Myelodysplastic syndrome
A myelodysplastic syndrome is one of a group of cancers in which blood cells in the bone marrow do not mature, and as a result, do not develop into healthy blood cells. Early on, no symptoms are typically seen. Later, symptoms may include fatigue, shortness of breath, bleeding disorders, anemia, or frequent infections. Some types may develop into acute myeloid leukemia.
Risk factors include previous chemotherapy or radiation therapy, exposure to certain chemicals such as tobacco smoke, pesticides, and benzene, and exposure to heavy metals such as mercury or lead. Problems with blood cell formation result in some combination of low red blood cell, platelet, and white blood cell counts. Some types of MDS cause an increase in the production of immature blood cells, in the bone marrow or blood. The different types of MDS are identified based on the specific characteristics of the changes in the blood cells and bone marrow.
Treatments may include supportive care, drug therapy, and hematopoietic stem cell transplantation. Supportive care may include blood transfusions, medications to increase the making of red blood cells, and antibiotics. Drug therapy may include the medications lenalidomide, antithymocyte globulin, and azacitidine. Some people can be cured by chemotherapy followed by a stem-cell transplant from a donor.
About seven per 100,000 people are affected by MDS; about four per 100,000 people newly acquire the condition each year. The typical age of onset is 70 years. The prognosis depends on the type of cells affected, the number of blasts in the bone marrow or blood, and the changes present in the chromosomes of the affected cells. The average survival time following diagnosis is 2.5 years. MDS was first recognized in the early 1900s; it came to be called myelodysplastic syndrome in 1976.
Signs and symptoms
Signs and symptoms are nonspecific and generally related to the blood cytopenias:- Anemia – chronic tiredness, shortness of breath, chilled sensation, sometimes chest pain
- Neutropenia – increased susceptibility to infection
- Thrombocytopenia – increased susceptibility to bleeding and ecchymosis, as well as subcutaneous hemorrhaging resulting in purpura or petechiae
- Neutropenia, anemia, and thrombocytopenia
- Splenomegaly or rarely hepatomegaly
- Abnormal granules in cells, abnormal nuclear shape and size
- Chromosome abnormality, including chromosomal translocations and abnormal chromosome number
Anemia dominates the early course. Most symptomatic patients complain of the gradual onset of fatigue and weakness, dyspnea, and pallor, but at least half the patients are asymptomatic and their MDS is discovered only incidentally on routine blood counts. Fever, weight loss and splenomegaly should point to a myelodysplastic/myeloproliferative neoplasm rather than pure myelodysplastic process.
Cause
Some patients have a history of exposure to chemotherapy or radiation, or both. Workers in some industries with heavy exposure to hydrocarbons, such as the petroleum industry, have a slightly higher risk of contracting the disease. Xylene and benzene exposures have been associated with myelodysplasia. Vietnam veterans exposed to Agent Orange are at risk of developing MDS. A link may exist between the development of MDS "in atomic-bomb survivors 40 to 60 years after radiation exposure". Children with Down syndrome are susceptible to MDS, and a family history may indicate a hereditary form of sideroblastic anemia or Fanconi anemia. GATA2 deficiency and SAMD9/9L syndromes each account for about 15% of MDS cases in children.Pathophysiology
MDS most often develops without an identifiable cause. Risk factors include exposure to an agent known to cause DNA damage, such as radiation, benzene, and certain chemotherapies; other risk factors have been inconsistently reported. Proving a connection between a suspected exposure and the development of MDS can be difficult, but the presence of genetic abnormalities may provide some supportive information. Secondary MDS can occur as a late toxicity of cancer therapy. MDS after exposure to radiation or alkylating agents such as busulfan, nitrosourea, or procarbazine, typically occurs 3–7 years after exposure and frequently demonstrates loss of chromosome 5 or 7. MDS after exposure to DNA topoisomerase II inhibitors occurs after a shorter latency of only 1–3 years and can have an 11q23 translocation. Other pre-existing bone-marrow disorders, such as acquired aplastic anemia following immunosuppressive treatment and Fanconi anemia, can evolve into MDS.MDS is thought to arise from mutations in the multipotent bone-marrow stem cell, but the specific defects responsible for these diseases remain poorly understood. Differentiation of blood precursor cells is impaired, and a significant increase in levels of apoptotic cell death occurs in bone-marrow cells. Clonal expansion of the abnormal cells results in the production of cells that have lost the ability to differentiate. If the overall percentage of bone-marrow myeloblasts rises over a particular cutoff, then transformation to acute myelogenous leukemia is said to have occurred. The progression of MDS to AML is a good example of the multistep theory of carcinogenesis in which a series of mutations occurs in an initially normal cell and transforms it into a cancer cell.
Although recognition of leukemic transformation was historically important, a significant proportion of the morbidity and mortality attributable to MDS results not from transformation to AML, but rather from the cytopenias seen in all MDS patients. While anemia is the most common cytopenia in MDS patients, given the ready availability of blood transfusion, MDS patients rarely experience injury from severe anemia. The two most serious complications in MDS patients resulting from their cytopenias are bleeding or infection. Long-term transfusion of packed red blood cells leads to iron overload.
Genetics
The recognition of epigenetic changes in DNA structure in MDS has explained the success of two of three commercially available medications approved by the U.S. Food and Drug Administration to treat MDS. Proper DNA methylation is critical in the regulation of proliferation genes, and the loss of DNA methylation control can lead to uncontrolled cell growth and cytopenias. The recently approved DNA methyltransferase inhibitors take advantage of this mechanism by creating a more orderly DNA methylation profile in the hematopoietic stem cell nucleus, thereby restoring normal blood counts and retarding the progression of MDS to acute leukemia.Some authors have proposed that the loss of mitochondrial function over time leads to the accumulation of DNA mutations in hematopoietic stem cells, and this accounts for the increased incidence of MDS in older patients. Researchers point to the accumulation of mitochondrial iron deposits in the ringed sideroblast as evidence of mitochondrial dysfunction in MDS.