You may find it confusing that this document on Waldenstrom macroglobulinemia 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 of Waldenstrom macroglobulinemia

Some of the signs and symptoms of people with Waldenstrom macroglobulinemia are similar to those of people with other types of non-Hodgkin lymphomas. 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." When the blood gets too thick, it has trouble traveling through blood vessels. This causes problems from poor circulation to the brain. If the abnormal protein only makes the blood 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. Not all patients with WM develop hyperviscosity, cryoglobulins or amyloidosis.

The most common symptoms of Waldenstrom macroglobulinemia are:

• weakness: This is the most common symptom of WM. 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 "thickness" of the blood caused by the abnormal protein increases. 
• loss of appetite: This occurs in about one-fourth of patients 
• 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 Waldenstrom macroglobulinemia can attack and damage nerves outside of the brain. This can lead to problems with numbness or a painful "pins and needles" sensation in the feet and legs.

Other problems that are seen 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 an inch or two in size in WM, but can be bigger in other lymphomas. 
• swollen abdomen: Lymphoma can cause the spleen or liver to enlarge, causing the belly to 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 "thick blood" causes poor brain circulation leading to problems like headache, confusion, and dizziness. Hyperviscosity syndrome can also cause symptoms like 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 Waldenstrom macroglobulinemia. 
• problems with vision: Blurred vision or blind spots may be due to bleeding around the small blood vessels inside the eyes. Slow circulation through these narrow blood vessels, which occurs because the abnormal antibody thickens the blood, can also interfere with vision. 
•  kidney problems: In amyloidosis, abnormal protein builds up in the kidneys, so they don't work well. The abnormal antibody protein can also damage the kidneys directly. 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 becomes deposited in the heart muscle making the heart weaker and harming its ability to pump blood properly. In addition, because the blood of people with Waldenstrom macroglobulinemia 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 "turns-off" normal antibody production. This makes it harder for the body to resist infections.

Laboratory tests to detect Waldenstrom macroglobulinemia

The diagnosis of Waldenstrom macroglobulinemia may be suspected if your doctor finds low blood counts or unusual protein levels on blood tests. This is followed by a serum electrophoresis to characterize the proteins. 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 Waldenstrom macroglobulinemia the level of IgM is high but the IgG level is often low.

Electrophoresis: The immunoglobulin produced in Waldenstrom macroglobulinemia (IgM) is abnormal because it is "monoclonal." Serum protein electrophoresis (SPEP) is a test to measure the total amount of immunoglobulins in the blood and find 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 Waldenstrom macroglobulinemia. 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 with 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 a monoclonal immunoglobulin in the urine is called urine protein electrophoresis (UPEP).

Viscosity: Viscosity measures how thick the blood is. If the IgM level is too high, it will cause the blood to become thick or viscous and it will not flow freely. Picture the flow of cold molasses compared to warm molasses. If the blood becomes too thick, the brain doesn't get enough blood and oxygen. This can be treated with plasmapheresis (see below).

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 malignant lymphoplasmacytoid cells. Although this protein itself doesn't cause any problems, it is a useful indicator of a patient’s prognosis (outlook). High levels mean a poor outlook.

Types of biopsies used to diagnose Waldenstrom macroglobulinemia and non-Hodgkin lymphoma

The symptoms of Waldenstrom macroglobulinemia and non-Hodgkin lymphoma are not unique enough for a doctor to know for certain whether 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 reach 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. Then, to do the bone marrow aspiration, a needle is inserted into the bone, and a syringe is used to remove some bone marrow. For bone marrow biopsy, a needle is used to remove a cylinder of bone and marrow, about 1/16-inch across and 1-inch long. There is some soreness in the biopsy area the when 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 a pathologist) 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 (FNA): FNA uses a very thin needle and an ordinary 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 discussion of imaging tests later in this section). The main advantage of FNA is that it does not require surgery. 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 can be useful for the diagnosis of some lymphomas, but it is less helpful for Waldenstrom macroglobulinemia because the diagnosis is usually made with a bone marrow biopsy.

Excisional or incisional biopsy: A surgeon cuts through the skin to remove an entire lymph node (excisional biopsy) or a small part of a large tumor (incisional biopsy). If the node is near the skin surface, this is a simple operation that can be done with local anesthesia (numbing medication). If the node is inside the chest or abdomen, general anesthesia is used (the patient is asleep). The excisional and incisional methods almost always provide enough tissue to diagnose the exact type of lymphoma. Lymph node biopsy is rarely used in people with Waldenstrom macroglobulinemia because the diagnosis is usually made with a bone marrow biopsy. It is very useful for other types of lymphoma.

Laboratory tests on biopsy specimens that diagnose and classify Waldenstrom macroglobulinemia and non-Hodgkin lymphoma

All biopsy specimens are examined under a microscope by a doctor with special training in recognizing cells from blood and lymphoid tissue diseases. The doctor, a pathologist, 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 due to 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, a microscope is used to examine the chromosomes inside cells. In some lymphomas, part of one chromosome is attached to part of a different chromosome, this is called a translocation. Normal human cells each contain 46 chromosomes (pieces of DNA that control the cells’ growth and metabolism). In WM it is more common for the lymphoma cells to be missing part of a chromosome (called a deletion).

Molecular genetic studies: These tests are not usually necessary to diagnose WM, but are sometimes needed to diagnose other types of non-Hodgkin lymphoma. Tests can be done in the laboratory 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 detect translocations and deletions that are too small to be seen when the chromosomes are examined under a microscope. In the future, as more is learned about lymphomas, this may become the most useful test for determining what kind of lymphoma is present. Usually genetic tests aren't needed to diagnose Waldenstrom macroglobulinemia, but they may be very useful for research.

Imaging studies used in Waldenstrom macroglobulinemia

Since this is a form of non-Hodgkin lymphoma, imaging tests may be used to look for enlarged lymph nodes, although these are not often very sizeable in people with Waldenstrom macroglobulinemia.

Chest x-ray

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

Computed tomography (CT)

The CT scan is an x-ray procedure that produces detailed cross-sectional images of your body. Instead of taking one picture, as does 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 just like other computerized devices, they are getting faster and your stay might be pleasantly short. You might feel a bit confined by the machine you lay within 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 (MRI)

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, medication 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 out. If you have problems with close spaces (claustrophobia), you should let your doctor know before the MRI scan.

Positron emission tomography (PET)

PET uses a form of sugar (glucose) that contains 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.