What Are Myelodysplastic Syndromes?

Myelodysplastic (myelo – bone marrow, dysplastic – abnormal growth) syndromes are a group of conditions caused by abnormal blood-forming cells of the bone marrow. In myelodysplastic syndromes (MDS), the bone marrow cannot produce blood cells effectively. Many of the blood cells formed are defective. These abnormal blood cells are usually destroyed before they leave the bone marrow or shortly after entering the bloodstream. As a result, patients have shortages of blood cells, which are reflected in their low blood counts.

Although MDS has not been considered cancer in the past, most hematologists (specialists in diseases of the blood) now consider it a form of cancer. The major reason is that MDS is a clonal disease, which means that there is a large population of abnormal cells that all came from a single, abnormal cell. These abnormal cells are exactly alike – just like identical twins – and they share abnormal growth properties. Clonal growth is typically seen in cancer where all the cells appear to have started from an original abnormal cell. Although MDS is a clonal disorder, there are many different forms, as described below.

A second reason MDS is considered a form of cancer is that in about 30% of MDS cases, the abnormal bone marrow cells eventually progress into acute myeloid leukemia, a rapidly growing cancer of bone marrow cells. Some doctors think MDS is an early form of leukemia although it often doesn’t progress into leukemia. In the past, myelodysplastic syndromes were called preleukemia or smoldering leukemia. (For more information on leukemia, see the American Cancer Society document, "Acute Myeloid Leukemia.")

What Are Myelodysplastic/Myeloproliferative Diseases?

Experts have realized that certain blood diseases that were once called myelodysplastic syndromes didn’t fit in that category. This is because they produced too many white blood cells. They actually resembled myeloproliferative diseases (myelo – bone marrow, proliferative – excessive growth) such as leukemia, where the problem is an overproduction of blood cells. As a result, the experts created this new category. The most common disease in this group is chronic myelomonocytic leukemia. Much less common are atypical chronic myeloid leukemia and juvenile myelomonocytic leukemia. All of these diseases have a high production of abnormal blood cells.

Normal Bone Marrow

Bone marrow is the soft, inner part of some bones such as the skull, shoulder blades, ribs, pelvis, and backbones. Bone marrow is made of blood-forming cells, fat cells, and supporting tissues that help blood-forming cells grow. A small fraction of the blood-forming cells are stem cells that continually reproduce to form new cells. Some of these new cells remain as stem cells, while others go through a series of changes to develop into one of 3 types of blood cells: red blood cells, white blood cells, or platelets.

Red blood cells contain hemoglobin, which carries oxygen from the lungs to all other tissues in the body while returning carbon dioxide. Having too few red blood cells (anemia) typically causes weakness, fatigue, and, when it is severe, shortness of breath.

Platelets are usually classified as a type of blood cell, but they are actually small fragments from a bone marrow cell called the megakaryocyte. Platelets are important in plugging damaged areas of blood vessels caused by cuts or bruises. A shortage of platelets, called thrombocytopenia, can result in too much bleeding or bruising when blood vessels are damaged.

White blood cells, also known as leukocytes, are important in defending the body against infection. The 2 major types of white blood cells are lymphocytes and granulocytes.

Granulocytes are a group of white blood cells that destroy bacteria. The granulocytes (neutrophils, basophils, and eosinophils) are distinguished by the size and color of their granules (spots seen inside the cells under the microscope). These granules contain enzymes and other substances that can destroy germs that cause infections. In the bone marrow, granulocytes develop from young cells called myeloblasts. Sometimes the first sign of MDS is a low white cell count or frequent infections.

Monocytes, which also belong in the granulocyte family, are also important in protecting the body against bacteria. They start in the bone marrow as immature monoblasts and mature to form monocytes. After circulating in the bloodstream for about a day, monocytes enter tissues to become macrophages, which can destroy germs by surrounding and digesting them. Macrophages are also important in helping lymphocytes to recognize germs and begin producing antibodies to fight them.

Lymphocytes are immune cells. They are responsible for producing antibodies that damage invading germs. They can also directly kill invading germs by producing toxic substances that damage the cells. Lymphocytes are not usually abnormal in MDS.

Types of MDS

The original classification of MDS was developed more than 20 years ago at an international conference attended mostly by doctors from France, the United States, and Great Britain. This system, known as the French-American-British (FAB) classification, helped doctors predict each patient's prognosis (the outlook for survival). It also guided doctors in deciding upon treatment.

Recently, the World Health Organization (WHO) developed a new classification that is even more helpful in predicting prognosis. There are 8 categories of MDS in the WHO system. These are listed below and described:

• refractory anemia
• refractory anemia with ringed sideroblasts
• refractory cytopenia with multilineage dysplasia
• refractory cytopenia with multilineage dysplasia and ringed sideroblasts
• refractory anemia with excess blasts-1(RAEB-1)
• refractory anemia with excess blasts-2(RAEB-2)
• myelodysplastic syndrome, unclassified (MDS-U)
• MDS associated with isolated del(5q)

Most of these categories are determined by the appearance of the cells in the bone marrow. Needless to say, when small differences in appearance define a category, doctors may disagree.

Refractory anemia: People with refractory anemia have only anemia. Only the early cells that develop into red blood cells have an abnormal appearance (called dysplasia). The number of very early cells (called blasts) is normal (less than 5%). About 5% to 10% of all MDS patients have refractory anemia. This type seldom, if ever, progresses to acute myeloid leukemia and patients with this type typically have long survivals.

Refractory anemia with ringed sideroblasts: People with this are similar to those with refractory anemia except that many of the red blood cells in the bone marrow contain characteristic ring-shaped iron deposits, and they are called ring sideroblasts. About 10% to 15% of all people with MDS have this type. This type rarely turns into leukemia, and the outcome for people with this type is generally the same as with refractory anemia.

Refractory cytopenia with multilineage dysplasia: At least 2 types of blood counts are low and have an abnormal appearance under the microscope (dysplasia). The number of blasts is less than 5%. About 25% of people with MDS have this type. It will change into leukemia in about 10% of patients. Having this type of MDS will shorten a person’s survival. One estimate is that half of patients will die within 2 years of diagnosis.

Refractory cytopenia with multilineage dysplasia and ringed sideroblasts: At least 2 types of blood counts are low and have an abnormal appearance under the microscope (dysplasia). The number of blasts is less than 5%. The number of ring sideroblasts in their bone marrow is greater than 15%. This type occurs about 15% of the time in patients with MDS. The chance of developing leukemia is about 10%. Having this type of MDS will shorten a person’s survival. One estimate is that half of patients will die within 2 years of diagnosis.

Refractory anemia with excess blasts (types 1 and 2): Any one of the cell types can be low and look abnormal under the microscope. The number of blasts is increased; it is less than 10% in type 1 and ranges from 10% to 20% in type 2. This type accounts for 40% of all patients with MDS. The chance of transforming into acute myeloid leukemia is 25% with type 1 and 33% with type 2. This type has the worst outlook and most patients die within 2 years.

Myelodysplastic syndrome, unclassified (MDS-U): Any one of the cell types can be low and either the white or megakaryocyte cell series looks abnormal under the microscope. The number of blasts is less than 5%. This type is uncommon and it doesn’t fall into one of the other categories. The chance of developing leukemia is very low.

MDS associated with isolated del(5q): These people only have anemia. Their most distinguishing characteristic is that part of chromosome number 5 is absent (deleted) in the MDS cells. For unknown reasons, this means that they have a very good prognosis and rarely will develop leukemia.

The tests for recognizing these types of blood cells and bone marrow cells under the microscope are discussed in the section, "How Are Myelodysplastic Syndromes Diagnosed?" Doctors have recently found that, in addition to examining cells under the microscope, new tests can help predict the outlook for patients with MDS. These tests include cytogenetic studies (examining the cells’ chromosomes), molecular genetic studies (examining genes within the chromosomes), and flow cytometry (antibody testing of blood cells that uses very sensitive instruments with lasers and computers to sort cells into categories).

In addition to classifying cases of MDS based on bone marrow and circulating blood cell counts, these syndromes can also be classified as primary or secondary. Primary MDS means that the patient has no apparent risk factor. Secondary MDS is linked to several causes discussed in the section, "What Are the Risk Factors for Myelodysplastic Syndromes?" Identifying MDS as primary or secondary is important because the secondary type is much less likely to respond to treatment.

Types of Myelodysplastic/Myeloproliferative Diseases (MDS/MPD)

There are only 3 diseases in this category.

Chronic myelomonocytic leukemia (CMML): This is by far the most common in this group. It is mainly a disease of older persons. Patients usually have a very high white blood cell count. Most of the cells are monocytes. Usually there are abnormal cells in the bone marrow, but the blast percentage is below 20%. Many patients have enlarged spleens (an organ that lies just below the left rib cage). About 15% to 30% of patients develop acute myeloid leukemia.

Some people with this disease can have normal blood counts although there are still too many monocytes in the blood. They still have abnormal cells in their bone marrows and are at risk of progressing to acute leukemia.

Atypical chronic myeloid leukemia (aCML): This is a rare disease that appears to be chronic myeloid leukemia (see the American Cancer Society document, “Chronic Myeloid Leukemia”). But these patients lack the special abnormal chromosome, called the Philadelphia chromosome that defines the typical chronic myeloid leukemia. This disease has a more serious prognosis than chronic myeloid leukemia and many patients quickly develop acute myeloid leukemia.

Juvenile myelomonocytic leukemia (JMML): Less than 3% of all leukemias in children are this type. It tends to occur in very young children, but has many of the same features as the adult type. About 10% to 20% of children with this develop acute myeloid leukemia.

Revised: 12/07/2006