Myelodysplastic Syndrome

Definition:
The myelodysplastic syndromes (MDS, formerly known as “preleukemia”)  are a group of disorders caused by poorly formed or dysfunctional blood cells.Myelodysplastic syndromes occur when something goes wrong in your bone marrow — the spongy material inside our bones where blood cells are made.

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Patients with MDS often develop severe anemia and require frequent blood transfusions. In most cases, the disease worsens and the patient develops cytopenias (low blood counts) due to progressive bone marrow failure. In about one third of patients with MDS, the disease transforms into acute myelogenous leukemia (AML), usually within months to a few years.

The myelodysplastic syndromes are all disorders of the stem cell in the bone marrow. In MDS, hematopoiesis (blood production) is disorderly and ineffective. The number and quality of blood-forming cells decline irreversibly, further impairing blood production.

There is no cure for myelodysplastic syndromes. Treatment for myelodysplastic syndromes usually focuses on reducing or preventing complications of the disease and of treatments. In certain cases, myelodysplastic syndromes are treated with a bone marrow transplant, which may help prolong life.

The median age at diagnosis of a MDS is between 60 and 75 years; a few patients are younger than 50; MDS diagnoses are rare in children. Males are slightly more commonly affected than females.

The exact number of people with MDS is not known because it can go undiagnosed and there is no mandated tracking of the syndrome. Some estimates are on the order of 10,000 to 20,000 new cases each year in the United States alone. The incidence is probably increasing as the age of the population increases, and some authors propose that the incidence in patients over 70 may be as high as 15 cases per 100,000 per year

Symptoms:
Myelodysplastic syndromes rarely cause signs or symptoms in the early stages of the disease.The symptoms are nonspecific and generally related to the blood cytopenias:

In time, myelodysplastic syndromes may cause:

*Anemia—chronic tiredness,fatigue, shortness of breath, chilled sensation, sometimes chest pain

*Neutropenia (low neutrophil count) —increased susceptibility to  frequent infections

*Pinpoint-sized red spots just beneath the skin caused by bleeding (petechiae)

*Thrombocytopenia (low platelet count) —increased susceptibility to bleeding and ecchymosis (bruising), as well as subcutaneous hemorrhaging resulting in purpura or petechia.

Many individuals are asymptomatic, and blood cytopenia or other problems are identified as a part of a routine blood count:

*neutropenia, anemia and thrombocytopenia (low cell counts of white and red blood cells, and platelets, respectively);

*splenomegaly or rarely hepatomegaly;

*abnormal granules in cells, abnormal nuclear shape and size; and/or

*chromosomal abnormalities, including chromosomal translocations and abnormal chromosome number.

Although there is some risk for developing acute myelogenous leukemia, about 50% of deaths occur as a result of bleeding or infection. Leukemia that occurs as a result of myelodysplasia is notoriously resistant to treatment.

Causes:
Myelodysplastic syndromes occur when something happens to disrupt the orderly and controlled production of blood cells. People with myelodysplastic syndromes have blood cells that are immature and defective, and instead of developing normally, they die in the bone marrow or just after entering your bloodstream. Over time, the number of immature, defective cells begins to surpass that of healthy blood cells, leading to problems such as anemia, infections and excess bleeding.

Doctors divide myelodysplastic syndromes into two categories based on their cause:

*Myelodysplastic syndromes with no known cause. Called de novo myelodysplastic syndromes, doctors don’t know what causes these. De novo myelodysplastic syndromes are often more easily treated than are myelodysplastic syndromes with a known cause.

*Myelodysplastic syndromes caused by chemicals and radiation. Myelodysplastic syndromes that occur in response to cancer treatments, such as chemotherapy and radiation, or in response to chemical exposure are called secondary myelodysplastic syndromes. Secondary myelodysplastic syndromes are often more difficult to treat.

Types of myelodysplastic syndromes:
The World Health Organization divides myelodysplastic syndromes into subtypes based on the type of cells involved. Myelodysplastic syndrome subtypes include:

*Refractory cytopenia with unilineage dysplasia. In this type, one or two blood cell types are low in number — most commonly, the red blood cells are affected. Also, one type of blood cell appears abnormal under the microscope.

*Refractory anemia with ringed sideroblasts. This differs from refractory anemia in that existing red blood cells contain excess amounts of iron (ringed sideroblasts).

*Refractory cytopenia with multilineage dysplasia. In this myelodysplastic syndrome, two of the three types of blood cells are abnormal, and less than 1 percent of the cells in the bloodstream are immature cells (blasts).

*Refractory anemia with excess blasts — types 1 and 2. In both these syndromes, any of the three types of cells — red blood cells, white blood cells or platelets — may be low in number and appear abnormal under a microscope.

*Myelodysplastic syndrome, unclassified. In this uncommon syndrome, there are reduced numbers of one of the three types of mature blood cells, and either the white blood cells or platelets look abnormal under a microscope.

*Myelodysplastic syndrome associated with isolated del(5q) chromosome abnormality. People with this syndrome have low numbers of red blood cells, and the cells have a specific defect in their DNA.
Risk Factors:
Factors that may increase your risk of myelodysplastic syndromes include:

*Older age. Most people with myelodysplastic syndromes are adults older than 60. Anyone can develop myelodysplastic syndromes, but they’re rare in younger people.

*Being male. Myelodysplastic syndromes occur more frequently in men than in women.

*Treatment with chemotherapy or radiation. Your risk of myelodysplastic syndromes is increased if you received chemotherapy or radiation, both of which are commonly used to treat cancer.

*Exposure to certain chemicals. Chemicals linked to myelodysplastic syndromes include tobacco smoke, pesticides and industrial chemicals, such as benzene.

*Exposure to heavy metals. Heavy metals linked to myelodysplastic syndrome include lead and mercury.

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Complications:
Complications of myelodysplastic syndromes include:

*Anemia. Reduced numbers of red blood cells can cause anemia, which can make you feel tired.

*Recurrent infections. Having too few white blood cells increases your risk of serious infections.

*Bleeding that won’t stop. Lacking platelets in your blood to stop bleeding can lead to excessive bleeding that won’t stop.

*Increased risk of cancer. Some people with myelodysplastic syndromes may eventually develop leukemia, a cancer of the blood cells.

Diagnosis:
MDS must be differentiated from anemia, thrombocytopenia, and/or leukopenia. Usually, the elimination of other causes of these cytopenias, along with a dysplastic bone marrow, is required to diagnose a myelodysplastic syndrome.

A typical investigation includes:
*Full blood count and examination of blood film. The blood film morphology can provide clues about hemolytic anemia, clumping of the platelets leading to spurious thrombocytopenia, or leukemia.

*Blood tests to eliminate other common causes of cytopenias, such as lupus, hepatitis, B12, folate, or other vitamin deficiencies, renal failure or heart failure, HIV, hemolytic anemia, monoclonal gammopathy. Age-appropriate cancer screening should be considered for all anemic patients.

*Bone marrow examination by a hematopathologist. This is required to establish the diagnosis, since all hematopathologists consider dysplastic marrow the key feature of myelodysplasia.

*Cytogenetics or chromosomal studies. This is ideally performed on the bone marrow aspirate. Conventional cytogenetics requires a fresh specimen, since live cells are induced to enter metaphase to enhance chromosomal staining. Alternatively, virtual karyotyping can be done for MDS,[10] which uses computational tools to construct the karyogram from disrupted DNA. Virtual karyotyping does not require cell culture and has dramatically higher resolution than conventional cytogenetics, but cannot detect balanced translocations.

*Flow cytometry is helpful to establish the presence of any lymphoproliferative disorder in the marrow.

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. Previous chemotherapy or radiation exposure is an important historic fact. Fever and weight loss should point to a myeloproliferative rather than myelodysplastic process. Children with Down syndrome are susceptible to MDS, and a family history may indicate a hereditary form of sideroblastic anemia or Fanconi anemia.

The average age at diagnosis for MDS is about 65 years, but pediatric cases have been reported. Some patients have a history of exposure to chemotherapy (especially alkylating agents such as melphalan, cyclophosphamide, busulfan, and chlorambucil) or radiation (therapeutic or accidental), or both (e.g., at the time of stem cell transplantation for another disease). Workers in some industries with heavy exposure to hydrocarbons such as the petroleum industry have a slightly higher risk of contracting the disease than the general population. Males are slightly more frequently affected than females. Xylene and benzene exposure has been associated with myelodysplasia. Vietnam veterans that were exposed to Agent Orange are at risk of developing MDS.

The features generally used to define a MDS are: blood cytopenias; ineffective hematopoiesis; dyserythropoiesis; dysgranulopoiesis; dysmegakaropoiesis and increased myeloblast.

Dysplasia can affect all three lineages seen in the bone marrow. The best way to diagnose dysplasia is by morphology and special stains (PAS) used on the bone marrow aspirate and peripheral blood smear. Dysplasia in the myeloid series is defined by:

Granulocytic series
1.Hypersegmented neutrophils (also seen in Vit B12/Folate deficiency)
2.Hyposegmented neutrophils (Pseudo-Pelger Huet)
3.Hypogranular neutrophils or pseudo Chediak Higashi large granules
4.Auer rods – automatically RAEB II (if blast count <5% in the peripheral blood and <10% in the bone marrow aspirate) also note Auer rods may be seen in mature neutrophils in AML with translocation t(8;21)
5.Dimorphic granules (basophilic and eosinophilic granules) within eosinophils
Erythroid series
1.Binucleated erythroid percursors and karyorrhexis
2.Erythroid nuclear budding
3.Erythroid nuclear strings or internuclear bridging (also seen in congenital dyserythropoietic anemias)
4.Loss of E-cadherin in normoblasts is a sign of aberrancy
5.PAS (globular in vacuoles or diffuse cytoplasmic staining) within erythroid precursors in the bone marrow aspirate (has no bearing on paraffin fixed bone marrow biopsy). Note: One can see PAS vacuolar positivity in L1 and L2 blasts (AFB classification; the L1 and L2 nomenclature is not used in the WHO classification)
6.Ringed sideroblasts seen on Prussian blue iron stain (10 or more iron granules encircling 1/3 or more of the nucleus and >15% ringed sideroblasts when counted amongst red cell precursors)
Megakaryocytic series (can be the most subjective)
1.Hyposegmented nuclear features in platelet producing megakaryocytes (lack of lobation)
2.Hypersegmented (osteoclastic appearing) megakaryocytes
3.Ballooning of the platelets (seen with interference contrast microscopy)
Other stains can help in special cases (PAS and napthol ASD chloroacetate esterase positivity) in eosinophils is a marker of abnormality seen in chronic eosinophilic leukemia and is a sign of aberrancy.

On the bone marrow biopsy high grade dysplasia (RAEB-I and RAEB-II) may show atypical localization of immature precursors (ALIPs) which are islands of immature precursors cells (myeloblasts and promyelcytes) localized to the center of intertrabecular space rather than adjacent to the trabeculae or surrounding arterioles. This morphology can be difficult to recognize from treated leukemia and recovering immature normal marrow elements. Also topographic alteration of the nucleated erythroid cells can be seen in early myelodysplasia (RA and RARS), where normoblasts are seen next to bony trabeculae instead of forming normal interstitially placed erythroid islands.

Myelodysplasia is a diagnosis of exclusion and must be made after proper determination of iron stores, vitamin deficiencies, and nutrient deficiencies are ruled out. Also congenital diseases such as congenital dyserythropoietic anemia (CDA I through IV) has been recognized, Pearson’s syndrome (sideroblastic anemia), Jordans anomaly – vacuolization in all cell lines may be seen in Chanarin-Dorfman syndrome, ALA (aminolevulinic acid) enzyme deficiency, and other more esoteric enzyme deficiencies are known to give a pseudomyelodysplastic picture in one of the cell lines, however, all three cell lines are never morphologically dysplastic in these entities with the exception of chloramphenicol, arsenic toxicity and other poisons.

All of these conditions are characterized by abnormalities in the production of one or more of the cellular components of blood (red cells, white cells other than lymphocytes and platelets or their progenitor cells, megakaryocytes).

 

Treatment :
No definitive cure or treatment for myelodysplastic syndromes exists. Instead, most people receive supportive care to help manage symptoms such as fatigue and to prevent bleeding and infections.

Blood transfusions
Blood transfusions can be used to replace red blood cells, white blood cells or platelets in people with myelodysplastic syndromes.

Medications :
Medications used to increase the number of healthy blood cells your body produces include:

*Medications that increase the number of blood cells your body makes. Called growth factors, these medications are artificial versions of substances found naturally in your bone marrow. Some growth factors, such as erythropoietin or darbepoietin, can reduce the need for blood transfusions by increasing red blood cells. Others may help prevent infections by increasing white blood cells in people with certain myelodysplastic syndromes.Medications that stimulate blood cells to mature, rather than remain immature.
*Medications such as azacitidine (Vidaza) and decitabine (Dacogen) may improve the quality of life of people with certain myelodysplastic syndromes and help delay progression to acute myelogenous leukemia. But these drugs aren’t effective in all people, and some can cause further blood cell problems. Medications that suppress your immune system.

*Medications used to suppress the immune system may be used in certain myelodysplastic syndromes.Medication for people with a certain genetic abnormality. If your myelodysplastic syndrome is associated with a genetic abnormality called isolated del(5q), your doctor may recommend lenalidomide (Revlimid). Lenalidomide may reduce the need for blood transfusions in people with this abnormality.

*Bone marrow stem cell transplant
During a bone marrow stem cell transplant, your defective blood cells are destroyed using powerful chemotherapy drugs. Then the abnormal bone marrow stem cells are replaced with healthy, donated cells (allogeneic transplant). Unfortunately, few people are candidates for this procedure because of the high risks involved in transplanting in older adults — those most likely to have myelodysplastic syndromes. Even among young, relatively healthy people, the number of transplant-related complications is high.

Prognosis:
Indicators of a good prognosis Younger age; normal or moderately reduced neutrophil or platelet counts; low blast counts in the bone marrow(<20%) and no blasts in the blood; no Auer rods; ringed sideroblasts; normal karyotypes of mixed karyotypes without complex chromosome abnormalities and in vitro marrow culture- non leukemic growth pattern.

Indicators of a poor prognosis Advanced age; Severe neutropenia or thrombocytopenia ; high blast count in the bone marrow (20-29%) or blasts in the blood; Auer rods; absence of ringed sideroblasts; abnormal localization or immature granulocyte precursors in bone marrow section all or mostly abnormal karyotypes or complex marrow chromosome abnormalities and in vitro bone emarrow culture-leukemic growth pattern.

Prognosis and karyotype Good: Normal, -Y, del(5q), del(20q)
Intermediate or variable: +8, other single or double anomalies
Poor; Complex (>3 chromosomal aberrations); chromosome 7 anomalies

The International Prognostic Scoring System (IPSS) is the most commonly used tool in MDS to predict long-term outcome.

Cytogenetic abnormalities can be detected by conventional cytogenetics, a FISH panel for MDS, or Virtual Karyotype.

Disclaimer: This information is not meant to be a substitute for professional medical advise or help. It is always best to consult with a Physician about serious health concerns. This information is in no way intended to diagnose or prescribe remedies.This is purely for educational purpose

Resources:
http://www.mayoclinic.com/health/myelodysplastic-syndromes/DS00596
http://en.wikipedia.org/wiki/Myelodysplastic_syndrome

http://www.bmj.com/content/314/7084/883.full

http://www.medicalook.com/Blood_disorders/Myelodysplastic_syndrome.html

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