Pathological dysplastic features are the hallmark of MDS. The diagnosis of MDS requires careful examination of the peripheral blood, bone marrow aspirate, and core biopsy. MDS is a diagnosis of exclusion, and no single dysplastic or morphological feature is pathogno-monic. The pathological examination should provide information regarding the presence of dysplasia, the cell lines involved, the percentage of bone marrow blasts, and the presence and percentage of ring sideroblasts.

The French-American-British (FAB) system served as the gold standard classification for MDS for more than 20 years.23 The new WHO classification was built on the FAB classification system with further attempts to refine the classification.4 Table (38.3) summarizes the WHO subtypes and the required criteria for the diagnosis of each. Briefly, the major changes in the WHO classification include the introduction of multi-lineage dysplasia (defined as more than 10% dysplastic progeny of two or more cell lines and less than 5% blasts) and preservation of the subtypes refractory anemia and refractory anemia with ring sideroblasts to uni-lineage dysplasia and less than 10% dysplasia in either the myeloid or the megakaryocytic cell lines. Refractory anemia with excess blasts is subdivided into type I (5-9% blasts) and type II (10-19%) blasts. Refractory anemia with excess blasts in transformation is eliminated and the threshold for diagnosis of AML is lowered to 20% blasts instead of 30% blasts. Chronic myelomonocytic leukemia is moved to a separate category (myelodysplastic/myeloproliferative disorders) along with atypical chronic myelogenous leukemia (CML) and JMML. Finally, the 5q- syndrome is recognized as a distinct entity due to its unique clinical presentation and favorable outcome.326248.

The recommendations for the diagnosis of MDS are the same in the WHO and FAB classifications.32 Peripheral blood and a bone marrow aspirate and biopsy should be examined. Cytogenetics should be tested when feasible. The standard stains (Romanowsky, hematoxylin and eosin) should be done, in addition to the Prussian blue stain for iron and the reticulin stain for fibrosis. Silver stains may reveal sideroblasts in cases of iron deficiency anemia.63 To determine the percentage of blasts, a 500-cell differential should be performed on the bone marrow and a 200-cell differentiation on the peripheral blood.

The dysplastic features in the bone marrow and peripheral blood include:

Dyserythropoietic features: In the bone marrow these include multinuclearity, nuclear fragments, mega-loblastoid changes, cytoplasmic abnormalities, and increased erythroblasts (Figure 38.1(a) and (b)). In the peripheral blood manifestations may include poikilo-cytosis, anisocytosis, nucleated red blood cells, and basophilic stippling.

Dysgranulopoietic features: These include hypolobula-tion, nuclear sticks, ring-shaped nuclei, and hypogranulation. The classical pseudo-Pelger-Huet neutrophils should be seen in more than 10% of the peripheral neutrophils (Figure 38.1(a)).

Dysmegakaryocytopoietic features: These include micromegakaryocytes, large mononuclear forms, and multiple small nuclei (Figure 38,1(c)). Abnormal sideroblasts: These are defined by five or more iron granules. When the granules encircle one third or more of the nucleus in iron stained smears, the term

Table 38.3 The WHO classification of MDS and required criteria for diagnosis

Percentage of

Table 38.3 The WHO classification of MDS and required criteria for diagnosis

Percentage of


MDS cases

Peripheral blood

Bone marrow

Refractory anemia (RA)

< 1 X 109 monocytes

Erythroid dysplasia

< 10 % myeloid or megakaryocyte dysplasia

< 15% sideroblasts

Refractory anemia with ring sideroblasts (RARS)

< 1 X109 monocytes

Erythroid dysplasia

< 10 % myeloid or megakaryocyte dysplasia

> 15% sideroblasts

Refractory cytopenia with multilineage dysplasia (RCMD)

< 1 X 109 monocytes

Dysplasia in > 10% of the cells in two or more cell lines

< 15% sideroblasts

Refractory anemia with multilineage dysplasia and ring sideroblasts (RCMD-RS)

< 1 X 109 monocytes

Dysplasia in > 10% of the cells in two or more cell lines < 5% blasts in BM > 15% sideroblasts

Refractory anemia with excess blasts type I and II (RAEB-1 & RAEB II)

Type II: 6-19% blasts

Uni or multilineage dysplasia Type I 5-9% blasts Type II 10-19% blasts

5q syndrome


Normal or elevated platelets < 5% blasts

Normal or increased megakaryocytes < 5% blasts

MDS unclassified ( MDS-U)


Cytopenia < 1% blasts

Unilineage dyplasia of myeloid or megakaryocyte line

"ringed sideroblast" is applied (Figure 38.1(d)). Ring sideroblast MDS subtypes have more than 15% ring sideroblasts and less than 5% blasts.

In addition to the aspirate, the bone marrow biopsy may give helpful information. A bone marrow biopsy allows for a better assessment of cellularity. MDS bone marrow is typically normo or hypercellular;64 however, hypoplastic MDS, an entity that resembles aplastic anemia, could be challenging to differentiate from aplastic anemia or hypocellular AML.65 A bone marrow biopsy can also help assess the degree of fibrosis, as in 50% of MDS cases some degree of fibrosis may be seen on reticulin stains.66 67 Dysmegakaryocytes may be easier to identify on a bone marrow biopsy. Finally, identification of abnormal localization of immature precursors (ALIP) may carry a poor prognosis. ALIP are defined as the presence of three or more foci of immature cells— myeloblasts or promyelocytes—displaced from the paratrabecular area to the intertrabecular areas.68

Cytochemical and immunocytochemical stains could be an adjunct in the diagnosis of MDS in identifying its subtypes. Peroxidase and Sudan Black stains are helpful in distinguishing the myeloid origin of the blasts, though peroxidase can decrease over the course of MDS.69 Esterase and double esterase stain can help distinguish dysplastic granulocytes from early mono-cytes.70 Staining megakaryocytes for GP Ilb/IIIa using alkaline phosphatase anti-alkaline phosphatase (APAAP)

can help distinguish small dysplastic megakaryocytes that could be mistaken for lymphocytes.71 Flow cytome-try can detect immunophenotypic abnormalities in cases when combined morphology and cytogenetics are nondiagnostic.72 Immunophenotypic myeloid dysplasia features include hypogranular neutrophils based on orthogonal scatter, CD64 negativity, and low CD11b, CD16, and CD13 expression. Erythroid immunopheno-typic dysplasia includes decreased CD71 (transferrin receptor) expression on glycophorin A+ precursors. Megakaryocytic lineage dysplasia is, however, difficult to recognize currently immunophenotypically.

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