory Anemia with Ringed Sideroblasts (RARS)
This disorder is responsible for about 10% of cases of MDS, has a median survival of
about 6 years, and has about a 1% chance of evolving into acute leukemia. Dysplasia
occurs only in the erythroid line, and at least 15% of the red cell precursors are ringed
sideroblasts. Cytogenetic abnormalities occur in <10% of cases.
Refractory Cytopenia with Multilineage Dysplasia (RCMD)
This disorder accounts for about 25% of MDS, and the diagnosis requires cytopenias and
dysplastic changes in at least two lines. When, in addition, ringed sideroblasts constitute
>15% of the erythroid precursors, the diagnosis is the subtype refractory cytopenia with
multilineage dysplasia and ringed sideroblasts (RCMD-RS), which accounts for about
15% of cases of MDS. The median survival for both is about 3 years, and the risk of
leukemia is approximately 10%. Cytogenetic abnormalities occur in up to 50% of cases.
Refractory Anemia with Excess Blasts (RAEB)
In this MDS, the blasts are increased above normal, but not sufficiently to meet the
criteria for leukemia, which is at least 20% of nucleated cells in the blood or bone
marrow. Two subtypes exist: RAEB-1 has 5% to 9% blasts in the bone marrow and <5%
in the blood; RAEB-2 has 10% to 19% blasts in the bone marrow and/or 5% to 19%
blasts in the blood. Those with Auer rods are also considered RAEB-2. These two
diseases account for approximately 40% of cases of MDS. About 25% of RAEB-1 and
33% of RAEB-2 develop acute leukemia, and their respective median survivals are 18

and 10 months. Approximately 33% to 50% of these patients have cytogenetic

abnormalities.
Myelodysplastic Syndrome, Unclassifiable (MDS-U)
Patients are put in this category when they have dysplasia restricted to either the
neutrophil or megakaryocytic lines. They fail to meet the criteria for the other MDSs. The
number of patients who belong in this group, their median survival, and the risk of
developing leukemia are uncertain.
Myelodysplastic Syndrome Associated
Abnormality (5q- Syndrome)

with

Isolated

del(5q)

Chromosome

Unlike the other MDSs, this entity is primarily defined not by hematologic findings but
by a cytogenetic abnormality, a deletion between bands q31 and 33 on chromosome 5,
with variability in the actual break points and the size of the deletion. Most patients are
middle-aged to older women, whose major problem is refractory macrocytic anemia.
Some patients have thrombocytosis. The bone marrow is usually hypercellular, dysplasia
is present in the erythroid precursors, many megakaryocytes have hypolobulated nuclei,
and blasts are <5%. Patients typically have a long survival, and progression to acute
leukemia occurs in <25% of cases.
Table 3.1 World Health Organization classification of the myelodysplastic
syndromes
Classification
Peripheral Blood
Bone Marrow
Refractory anemia
Anemia
Erythroid
dysplasia
only
No or rare blasts
<5%
blasts
<15% ringed sideroblasts
Refractory anemia with ringedAnemia
>15% ringed sideroblasts
sideroblasts
No blasts
Erythroid
dysplasia
only
<5% blasts
Refractory
cytopenia
withCytopenias
Dysplasia in >10% of the cells
multilineage dysplasia
(bicytopenia
orof two or more myeloid lines
pancytopenia)
<5% blasts in the marrow
No or rare blastsNo
Auer
rods
No
Auer
rods<15% ringed sideroblasts
<1

109/L
monocytes
Refractory
cytopenia
withCytopenias
Dysplasia in >10% of the cells
multilineage dysplasia and ringed(bicytopenia
orof two or more myeloid lines
sideroblasts
pancytopenia)
<5% blasts in the marrow
No or rare blasts>15% ringed sideroblasts
No
Auer
rodsNo Auer rods
<1

109/L
monocytes

Refractory anemia with excessCytopenias

Unilineage or multilineage
blasts 1
<5%
blastsdysplasia
No
Auer
rods5%
to
9%
blasts
9
<1

10 /LNo Auer rods

monocytes
Refractory anemia with excessCytopenias
Unilineage or multilineage
blasts 2
5% to 19% blastsdysplasia
Auer rods present10%
to
19%
blasts
9
<1

10 /LAuer rods present

monocytes
Myelodysplastic
syndrome,Cytopenias
Unilineage dysplasia: one
unclassified
No or rare blastsmyeloid
cell
line
No Auer rods
<5%
blasts
No Auer rods
5q- syndrome
Anemia
Normal
to
increased
Usually normal ormegakaryocytes
with
increased
platelethypolobated
nuclei
count
<5%
blasts
<5% blasts
Isolated del(5q) cytogenetic
abnormality
No Auer rods
Reprinted with permission from Wintrobe's Clinical Hematology, 11th Edition, page
2209.
Table 3.2 Morphologic abnormalities in myelodysplastic syndromes
Lineage
Peripheral Blood
Bone Marrow
Erythroid
Ovalomacrocytes
Megaloblastoid erythropoiesis
Elliptocytes
Nuclear budding
Acanthocytes
Ringed sideroblasts
Stomatocytes
Internuclear bridging
Teardrops
Karyorrhexis
Nucleated erythrocytes
Nuclear fragments
Basophilic stippling
Cytoplasmic vacuolization
Howell-Jolly bodies
Multinucleation
Myeloid
Pseudo-Pelger-Hu't anomaly
Defective granulation
Auer rods
Maturation arrest at myelocyte stage
Hypogranulation
Increase in monocytoid forms
Nuclear
sticksAbnormal localization of immature
Hypersegmentation
precursors
Ring-shaped nuclei
MegakaryocyteGiant
plateletsMicromegakaryocytes
Hypogranular or agranularHypogranulation
platelets
Multiple small nuclei
Reprinted with permission from Wintrobe's Clinical Hematology, 11th Edition, page
2211.

Table 3.3 Predisposing factors and epidemiologic associations

Heritable
predisposition
Constitutional
genetic
disorders
Down
syndrome
(trisomy
21)
Trisomy
8
mosaicism
Familial
monosomy
7
Neurofibromatosis
1
Germ
cell
tumors
(embryonal
dysgenesis)
Congenital neutropenia (Kostmann syndrome or Shwachman-Diamond syndrome)
DNA
repair
deficiencies
Fanconi
anemia
Ataxia
telangiectasia
Bloom
syndrome
Xeroderma
pigmentosum
Mutagen
detoxification
(GSTq1-null)
Acquired
Senescence
Mutagen
exposure
Genotoxic
therapy
Alkylators
Topoisomerase
II
interactive
agents
-Emitters
(phosphorus-32)
Autologous
bone
marrow
transplantation
Environmental
or
occupational
exposure
(e.g.,
benzene)
Tobacco
Aplastic
anemia
Paroxysmal
nocturnal
hemoglobinuria
Polycythemia vera
Reprinted with permission from Wintrobe's Clinical Hematology, 11th Edition, page
2214.