Waldenström's macroglobulinemia is a rare, chronic cancer of the immune system that is characterized by hyperviscosity, or thickening, of the blood.
Waldenström's (Waldenström, Waldenstroem's) macroglobulinemia (WM) is a lymphoma, or cancer of the lymphatic system. It was first identified in 1944, by the Swedish physician Jan Gosta Waldenström, in patients who had a thickening of the serum, or liquid part, of the blood. Their blood serum contained a great deal of a very large molecule called a globulin. Thus, the disorder is called macroglobulinemia.
Lymphomas are cancers that originate in tissues of the lymphatic system. All lymphomas other than Hodgkin's disease, including WM, are known collectively as non-Hodgkin's lymphomas. There are 13 major types of non-Hodgkin's lymphomas, and others that are very rare. Other names that are sometimes used for WM include: lymphoplasmacytic lymphoma, lymphoplasmacytic leukemia, macroglobulinemia of Waldenström, primary macroglobulinemia, Waldenström's syndrome, Waldenström's purpura, or hyperglobulinemic purpura. Purpura refers to purple spots on the skin, resulting from the frequent bleeding and bruising that can be a symptom of WM.
WM is classified as a low-grade or indolent form of lymphoma because it is a slow-growing cancer that produces fewer symptoms than other types of lymphomas. WM most often affects males over the age of 65. Frequently, this disease produces no symptoms and does not require treatment. It has not been studied as extensively as other types of lymphoma.
The lymphatic system
The lymphatic system is part of the body's immune system, for fighting disease, and part of the blood-producing system. It includes the lymph vessels and nodes, and the spleen, bone marrow, and thymus. The narrow lymphatic vessels carry lymphatic fluid from throughout the body. The lymph nodes are small, pea-shaped organs that filter the lymphatic fluid and trap foreign substances, including viruses, bacteria, and cancer cells. The spleen, in the upper left abdomen, removes old cells and debris from the blood. The bone marrow, the spongy tissue inside the bones, produces new blood cells.
B lymphocytes or B cells are white blood cells that recognize disease-causing organisms. They circulate throughout the body in the blood and lymphatic fluid. Each B lymphocyte recognizes a specific foreign substance, or antigen. When it encounters its specific antigen, the B cell begins to divide and multiply, producing large numbers of identical (monoclonal), mature plasma cells. These plasma cells produce large amounts of antibody that are specific for the antigen. Antibodies are large proteins called immunoglobulins (Igs) that bind to and remove the specific antigen.
A type of Ig, called IgM, is part of the early immune response. The IgM molecules form clusters in the bloodstream. When these IgM clusters encounter their specific antigen, usually a bacterium, they cover it so that it can be destroyed by other immune system cells.
Plasma cell neoplasm
WM is a type of plasma cell neoplasm or B-cell lymphoma. These are lymphomas in which certain plasma cells become abnormal, or cancerous, and begin to grow uncontrollably. In WM, the cancerous plasma cells overproduce large amounts of identical (monoclonal) IgM antibody. This IgM also is called M protein, for monoclonal or myeloma protein.
Macroglobulinemia refers to the accumulation of this M protein in the serum of the blood. This large amount of M protein can cause the blood to thicken, causing hyperviscosity. The malignant plasma cells of some WM patients also produce and secrete partial immunoglobulins called light chains, or Bence-Jones proteins. The malignant plasma cells can invade various tissues, including the bone marrow, lymph nodes, and spleen, causing these tissues to swell.
WM accounts for about 1-2% of non-Hodgkin's lymphomas. It is estimated that it may affect about five out of every 100,000 people. It usually affects people over the age of 50, and most often develops after age 65. It is more common in men than in women. In the United States, WM is more common among Caucasians than among African Americans. The disease can run in families.
Causes and symptoms
The cause of WM is not known.
Many individuals with WM have no symptoms of the disease. This is known as asymptomatic macroglobulinemia. When symptoms of WM are present, they may vary greatly from one individual to the next.
At least 50% of individuals with WM have hyperviscosity syndrome, an increased viscosity or thickening of the blood caused by the accumulation of IgM in the serum. Hyperviscosity can cause a slowing in the circulation through small blood vessels. This condition can lead to a variety of symptoms:
- nose bleeds
- gastrointestinal bleeding
- weight loss
- night sweats
- increased and recurrent infections
- poor blood circulation in the extremities
Poor blood circulation, or Raynaud's phenomenon, can affect any part of the body, but particularly the fingers, toes, nose, and ears.
Cold weather can cause additional circulatory problems, by further thickening the blood and slowing down circulation. In some cases, the excess blood protein may precipitate out of the blood in the cold, creating particles that can block small blood vessels. This is called cryoglobulinemia. The extremities may turn white, or a patchy red and white. The hands, feet, fingers, toes, ears, and nose may feel cold, numb, or painful.
Hyperviscosity may affect the brain and nervous system, leading to additional symptoms. These symptoms include:
- peripheral neuropathy, caused by changes in the nerves, leading to pain or numbness in the extremities
- vision problems or loss of vision
- mental confusion
- poor coordination
- temporary paralysis
- mental changes
Hyperviscosity can clog the tubules that form the filtering system of the kidneys, leading to kidney damage or kidney failure. Existing heart conditions can be aggravated by WM. In extreme cases, WM may result in heart failure. Late-stage WM also may lead to mental changes that can progress to coma.
The accumulation of IgM in the blood causes an increase in the volume of the blood plasma. This effectively dilutes out the red blood cells and other blood components. The lowered concentration of red blood cells can lead to anemia and cause serious fatigue. Likewise, a deficiency in platelets (thrombocytopenia), which cause the blood to clot, can result in easy bleeding and bruising. As the cancer progresses, there may be abnormal bleeding from the gums, nose, mouth, and intestinal tract. There may be bluish discoloration of the skin. In the later stages of the disease, leukopenia, a deficiency in white blood cells, also can develop.
In 5-10% of WM cases, the IgM may be deposited in tissues. Thus, some individuals with WM have enlargement of the lymph nodes, the spleen, and/or the liver.
If Bence-Jones proteins are produced by the malignant plasma cells, they may be deposited in the kidneys. There they can plug up the tiny tubules that form the filtering system of the kidneys. This can lead to kidney damage and kidney failure.
Since many individuals with WM have no symptoms, the initial diagnosis may result from blood tests that are performed for some other purpose. Blood cell counts may reveal low red blood cell and platelet levels. A physical examination may indicate enlargement of the lymph nodes, spleen, and/or liver. A retinal eye examination with an ophthalmoscope may show retinal veins that are enlarged or bleeding.
Blood and urine tests
Serum protein electrophoresis is used to measure proteins in the blood. In this laboratory procedure, serum proteins are separated in an electrical field, based on the size and electrical charge of the proteins. Serum immunoelectrophoresis uses a second antibody that reacts with IgM. A spike in the Ig fraction indicates a large amount of identical or monoclonal IgM in individuals with WM.
Normal serum contains 0.7-1.6 gm per deciliter (g/dl) of Ig, with no monoclonal Ig present. At serum IgM concentrations of 3-5 g/dl, symptoms of hyperviscosity often are present. However some individuals remain asymptomatic with IgM levels as high as 9 g/dl.
Urinalysis may indicate protein in the urine. A urine Bence-Jones protein test may indicate the presence of these small, partial Igs.
Abnormal blood tests usually are followed by a bone marrow biopsy. In this procedure, a needle is inserted into a bone and a small amount of marrow is removed. Microscopic examination of the marrow may reveal elevated levels of lymphocytes and plasma cells. However, less than 5% of patients with WM have lytic bone lesions, caused by cancerous plasma cells in the bone marrow that are destroying healthy cells. Bone lesions can be detected with x rays.
WM usually is diagnosed and treated by a hematologist/oncologist, a specialist in diseases of the blood. Asymptomatic macroglobulinemia is followed closely by the patient's physician for the development of symptoms.
Clinical staging, treatments, and prognosis
Clinical staging, to define how far a cancer has spread through the body, is the common method for choosing a cancer treatment. However, there is no generally accepted staging system for WM.
There also is no generally accepted course of treatment for WM. Treatment may not be necessary for asymptomatic macroglobulinemia. However, if IgM serum levels are very high, treatment may be initiated even in the absence of symptoms. If symptoms are present, treatment is directed at relieving symptoms and retarding the disease's development. Of major concern is the prevention or alleviation of blood hyperviscosity. Therefore, the initial treatment depends on the viscosity of the blood at diagnosis.
Plasmapheresis, or plasma exchange transfusion, is a procedure for thinning the blood. In this treatment, blood is removed and passed through a cell separator that removes the plasma, containing the IgM, from the red and white blood cells and platelets. The blood cells are transfused back into the patient, along with a plasma substitute or donated plasma. Plasmapheresis relieves many of the acute symptoms of WM. Individuals with WM may be given fluid to counter the effects of hyperviscous blood.
Low blood cell counts
Treatments for low blood cell levels include:
- the drug Procrit to treat anemia
- transfusions with packed red blood cells to treat anemia in later stages of the disease
- antibiotics to treat infections caused by a deficiency in white blood cells
- transfusions with blood platelets
Chemotherapy, the use of anti-cancer drugs, helps to slow the abnormal development of plasma cells, but does not cure WM. It can reduce the amount of IgM in the bone marrow. In particular, chemotherapy is used to treat severe hyperviscosity and anemia that are caused by WM.
Chlorambucil (Leukeran), possibly in combination with prednisone, is the typical chemotherapy choice for WM. This treatment is effective in 57% of cases. These drugs are taken by mouth. Prednisone is a corticosteroid that affects many body systems. It has anti-cancer and anti-inflammatory effects and is an immune system suppressant. Other drug combinations that are used to treat WM include cyclophosphamide (Cytoxan), vincristine, and prednisone, with or without doxorubicin. Fludarabine, 2-chlorodeoxyadenosine, and corticosteroids also may be used.
Side effects of chemotherapy may include:
- Mouth sores
- Nausea and indigestion
- Hair loss (alopecia)
- Increased appetite
These side effects disappear after the chemotherapy is discontinued.
The long-term management of WM usually is accomplished through a combination of plasmapheresis and chemotherapy.
Alternative and complementary therapies
Biological therapy or immunotherapy, with the potent, immune system protein interferon alpha, is used to relieve the symptoms of WM. Interferon alpha works by boosting the body's immune response. Interferon can cause flu-like symptoms, such as fever, chills, and fatigue. It also can cause digestive problems and may affect blood pressure.
The drug rituximab, an antibody that is active against antibody-producing cells, is effective in about 30% of individuals with WM. Rituximab is a monoclonal antibody produced in the laboratory. Monoclonal antibody treatment may cause a an allergic reaction in some people.
There is no cure for WM. In general, patients go into partial or complete remission following initial treatments. However the disease is not cured and follow-up treatment may be necessary.
The prognosis for this cancer depends on an individual's age, general health, and genetic (hereditary) makeup. Males, individuals over age 60, and those with severe anemia have the lowest survival rates. The Revised European American Lymphoma (REAL) classification system gives WM a good prognosis following treatment, with an average five-year survival rate of 50-70%. However, many people with WM live much longer, some without developing any symptoms of the disease. About 16-23% of individuals with WM die of unrelated causes.
Clinical studies for the treatment of WM are ongoing. These studies are focusing on new anti-cancer drugs, new combinations of drugs for chemotherapy, and new biological therapies to boost the immune system. The drug thalidomide is a promising new treatment for WM. Its mode of action is unclear; the drug appears to have various effects on the immune system and may inhibit cancerous plasma cells, both directly and indirectly. If thalidomide is taken during pregnancy, it can cause severe birth defects or death of the fetus.
Biological therapies in clinical trial include monoclonal antibodies that contain radioactive substances (radioimmunotherapy), in combination with autologous peripheral blood stem cell rescue or transplantation (PBSCT). With PBSCT, the patient's peripheral blood stem cells (immature bone marrow cells found in the blood) are collected and frozen prior to radioimmunotherapy, which destroys bone marrow cells. A procedure called apheresis is used to collect the stem cells. Following the therapy, the stem cells are reinjected into the individual. The procedure is autologous because it utilizes the individual's own cells. A similar procedure that utilizes chemotherapy with PBSCT also is being tested.
There is no known prevention for WM.
WM is a rare disorder and many physicians and even hematologists may not have had experience with it. Furthermore, there is not a clear consensus among professionals as to what constitutes a diagnosis of WM; nor is there a defined course of treatment or accurate prognosis. Thus, it is important that the patient obtain all available information, including seeking second opinions and additional consultations.
- Any condition in which the red blood cell count is below normal.
- Immunoglobulin produced by immune system cells that recognizes and binds to a specific foreign substance (antigen).
- Foreign substance that is recognized by a specific antibody.
- Autosomal dominant
- Genetic trait that is expressed when present on only one of a pair of non-sex-linked chromosomes.
- B cell (B lymphocyte)
- Type of white blood cell that produces antibodies.
- Bence-Jones protein
- Light chain of an immunoglobulin that may be overproduced in Waldenström's macroglobulinemia; it is excreted in the urine.
- Removal of a small sample of tissue for examination under a microscope; used in the diagnosis of cancer.
- Condition in which protein in the blood forms particles in the cold, blocking blood vessels and leading to pain and numbness of the extremities.
- Thick, viscous blood, caused by the accumulation of large proteins, such as immunoglobulins, in the serum.
- Use of an electrical field to separate proteins in a mixture (such as blood or urine), on the basis of the size and electrical charge of the proteins; followed by the detection of an antigen (such as IgM), using a specific antibody.
- Immunoglobulin (Ig)
- Antibody such as IgM; large protein produced by B cells that recognizes and binds to a specific antigen.
- Interferon alpha
- Potent immune-defense protein; used as an anti-cancer drug.
- Lymphatic system
- The vessels, lymph nodes, and organs, including the bone marrow, spleen, and thymus, that produce and carry white blood cells to fight disease.
- Cancer that originates in lymphatic tissue.
- M protein
- Monoclonal or myeloma protein; IgM that is overproduced in Waldenström's macroglobulinemia and accumulates in the blood and urine.
- Identical cells or proteins; cells (clones) derived from a single, genetically distinct cell, or proteins produced by these cells.
- Plasma cell
- Type of white blood cell that produces antibodies; derived from an antigen-specific B cell.
- Plasma exchange transfusion; the separation of serum from blood cells to treat hyperviscosity of the blood.
- Cell that is involved in blood clotting.
- Stem cell
- Undifferentiated cell that retains the ability to develop into any one of numerous cell types.
QUESTIONS TO ASK THE DOCTOR
- Why have you diagnosed Waldenström's macroglobulinemia?
- Is my disease likely to progress?
- Do you recommend treatment, and if so, why?
- What are my treatment options?
- What is my prognosis?