Pathology > Basic Hematology > White Cell Disorders > Leukemia: Myelodysplastic Syndromes

Leukemia: Myelodysplastic Syndromes

Myelodysplastic syndromes are a diverse group of closely related disorders characterized by ineffective hematopoiesis. The impaired production and maturation of hematopoietic is manifest by morphologic dysplasia (usually trilineage) in the erythroid (dyserythropoiesis), myeloid (dysmyelopoiesis) and megakaryocytic (dysmegakaryocytopoiesis) cell lines.

The myelodysplastic syndromes (MDS) are neoplastic clonal stem cell proliferations which gradually replace the normal marrow elements. The MDS cells have been demonstrated to suppress normal marrow elements.

The average age at diagnosis is usually >60 years; less than 10% diagnosed before the age of 50 years. Presenting features of MDS at diagnosis are identical to those seen in de novo acute leukemia.

MDS are sometimes referred to as smoldering leukemia, subacute leukemia, or preleukemia.

The myelodysplastic syndromes are varied in their presentation and course. The peripheral blood may show only mild anemia and reticulocytopenia and variable marrow erythroid hyperplasia ± dyserythropoiesis or there may be pancytopenia with severe dysplastic changes in all marrow cell lines and excess blasts bordering on an acute nonlymphocytic leukemia.

Because of the spectrum of dysplasia the myelodysplastic syndromes have been divided into five subgroups shown on the next card.

Second Year Medical Students should recognize the five syndromes (below) by name; know which are the most serious disorders, and appreciate the degree of dysplasia described by each.

MDS

Peripheral Blood

Bone Marrow

Refractory anemia (RA)

anemia (macrocytic or dimorphic) with reticulocytopenia; variable dyserythropoiesis; <1% blasts neutropenia, dysmyelopoiesis & dysmegakaryopoiesis are rare

normal - hypercellular; erythroid hyperplasia with variable dyserythropoiesis; normal myeloid & megakaryocytic lines; <5% blasts

Refractory anemia with ringed sideroblasts (RAS)

anemia (macrocytic or dimorphic) with reticulocytopenia; variable dyserythropoiesis; <1% blasts neutropenia, dysmyelopoiesis & dysmegakaryopoiesis are rare

ringed sideroblasts >15% nucleated cells

Refractory anemia with excess blasts (RAEB)

 

2 or more of dyserythropoiesis, dysmyelopoiesis, and dysmegakaryopoiesis; <5% blasts

hypercellular; dyserythropoiesis, dysmyelopoiesis, and dysmegakaryopoiesis; 5-20% blasts ± ringed sideroblasts

Chronic myelomonocytic leukemia (CMML)

monocytosis (>1.0x109/L);
<5% blasts; ± dysmyelopoiesis

as in RAEB, but increased early monocytic forms; <5% blasts

Refractory anemia with excess blasts in transformation (RAEBIT)

 

as in RAEB, but „5% blasts

 

as in RAEB, but 20-30% blasts or Auer rods

MDS in the peripheral blood may be manifest by pancytopenia (anemia, neutropenia, and thrombocytopenia), monocytosis, and occassionally a granulocytosis or a leukoerythroblastic picture.

Morphologic abnormalities of dysmyelopoiesis include hyposegmentation, hypersegmentation, abnormal chromatin (numerous nuclear projections or "sticks"; block clumping of chromatin) and abnormal cytoplasmic granulation including hypogranular neutrophils.

Hyposegmented/
hypogranular neutrophi

Hypersegmented neutrophil
with nuclear "sticks".

Morphologic abnormalities of dysmyelopoiesis include acquired Pelger-Huet-like hyposegmentation, abnormal chromatin formations including ring nuclei and abnormal cytoplasmic granulation.

Acquired Pelger-Huet
hyposegmentation

Abnormal ring nucleus with
abnormal granulation pattern.

 

 

 

Dyserythropoiesis in MDS includes a "dimorphic" blood picture macrocytosis, schistocytes, Howell-Jolly bodies, heavy basophilic stippling; occassional NRBCs.

Dysmegakaryocytopoiesis is evidenced by large hypo- or hypergranular, sometimes vacuolated platelets.

The bone marrow in MDS is usually hypercellular (ineffective hematopoiesis) but may be normocellular or hypocellular.

Dysmyelopoiesis is similar to that seen in the peripheral blood but with abnormal myelocyte granulation. The cytoplasm may become a diffuse copper color.

Dyserythropoiesis is evidenced by bizarre erythroid precursors (clover-leaf nuclei; ringed sideroblasts) and maturation defects (megaloblastoid) of the erythroid series.

Dysmegakaryocytopoiesis is indicated by megakaryocytes that are usually normal in number, but are often small (dwarf) and may be hypogranulated.

Small mononuclear or hypolobated megakaryocyte forms are associated with the 5q&endash; syndrome. There is a chromosome abnormality with loss of the short arm of 5; hypolobation of megakaryocytes, and usually increased platelets and macrocytic anemia).

Cytogenetic studies are of important prognostic significance in MDS. Clonal chromosomal abnormalities are detected in 40-70% of MDS. The most common abnormality is the loss of whole or partial chromosomes by deletion or unbalanced translocations. These include loss of chromosome 5 or 7 and deletions of the long arm of 5 or 7 and deletions of 13 and 20. Trisomy 8 is also common. The incidence of chromosomal abnormalities is higher in RAEB, CMML, and RAEBIT than in RA or RAS.

Chromosome abnormalities in 1° MDS are of independent prognostic significance. Patients with normal karyotypes have longer survivals than those with abnormalities. Patients with an isolated 5q&endash; with <5% blasts (the 5q&endash; syndrome) have a stable course although becoming transfusion dependent. Trisomy 8 marks an intermediate prognosis. Monosomy 7 or deletions of 7q portend a poor prognosis. In general, the more chromosome abnormalities, the worse the prognosis.

Secondary MDS (therapy or mutagen related) has a high incidence of chromosomal abnormalities (>80%).

The clinical course of MDS is characterized by hemorrhage (thrombocytopenia), infection (neutropenia) and in nearly 40% evolution to acute leukemia.

Clearly, RAEB, RAEBIT and CMML are more serious disorders than RA and RAS.

MDS - median survival

Refractory anemia (RA)

64 months

Refractory anemia with ringed sideroblasts (RAS)

71 months

Refractory anemia with excess blasts (RAEB)

7 months

Chronic myelomonocytic leukemia (CMML)

8 months

Refractory anemia with excess blasts in transformation (RAEBIT)

5 months

RAEB, RAEBIT and CMML are more likely to progress to acute leukemia.

Why should you test B12 and folate levels when entertaining a diagnosis of MDS?

Chemotherapy, bone marrow transplantation, and hematopoietic growth factors (GM-CSF;G-CSF) are current options for treatment of MDS.

The theraputic goal is to eliminate the abnormal clonal population of cells and to replace it with normal hematopoietic elements.

Chemotherapy alone or with bone marrow transplantation attempts to accomplish this goal.

Hematopoietic growth factors are used in an attempt to enhance normal hematopoietic cell growth and to cause or induce the differentiation of the abnormal hematopoietic cells to the point of clonal extinction.

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