1. Biopsies
The symptoms of waldenstrom macroglobulinemia (WM) and non-Hodgkin lymphoma (NHL) are not distinctive enough for a doctor to know for certain if person has one of them, based on symptoms alone. Most symptoms can also be caused by non-cancerous problems like infections or by other kinds of cancers. Blood tests can help point to the correct diagnosis, but a biopsy (removing samples of affected tissue to look at under a microscope) is the only way to be sure. There are several types of biopsies.
Bone Marrow Aspiration and Biopsy. This is the most important type of biopsy for waldenstrom macroglobulinemia (WM), and is needed to confirm the diagnosis. It can be done at the doctor’s office or at the hospital. The bone marrow aspiration and biopsy are usually done at the same time. The samples are taken from the back of the pelvic (hip) bone, although in some cases they may be taken from the sternum (breast bone) or other bones.
In bone marrow aspiration, you lie on a table (either on your side or on your belly). After cleaning the skin over the hip, the doctor numbs the area and the surface of the bone by injecting a local anesthetic, which may cause a brief stinging or burning sensation. A thin, hollow needle is then inserted into the bone and a syringe is used to suck out a small amount of liquid bone marrow. Even with the anesthetic, most patients still have some brief pain when the marrow is removed.
A bone marrow biopsy is usually done just after the aspiration. A small piece of bone and marrow is removed with a slightly larger needle that is twisted as it is pushed down into the bone. The biopsy may also cause some brief pain. Once the biopsy is done, pressure will be applied to the site to help stop any bleeding. There will be some soreness in the biopsy area when the numbing medicine wears off. Most patients can go home right after the procedure.
The bone marrow samples are then sent to a lab, where a doctor called a pathologist will look at them under the microscope and do other tests (discussed below) to see if they contain lymphoma cells. To diagnose waldenstrom macroglobulinemia, at least 10% of the cells in the bone marrow must be lymphoplasmacytoid lymphoma cells.
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). These biopsies are rarely needed in people with waldenstrom macroglobulinemia because the diagnosis is usually made with a bone marrow biopsy. They are used more often for other types of lymphoma. If the area to be biopsied is near the skin surface, this can be done using local anesthesia (numbing medicine). If the area is inside the chest or abdomen, general anesthesia or deep sedation is used (where the patient is asleep). These types of biopsies almost always provide enough tissue to diagnose the exact type of lymphoma.
Fat Pad Fine Needle Aspiration. This type of biopsy may be used in some people with waldenstrom macroglobulinemia to check for amyloid. In this procedure, a needle with a syringe attached is inserted into an area of fat (usually under the skin of the abdomen/belly). A small amount of fat is removed and sent to the lab for testing.
Fine Needle Aspiration (FNA) Biopsy. An FNA biopsy uses a very thin, hollow needle with a syringe to withdraw a small amount of tissue from a tumor or lymph node. This type of biopsy is useful for sampling lymph nodes to see if they are enlarged because of cancer or another cause such as infection. FNA can help diagnose some lymphomas, but waldenstrom macroglobulinemia is usually diagnosed with a bone marrow biopsy instead.For an FNA on an enlarged node near the surface of the body, the doctor can aim the needle while feeling the node. If the enlarged node (or tumor) is deep inside the body, the needle can be guided while it is viewed by a computed tomography ( CT) scan or ultrasound (see the descriptions of imaging tests later in this section).
The main advantage of FNA is that it does not require surgery and can often be done in a doctor’s office. The main drawback is that in some cases it might not get enough tissue to make a definite diagnosis of lymphoma. However, advances in lab tests (discussed later in this section) and the growing experience of many doctors with FNA have improved the accuracy of this procedure.
2. Imaging tests
Imaging tests use x-rays, magnetic fields, sound waves, or radioactive particles to produce pictures of the inside of the body. These tests are not needed to diagnose waldenstrom macroglobulinemia, but one or more of them might be done to help determine the extent of the disease (such as looking for an enlarged spleen or lymph nodes).
Computed Tomography (CT). The CT scan is an x-ray test that produces detailed cross-sectional images of your body. Unlike a regular x-ray, CT scans can show the detail in soft tissues (such as internal organs). This scan can help tell if any lymph nodes or organs in your body are enlarged. CT scans are useful for looking for signs of lymphoma in the chest, abdomen, and pelvis.
Before the test, you may be asked to drink a contrast solution and/or get an intravenous (IV) injection of a contrast dye to better outline abnormal areas in the body. You might need an IV line through which the contrast dye is injected. The injection can cause some flushing (a feeling of warmth, especially in the face). Some people are allergic to the dye and get hives or a flushed feeling or, rarely, have more serious reactions like trouble breathing and low blood pressure. Be sure to tell the doctor if you have any allergies or have ever had a reaction to any contrast material used for x-rays. Medication can be given to help prevent and treat allergic reactions.
A CT scanner has been described as a large donut, with a narrow table in the middle opening. You will need to lie still on the table while the scan is being done. CT scans take longer than regular x-rays, and you might feel a bit confined by the ring while the pictures are being taken. Instead of taking one picture like an x-ray, a CT scanner takes many pictures as it rotates around your body. A computer combines these pictures into detailed images of the part of the body that is being studied.
In some cases, a CT can be used to guide a biopsy needle precisely into a suspicious area. For this procedure, called a CT-guided needle biopsy, you remain on the CT scanning table while a radiologist moves a biopsy needle through the skin and toward the location of the mass. CT scans are repeated until the needle is within the mass. A biopsy sample is then removed and looked at under a microscope.
Magnetic Resonance Imaging (MRI). This test is rarely used in waldenstrom macroglobulinemia, but if your doctor is concerned about the brain or spinal cord, MRI is very useful for looking at these areas. 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.
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 take longer than CT scans – often up to an hour. You may have to lie inside a tube, which is confining and can upset people with a fear of enclosed spaces. Newer, more open MRI machines might be another option. The machine makes loud buzzing and clicking noises that some people find disturbing. Some places provide headphones with music to block this noise out.
Positron Emission Tomography (PET). For a PET scan, a form of radioactive sugar (known as fluorodeoxyglucose or FDG) is injected into the blood. Because cancer cells in the body grow rapidly, they absorb large amounts of the radioactive sugar. After about an hour, you will be moved onto a table in the PET scanner. You lie on the table for about 30 minutes while a special camera creates a picture of areas of radioactivity in the body. The picture is not finely detailed like a CT or MRI scan, but it can provide helpful information about your whole body.
PET scans can help tell if an enlarged lymph node contains lymphoma or is benign. It can also help spot small areas that might be lymphoma, even if the area looks normal on a CT scan. These tests can be used to tell if a lymphoma is responding to treatment. They can also be used after treatment to help decide whether an enlarged lymph node still contains lymphoma or is merely scar tissue. Many medical centers now use a machine that combines the PET scan with a CT scan (PET/CT scan). This lets the doctor compare areas of higher radioactivity on the PET scan with the detailed appearance of that area on the CT.
Ultrasound. Ultrasound uses sound waves and their echoes to produce a picture of internal organs or masses. Ultrasound can be used to look at lymph nodes near the surface of the body or to look inside your abdomen for enlarged lymph nodes or organs such as the liver, spleen, and kidneys. (It can’t be used to look at organs or lymph nodes in the chest because the ribs block the sound waves.)
For this test, a small, microphone-like instrument called a transducer is placed on the skin (which is first lubricated with a gel). It gives off sound waves and picks up the echoes as they bounce off the organs. The echoes are converted by a computer into a black and white image that is displayed on a computer screen. This is an easy test to have done, and it uses no radiation. For most ultrasounds, you simply lie on a table, and a technician moves the transducer over the part of your body being looked at.
Chest X-ray. Plain x-rays of the chest might be done to look for enlarged lymph nodes in the chest.
3. Lab Tests
The diagnosis of waldenstrom macroglobulinemia may be suspected if your doctor finds you have low blood cell counts or unusual protein levels on blood tests. If so, your doctor may order a blood test called serum protein electrophoresis to determine what the abnormal proteins are. It is usually only after these tests are done that a biopsy of either the bone marrow or a lymph node is considered.
Beta-2 Microglobulin. This test measures another protein made by the cancer cells in waldenstrom macroglobulinemia. This protein itself doesn’t cause any problems, but it is a useful indicator of a patient’s prognosis (outlook). High levels are linked with a worse outlook.
Blood Cell 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.
Cold Agglutinins. Cold agglutinins are antibodies that attack and kill red blood cells, especially at cooler temperatures. These dead cells can then build up and block blood vessels. A blood test can be used to detect these antibodies.
Cryocrit. This test measures the amount of cryoglobulin (a protein that clumps together and blocks blood vessels in cool temperatures) in the blood.
Electrophoresis. The immunoglobulin produced in waldenstrom macroglobulinemia is an abnormal IgM antibody. This antibody is monoclonal, meaning that it is many copies of the exact same antibody. Serum protein electrophoresis (SPEP) is a test that measures the total amount of immunoglobulins in the blood and finds any monoclonal immunoglobulin. Another test, such as immunofixation or immunoelectrophoresis, is then used to determine the type of antibody that is abnormal (IgM or some other type). Finding a monoclonal IgM antibody in the blood is needed to diagnose waldenstrom macroglobulinemia. The abnormal protein in waldenstrom macroglobulinemia is known by several different names, including monoclonal immunoglobulin M, IgM protein, IgM spike, IgM paraprotein, M protein, and M-spike. Other types of monoclonal immunoglobulins, like IgA or IgG, are seen in different disorders (like multiple myeloma and some lymphomas).
Quantitative Immunoglobulins. This test measures the levels of the different antibodies (immunoglobulins) in the blood – IgA, IgE, IgG, and IgM – to see if any are abnormally high or low. In awldenstrom macroglobulinemia the level of IgM is high but the IgG level is often low.
Viscosity. Viscosity is a measure of 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).
4. Lab Tests on Biopsy Specimens
All biopsy specimens are looked at under a microscope by a pathologist – a doctor with special training in using lab tests to diagnose diseases. In some cases, a hematopathologist, a doctor with additional training in diagnosis blood and lymph node diseases, might also look at the biopsy. The doctors look 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 lab tests are needed.
Cytogenetics. This technique allows doctors to evaluate the chromosomes (long strands of DNA) in the lymphoma cells. 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 looked at under a microscope. Because it takes time for the cells to start dividing, this test can take weeks.
Normal human cells each contain 46 chromosomes. In some lymphomas, the cells may have too many chromosomes, too few chromosomes, missing parts of chromosomes (called a deletion), or other abnormalities. These changes can help identify the type of lymphoma. In waldenstrom macroglobulinemia, deletions are the most common type of chromosome change.
Flow Cytometry. In this test, cells are treated with special man-made antibodies and passed in front of a laser beam. Each antibody sticks only to certain types of cells. If the cells now have antibodies attached to them, the laser will cause them to give off light, which is measured and analyzed by a computer.
This is the most common test for immunophenotyping – classifying lymphoma cells according to the substances (antigens) on their surfaces. Different types of lymphocytes have different antigens on their surface. These antigens may also change as each cell matures. This test can help determine whether lymph node swelling is because of lymphoma, some other cancer, or a non-cancerous disease. It has become very important in helping doctors determine the exact type of lymphoma so they can select the best treatment.
Immunohistochemistry. In this test, a part of the biopsy sample is treated with special man-made antibodies that attach only to specific molecules on the surface of the cells. These antibodies cause color changes, which can be seen under a microscope. This test may help distinguish different types of lymphoma from one another and from other diseases.
Molecular Genetic Tests. Molecular tests such as fluorescent in situ hybridization (FISH) and polymerase chain reaction (PCR) are not usually needed to diagnose waldenstrom macroglobulinemia, but they are sometimes used to diagnose other types of non-Hodgkin lymphoma (NHL). These tests look at the cells’ DNA without having to grow the cells in the lab first. The tests can give results in less time than cytogenetics and can be done on cells from different sources (like lymph nodes, blood, and bone marrow). They are generally used to look for specific chromosome or gene changes, not just any change.
5. Medical History and Physical Exam
If you have signs or symptoms that suggest you might have waldenstrom macroglobulinemia, your doctor will want to get a thorough medical history, including information about your symptoms, possible risk factors, family history, and other medical conditions. Next, the doctor will do a physical exam, paying special attention to the lymph nodes and other areas of the body that might be involved, including the eyes, nerves, spleen, and liver. The doctor might also look for signs of infection, which can cause many of the same symptoms. If the doctor suspects that waldenstrom macroglobulinemia (or another type of lymphoma) might be causing your symptoms, he or she will likely order blood tests as the next step.