If a child's signs and symptoms suggest neuroblastoma might be present, additional blood and urine tests, examination of tissue samples, and imaging studies will probably be needed. These tests are important because many of the symptoms and signs of neuroblastoma can also be caused by other cancers or by noncancerous diseases.

Signs and Symptoms

The signs and symptoms of neuroblastoma depend on the location of the original tumor and the extent of spread to nearby or distant parts of the body.

The most common sign of a neuroblastoma is an unusual lump or mass. These are usually found in the child's abdomen, causing it to swell. The child may complain of abdominal fullness, discomfort, or pain, the direct result of a tumor being present. But the lump itself is usually not tender or sore to the touch. Masses can occur in other places such as the neck. Or the neuroblastoma can spread to the back of the eye, causing it to protrude (stick out slightly).

Neuroblastoma frequently spreads to bones. If metastasis to bones has occurred, a child who can talk may complain of pain in the bones. The pain may be so bad that the child limps, refuses to walk, or is unable to walk. If it spreads to the backbone, tumors may compress the spinal cord and cause weakness, numbness, or paralysis.

In about 1 case of 4, the child may develop a fever. Less common symptoms include:

• persistent diarrhea
• high blood pressure (causing irritability)
• rapid heartbeat
• reddening (flushing) of the skin
• sweating

These symptoms and signs result from hormones released by the neuroblastoma cells.

Another uncommon symptom is called the opsoclonus-myoclonus-ataxia syndrome or “dancing eyes, dancing feet.” In this situation, the child has an unsteady, trembling gait, myoclonus (brief, shock-like muscle spasms), and opsoclonus (irregular, rapid eye movements). They may also have difficulty speaking,. For unknown reasons, neuroblastoma tumors that produce this syndrome are less life-threatening than other forms of the disease.

Sometimes, swelling may affect parts of the body that do not contain any cancer cells, especially the legs and, in males, the scrotum. This happens when tumors in the abdomen or chest press against or invade and clog the blood and lymph vessels, preventing fluids from circulating back to the heart. In some cases the pressure from the growing tumor causes problems with the child's bladder or bowel. Pressure from the tumor on, or invasion into, the superior vena cava (the large vein in the chest that returns blood from the head and neck to the heart) can cause swelling in the face or throat. This, in turn, can make it hard for the child to breathe or swallow.

Neuroblastomas that compress certain nerves in the chest or neck can sometimes cause additional symptoms, such as drooping eyelids and small pupils. Pressure on other nerves near the spine can cause the child to lose the ability to move the arms or legs.

Blue or purple patches, resembling small bruises, may indicate spread to the skin. Sometimes there is bruising around the eyes.

If the bone marrow (the tissue that makes blood cells) is affected, the child may not have enough red blood cells, white blood cells, or blood platelets. These shortages of blood cells can result in weakness, frequent infections, and excessive bleeding from small cuts or scrapes.

Rarely, bleeding can be caused by loss of clotting factors in the blood, which is due to clotting and excessive breakdown of tissue inside a large tumor. This is known as a consumption coagulopathy and can be life threatening.

Finally, there is a special form of disseminated neuroblastoma that only occurs during the first few months of life. In this special form, also called 4S (s for special), the neuroblastoma has spread to the liver, to the skin, and to the bone marrow. The liver can enlarge significantly, and the skin lesions have been compared to blueberries (thus the name ‘blueberry syndrome’ that is given to this presentation of neuroblastoma). Despite this aggressive presentation, stage 4S neuroblastoma is very treatable, and almost all children can be cured, most of the times with minimal treatment.

Blood and Urine Tests

Normal nerve cells communicate with each other by releasing certain chemicals called neurotransmitters. The main neurotransmitters produced by the sympathetic nervous system are called catecholamines. Eventually the body breaks down the catecholamine molecules into metabolites (smaller pieces), which are then passed out of the body in the urine.

In about 90% of cases, neuroblastoma cells produce enough catecholamines to be detected by blood or urine tests. The 2 catecholamine metabolites most often measured are:

• homovanillic acid (HVA)
• vanillylmandelic acid (VMA)

Some of the symptoms associated with neuroblastoma, such as high blood pressure, rapid heartbeat, and diarrhea are directly due to the effects of increased catecholamines.

Your child’s doctor will probably also order other blood tests to check blood cell counts, liver and kidney function, and the salt balance in the body. A urinalysis may also be done to further check kidney function.

Imaging Tests

Because neuroblastoma patients are generally quite young, performing these tests can be hard. Much patience is needed from parents and medical staff.

X-rays: A standard chest x-ray is done if doctors suspect that the tumor has invaded the chest, as well as to rule out spread to the lungs or to lymph nodes (bean-shaped collections of immune system cells) in the chest. An x-ray of the head may also be done to be look for evidence of spread to the skull bones. Spread to other bones is usually checked with a radionuclide bone scan.

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

If the child is having a CT scan of the abdomen, before the pictures are taken, the child may be asked to drink 1 to 2 pints of a radiocontrast agent or dye. This helps outline the intestine so that it is not mistaken for tumors. The child may also receive an intravenous (IV) injection of a radiocontrast material. This helps better outline structures in the body. An IV line through which the contrast dye is injected will be needed.

The solution and the injection can cause some flushing. Some people are allergic to the dye and get hives or, rarely, have more serious reactions like trouble breathing and low blood pressure. Be sure to tell the doctor if your child has ever had a reaction to any contrast material used for x-rays. A second set of pictures is then taken.

CT scans take longer than regular x-rays. The child needs to lie still on a table while the part of the body to be examined is placed within the scanner, a doughnut-shaped machine that completely surrounds the table.

A special kind of CT, the spiral CT, uses a rapid scanner that diminishes organ movement from the patient taking breaths and can provide greater detail.

CT scans can also be used to precisely guide a biopsy needle into a tumor. For this procedure, called a CT-guided needle biopsy, the patient remains on the CT scanning table while a radiologist advances 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 sample (tiny fragment of tissue) or a core needle biopsy sample (a thin cylinder of tissue about 1/2-inch long and less than 1/8-inch in diameter) is removed and examined under a microscope. In children, this procedure is always done under general anesthesia.

Magnetic resonance imaging (MRI or MRI scan): 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 also produces slices that are parallel with the length of your body. A contrast material might be injected just as with CT scans but is used less often. MRI scans are more helpful in examining the brain and spinal cord.

Experts feel that MRI may be slightly better at evaluating the extent of neuroblastoma, but it is more difficult for the child. MRI scans are more uncomfortable than CT scans. First, they take longer – about an hour. Also, the child must lie inside a narrow tube, which is confining and can upset children with a fear of enclosed spaces. The machine also makes a thumping noise. Earplugs can be used, or some places provide headphones with music to block this noise out. Young children often require sedation to keep them still during the MRI scan. One advantage is that the child need not drink a contrast agent as in CT scans. Also, there is no radiation, which is not a problem for a single CT scan, but may be a problem when there are many CT scans.

Ultrasound: Ultrasound uses sound waves whose echoes produce a picture of internal organs or masses. A small microphone-like instrument called a transducer emits sound waves. These high-frequency sound waves are transmitted into the area of the body being studied and echoed back. The sound wave echoes are picked up by the transducer and converted by a computer into an image which is displayed on a computer screen.

Ultrasound is an easy procedure. It uses no radiation, which is why it is often used to look at developing fetuses. To have an ultrasound examination, the child simply lies on a table and a technician moves the transducer over the skin overlying the part of the body being examined. Usually, the skin is lubricated with oil first. Sometimes an ultrasound is used to find masses in the abdomen. It can also detect if kidneys have become swollen because the outflow of urine has been blocked by enlarged lymph nodes. It is particularly useful in checking to see if internal tumors are shrinking. It is easy to do and there is no radiation. The parent may even be able to hold the child.

Positron emission tomography (PET or PET scan): PET scans use glucose (a form of sugar) that contains a radioactive atom. A special camera detects the radioactivity. Cancer cells absorb high amounts of the radioactive sugar because of their high rate of metabolism. PET scans can be more helpful than several different x-rays because they scan the whole body. They are combined with CT scans to better pinpoint the image.

MIBG scans: This scan uses radioactive meta-iodobenzylguanidine (MIBG). MIBG attaches to neuroblastoma cells after it has been injected into the bloodstream. This allows doctors to find the neuroblastoma and spot whether it has spread to bone and other parts of the body. This test is preferred by many doctors and is considered a standard way to evaluate children with neuroblastoma. It can be repeated after treatment to see if the treatment has been effective. Furthermore, it is good to know if the tumor uptakes the MIBG because in some cases, this radioactive molecule can be used (at higher doses) to treat the neuroblastoma.

Bone scan: In this test, a radioactive tracer called technetium99 is used. After it is injected, it travels to areas of the bone that are damaged. Neuroblastoma in bone often causes bone damage, which a bone scan will find. But a bone scan may also pick up non-cancerous problems such as arthritis and fractures. Although this used to be a standard test, it has been largely replaced by the MIBG scan.

Biopsies

Although signs and symptoms, blood and urine tests, and imaging studies may indicate that a neuroblastoma is probably present, a conclusive diagnosis can be made only when neuroblastoma cells in tissue samples are seen under a microscope.

In most cancers, including those of children, doctors take a sample of the primary tumor mass. This may be done by simply placing a needle into the tumor (usually under anesthesia for children) and removing a sample. Otherwise a small incision may need to be made to remove a piece of the tumor.

Some cases of neuroblastoma are easily recognized under a microscope when examined by doctors experienced in testing children's tumor samples. Other cases of neuroblastoma, however, have features easily confused with other types of children's cancers. In these situations, special tests such as immunohistochemistry of the tissue samples must be done. In this test, a part of the biopsy sample is treated with special laboratory antibodies. Certain antibodies are attracted to neuroblastoma cells and can help distinguish neuroblastoma from other types of cancer.

If the disease has spread to the marrow (in about half of patients) and blood or urine levels of catecholamines or their metabolites are increased, then finding cancer cells in a bone marrow sample is sufficient evidence for a diagnosis of neuroblastoma. Bone marrow can be sampled in 2 ways, and both are generally done at the same time.

Bone marrow aspiration and biopsy: Bone marrow aspiration removes small bits of bone marrow tissue and fluid. Usually the sample is taken from the back of the pelvic bone. Usually this is done on both sides of the pelvis. The bone is numbed with a local anesthetic. In some cases, the child is also given medicine to reduce pain or to put her or him to sleep during the procedure. The needle is then put through the outer bone into the marrow space, where some marrow is removed.

A biopsy follows, during which a small cylindrical piece of bone and bone marrow (about 1/16-inch in diameter and 1/2-inch long) is removed. Both samples generally are taken at the same time. These tests can be used for the initial diagnosis and for staging (to see how far the cancer has spread).

Revised: 08/04/2006