Embryonic stem cells have received tremendous attention because of their potential to heal a variety of diseases. But stem cells — immature cells that have the ability to turn into different types of tissue — aren't found only in embryos. Adults, too, have a small number of these cells in their skin, brain, liver, muscle and bone marrow.

Within the bone marrow, stem cells normally develop into mature blood cells. But in people who have one of a group of disorders called myelodysplastic syndromes or myelodysplasia, the stem cells don't mature or function properly, leading to a lack of healthy cells and to potentially life-threatening complications.

No truly effective treatment exists for most people with myelodysplastic syndromes, and therapy for myelodysplastic syndromes usually focuses on reducing or preventing complications of the disease and of treatments. Some younger people with myelodysplastic syndromes who are in otherwise good health may be candidates for a bone marrow transplant, which may help prolong life.

People with a myelodysplastic syndrome rarely have problems in the early stages of the disease. But as the bone marrow continues producing a limited number of healthy blood cells, signs and symptoms begin to appear, including:

• Fatigue
• Shortness of breath
• Unusual paleness (pallor) due to anemia
• Easy or unusual bruising or bleeding
• Pinpoint-sized red spots just beneath the skin caused by bleeding (petechiae)
• Unintentional weight loss
• Frequent infections

Myelodysplastic/myeloproliferative diseases are a group of disorders that were once included under the myelodysplastic syndromes umbrella. They've since been given a separate classification because in these diseases, the bone marrow produces too many blood cells rather than too few. Signs and symptoms are similar to those of myelodysplastic syndromes, although people with myelodysplastic/myeloproliferative diseases may also have an enlarged spleen and swollen lymph nodes.

Blood cells are produced in the bone marrow, the spongy tissue inside certain bones. In childhood, most of your bones make blood cells, but as you age, blood cells are formed mainly in your vertebrae, shoulder blades, ribs and pelvis.

All blood cells begin as undifferentiated stem cells (pluripotent stem cells). Normally, about 5 percent of these cells remain immature and are held in reserve until your body needs them. The rest go through a series of maturing stages, during which they're called blast cells, until they finally develop into one of three types of specialized blood cells:

• Red blood cells (erythrocytes). These are the most abundant blood cells in your body — you have about 600 red blood cells for every white cell. Red blood cells contain hemoglobin, a protein that gives blood its characteristic color and that carries oxygen from your lungs to the rest of your tissues. A lack of healthy red blood cells (anemia) can cause most of the problems associated with myelodysplastic syndromes — fatigue, weakness, unusually pale skin and, eventually, shortness of breath.
• White blood cells (leukocytes). As part of the immune system, white blood cells help fight infection and defend your body against a variety of invading pathogens. The white blood cell system is complex and includes five main types of cells: monocytes, lymphocytes, neutrophils, basophils and eosinophils. The last three, collectively known as granulocytes, are instrumental in destroying bacteria. A shortage of these cells can lead to frequent infections, often one of the first signs of a myelodysplastic syndrome.
• Platelets. Although classified as blood cells, these are actually fragments of a type of bone marrow cell (megakaryocyte). Platelets contain chemicals that help form clots to control bleeding and stimulate the repair of damaged blood vessels. Having too few of these cells (thrombocytopenia) can lead to unusual bleeding or bruising.

Once they mature, red blood cells, white cells and platelets are released into your bloodstream where they live out their expected life spans — 120 days, on average, for red blood cells and as little as a few hours to a few days for some white cells and platelets. Every day, your bone marrow produces millions of cells and millions more die. As a result your body must strike a delicate balance between new and old cells, a process that's controlled, in part, by hormone-like substances in the bone marrow called growth factors.

But in the various myelodysplastic syndromes, the orderly and controlled production of cells fails at the most fundamental level — that of the stem cells. The immature cells are often defective, and instead of developing normally, they die in the bone marrow or just after entering the bloodstream. This not only leads to low numbers of healthy cells, but also to less room for cell production overall. And because the cycle is ongoing, the problem tends to become worse over time.

Are myelodysplastic syndromes cancer?
Many experts consider myelodysplastic syndromes a form of blood and bone marrow cancer because, as in other cancers, all the abnormal cells seem to originate from a single defective cell and all appear identical. Eventually, close to one in three people with a myelodysplastic syndrome develop acute myelogenous leukemia, a rapidly progressing cancer that affects immature blood cells. Still, whether or not myelodysplastic syndromes are actually cancer remains a matter of some debate.

Myelodysplastic syndrome subtypes
Like many complex diseases, myelodysplastic syndromes have proved difficult to classify. Yet breaking disorders into subclassifications helps doctors and researchers learn more about disease as they follow the course of different conditions in large groups of people.

The original myelodysplastic syndromes classification system, devised by an international group of doctors, was reworked in the late 1990s by the World Health Organization (WHO). That system, though still debated by some experts in the field, is increasingly common in clinical practice.

The WHO recognizes eight subtypes of myelodysplastic syndromes based on changes in the bone marrow and circulating blood cell counts:

• Refractory anemia. People with this myelodysplastic syndrome have anemia due to low numbers of red blood cells, but their white cells and platelets are normal.
• 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 cytopenia with multilineage dysplasia and ringed sideroblasts. This syndrome differs from refractory cytopenia in that a greater percentage of red blood cells contain excess iron.
• Refractory anemia with excess blasts — types 1 and 2. In both these syndromes, any of the three types of cells — red blood cells, white cells or platelets — may be low in number and appear abnormal under a microscope. Up to one-third of people with type 2 refractory anemia may go on to develop leukemia.
• 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 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, but a normal or increased number of platelets. Although a genetic defect occurs with this syndrome, the prognosis is usually much better than it is for the other subtypes.

What causes abnormal bone marrow and blood cells?
Most myelodysplastic syndromes develop for no apparent reason. Syndromes with an identifiable cause are called secondary myelodysplastic syndromes and are usually more difficult to treat than are myelodysplastic syndromes without a known cause (primary, or de novo, myelodysplastic syndromes).

It's likely that different factors cause different myelodysplastic syndrome subtypes, but researchers haven't yet found these causal connections. They do know that the following factors can cause myelodysplastic syndromes in general:

• Prior cancer therapy. Probably the most clear-cut cause of myelodysplastic syndromes is treatment with certain chemotherapy drugs, among them mechlorethamine, procarbazine and chlorambucil. These drugs are toxic to the bone marrow and may be even more so if used in combination with radiation. Most secondary myelodysplastic syndromes occur after treatment for non-Hodgkin's lymphoma, Hodgkin's disease and acute lymphocytic leukemia, but they can also develop following chemotherapy for other cancers, including cancer of the breast, lung, testicles and intestinal tract, as well as for some autoimmune diseases. In addition, myelodysplastic syndromes can affect people who have had stem cell transplants because high doses of chemotherapy drugs are administered before transplantation.
• Environmental toxins. Exposure to large amounts of ionizing radiation and to benzene and certain other chemicals can lead to myelodysplastic syndromes. Benzene, a widely used industrial chemical, is found in gasoline, furniture polish, detergents, cigarette smoke and sometimes in contaminated well water. Some research also suggests a link between myelodysplastic syndromes and long-term exposure to heavy metals, pesticides, herbicides and chemical fertilizers.

In addition to treatment with certain chemotherapy drugs and exposure to high-dose radiation and some chemicals, these factors may increase your risk of myelodysplastic syndromes:

• Age. Most myelodysplastic syndromes develop after age 60, often in the seventh or eighth decade of life. The syndromes are rare in children and young adults, although cases in children are increasing as more young people survive treatment with chemotherapy regimens. For the same reason, myelodysplastic syndromes are also increasing among older adults.
• Your sex. Men are slightly more likely to develop myelodysplastic syndromes than women are.
• Smoking. Because benzene and other cancer-causing substances in cigarettes are absorbed into your bloodstream, they can affect the bone marrow and blood cells. Researchers don't yet know whether secondhand smoke has a similar effect.
• Certain congenital diseases. Having Fanconi anemia, a rare, genetic disorder, increases the likelihood of developing a myelodysplastic syndrome. Children born with other birth defects, including Down syndrome, may also be more susceptible to bone marrow disorders.

See your doctor if you develop any of the signs and symptoms associated with myelodysplastic syndromes, especially if you have been treated with chemotherapy in the past or have been exposed to chemicals known to affect the bone marrow.

The first step in diagnosing myelodysplastic syndromes is usually a routine blood test (complete blood count) that checks the number of red blood cells and platelets, the number and type of white blood cells, and the amount of hemoglobin that your red blood cells contain. You're also likely to have a peripheral blood smear, a test that examines a sample of blood for unusual changes in the size, shape and appearance of the various blood cells.

But although blood tests can suggest myelodysplastic syndromes, bone marrow tests are needed to confirm the diagnosis.

• Bone marrow aspiration and biopsy. In this dual procedure, a doctor or nurse first uses a fine needle to withdraw a small amount of liquid bone marrow, usually from a spot on the back of your hipbone called the posterior iliac crest. Then a small piece of bone and the enclosed marrow is also removed (the biopsy). The samples are examined by a pathologist or by a specialist in blood diseases (hematologist) and sometimes by both. A bone marrow aspiration and biopsy can be uncomfortable, but you'll often be given medication to reduce the discomfort. Risks of the procedure, though rare, include persistent bleeding and infection, both of which are more likely to occur in people with myelodysplastic syndromes.
• Cytochemistry. In this test, blood or bone marrow cells are stained with dyes that are absorbed only by certain abnormal cells. For instance, the granules inside a defective white cell might appear dark under a microscope whereas a normal white cell wouldn't show this change.
• Flow cytometry. This complex technique uses the light-reflecting properties of cells to differentiate among myelodysplastic syndrome subtypes. During the test, cells from a bone marrow sample are treated with antibodies that adhere only to certain types of cells. The sample is then passed in front of a laser beam, which causes any abnormal cells that might be present to give off light. A computer keeps track of the number of illuminated cells.
• Immunocytochemistry. This test also helps identify specific subtypes of myelodysplastic syndromes. As in flow cytometry, cells from a bone marrow sample are treated with antibodies. But instead of a laser, immunocytochemistry uses color changes to detect the presence of abnormal cells.
• Cytogenetics. Many people with myelodysplastic syndromes have abnormal chromosome changes in their bone marrow cells. In some cases, one or more chromosomes or parts of chromosomes are missing — commonly chromosome 5 or 7. In others, there may be extra copies of certain chromosomes or translocations, which occur when portions of chromosomes trade places. Cytogenetic testing checks for these chromosomal abnormalities. DNA testing, which is faster and more sensitive than cytogenetics, usually isn't necessary to diagnose myelodysplastic syndromes.

Even with an array of sophisticated and highly accurate tests, myelodysplastic syndromes are often a diagnosis of exclusion. That is, they're often diagnosed only after similar problems, including leukemia, have been ruled out.

Staging myelodysplastic syndromes
Doctors categorize most cancers based on tumor size and on how far the cancer has spread from the original site. This process, called staging, helps determine the long-term outlook and most appropriate treatment options for each person.

Myelodysplastic syndromes are also staged, but because abnormal cells are likely to circulate throughout the bloodstream, a different method, the International Prognostic Scoring System, was developed specifically for these disorders. The system rates three factors:

• The percentage of blasts in the bone marrow
• The presence and type of chromosomal abnormalities, if any
• The number of healthy red blood cells, white cells and platelets

Each factor is assigned a score, and the overall score, which can range from low to high risk, helps predict how people with myelodysplastic syndromes will fare. The system isn't foolproof, however, because a number of variables come into play, including the way the bone marrow findings are interpreted.

Most complications of myelodysplastic syndromes result from low counts of one or more blood types:

• Anemia from reduced numbers of red blood cells
• Recurrent infections from too few white cells
• Abnormal bleeding from a lack of platelets

According to some estimates, up to 40 percent of deaths from myelodysplastic anemia are due to infection, bleeding or both. In addition, between 20 percent and 40 percent of people may eventually develop leukemia, another serious complication of these syndromes.

Because no definitive cure or treatment for myelodysplastic syndromes exists, most people receive supportive care, which is intended to help manage symptoms such as fatigue and to prevent bleeding and infections. Supportive care may include the following:

• Transfusion therapy. People with anemia induced by myelodysplastic syndromes are likely to receive transfusions of red blood cells, which help relieve anemia and fatigue. Much of the news about transfusion therapy is positive: Doctors usually have no trouble finding a matching blood type, transfused blood cells generally remain in the body a month or more, and there's no limit to the number of transfusions you can receive. And although some people have legitimate concerns about the safety of transfused blood, the blood supply is closely monitored and accidental disease transmissions are rare. Some problems exist, however. Over time, you may develop antibodies to transfused blood cells, making them less effective at relieving symptoms. And donor red blood cells contain iron that can build up in the body, causing liver and heart damage, especially in people who have had multiple transfusions over a period of years. To reduce the risk of iron overload, doctors use vitamin C along with an intravenous chelating agent that binds with iron, reducing its toxic effect.

  Platelets can also be transfused, although the process is more complicated because the donor blood must be circulated through a machine to separate out the platelets. What's more, you can develop antibodies to donor platelets fairly quickly. White cells, because they are so short-lived, aren't usually transfused separately.

• Drug therapy. Hematopoietic growth factors stimulate the production of blood cells. They occur naturally in the bone marrow but are also produced artificially. Some growth factors may help prevent infections by increasing white blood cells in people with certain myelodysplastic syndromes; others can reduce the need for blood transfusions by increasing red blood cells. Researchers are also studying growth factors that may encourage the bone marrow to produce platelets. Side effects of growth factors are usually minor and include temporary bone pain and fever.

  Rather than encouraging blood cell production, drugs called differentiation agents, among them azacitidine, arsenic trioxide and retinoids, stimulate blasts to develop into mature blood cells. These drugs aren't effective in all people and some, such as azacitidine, can cause further blood cell problems.

  Research into supportive drugs is ongoing. Lenalidomide, a drug chemically related to thalidomide that's currently being studied in clinical trials, has generated particular interest because it may eliminate the need for blood transfusions in people with myelodysplastic syndrome associated with isolated del (5q) chromosome abnormality and because it appears to have few side effects.

Other therapies
Although supportive care is the treatment of choice for most people with both primary and secondary myelodysplastic syndromes, other treatments sometimes may be an option:

• Chemotherapy. This is sometimes used to destroy blasts in people with severe disease. But chemotherapy is seldom effective, and the risks usually far outweigh the benefits, especially in older adults.
• Stem cell transplant. Replacing abnormal stem cells with healthy, donated cells (allogeneic transplant) has the most potential for prolonging life. Unfortunately, few people are candidates for this procedure because of the high risks involved in transplanting the older adults — those most likely to have myelodysplastic syndromes. Even among young, relatively healthy people, the number of transplant-related deaths is high. A new approach called nonmyeloablative transplantation may make stem cell transplants less dangerous for older adults and improve outcomes overall. Instead of using chemotherapy to completely destroy the host's stem cells before transplantation, this procedure suppresses the immune system just enough to prevent rejection of the donated cells.

With some diseases, especially those linked expressly to lifestyle factors such as smoking, obesity or poor diet, prevention advice is fairly straightforward. But that's not the case with myelodysplastic syndromes. Although you can reduce your risk by not smoking and by avoiding cancer-causing industrial chemicals such as benzene, these factors play a role in only a small percentage of cases.

Instead, most secondary myelodysplastic syndromes develop in people who have received chemotherapy and radiation for other cancers. Although researchers are trying to find ways to make these treatments less toxic, they continue to pose a small risk, which must be weighed against the benefits of treatment.

Because people with certain myelodysplastic syndromes have low white cell counts, they're subject to recurrent, and often serious, infections. Chemotherapy, either on its own or before a stem cell transplant, only increases the risk. Experts recommend the following measures to help reduce the chance of infection:

• Wash your hands. Frequent hand washing is the best way to control infection. Wash your hands thoroughly with hot, soapy water, especially before eating or preparing food. Carry an alcohol-based hand rub for times when water isn't available.
• Take care with food. Thoroughly cook all meat and fish. Avoid fruits and vegetables that you can't peel, especially lettuce, and wash all produce you do use before peeling. To be absolutely safe, you may want to avoid raw foods entirely.
• Avoid people who are ill. Because myelodysplastic syndromes can affect the immune system, try to avoid close contact with anyone who is sick, especially family members and co-workers.