eMedicine Specialties > Hematology > Stem Cells and Disorders

Myelodysplastic Syndrome

Author: Emmanuel C Besa, MD, Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, Thomas Jefferson University
Coauthor(s): Ulrich Woermann, MD, Consulting Staff, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland
Contributor Information and Disclosures

Updated: Apr 28, 2009

Introduction

Background

Myelodysplastic syndrome (MDS) refers to a heterogeneous group of closely related clonal hematopoietic disorders. All are characterized by a hypercellular or hypocellular marrow with impaired morphology and maturation (dysmyelopoiesis) and peripheral blood cytopenias, resulting from ineffective blood cell production.¹ All 3 cell lineages in myeloid hematopoiesis can be involved, including erythrocytic, granulocytic, and megakaryocytic cell lines. Although clonal, myelodysplastic syndrome (MDS) is considered a premalignant condition in a subgroup of patients that often progresses to acute myeloid leukemia (AML) when additional genetic abnormalities are acquired.

Pathophysiology

Myelodysplastic syndrome (MDS) can be classified as primary (no known exposure) or secondary as a complication of aggressive treatment of other cancers with exposure to radiation, alkylating agents, or topoisomerase II inhibitors and heavily pretreated patients with autologous bone marrow transplants.

The initial hematopoietic stem cell injury can be from cytotoxic chemotherapy, radiation exposure, viral infection, chemical exposure to genotoxins like benzene, or genetic predisposition. A clonal mutation predominates over bone marrow, suppressing healthy stem cells.

In early stages, the main cause of cytopenias is increased apoptosis (programmed cell death). As the disease progresses and converts into leukemia, further (a rare) gene mutation occurs, and a proliferation of leukemic cells overwhelms the healthy marrow.

Frequency

United States

The actual incidence of myelodysplastic syndrome (MDS) is unknown. Myelodysplastic syndrome (MDS) was first considered a separate disease in 1976, and its occurrence was estimated at 1500 new cases every year. At that time, only patients with less than 5% blasts were considered to have this disorder. The perception that the incidence of myelodysplastic syndrome (MDS) is increasing may be due to improvements in recognition and criteria for the diagnosis. Statistics from 1999 show that 13,000 new cases occur per year (approximately 1000 cases each year in children), surpassing chronic lymphocytic leukemia as the most common form of leukemia in the Western Hemisphere.

Data from 2001 through 2003 of the first National Cancer Institute's Surveillance, Epidemiology & End Reports (SEER) indicate 86% of myelodysplastic syndrome (MDS) cases were diagnosed in individuals who were >60 years of age (median age: 76y), and men had a significantly higher incidence rate than women (4.5 vs 2.7 per 100,000).²

Other data from SEER also show that the estimated incidence of myelodysplastic syndrome (MDS) increases significantly with age, ranging from 0.7/100,000 during the fourth decade to 20.8 to 36.3/100,000 after age 70 years. There is a five-fold difference in risk between age 60 and >80 years (P = 0.001). The prevalence of myelodysplastic syndrome (MDS)is currently estimated at 35,000 to 55,000 cases in the USA.^3,4 The apparent increasing number is believed to be due to higher numbers in the aging population.

International

Myelodysplastic syndrome (MDS) is found worldwide and is similar in characteristics throughout the world. Data based mainly in European numbers from Germany and Sweden were very similar to the USA numbers.

Mortality/Morbidity

The disease course of myelodysplastic syndrome (MDS) differs, with some patients having an indolent disease and others having aggressive disease with a very short clinical course that converts into an acute form of leukemia.

An international group of hematologists, the French-American-British (FAB) Cooperative Group, classified these disorders into 5 subgroups, differentiating them from acute myeloid leukemia.⁵ An underlying trilineage dysplastic change in the bone marrow cells of the patients is found in all subtypes.

• The 2 subgroups of refractory anemia (RA) characterized by 5% or less myeloblasts in bone marrow are (1) RA and (2) RA with ringed sideroblasts (RARS), defined morphologically as having 15% erythroid cells with abnormal ringed sideroblasts, reflecting an abnormal iron accumulation in the mitochondria. Both conditions have a prolonged clinical course and a low prevalence of progression to acute leukemia.
• The 2 subgroups of RAs with greater than 5% myeloblasts are (1) RA with excess blasts (RAEB), defined as 6-20% myeloblasts, and (2) RAEB in transformation (RAEB-T), with 21-30% myeloblasts. The higher the percentage of myeloblasts present, the shorter the clinical course and the closer the disease is to acute myelogenous leukemia.
  • Patient transition from early to more advanced stages indicates these subtypes are merely stages of disease rather than distinct entities. Elderly patients with myelodysplastic syndrome (MDS) with trilineage dysplasia and greater than 30% myeloblasts who progress to acute leukemia are often considered to have poor prognoses because their disease response to chemotherapy is worse than that of de novo acute myeloid leukemia patients.
  • The 1999 World Health Organization (WHO) classification proposed including all cases of RAEB-T (patients with >20% myeloblasts) in the category of acute leukemia because these patients have similar prognostic outcomes.⁶ However, the response to therapy is worse than in patients with the de novo or more typical acute myelogenous leukemia or acute nonlymphocytic leukemia.
• The fifth type of myelodysplastic syndrome (MDS), the most difficult to classify, is called chronic myelomonocytic leukemia (CMML). This subtype can have any percentage of myeloblasts but manifests as a monocytosis of 1000/μL or more. CMML may be associated with splenomegaly. This subtype overlaps with a myeloproliferative disorder (MPD) and may have an intermediate clinical course.
  • CMML must be differentiated from the classic chronic myelocytic leukemia, which is characterized by a negative Ph chromosome. The 1999 WHO classification proposed that juvenile and proliferative CMML be listed separately from the FAB classification under MDS/MPD with splenomegaly and greater than 13,000/μL total white blood cell (WBC) count.
  • CMML in the FAB classification under myelodysplastic syndrome (MDS) is limited to monocytosis, has less than 13,000/μ L total leukocytes, and requires trilineage dysplasia.

Sex

A slight male predominance is noted in all age groups of those with myelodysplastic syndrome (MDS).

Age

Myelodysplastic syndrome (MDS) primarily affects elderly people, with the median onset in the seventh decade of life.

• The median age of these patients is 65 years, with ages ranging from the early third decade of life to older than 80 years.
• Myelodysplastic syndrome (MDS) may occur in persons of any age group, including the pediatric population.

Clinical

History

The development of myelodysplastic syndrome (MDS) may be preceded by a few years by an unexplained macrocytic anemia with no evidence of megaloblastic anemia and a mild thrombocytopenia or neutropenia.

• Clinical symptoms that should prompt a workup for myelodysplastic syndrome (MDS) are due to low peripheral blood counts, usually from the anemia or thrombocytopenia or neutropenia.
• Fatigue, malaise, and a general feeling of tiredness are due to anemia.
  • Patients with underlying cardiac problems may manifest congestive heart failure, depending on the degree of anemia.
  • Most often, these patients require red blood cell (RBC) transfusions to maintain their lifestyle.
• Petechiae, ecchymoses, and nose and gum bleeding are common manifestations of a low platelet count.
  • If underlying dysplastic changes were missed initially, thrombocytopenia as the presenting symptom may be mistaken for immune thrombocytopenia.
  • Poor platelet function is another cause of increased risk of hemorrhage.
• Fever, cough, dysuria, or shock may be manifestations of serious bacterial or fungal infections associated with neutropenia.
• Poor granulocytic function of the existing neutrophils is also attributed to an increased risk of infection.

Physical

• Petechiae or ecchymoses manifest themselves because of bleeding under the skin.
• Epistaxis and gum bleeding are commonly associated with severe thrombocytopenia.
• Hemoptysis, hematuria, and blood in stools may occur.
• Pallor of the skin and mucosal membranes or evidence of fatigue, tachycardia, or congestive heart failure may be manifestations of severe anemia.
• An enlarged spleen may be found in persons with CMML, often indicating an overlap syndrome with a myelodysplastic syndrome (MDS). CMML must be differentiated from CML.
• The presence of fever and infections, such as pneumonias and urinary tract infections, may be due to the neutropenia associated with the disease.

Causes

Based on the cytogenetic findings in myelodysplastic syndrome (MDS) and AML, patients can have (1) a normal karyotype, (2) a balanced chromosomal abnormality causing the generation of fusion oncogenes, and (3) complex karyotypes (usually >3 abnormalities) with this group showing worse prognosis and response to treatment. This bad prognosis group occurs in 30% of de novo myelodysplastic syndromes (MDSs) (only 20% in de novo AML) and up to 50% of therapy-related AML and myelodysplastic syndrome (MDS) with an urgent need to improve therapy in this group.

Balanced translocation abnormalities lead to the generation of fusion oncogenes such as Bcr-Abl in CML and PML-Rar alpha in APL; whereas unbalanced recurrent aberrations, most commonly -5, 5q-,-7, 7q-, +8, 11q-, 13q-, and 20q-, suggest that genes within these regions have a role in MDS/MPD pathogenesis, which is based on loss of tumor suppressor genes or haploinsufficiency of genes necessary for normal myelopoiesis.

• Patients who survive cancer treatment with alkylating agents, with or without radiotherapy, have a high risk of developing myelodysplastic syndrome (MDS) or secondary acute leukemia.
• Approximately 60-70% of patients do not have an obvious exposure or cause for myelodysplastic syndrome (MDS) and are classified as primary myelodysplastic syndrome (MDS) patients.
• Secondary myelodysplastic syndrome (MDS) describes the development of myelodysplastic syndrome (MDS) or acute leukemia after known exposures to chemotherapy drugs that can cause bone marrow damage. These drugs are associated with a high prevalence of chromosomal abnormalities (following exposure and at the time of myelodysplastic syndrome [MDS] or acute leukemia diagnosis).
• Primary, or idiopathic, myelodysplastic syndromes (MDSs) are the most common. However, a nonspecific history of exposure to indeterminable chemicals or radiation 10-15 years previous to the onset of disease may be present in approximately 50% of patients. This relationship to pathogenesis remains unproven.
  • Other chemicals are leukemogenic.
  • Compounds such as benzene have been implicated.
  • Insecticides, weed killers, and fungicides are possible causes of myelodysplastic syndrome (MDS) and secondary leukemia.⁷
  • Less evidence supports genetic predisposition, but familial incidences have been described.
  • Viral infections have also been implicated.

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