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1342 Part X: Malignant Myeloid Diseases Chapter 87: Myelodysplastic Syndromes 1343

myeloblasts, oligoblastic myelogenous leukemia (refractory anemia subsets to nosology based on DNA mutation patterns, clonal architec-
with excess blasts), and a greater risk of progression to AML. ture, and predicted evolution to AML. 4
Despite their phenotypic variability, MDS share a common patho- Although anemia had been recognized since the early 19th century
physiology. They are neoplasms derived from the clonal expansion of a as a specific deficiency of red cells (also known as “colored corpuscles,”
somatically mutated, multipotent hematopoietic progenitor cell. A wide a term that distinguished these cells from leukocytes in the era before
range of genetic aberrations can contribute to the development and histological stains), marrow biopsies were not regularly performed on
progression of MDS and these somatic mutations can exist in an even living patients until after the 1920s. Therefore, conditions such as MDS
5
greater variety of combinations. The specific profile of genetic lesions that are associated with and defined by specific marrow findings could
present in a given case contributes to the eventual disease phenotype. not be described as distinct syndromes until the first half of the 20th
MDS are closely related to other myeloid neoplasms such as AML century. Still, early suggestive reports can be found in the medical lit-
and some myeloproliferative neoplasms. The dysmorphia of neoplasia erature: a 1907 report by Luzzatto of megaloblastic “pseudo-aplastic
(commonly referred to as dysplasia in describing MDS) refers to the anemia,” for example, could have included MDS cases.
6
abnormal morphology than can be observed in neoplastic mature blood In the mid-1920s, Di Guglielmo in Naples described a group of
cells and maturing marrow erythroid, granulocytic, and megakaryo- marrow disorders associated with bizarrely shaped erythrocytes and
7
cytic precursor cells, and is one of the distinguishing characteristics of cytopenias, which in some cases ultimately proved fatal. For many
MDS. The dysmorphia is essential in diagnosis, but is an epiphenom- years thereafter, a heterogeneous group of marrow disorders associated
enon. The essential abnormality is the neoplastic transformation of a with anemia and erythroid dysmorphology were called “Di Guglielmo
primitive multipotential myeloid cell. A lower fraction of myeloblasts syndrome” by hematologists, a term that was used variably and is still
in the marrow is a reflection of its being at the less-severe end of the employed occasionally as an eponymous description of erythroleuke-
spectrum of myelogenous leukemia and is a feature of the diagnosis, mia (AML M6). Some cases of Di Guglielmo syndrome would be called
creating an arbitrary division between MDS and AML. The diagnos- MDS today.
tic criteria that separate various myeloid neoplasms (and MDS sub- The first MDS-specific term familiar to contemporary hematolo-
types) from each other are somewhat ambiguous because they are so gists, “refractory anemia,” was coined in the 1930s to describe patients
closely related. This is evident at the molecular level where no particular who had unexplained anemia as a consequence of marrow underpro-
genetic abnormality or mutation profile is entirely unique to MDS. Both duction and who failed to respond to treatment with the available hema-
somatic mutations and chromosomal abnormalities found in MDS are tinics: iron salts and the liver extract found by Minot and Murphy in the
8,9
observed in related disorders, albeit often with different frequency. early 1920s to cure pernicious anemia. It is not clear how many of the
RNA splicing factors and epigenetic regulators are the most common 100 cases of refractory anemia in the classic 1938 series of Rhoads and
classes of genes affected by mutations in MDS followed by mutations in Barker in New York City actually had MDS—many appear to have had
transcription factors, tyrosine kinase signaling genes, and TP53. MDS anemia of chronic disease from infections or associated malignancies,
should be thought of as a minimal to moderately deviated neoplasm in such as Hodgkin lymphoma—but this term and its cognate, “refractory
the spectrum of myelogenous leukemias (Chap. 83). cytopenias,” are still used today to describe some of the lower-risk forms
A minority of MDS cases are attributable to prior exposure to of MDS with blast proportions less than 5 percent. 9,10
DNA-damaging agents, including chemotherapy, high-dose ionizing In 1942, Chevallier and colleagues in France discussed syndromes
radiation, and benzene-containing compounds. The latter external they labeled as “odo-leukemias.” The French investigators chose the
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factor requires an exposure of sufficient duration and magnitude to be Greek word odo, meaning threshold, to highlight disorders on the thresh-
considered causal, rare now in countries with regulations regarding the old of leukemia, and proposed leucoses as a generic term for the leukemias
content of benzene in products such as paints and solvents. Cigarette so that marked variations in white cell counts and other highly variable
smoking is considered a risk factor for AML by the U.S. Public Health presenting features would not engender inappropriate terminology. How-
Service and, presumably, this should apply to MDS, although it has not ever, this proposal was neglected, in part because the paper was published
been studied as extensively. Other chemical exposures have not been in French and there was no international network of hematologists with
established as causative agents by the International Agency for Research which to discuss such concepts in the 1940s.
on Cancer. A small number of patients come from families with a high Despite such provincialism, the idea that what would later be
penetrance of MDS and related myeloid disorders or have an inherited known as MDS could precede and terminate in AML soon made its way
or congenital syndrome predisposing to MDS. Although rare, identifi- in the English medical literature. In 1949, Hamilton-Paterson in London
cation of the genetic abnormalities in many of these cases has informed used the term preleukaemic anemia to describe patients with refractory
our understanding of the molecular pathophysiology of MDS in gen- anemia antecedent to AML. In 1953, Block and coworkers in Chicago
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eral. Yet, the vast majority of MDS cases are age-related without a clear expanded the concept to include cytopenias of all lineages and described
precipitating factor. Although MDS can occur at any age, including rare cases that closely fit with our current concepts of a clonal myeloid
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pediatric forms, its incidence increases exponentially after 40 years of hemopathy prior to evolution to overt AML. In 1956, Björkman in
age, making it one of the most common myeloid neoplasms of older Malmö, Sweden described four cases of idiopathic refractory siderob-
adults. This pattern is related to the evidence that somatic mutations in lastic anemia, one of which terminated in AML. Descriptive terms,
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primitive hematopoietic cells increase significantly with age. 1 such as herald state of leukemia, refractory anemia, sideroachrestic ane-
mia, pancytopenia with hyperplastic marrow, and others, were coined
HISTORY to describe the various hematopoietic derangements that preceded the
onset of florid AML. By the 1970s, the relationship of acquired idio-
MDS have historically been subject to confusing and shifting termi- pathic cytopenias to the subsequent onset of AML had become broadly
nology and definitions related to incomplete biologic understanding of appreciated, although such cases were still thought to be rare. In a
2,3
disease. With the advent of routine molecular analysis of primary 1973 review, Saarni and Linman found only 143 cases of “preleukemic
patient samples and increasing insight into disease pathobiology, clas- anemia” in the medical literature. 15
sification of MDS is likely to evolve from the current systems based In 1970, Dreyfus proposed the designation “les anémies réfractaires
on cytologic morphology and enumeration of marrow and blood cell avec excès de myeloblasts” (i.e., refractory anemia with excess

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