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Waldenströms Macroglobulinemia

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What is Waldenstrom macroglobulinemia?

Waldenstrom macroglobulinemia (WM) is a type of non-Hodgkin lymphoma (NHL) that produces large amounts of an abnormal protein (called a macroglobulin). Another name for WM is lymphoplasmacytic lymphoma. This condition used to be called Waldenstrom's macroglobulinemia, so some people refer to it as Waldenstrom's.

The lymphoma cells in WM grow mainly in the bone marrow, where they can crowd out the normal cells that make the different blood cells. This can lead to low levels of red blood cells (called anemia), which can make people feel tired and weak. It can also cause low numbers of white blood cells, which makes it hard for the body to fight infection. The numbers of platelets in the blood can also drop, leading to increased bleeding and bruising.

Lymphoma cells can also grow in organs like the liver and spleen, causing these organs to swell, leading to abdominal pain. The macroglobulin made by the lymphoma cells can cause other problems as well.

Lymphoid tissue and the immune system

Lymphoid tissue contains several types of immune system cells that work together to resist infections. Lymphoid tissue also reacts to transplanted tissues (like blood transfusions or organ transplants) from other people and is involved in fighting some types of cancer.

Lymphoid tissue is found in lymph nodes, which are pea-sized collections of immune system cells found in the underarm area, in the groin, on the sides of the neck, inside the chest, and inside the abdomen. Lymphoid tissue is in the bone marrow as well as other organs such as the thymus (which is behind the chest bone and in front of the heart), the spleen (which is on the left side of the abdomen next to the stomach), and the tonsils and adenoids. Lymphoid tissue is also scattered throughout the body within other systems like the digestive system and respiratory system.

Lymphocytes (lymph cells) are the main cells of lymphoid tissue. There are 2 types of lymphocytes: T cells and B cells. B cells respond to an infection by changing into a different type of cell called a plasma cell. Plasma cells make the antibodies (also called immunoglobins) that help the body attack and kill disease-causing germs like bacteria. The main job of T cells is to help direct the immune response, but they also can directly kill invading germs.

Cells responsible for Waldenstrom macroglobulinemia

WM is a cancer of B cells. The cancer cells in people with WM are similar to those of 2 other types of cancer: multiple myeloma and non-Hodgkin lymphoma. Multiple myeloma is considered a cancer of plasma cells and non-Hodgkin lymphoma is a cancer of lymphocytes. WM cells have features of both plasma cells and lymphocytes and are called lymphoplasmacytoid. These cells produce large amounts of an abnormal type of a certain antibody protein (immunoglobulin M, or IgM) that causes many of the symptoms of WM, including excessive bleeding, problems with vision, and nervous system problems.

What are the risk factors for Waldenstrom macroglobulinemia?

A risk factor is anything that affects your chance of getting a disease such as cancer. Different cancers have different risk factors. For example, unprotected exposure to strong sunlight is a risk factor for skin cancer. Smoking is a risk factor for many cancers.

Researchers have found a few risk factors that make a person more likely to develop Waldenstrom macroglobulinemia (WM). But most people with these risk factors never develop the disease. Even if a patient with WM does have one or more risk factors, it is impossible to know for sure how much that risk factor contributed to causing the cancer.

Monoclonal gammopathy of undetermined significance

Monoclonal gammopathy of undetermined significance (MGUS) is an abnormality of antibody-producing cells that is related to multiple myeloma and WM. In MGUS, like WM and multiple myeloma, abnormal cells in the bone marrow make a large amount of one particular antibody -- this is called a monoclonal gammopathy. As long as the patient has no problems from the abnormal cells or the antibody, it is called MGUS. Generally, the abnormal cells in MGUS make up less than 10% of the bone marrow and the amount of abnormal protein in the blood is not very high (<3g/dl). In most cases, MGUS causes no health problems, but up to 25% of people with MGUS will go on to be diagnosed with a cancer or related serious health problem (like multiple myeloma, WM, another lymphoma, or amyloidosis) over the 20 years after diagnosis.

Age : The risk of WM goes up with age. It is rare among people younger than 50 years old.

Race: WM is more common among whites than among African Americans. In contrast, multiple myeloma is about twice as common among African Americans as white Americans. The reasons for these differences are not known.

Sex : Men are more likely than women to develop this disease.

Heredity : Genetic factors may play a role. In one study, about 5% of patients with WM had a close relative with the disease, and another 15% of WM patients had a relative with another type of lymphoma.

Hepatitis C : A recent study has shown that people with chronic hepatitis C infection develop WM more than twice as often as people without the virus.

Do we know what causes Waldenstrom macroglobulinemia?

Scientists have made great progress in understanding how certain changes in DNA can cause normal lymphocytes to become lymphoma or multiple myeloma cells. They are also beginning to understand how changes in the DNA of some lymphomas cause their cells to produce high levels of IgM, which causes most of the symptoms of Waldenstrom macroglobulinemia (WM).

DNA is the chemical that carries the instructions for nearly everything our cells do. We resemble our parents because they are the source of our DNA. But DNA affects more than the way we look. Some genes (parts of our DNA) contain instructions for controlling when cells grow and divide. Certain genes that promote cell division are called oncogenes. Others that slow down cell division or cause cells to die at the right time are called tumor suppressor genes. We know that cancers can be caused by DNA mutations (defects or changes) that turn on oncogenes or turn off tumor suppressor genes. Some people with certain types of cancer have DNA changes they inherited from a parent, which increased their risk for the disease. Researchers are studying families that have many cases of WM to try to find the gene that may cause this disorder in some people.

Many changes in DNA have been found in WM cells. These DNA changes are usually acquired after birth (not passed on from a parent). Acquired changes may result from exposure to something in the environment, such as radiation or cancer-causing chemicals. Often these changes occur for no apparent reason. Every time a cell prepares to divide into 2 new cells, it must duplicate its DNA. This process is not perfect and sometimes copying errors occur. Fortunately, cells have repair enzymes that "proofread" DNA. But some errors may slip past, especially if the cells are growing rapidly.

Human DNA is packaged in 23 pairs of chromosomes. Sometimes, a piece of a chromosome is missing - this is called a deletion. The most common defect seen in WM is a deletion of part of chromosome 6. Another type of chromosome defect in WM is called a translocation. In a translocation, a piece of one chromosome becomes attached to a different chromosome. Chromosome changes like these can cause oncogenes to be turned on or tumor suppressor genes turned off.

Researchers have found that some patients with WM have important changes or defects in other bone marrow cells. These changes may also cause excess growth of the cancer cells. Certain cells in the bone marrow called dendritic cells release a hormone called interleukin-6 (IL-6) that helps normal plasma cells and plasmacytoid lymphocytes grow. Excess IL-6 production by these cells appears to be an important factor in the development of WM.

Can Waldenstrom macroglobulinemia be prevented?

Most of the risk factors for Waldenstrom macroglobulinemia (WM), such as aging or monoclonal gammopathy of undetermined significance, cannot be changed or controlled by a person. For these reasons, there is no known way to prevent this disease.

Some patients with hepatitis C go on to develop WM. There is currently no treatment to prevent this from occurring, but taking steps to avoid hepatitis C infection might be able to lower the chance of getting WM.

Can Waldenstrom macroglobulinemia be found early?

Many cases of Waldenstrom macroglobulinemia (WM) are found early, but at this time, no special tests are recommended to do so. The best strategy for early diagnosis is prompt attention to the signs and symptoms of this disease.

How is Waldenstrom macroglobulinemia diagnosed?

If signs or symptoms suggest that a person may have Waldenstrom macroglobulinemia (WM), more exams and tests will be done. The most important ones will look for the abnormal protein in the blood and the abnormal cells in the bone marrow.

You may find it confusing that this document on WM also discusses ways to diagnose non-Hodgkin lymphoma. But WM is a type of lymphoma. Like other lymphomas, it invades the bone marrow, lymph nodes and other organs.

Signs and symptoms

Some of the signs and symptoms of people with WM are similar to those of people with other types of non-Hodgkin lymphomas (NHL). For example, weight loss, fever, night sweats, and swollen lymph nodes can be seen in many types of NHL.

Other WM symptoms are caused by the abnormal antibody produced by the cancer cells. In hyperviscosity syndrome, too much of this protein can cause the blood to become too "thick." (This is not the kind of thickness that can be treated with drugs known as "blood thinners.") When the blood gets too thick, it has trouble traveling through blood vessels. This causes poor circulation to the brain which can lead to problems similar to a stroke.

If the abnormal protein only causes the blood to become thick at cooler temperatures (like in the hands and feet), it is called a cryoglobulin. Cryoglobulins can cause the hands and feet to become painful in cool temperatures.

A condition called amyloidosis occurs when a part of the abnormal antibody (called the light chain) builds up in organs like the heart and kidneys. The protein buildup can interfere with the function of these organs, leading to heart and kidney problems.

Not all patients with WM develop hyperviscosity, cryoglobulins or amyloidosis.

The most common symptoms of WM are:

Weakness : The most common symptom of WM is weakness. It can be caused by anemia (low red blood cells) which can happen when the lymphoma cells crowd out normal cells in the bone marrow. Some people also feel weak when the blood becomes thick from the abnormal protein.

Loss of appetite : About one-fourth of patients lose their appetite.

Fever : Lymphoma can cause fevers (without an infection), drenching night sweats, and weight loss. Together, these 3 symptoms are called B-symptoms.

Neuropathy: The abnormal antibody in some people with WM can attack and damage nerves outside the brain. This can lead to problems with numbness or a painful "pins and needles" sensation in the feet and legs, which is called neuropathy

Other problems include:

Enlarged lymph nodes : These will usually appear as bumps under the skin around the neck, in the groin, or in the armpits. Enlarged lymph nodes are usually about 1 or 2 inches in size in WM, but can be bigger in other lymphomas.

Swollen abdomen : Lymphoma can cause the spleen or liver to enlarge, making the belly look swollen. In the upper part of the abdomen, the liver is on the right and the spleen on the left. When the spleen gets larger, it can press on the stomach — which makes people feel full when they eat only a small amount.

Nervous system symptoms : In hyperviscosity syndrome, the thickened blood causes poor brain circulation leading to problems like headache, confusion, and dizziness. It can also cause symptoms like those seen with a stroke, including slurred speech and weakness on one side of the body. Patients with these symptoms should contact their doctor right away.

Abnormal bleeding: High levels of abnormal antibody protein can damage blood vessels. Nosebleeds and bleeding gums are common symptoms of people with WM.

Vision problems: Bleeding around the small blood vessels inside the eyes might cause blurred vision or blind spots. If the blood becomes thick from the abnormal antibody protein, it leads to slow circulation through the blood vessels in the eye, which can also interfere with vision.

Kidney problems : WM can damage the kidneys in 2 ways. First of all, the abnormal antibody protein can damage the kidneys directly. Secondly, if amyloidosis develops, the abnormal protein builds up in the kidneys, so they don't work well. When the kidneys aren't working well, excess salt, fluid, and body waste products stay in the blood. The resulting symptoms include weakness, trouble breathing, and fluid buildup in body tissues.

Heart problems : There are several causes of heart problems in WM. High levels of abnormal antibody protein can directly damage heart tissue. Also, in amyloidosis, this abnormal protein builds up in the heart muscle. This makes the heart weaker and impairs its ability to pump blood properly. In addition, because the blood of people with WM is "thicker" than normal, their hearts have to work harder to pump blood throughout the body. This strain can cause the heart to "wear out," a condition called congestive heart failure. Symptoms of congestive heart failure include weakness, shortness of breath, and swelling in the feet and legs.

Infections : The high levels of abnormal antibody in WM "turn-off" normal antibody production. This makes it harder for the body to resist infections.

Laboratory tests

The diagnosis of WM may be suspected if your doctor finds low blood counts or unusual protein levels on blood tests. This is followed by a test to characterize the proteins called serum electrophoresis. It is usually only after these tests are done that a biopsy of either the bone marrow or a lymph node is considered.

Blood counts : The complete blood count (CBC) is a test that measures the levels of red cells, white cells, and platelets in the blood. If the lymphoma cells occupy too much of the bone marrow, these levels will be low.

Quantitative immunoglobulins : This test measures the blood levels of the different antibodies. There are several different types of antibodies in the blood: IgA, IgE, IgG, and IgM. The levels of these immunoglobulins are measured to see if any are abnormally high or low. In WM the level of IgM is high but the IgG level is often low.

Electrophoresis : The immunoglobulin produced in WM is IgM. It is abnormal because it is monoclonal — meaning that it is just many copies of the exact same antibody. Serum protein electrophoresis (or SPEP) is a test that measures the total amount of immunoglobulins in the blood and finds any abnormal (monoclonal) immunoglobulin. Then, another test, such as immunofixation or immunoelectrophoresis, is used to determine the type of antibody that is abnormal (IgM or some other type).

Finding a monoclonal IgM immunoglobulin in the blood is necessary to make a diagnosis of WM. The abnormal protein in WM is known by several different names, including monoclonal immunoglobulin M, IgM protein, IgM spike,IgM paraprotein, and M-spike. Other types of monoclonal immunoglobulins, like IgA or IgG, are seen in different disorders (like multiple myeloma and some lymphomas).

Sometimes pieces of the IgM protein are excreted by the kidneys into the urine. The procedure used for finding that protein is called urine protein electrophoresis (or UPEP).

Viscosity: Viscosity measures how thick the blood is. If the IgM level is too high, it will cause the blood to become thick (viscous) so that it can't flow freely. Think about pouring honey compared to pouring water. If the blood becomes too thick, the brain doesn't get enough blood and oxygen. This can be treated with plasmapheresis.

Cryocrit: This tests the blood for a cryoglobulin (a protein that causes the blood to clump together in cool temperatures).

Beta-2-microglobulin: This is another protein produced by the cancer cells in WM. This protein itself doesn't cause any problems, but it is a useful indicator of a patient’s prognosis (outlook). High levels mean a poor outlook.

Types of biopsies

The symptoms of WM and NHL are not unique enough for a doctor to know for certain if cancer is present. Most symptoms can also be caused by non-cancerous problems like infections or by other kinds of cancers. A biopsy is the only way to make an accurate diagnosis. There are several biopsy procedures. Doctors choose which to use based on the unique aspects of each patient's situation.

Bone marrow aspiration and biopsy: This test is necessary to diagnose WM. It can be done at the doctor's office or at the hospital. First, an area at the back of the hip/pelvis bone is numbed with a local anesthetic. Then, to do the bone marrow aspiration, a needle is inserted into the bone, and a syringe is used to remove some bone marrow. Even with the numbing medicine, this often causes a brief, sharp pain.

For the bone marrow biopsy, a needle is used to remove a cylinder of bone and marrow, about 1/16-inch across and 1-inch long. With the numbing medicine, most patients feel pressure for this part, but not pain.

There is some soreness in the biopsy area when the numbing medicine wears off. Most patients can go home immediately after the procedure. The bone marrow is then examined under the microscope (by a doctor called apathologist) to see if lymphoma cells are present. In WM, at least 10% of the cells in the bone marrow are lymphoplasmacytoid lymphoma.

Fine needle aspiration biopsy: Fine needle aspiration (FNA) biopsy uses a very thin needle with a syringe to withdraw a small amount of tissue from a tumor or lymph node. The doctor can aim the needle while feeling an enlarged node near the surface of the body. If the tumor is deep inside the body, the needle can be guided while it is viewed by a computed tomography (CT) scan (see the descriptions of imaging tests later in this section).

The main advantage of FNA is that the patient will not require surgery for this procedure. The disadvantage is that in some cases the thin needle cannot remove enough tissue for a definite diagnosis of lymphoma. However, advances in performing flow cytometry and molecular genetic studies (discussed later in this section) and the growing experience of many doctors with FNA have improved the accuracy of this procedure.

FNA is very useful in diagnosing cancers that have spread to nodes from other organs and in identifying nodes swollen by infection that don’t need to be removed. FNA is useful in diagnosing some lymphomas, but it is less helpful for WM because the diagnosis is usually made with a bone marrow biopsy.

Fat pad aspiration: In this procedure, a needle with a syringe attached is inserted into an area of fat (usually the skin of the abdomen/belly). Then, a small amount of fat is removed and sent to the lab for testing. This may be used in WM to check for amyloid.

Excisional or incisional biopsy : For these types of biopsies, a surgeon cuts through the skin to remove an entire lymph node or tumor (excisional biopsy) or a just a small part of a large tumor or lymph node (incisional biopsy). If the area to be biopsied is near the skin surface, this can be done using just a local anesthesia (numbing medicine). If the area is inside the chest or abdomen, general anesthesia or deep sedation is used (the patient is asleep). The excisional and incisional methods almost always provide enough tissue to diagnose the exact type of lymphoma. These biopsies are rarely needed in people with WM because the diagnosis is usually made with a bone marrow biopsy. They are used more often for other types of lymphoma.

Laboratory tests on biopsy specimens

All biopsy specimens are examined under a microscope by a pathologist – a doctor with special training in recognizing cells from blood and lymphoid tissue diseases. The doctor looks at the size and shape of the cells and how the cells are arranged in the lymph node or bone marrow. Sometimes this exam does not provide a definite answer and other laboratory tests are needed.

Immunohistochemistry :In this test, a part of the biopsy sample is treated with special laboratory antibodies so that certain types of cells change color. The color change can be seen under a microscope. This test may be helpful in distinguishing different types of lymphoma from one another and from other diseases.

Flow cytometry: In this test, cells are treated with special laboratory antibodies and passed in front of a laser beam. Each antibody sticks only to certain types of cells. If the sample contains those cells, the laser light will cause them to give off light of a different color, which is measured exactly and analyzed by a computer. This test can help determine whether lymph node swelling is because of lymphoma, some other cancer, or a non-cancerous disease. It has become increasingly important in helping doctors determine the exact type of lymphoma so they can select the best treatment.

Cytogenetics: For this technique, cells (usually from the bone marrow) are cultured in the lab to get them to divide so that the chromosomes can be seen. Then the chromosomes are stained and a microscope is used to examine them. Because it takes time for the cells to start dividing, this test can take weeks.

Normal human cells each contain 46 chromosomes (pieces of DNA that control the cells’ growth and metabolism). In some lymphomas, part of one chromosome is attached to part of a different chromosome, this is called atranslocation. In WM it is more common for the lymphoma cells to be missing part of a chromosome (called adeletion).

Molecular genetic studies : These tests are not usually necessary to diagnose WM, but are sometimes used to diagnose other types of NHL. These tests look at the cells’ DNA without having to grow the cells in the lab first, and can be done on cells from different sources (like lymph nodes, blood, and bone marrow)._They are generally used to look for certain genetic changes, not just any change.

One test that can be done is to look at the DNA that contains information on each cell's antigen receptors. Normal lymphoid tissue contains cells with many different antigen receptors, helping the body respond to many types of infection. Because lymphoma starts from a single abnormal cell, all cells in each patient have the same antigen receptor. This is a complex test and may not be needed in every case.

Tests of lymphoma cell DNA can also find chromosome changes that are characteristic of certain types of NHL. This can be helpful in determining what kind of lymphoma is present.

Usually genetic tests aren't needed to diagnose WM, but they may be very useful for research.

Imaging tests

Imaging tests may be done to look for an enlarged spleen and lymph nodes. Finding these is not needed to diagnose WM.

Chest x-ray: Plain x-rays may detect enlarged lymph nodes in the chest.

Computed tomography: The computed tomography (CT) scan is an x-ray procedure that produces detailed cross-sectional images of your body. Instead of taking one picture, like a conventional x-ray, a CT scanner takes many pictures as it rotates around you. A computer then combines these pictures into an image of a slice of your body. The machine creates multiple images of the part of your body that is being studied. A CT scan is useful for looking at lymphoma in the abdomen, pelvis, and chest.

You may be asked to drink 1 to 2 pints of a solution of contrast material before the scan. This helps outline the intestine so that it is not mistaken for tumors. You may also receive an intravenous (IV, in the vein) line through which a different contrast dye is injected. This helps better outline structures in your body. The injection can cause a feeling of warmth throughout the body (flushing). Some people are allergic to the IV contrast and get hives. Rarely, more serious reactions like trouble breathing and low blood pressure can occur. Medication can be given to prevent and treat allergic reactions. Be sure to tell the doctor if you have ever had a reaction to any contrast material used for x-rays.

CT scans can take longer than regular x-rays. You must lie still on a table while they are being done. But many just take a few minutes. You might feel a bit confined by the machine you lie in when the pictures are being taken.

CT scans can also be used to precisely guide a biopsy needle into an enlarged lymph node. For this procedure, called a CT-guided needle biopsy, the patient remains on the CT scanning table while a radiologist moves a biopsy needle toward the mass. CT scans are repeated until the doctors are sure that the needle is within the mass. A fine needle biopsy (tiny fragment of tissue) or a core needle biopsy (a thin cylinder of tissue about ½-inch long and less than 1/8-inch in diameter) sample is removed and examined under a microscope.

Magnetic resonance imaging : Magnetic resonance imaging (MRI) scans use radio waves and strong magnets instead of x-rays. The energy from the radio waves is absorbed and then released in a pattern formed by the type of tissue and by certain diseases. A computer translates the pattern of radio waves given off by the tissues into a very detailed image of parts of the body. Not only does this produce cross-sectional slices of the body like a CT scanner, it can also produce slices that are parallel with the length of your body. Sometimes a contrast material is injected into a vein to make some structures clearer. This contrast is not the same as the contrast used for CT scans, but allergic reactions can still occur. Again, medicine can be given to prevent and treat allergic reactions.

MRI scans are helpful in examining the brain and spinal cord. MRI scans are a little more uncomfortable than CT scans. First, they take longer -- about an hour. Also, you have to lie inside a tube, which is confining and can upset people with a fear of enclosed spaces. The machine also makes a thumping noise that some people find disturbing. Some places provide headphones with music to block this noise out. If you have problems with close spaces (claustrophobia), you should let your doctor know before the MRI scan.

Positron emission tomography : A positron emission tomography (PET) scan uses a form of sugar (glucose) that has a radioactive atom. A special camera can detect the radioactivity. Cancer cells absorb higher amounts of the radioactive sugar than normal tissue does because of their high rate of metabolism. PET is useful to look for lymphoma throughout your body. It is sometimes used to tell if an enlarged lymph node contains lymphoma or is benign. This can be helpful after treatment to see if an enlarged lymph node still contains lymphoma or is merely scar tissue.

How is Waldenstrom macroglobulinemia staged?

Staging is the process of learning how much the cancer has spread. This can be helpful in predicting outcomes and in deciding treatment for most forms of cancer. There is no standard staging system for Waldenstrom macroglobulinemia (WM). It can be staged like other non-Hodgkin lymphomas, but since the stage isn't important in deciding treatment, this is rarely done.

Instead, doctors looked at the blood counts, the amount of immunoglobulin in the blood, and the level of another protein in the blood called beta-2-microglobulin. People with a level of beta-2-microglobulin below 3 mg/L live longer than those whose level is above 3. Patients with WM who are anemic or have a low blood platelet count also have a shorter survival. Being older also leads to a poorer outlook.

In 2008, experts used these factors to develop a system that could help predict prognosis (outlook) for patients with WM. It is called the International Prognostic Scoring System for Waldenstrom Macroglobulimia (IPSSWM). This system takes into account the factors that seem to predict a poorer outcome, such as:

Age more than 65 years old

Hemoglobin level less than 11.5

Platelet count 100 or less

Beta-2-microglobulin more than 3 mg/L

Monoclonal IgM level more than 7 g/dL

Except for age, each of these factors is worth a single point. The points are added to make a score. The score is used to group patients into 3 risk groups: low, intermediate, and high. The low risk group includes patients younger than 65 who have no more than 1 point. The intermediate group includes those who are at least 65 and/or have 2 points. The high risk group includes those who have at least 3 points. These groups can be used to help predict survival (discussed in more detail in the next section).

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