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

myeloblasts) and in 1976 he and colleagues proposed a preliminary TABLE 87–1. World Health Organization Classification of
classification of these syndromes. Dreyfus published a paper in which
refractory anemia with an excess of myeloblasts was amplified, paren- the Myelodysplastic Syndromes
thetically, as smoldering acute leukemia. 16,17 The synonym, oligoblastic 1. Refractory cytopenia with unilineage dysplasia (RCUD)
leukemias, had been used also to describe those cases with low propor- Dysplasia in ≥10% of cells from a single myeloid lineage
tions of leukemic myeloblasts and relatively protracted courses. 18,19 <5% marrow blasts, <1% blood blasts, and no Auer rods
In 1975, at a conference held in Paris, Bessis and Bernard used the <15% of erythroid precursors are ring sideroblasts
term hematopoietic dysplasia, later shortened to myelodysplasia, for the
group of disorders having a more indolent course than AML. The con- Most often is refractory anemia (RA) but can be refractory neutrope-
cept that neoplasia is a tissue abnormality defined by its origin in the nia (RN) or refractory thrombocytopenia (RT) in rare cases
mutation(s) within a single cell (monoclonality) and that dysplasia is 2. Refractory anemia with ring sideroblasts (RARS)
a polyclonal tissue change, not neoplasia, was ignored and took a back Isolated erythroid dysplasia
seat to the participants’ primary interest in the dysmorphia of cells that <5% marrow blasts, <1% blood blasts, and no Auer rods
characterized most of these syndromes, hence the application of the ≥15% of erythroid precursors are ring sideroblasts
term dysplasia, which has become entrenched. The cutoff for ring sideroblasts is arbitrary and does not reflect the
In the year following the Paris conference, a group of seven clinical behavior of this subtype as accurately as the frequently
hematopathologists from France, the United States, and England—the associated mutations of SF3B1
“French-American-British (FAB) Co-Operative Group”—instituted the 3. Myelodysplastic syndromes (MDS) associated with isolated
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classification of acute leukemia, developed by Dalton and Dacie, and del(5q)
called it the FAB classification. In the FAB classification, acute leuke-
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mia was defined by the presence of 30 percent blasts in the marrow; the 5q31 deletion as the sole chromosomal abnormality
original report also included two preleukemic syndromes that should be Normal to increased megakaryocytes with hypolobated nuclei
distinguished from acute leukemia, refractory anemia with excess blasts Normal to increase platelet count
(RAEB), and chronic myelomonocytic leukemia (CMML), defined by <5% marrow blasts, <1% blood blasts, and no Auer rods
greater than 1000/μL of blood monocytes. Because most patients with This subtype overlaps with, but is not entirely synonymous with the
preleukemia do not go on to develop leukemia, the FAB group proposed “5q-minus syndrome” recognized prior to the establishment of the
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the term “dysmyelopoietic syndrome” as an alternative to preleukemia. WHO classification system for MDS
A few years later, “dysmyelopoietic syndrome” was revised to become 4. Refractory cytopenia with multilineage dysplasia (RCMD)
the “myelodysplastic syndrome(s)” still used today. Dysplasia in ≥10% of cells from two or more myeloid lineages
The 1976 FAB classification included only two subtypes of dysmy-
elopoietic syndromes, but in 1982 the FAB proposed a specific MDS <5% marrow blasts, <1% blood blasts, and no Auer rods
9
classification that included five entities: refractory anemia (RA), refrac- Blood monocyte count <1 × 10 /L
tory anemia with ring sideroblasts (RARS), RAEB (defined by 5 to 19 5. Refractory anemia with excess blasts (RAEB)
percent marrow blasts), refractory anemia with excess blasts in trans- Type 1: 5–9% marrow blasts, <5% blood blasts, and no Auer
formation (RAEB-t, defined by 20 to 29 percent marrow blasts), and rods
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CMML. The 1982 FAB classification, while not without limitations, Type 2: 10–19% marrow blasts, 5–19% blood blasts, or Auer
proved influential and was the basis of subsequent classifications of rods
MDS and related disorders by the World Health Organization (WHO). Blood monocyte count <1 × 10 /L
9
Subsequent developments in prognostic scoring systems and biologic
understanding of MDS are described below. 6. Unclassifiable MDS (MDS-U)
Minimal dysplasia in the presence of a clonal cytogenetic
lesion considered presumptive evidence of MDS
CLASSIFICATION <5% marrow blasts, <1% blood blasts, and no Auer rods
A classification of MDS and related disorders was defined by the note: Other acute and chronic clonal myeloid diseases are catego-
WHO in 2001 and revised in 2008. It includes six major subtypes of rized in Chap. 83, Table 83–1.
disease distinguished by the type and number of dysplastic lineages,
the proportion of marrow blasts, and in one subtype, the presence of a
specific chromosomal abnormality, del(5q). These subtypes include
(1) refractory cytopenia with unilineage dysplasia (RCUD), which is progression or response to therapy. Clonal cytopenias with dysmorphia
typically RA, (2) RARS, (3) RA with ringed sideroblasts and thrombo- may also be present in patients with myeloproliferative features such
cytosis (RARS-t), (4) MDS with isolated del(5q), (5) refractory cytope- as thrombocytosis or monocytosis. CMML, for example, was previ-
nia with multilineage dysplasia, (6) RAEB (type 1 or type 2 depending ously considered an MDS subtype in the FAB classification, but is now
in the proportion of marrow or blood blasts), and (7) unclassifiable recognized as a myelodysplastic/myeloproliferative neoplasm (MDS/
MDS (Table 87–1). MDS patients with 20 to 29 percent marrow blasts, MPN) overlap syndrome. Some patients diagnosed with MDS may have
previously defined as RAEB-t, are considered to have AML in the WHO their diagnosis change to CMML once their monocyte count exceeds
classification. However, this sharp cutoff is arbitrarily defined. In prac- 1 × 10 /L. Similarly, RARS may be reclassified as RARS-t, if the platelet
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tice, patients with blast proportions in this range have comparable out- count rises above 450 × 10 /L. CMML, RARS-t, and related MDS/MPN
comes to patients with RAEB-2, including similar rates of benefit from subtypes are discussed separately in Chap. 89 with the chronic myelog-
MDS-directed therapy. enous leukemias.
The boundaries between subtypes involving percentages of mye- Classification systems for MDS have descriptive merit, but do not
loblasts or ring sideroblasts are also arbitrarily defined. Patients may capture many disease variables with clinical significance. The WHO
see their disease classification change over time as a result of clinical subtypes of MDS identify patients with similar prognoses because

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