The
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CHARACTERISTICS AND PATHOLOGY OF
MYELODYSPLASTIC SYNDROME
Myelodysplastic syndrome (MDS) is a disease of the
blood whose etiology is unclear. There is little that can be
done therapeutically, and the prognosis for patients with
this disease is poor. The main hematologic finding is ane-
mia, but MDS responds poorly to the various kinds of drugs
used to treat anemia, and in the past it was called refractory
anemia. Moreover, 25% to 40% of MDS patients develop
acute leukemia, so MDS has also been referred to as
preleukemia or a preleukemic condition. When blood dis-
eases are classified as either erythrocytic or leukocytic, it is
often unclear into which category MDS falls.
Although MDS sometimes occurs in young adults and
children, it most often appears in older patients. Diagnosis
is confirmed in laboratory tests by a reduction in peripheral
blood cells, an abundance of cells in the bone marrow (cel-
lular marrow), abnormal cellular morphology, and chromo-
somal abnormalities. In primary cases there is no history of
underlying disease or administration of drugs that is toxic to
the marrow. The course of the disease is chronic but irre-
versible, and in a high percentage of cases it either develops
into acute leukemia or the patient succumbs to infection or
hemorrhage (death due to bone marrow failure).
In general, all blood cells arise from a single type of
pluripotent hematopoietic stem cell in the marrow. In
MDS, the hematopoietic stem cells acquire mutations and
cannot produce sufficient numbers of mature blood cells
(Fig. 1). In aplastic anemia the hematopoietic stem cells
are also abnormal, and blood cell production in the marrow
Hematological findings Cytopenia, cellular marrow
Blood cell production Ineffective hematopoiesis
Blood cell differentiation Lack of differentiation
Blood cell morphology Dysplasia
Blood cell function Functional abnormalities
Figure 1. Pathology of myelodysplastic syndrome.
The Oncologist 1996;1:284-287
generally declines. In MDS, however, there are sufficient
numbers of blood cells of each lineage along the path from
hematopoietic stem cell to mature blood cell, but the cells
do not completely mature and differentiate. Because of this
deficiency in the differentiation process, the cells die in the
marrow without maturing and differentiating (ineffective
hematopoiesis). Furthermore, blood cells that escape death
in the bone marrow and are released into the peripheral
blood have both morphological and functional abnormali-
ties compared with normal blood cells. In other words,
MDS is an abnormality at the hematopoietic stem cell level,
and it is characterized by the presence of clonal blood cells
that are abnormal both in quality (morphology, function,
differentiation) and quantity (cytopenia) [1].
Because these abnormalities are found in multiple blood
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cell lineages, they are believed to be clonal abnormalities that
originate in the pluripotent hematopoietic stem cells. The
reason why the stem cells become abnormal is still unclear.
However, MDS can arise following treatment with antineo-
plastic agents such as alkylating agents or radiation treat-
ments (therapy-related MDS), and it has been proposed that
MDS is caused by cumulative DNA damage in stem cells
from mutagenic substances such as antitumor drugs [2].
DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS
Screening for MDS should begin with the fact that
there is chronic, progressive cytopenia, the marrow is
normal or hyperplastic, and there is no underlying disease
(such as disseminated intravascular coagulation [DIC],
portal hypertension, collagen disorder, etc.) that could
otherwise cause these conditions (Table 1). MDS is most
likely to occur in middle-aged and elderly patients, but
because it can also occur in the young, age is not a deter-
mining factor for diagnosis. Diagnosis is verified by inef-
fective hematopoiesis and blood cells with morphological
abnormalities in the marrow and peripheral blood.
Cytopenia/pancytopenia; marrow puncture and biopsy
Iron metabolism, ferritin, serum iron
Delayed differentiation, differentiation damage
Megakaryoblasts, abnormalities in neutrophil nuclei/granules,
morphological abnormalities in megakaryocytes
Abnormal functions in erythrocytes, neutrophils, platelets, and
lymphocytes
285 Physician Education

Table 1. 1.

Diagnostic standards for myelodysplastic syndrome

1. Peripheral blood cytopenia
2. Cellular bone marrow
3. Chronic and refractory course
2.
4. Exclusion of underlying illnesses or administration of drugs
5. Exclusion of other known blood disorders
Verification standards
3.
1. Ineffective hematopoiesis
4.
2. Abnormal morphology of blood cells

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Although there are, for example, ferrokinetic studies for
erythroid cells, etc., it is impossible to make an accurate
evaluation of ineffective hematopoiesis based only on
abnormal laboratory test results. Therefore, if chronic
cytopenia and cellular marrow are both present, then abnor-
mal morphology of blood cells becomes the deciding factor
in diagnosis.
5.
Typical morphological abnormalities in MDS include
megaloblasts (photo 1), dissociated maturation of the 6.
nucleus and cytoplasm (photo 2), abnormal multinucle-
ated erythroblasts with three or more nuclei (photo 1),
and ringed sideroblasts (photo 3) in the erythrocytic lin-
eage; hypersegmented (photo 4) or hyposegmented neu-
trophils (pseudo Pelger-Hut nuclear anomaly, photo 5), 7.
reduced or missing granules (photos 4 and 5), and perox-
idase-negative neutrophils in the granulocytic lineage;
and micromegakaryocytes (photo 6), megakaryocytes
with multiple, isolated disc-shaped nuclei (photo 7) and
giant platelets (photo 8) in the megakaryocytic lineage. 8.
However, these morphological abnormalities are not spe-
cific to MDS, and they are also seen in pernicious ane- 1. Giant multinucleated erythroblast
mia, acute myelocytic leukemia, etc. Therefore, a 2. Megaloblast showing dissociated maturation of
diagnosis of MDS must exclude these other diseases with nucleus and cytoplasm
which we are already familiar.
3. Ringed sideroblast
Once MDS is confirmed, then the type of MDS is deter-
mined in accordance with FAB classification [1] (Fig. 2). 4. Large, hypersegmented neutrophil (few granules in
Differential diagnosis applies to all cases presenting cytoplasm)
with cytopenia. Various types of anemia such as aplastic 5. Mature neutrophil without nuclear lobes
anemia, hemolytic anemia, secondary anemia, etc., blood
(hyposegmentation)
disorders such as idiopathic thrombocytopenic purpura,
chronic neutropenia, etc., as well as collagen diseases, 6. Micromegakaryocyte
portal hypertension, DIC, etc., can all be differentiated 7. Micromegakaryocyte with disc-shaped, separated
from MDS based on their characteristic symptoms and nuclei
laboratory test results. However, atypical forms of MDS
[3, 4] also occur, such as hypoplastic marrow MDS, MDS 8. Giant platelets
 Physician Education 286

immature cells (blast cells) that have escaped apoptosis and

Peripheral blood cytopenia
have acquired the ability to proliferate [6]. Antileukemic
drugs act by inducing apoptosis in leukocytes, and it is
Normal to likely that acute leukemia from MDS is intractable because
hyperplastic MDS with hypoplastic marrow
it has managed to bypass the mechanism of apoptosis.
marrow
Research is now focused on the detection of excessive
Minimal dysplasia Dysplasia Dysplasia apoptosis in vivo in MDS patients and the relationship
between apoptosis and the development of MDS.

Early MDS? Typical MDS Hypoplastic marrow MDS ORIGIN OF BLOOD CELL CLONING
Chromosomal analysis of bone marrow cells is effec-
tive as an everyday laboratory test to verify clonality, but
it lacks sensitivity. The FISH method is useful for deter-
Peripheral blood <1% <5% 15% 530%
blast cells mining clonality at the level of individual blood cells,

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Marrow blast cells <5% 520% 520% 2030% but cannot be used in patients with no chromosomal
abnormalities. DNA polymorphism of enzymes mapped
Increase in ringed Increase in on the X chromosome can only be used in females, but
sideroblasts monocytes
interesting research is being conducted on the clonality
of lymphocytes and the possible survival of normal
No Yes hematopoietic clones.

RA RARS CMML RAEB RAEB-t

Figure 2. Flow chart for diagnosis of forms of MDS. The range of typical
forms of MDS is represented in pink. Hypoplastic marrow MDS is represented
in blue. MDS with minimal dysplasia is represented in green. It is clear that
non-typical forms of MDS exist.

with minimal dysplasia, amegakaryocytic MDS, etc.

Meticulous microscopic examination of blood cell mor-
phology and careful observation of the clinical course are
essential, in addition to bone marrow biopsy, chromosomal
studies of marrow cells, blood cell clonality analysis, etc.

RECENT DEVELOPMENTS

APOPTOSIS
One biological characteristic of MDS is the presence
of blood cells of abnormal clones derived from abnormal
hematopoietic stem cells. These abnormal clones demon-
strate ineffective hematopoiesis, which is reflected in the
contradictory phenomena of normal or hyperplastic bone
marrow concurrent with cytopenia in the peripheral blood.
This is a result of premature cell death in the bone marrow
that accompanies the abnormal blood cell differentiation
found in MDS. Therefore, it has been proposed that it is
very likely this early cell death takes the form of apoptosis,
and, little by little, experimental results supporting this
view have been published [5-7]. The development of MDS
into acute leukemia is thought to be due to the survival of Pathology of myelodysplastic syndrome.
287
ONSET AND PROGRESSION
Unstable clones with functional deficiencies are
produced by abnormal stem cells. From the standpoint
of chromosomal research, it is believed that MDS
occurs not from a single type of stem cell damage, but
from an accumulation of multiple and random stem
cell damage. MDS is a prime candidate for research on
the onset of human leukemia, and when we combine
what we know about MDS with its development into
leukemia, we can understand the development of MDS
from the standpoint of apoptosis, genetic abnormali-
ties, chromosomal abnormalities and progression of
cloning.
R EFERENCES
1. Bennett JM, Catovsky, Daniel MT et al. Proposals for the
classification of the myelodysplastic syndromes. Br J
Haematol 1982;51:189-199.
2. West RR, Stafford DA, Farrow A et al. Occupational and
environmental exposures and myelodysplasia: a case-control
study. Leuk Res 1995;19:127-139.
3. Yoshida Y, Stephenson J, Mufti GJ. Myelodysplastic syndromes
from morphology to molecular biology. Part I. Classification, nat-
ural history and cell biology of myelodysplasia. Int J Hematol
1993;57:87-97.
Physician Education
RISK FACTORS
Many risk factors for MDS have been proposed, and it
has been confirmed internationally that the four major risk
factors are the blast cell ratio in the bone marrow, advanced
age, chromosomal abnormalities, and thrombocytopenia.
Yataro Yoshida, M.D.
Professor
Division of Human Environment
The Center for South East Asian Studies
Kyoto University
Kyoto, Japan
Editor-in-Chief, International Journal of Hematology
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4. Yoshida Y, Oguma, S, Uchino H et al. Refractory myelodys-
plastic anemia with hypocellular bone marrow. J Clin Pathol
1988;41:763-767.
5. Yoshida Y. Hypothesis. Apoptosis may be responsible for the
premature intramedurally cell death in the myelodysplastic
syndromes. Leukemia 1993;7:144-146.
6. Yoshida Y, Anzai N, Kawabata H. Apoptosis in myelodyspla-
sia. A paradox or paradigm? Leuk Res 1996;19:887-891.
7. Raza A, Mundle S, Shetty V et al. Novel insight into the biol-
ogy of myelodysplastic syndromes. Excessive apoptosis and
the role of cytokines. Int J Hematol 1996;63:265-278.