How is non-Hodgkin lymphoma diagnosed in children?

Certain signs and symptoms might suggest that a child may have non-Hodgkin lymphoma, but tests are needed to confirm the diagnosis. The exams and tests below are used to diagnose the disease, to help determine what type of lymphoma it is, and to measure how advanced it may be.

Signs and symptoms

Childhood non-Hodgkin lymphoma may cause many different signs and symptoms, depending on where it starts. In some cases it may not cause any symptoms until it grows quite large.

Lymph nodes near the skin

Non-Hodgkin lymphoma may grow in lymph nodes close to the surface of the body (on the sides of the neck, in the underarm area, above the collar bone, or in the groin area). This causes the nodes to enlarge, and they are often seen or felt as lumps under the skin. These are often noticed by the child, parent, or a health care professional. Enlarged lymph nodes are more often caused by infections than by non-Hodgkin lymphoma.

Abdomen

If the lymphoma grows inside the abdomen, it can cause it to become swollen and painful. There may also be a buildup of fluid that causes even more swelling. Lymphoma can sometimes cause the spleen to become enlarged and press on the stomach. This can cause a child to feel full after eating only a small amount of food.

When lymphoma causes swelling near the intestines, the passage of stool may be blocked, which may lead to abdominal pain. The pressure or blockage can also cause nausea or vomiting.

The lymphoma may also block urine from leaving the kidney. This can lead to kidney problems, which may cause low urine output, tiredness, loss of appetite, nausea, or swelling in the hands or feet.

Chest

When the lymphoma starts in the thymus or lymph nodes in the chest, it may press on the nearby trachea (windpipe). This can lead to coughing, shortness of breath, and trouble breathing.

The superior vena cava (SVC) is a large vein that carries blood from the head and arms back to the heart. It passes next to the thymus and lymph nodes inside the chest. Lymphomas in this area may push on the SVC, which can cause the blood to back up in the veins. This is can lead to swelling in the face, neck, arms, and upper chest (sometimes with a bluish-red skin color). It can also cause trouble breathing, as well as headaches, dizziness, and a change in consciousness if it affects the brain. This condition, known as SVC syndrome, can be life-threatening, and needs to be treated right away.

Brain and spinal cord

Some types of lymphoma can spread to the area around the brain and spinal cord. This can cause problems such as headache, vision changes, facial numbness, and trouble speaking.

Skin

Some lymphomas may affect the skin itself. They can cause itchy, red or purple lumps or nodules under the skin.

Bone marrow

Lymphomas sometimes spread to the bone marrow, the soft inner part of certain bones where new blood cells are made. If the lymphoma cells crowd out the normal blood-making cells, it can lead to shortages of some types of blood cells. This can lead to symptoms, such as easy bruising or bleeding (from lack of blood platelets), frequent infections (from a lack of white blood cells), or fatigue and pale skin (from a lack of red blood cells).

General symptoms

Along with causing symptoms and signs in the part of the body where it starts, non-Hodgkin lymphoma can also cause general symptoms such as:

• Fever and chills
• Sweating (particularly at night)
• Unexplained weight loss

When talking about lymphoma, doctors sometimes call these B symptoms. The presence of B symptoms is often found in more rapidly growing lymphomas.

Medical history and physical exam

If any signs and symptoms suggest the possibility of lymphoma, the doctor will want to get a thorough medical history, including how long symptoms have been present. The doctor may also ask about whether there is any history of possible risk factors, such as immune system problems.

During the physical exam, the doctor will probably focus on any enlarged lymph nodes or other areas of concern. For example, the abdomen may be felt for signs of an enlarged spleen or liver. Because infections are the most common cause of enlarged lymph nodes, the doctor will look for an infection in the part of the body near any swollen lymph nodes.

The diagnosis of lymphoma in a child can be difficult and may be delayed because enlarged lymph nodes in children are much more commonly caused by infections. There is usually little cause for concern in children with swollen lymph nodes unless they are very enlarged (greater than 1 inch across).

Even in these instances, the child is usually given a course of antibiotics first to see if the nodes will shrink. If not, further testing is done, usually by removing a small piece of a lymph node, or possibly the whole node, in a biopsy (see next section). But if the lymph nodes seem to be growing quickly or the child’s health seems to be getting worse, a biopsy may be needed right away.

Biopsy

Many of the symptoms of non-Hodgkin lymphoma are not specific enough to say for certain if a child has lymphoma. Most of these symptoms are more often caused by non-cancerous problems, like infections. They may also be caused by other kinds of cancers. The main types of childhood non-Hodgkin lymphoma can all cause many of the same symptoms, but they require slightly different treatments, so it is important to tell them apart.

For these reasons, an accurate diagnosis is needed, and the only way to do this is to remove some or all of an abnormal lymph node for viewing under a microscope and other lab tests. This is called a biopsy.

Types of biopsies used to diagnose non-Hodgkin lymphoma

There are several types of biopsies. Doctors choose which one to use based on the aspects of each situation. The goal is to obtain a sample large enough to make an accurate diagnosis as quickly as possible, with as few side effects as possible.

Fine needle aspiration (FNA) or core needle biopsy: In an FNA biopsy, the doctor uses a very thin, hollow needle attached to a syringe to withdraw (aspirate) a small amount of tissue from an enlarged lymph node or a tumor mass. For a core needle biopsy, the doctor uses a larger needle to remove a slightly larger piece of tissue.

For an enlarged node near the surface of the body, the doctor can aim the needle while feeling the node. If the enlarged area is deep inside the body (such as in the thymus or nodes of the abdomen), the doctor can guide the needle while viewing it on a CT scan or ultrasound (see discussion of imaging tests later in this section).

The main advantage of a needle biopsy is that it does not require surgery. In adults, these types of biopsies can often be done using just local anesthesia to numb the area. In children, they may require sedation, or even general anesthesia (where the child is in a deep sleep).

The main drawback of needle biopsies is that in some cases the needle may not remove enough of a sample to make a definite diagnosis. Most doctors do not use needle biopsies if they strongly suspect lymphoma. But if the doctor suspects that lymph node swelling is caused by an infection (even after antibiotics), a needle biopsy may be the first type of biopsy done. An excisional biopsy (see below) may still be needed to diagnose and classify lymphoma, even after a needle biopsy has been done.

Once lymphoma has been diagnosed, needle biopsies are sometimes used to check areas in other parts of the body that might be lymphoma spreading or coming back after treatment.

Excisional or incisional biopsy: These are the most common types of biopsy if lymphoma is suspected. In these procedures, a surgeon cuts through the skin to remove either the entire 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 may be done with either local anesthesia (numbing medicine used only at the biopsy site) and sedation or general anesthesia (where the child is in a deep sleep). If the node is inside the chest or abdomen, then general anesthesia is used.

This method almost always provides enough of a sample to make a diagnosis of the exact type of non-Hodgkin lymphoma.

Other types of biopsies

These types of biopsies are not normally done to diagnose lymphoma, but they may be done to help determine the extent of spread if a lymphoma has already been diagnosed.

Bone marrow aspiration and biopsy: These tests help determine if a lymphoma has reached the bone marrow. The 2 tests are usually done at the same time. The biopsy samples are usually taken from the back of the pelvic (hip) bones, although in some cases they may be taken from the front of the hip bones or from other bones.

For a bone marrow aspiration, the skin over the hip and the surface of the bone is numbed with local anesthetic to make the procedure less uncomfortable. In most cases, children will be given other medicines to make them drowsy or brief general anesthesia so they are asleep during the biopsy. 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.

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 put into the bone. Once the biopsy is done, pressure will be applied to the site to help stop any bleeding.

Lumbar puncture (spinal tap): This test is used to look for lymphoma cells in the cerebrospinal fluid (CSF), which is the liquid that bathes the brain and spinal cord.

For this test, the doctor first numbs an area in the lower part of the back near the spine. The doctor usually also gives the child medicine to make him or her sleep during the procedure. A small, hollow needle is then placed between the bones of the spine to withdraw some of the fluid.

In children already diagnosed with lymphoma, a lumbar puncture can also be used to give chemotherapy drugs into the CSF to try to prevent or treat the spread of lymphoma to the spinal cord and brain.

Pleural or peritoneal fluid sampling: Spread of lymphoma to the thin membranes that line the inside of the chest and abdomen can cause fluid to build up. Pleural fluid (inside the chest) or peritoneal fluid (inside the abdomen) can be removed by placing a hollow needle through the skin into the chest or abdomen.

Before the procedure, the doctor uses a local anesthetic to numb the skin and may give the child other medicines so they are drowsy or asleep during the procedure. The fluid is then withdrawn and looked at under the microscope to check for lymphoma cells.

When this procedure is used to remove fluid from the chest, it is called a thoracentesis. When it is used to collect fluid from inside the abdomen, it is known as a paracentesis.

Lab tests on biopsy samples to diagnose and classify lymphoma

All biopsy samples and fluids are looked at under a microscope by a pathologist (a doctor with special training in identifying cancer cells). The doctor looks at the size and shape of the cells and how they are arranged. This may reveal not only if a child has lymphoma, but also what type of lymphoma it is. Because diagnosing lymphoma can be tricky, it helps if the pathologist specializes in diseases of the blood.

Pathologists can sometimes tell which kind of lymphoma a child has by looking at the cells, but usually other types of lab tests need to be done on the samples to confirm the diagnosis.

Immunohistochemistry

In this test, a part of the biopsy sample is treated with special antibodies (man-made versions of immune system proteins) that attach only to specific molecules on the cell surface. These antibodies cause color changes, which can be seen under a microscope. This test may be helpful in distinguishing different types of non-Hodgkin lymphoma from one another and from other diseases.

Flow cytometry

Like immunohistochemistry, this test looks for certain substances on the outside surface of cells that help identify what types of cells they are. But this test can look at many more cells than immunohistochemistry can.

For this test, a sample of cells is treated with special antibodies that stick to the cells only if these substances are present on their surfaces. The cells are then passed in front of a laser beam. If the cells now have antibodies attached to them, the laser will cause them to give off light, which can be measured and analyzed by a computer. Groups of cells can be separated and counted by these methods.

This is the most commonly used 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.

Flow cytometry can help determine whether lymph node swelling is due to lymphoma, some other cancer, or a non-cancerous disease. It has also become very useful in helping doctors determine the exact type of lymphoma so that they can select the best treatment.

Cytogenetics

This technique allows doctors to evaluate the chromosomes (long strands of DNA) in the lymphoma cells. They look at the cells under a microscope to see if the chromosomes have any translocations (where part of one chromosome has broken off and is now attached to another chromosome), as happens in certain types of lymphoma. Some lymphoma cells may also have too many chromosomes, too few chromosomes, or other chromosome abnormalities. These changes can be used to help identify the type of lymphoma.

Cytogenetic testing usually takes about 2 to 3 weeks because the lymphoma cells must grow in lab dishes for a couple of weeks before their chromosomes are ready to be viewed under the microscope.

Molecular genetic tests

These tests look more closely at lymphoma cell DNA. They can detect most changes that are visible under a microscope in cytogenetic tests, as well as others that can’t be seen.

Fluorescent in situ hybridization (FISH): FISH is similar to cytogenetic testing. It uses special fluorescent dyes that only attach to specific parts of chromosomes. It can find most chromosome changes (such as translocations) that can be seen under a microscope in standard cytogenetic tests, as well as some changes too small to be seen with usual cytogenetic testing.

FISH can be used to look for specific changes in chromosomes. It can be used on regular blood or bone marrow samples. It is very accurate and can usually provide results within a couple of days, which is why this test is now used in many medical centers.

Polymerase chain reaction (PCR): This is a very sensitive DNA test that can also find some chromosome changes too small to be seen under a microscope, even if there are very few lymphoma cells in a sample.

These tests can also detect certain genes that have been “turned on” and are contributing to the lymphoma cells’ abnormal growth. As researchers learn more about lymphomas, these may become even more important.

Blood tests

Blood tests measure the amounts of certain types of cells and chemicals in the blood. They are not used to diagnose lymphoma, but they can sometimes help determine how advanced the lymphoma is.

The complete blood count (CBC) is a test that measures the levels of different cells in the blood, such as the red blood cells, the white blood cells, and the platelets. The CBC is often done with a differential (or “diff”), which counts the number of different types of white blood cells. In children already known to have lymphoma, low blood cell counts might mean that the lymphoma is growing in the bone marrow and damaging new blood cell production.

Blood levels of a chemical called LDH will often be abnormally high in patients with fast-growing lymphomas.

Blood chemistry tests can help detect liver or kidney problems caused by the spread of lymphoma cells or certain chemotherapy drugs. Blood tests can also help determine if treatment is needed to correct low or high blood levels of certain minerals. Tests may also be done to make sure the blood is clotting properly.

For some types of lymphoma, the doctor may also want to order other blood tests to see if the child has been infected with certain viruses, such as the Epstein-Barr virus (EBV), hepatitis B virus (HBV), or human immunodeficiency virus (HIV). Infections with some of these viruses may affect your child’s treatment.

Imaging tests to diagnose and stage non-Hodgkin lymphoma

Imaging tests use x-rays, sound waves, magnetic fields, or radioactive substances to create pictures of the inside of the body. Imaging tests may be done for a number of reasons, including to help find a suspicious area that might be cancerous, to learn how far a cancer may have spread, or to help determine if treatment has been effective. Children with non-Hodgkin lymphoma usually get some (but not all) of the following imaging tests.

Chest x-ray

A chest x-ray may be done to look for enlarged lymph nodes inside the chest.

Computed tomography (CT or CAT) scan

The CT scan is an x-ray test that produces detailed, cross-sectional images of the body. Unlike a regular x-ray, CT scans can show the detail in soft tissues (such as internal organs). They can help tell if any lymph nodes or organs in the body are enlarged. CT scans can be used to look for enlarged lymph nodes or other masses in the chest, abdomen, pelvis, head, and neck.

Instead of taking one picture, like a standard x-ray does, a CT scanner takes many pictures as it rotates around the child. A computer then combines these pictures into images of slices of the part of the body being studied.

Before the scan, your child may be asked to drink a contrast solution and/or get an intravenous (IV) injection of a contrast dye that helps better outline abnormal areas in the body. Your child may need an IV line through which the contrast dye will be injected. The injection can cause some flushing (redness and warm feeling). Some people are allergic and get hives or, rarely, more serious reactions like trouble breathing and low blood pressure. Be sure to tell the doctor if your child has any allergies or has ever had a reaction to any contrast material used for x-rays.

Your child will need to lie still on a table while the scan is being done. Some younger children may be given medicine to help keep them calm or even asleep during the test. For the exam itself, the table slides in and out of the scanner, a ring-shaped machine that completely surrounds the table. Many medical centers now use spiral CT (also known as helical CT), which completes the scan more quickly (using less radiation) and also creates more detailed pictures.

CT scans can also be used to guide a biopsy needle precisely into a suspected tumor or enlarged lymph node. For this procedure, called a CT-guided needle biopsy, the child remains asleep on the CT scanning table, while a radiologist advances a biopsy needle through the skin and toward 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.

Ultrasound (sonogram)

Ultrasound uses sound waves and their echoes to produce a picture of internal organs or masses. For this test, a small, microphone-like instrument called a transducer is placed on the skin (which is first lubricated with gel). The transducer 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 on a computer screen.

This is usually an easy test to have, and it uses no radiation. Your child simply lies on a table, and a technician moves the transducer over the part of the body being looked at.

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 and spleen. (It can’t be used to look at organs or lymph nodes in the chest because the ribs block the sound waves.) It is sometimes used to help guide a biopsy needle into an enlarged lymph node. It can also be used to detect if kidneys have become swollen because the outflow of urine has been blocked by enlarged lymph nodes.

Magnetic resonance imaging (MRI) scan

Like CT scans, MRI scans provide detailed images of soft tissues in the body. But 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 body tissue and by certain diseases. A computer translates the pattern into very detailed images of parts of the body.

A contrast material called gadolinium is often injected into a vein before the scan to better see details. The contrast material usually does not cause allergic reactions.

This test is not used as often as CT scans for lymphoma, but MRI is very useful for looking at the brain and spinal cord if a child has symptoms that might be caused by problems in the nervous system.

MRI scans take longer than CT scans, often up to an hour. Your child may have to lie inside a narrow tube, which is confining and can be distressing, so sedation is sometimes needed. Newer, more open MRI machines may be another option. The MRI machine makes loud buzzing and clicking noises that your child may find disturbing. Some places provide headphones or earplugs to help block this noise out.

Nuclear medicine tests

For these tests, a slightly radioactive solution is injected into the blood. It travels throughout the body and, depending on the substance used, collects in a specific area. A special type of camera is then used to get a picture of the active areas. These tests can often give information about how active tumors are, as opposed to just creating a picture of their structure.

Positron emission tomography (PET) scan: 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 are growing rapidly, they absorb large amounts of the sugar. After about an hour, your child will be moved onto a table in the PET scanner. He or she will 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 provides helpful information about the 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.

PET scans can be used to tell if a lymphoma is responding to treatment. Some doctors will repeat the PET scan after 1 or 2 courses of chemotherapy. If the chemotherapy is working, the lymph nodes will no longer take up as much of the radioactive sugar. PET scans can also be used after treatment in helping decide whether an enlarged lymph node still contains lymphoma or is merely scar tissue.

Some newer machines are able to do both a PET and CT scan at the same time (PET/CT scan). This lets the doctor compare areas of higher radioactivity on the PET scan with the more detailed appearance of that area on the CT.

Gallium scan: For this test, a solution containing slightly radioactive gallium is injected into a vein. It is attracted to lymph tissue in the body. A few days later, a special camera is used to detect the radioactivity, showing the location of the gallium. These tests can find lymphoma tumors in bones and other organs.

This test is not used as much now as in the past, as many doctors may do a PET scan instead. It can still sometimes be useful in finding areas of lymphoma that the PET scan may miss. It can also help distinguish an infection from lymphoma when the diagnosis is uncertain.

Bone scan: For bone scans, a different radioactive substance (technetium) is used. After it is injected into a vein, it travels to damaged areas of the bone. Lymphoma in bone often causes damage, which a bone scan will detect. But a bone scan may also pick up non-cancerous problems, such as arthritis and fractures.

This test is not usually done unless a child is having bone pain or has lab test results that suggest the lymphoma may have reached the bones.