How is neuroblastoma diagnosed?

Neuroblastomas are usually found as a result of signs or symptoms that a child is having. If a tumor is suspected, tests will be needed to confirm the diagnosis.

Signs and symptoms

The signs and symptoms of neuroblastoma can vary widely, depending on the size and location of the tumor, the extent of spread to other parts of the body, and whether or not the tumor cells secrete hormones.

Many of the signs and symptoms below are more likely to be caused by something other than neuroblastoma. Still, if your child has any of these symptoms, check with your doctor so that the cause can be found and treated, if needed.

Signs or symptoms caused by the main tumor

One of the most common signs of a neuroblastoma is an unusual lump or mass. These are usually in the child’s abdomen, causing it to swell. The child may not want to eat (which can lead to weight loss). If the child is old enough, he or she may complain of feeling full or having belly pain. But the lump itself is usually not painful to the touch. Lumps can also occur in other places such as the neck.

Sometimes, swelling from a tumor in the abdomen may affect parts of the body that do not contain cancer, especially the legs and, in boys, the scrotum. This happens when a tumor presses against or invades and clogs the blood and lymph vessels, preventing fluids from getting back to the heart.

In some cases the pressure from a growing tumor can affect the child’s bladder or bowel, which can cause problems with urination, diarrhea, or constipation.

If the tumor is in the chest, it may press on the superior vena cava (the large vein in the chest that returns blood from the head and neck to the heart). This can cause swelling in the face, neck, arms, and upper chest (sometimes with a bluish-red skin color). It can also cause headaches, dizziness, and a change in consciousness if it affects the brain. The tumor may also press on the throat or windpipe, which may cause coughing and trouble breathing or swallowing.

Neuroblastomas that press on certain nerves in the chest or neck can sometimes cause other symptoms, such as a drooping eyelid and small pupil (the black area in the center of the eye). Pressure on other nerves near the spine may affect the child's ability to feel or move the arms or legs.

Signs or symptoms caused by the spread of the tumor

About 2 out of 3 cases of neuroblastoma have spread to the lymph nodes or other parts of the body by the time they are found.

Lymph nodes are bean-sized collections of immune cells found throughout the body. Cancer that has spread to the lymph nodes may cause them to swell. These nodes can sometimes be felt as lumps under the skin, especially in the neck, above the collarbone, under the arm, or in the groin. Enlarged lymph nodes in children are much more likely to be a sign of infection than cancer, but they should be checked by a doctor.

Neuroblastoma frequently spreads to bones. A child who can talk may complain of pain in the bones. The pain may be so bad that the child limps or refuses to walk. If it spreads to the backbone, tumors may press on the spinal cord and cause weakness, numbness, or paralysis in the arms or legs. Spread to the bones around the eyes is common and can lead to bruising around the eyes or cause an eyeball to stick out slightly. The cancer can also spread to other bones in the skull, causing bumps under the scalp.

If the cancer spreads to the bone marrow (the inner part of certain bones that makes blood cells), the child may not have enough red blood cells, white blood cells, or blood platelets. These shortages of blood cells can result in tiredness, irritability, weakness, frequent infections, and excess bruising or bleeding from small cuts or scrapes.

Rarely, large tumors can start to break down, leading to a loss of clotting factors in the blood. This can result in a high risk of serious bleeding, which is known as a consumption coagulopathy and can be life threatening.

A special widespread form of neuroblastoma (known as stage 4S) occurs only during the first few months of life. In this special form, the neuroblastoma has spread to the liver, to the skin, and/or to the bone marrow (in small amounts). Blue or purple bumps that look like small blueberries may be a sign of spread to the skin. The liver can become very large and can be felt as a mass on the right side of the belly. Despite the fact that the cancer is already widespread when it is found, stage 4S neuroblastoma is very treatable, and often shrinks or goes away on its own. Almost all children with this form of neuroblastoma can be cured.

Signs or symptoms caused by hormones from the tumor

Neuroblastoma is one of the few cancers in children that release hormones that can cause problems with distant tissues and organs, even though the cancer has not spread to those tissues or organs. These problems are called paraneoplastic syndromes.

Symptoms of paraneoplastic syndromes can include:

• Constant diarrhea
• Fever
• High blood pressure (causing irritability)
• Rapid heartbeat
• Reddening (flushing) of the skin
• Sweating

An uncommon symptom is called the opsoclonus-myoclonus-ataxia syndrome or “dancing eyes, dancing feet.” In this situation, the child has irregular, rapid eye movements (opsoclonus), twitch-like muscle spasms (myoclonus), and appears uncoordinated when standing or walking (ataxia). He or she may also have trouble speaking. For reasons that are not clear, neuroblastomas that cause this syndrome tend to be less life-threatening than other forms of the disease.

Medical history and physical exam

If your child has signs or symptoms that may suggest a neuroblastoma, the doctor will want to take a complete medical history to learn more about the symptoms. A physical exam can provide information about signs of a neuroblastoma and other health problems. For example, the doctor may be able to see or feel an abnormal mass in the body or may find a child has lumps or bumps under the skin or high blood pressure. Neuroblastomas can sometimes grow close to the spinal cord, so the doctor may pay close attention to movement and strength in the child’s arms and legs.

Some signs that could be caused by neuroblastoma, such as fever and enlarged lymph nodes, are much more likely to be caused by an infection, so the doctor may look for other signs of infection at first.

If symptoms or the results of the physical exam suggest a child might have a neuroblastoma (or another type of tumor), other tests will be done. These might include blood and urine tests, imaging tests, and biopsies. These tests are important because many of the symptoms and signs of neuroblastoma can also be caused by other diseases, such as infections, or even other types of cancer.

Blood and urine tests

Blood or urine catecholamine tests

Neuroblastoma can often be found by detecting catecholamines in the blood or urine. Sympathetic nerve cells normally release hormones called catecholamines, such as epinephrine (adrenaline) and norepinephrine, which enter the blood. Eventually the body breaks these down into metabolites (smaller pieces), which are then passed out of the body in the urine.

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

• Homovanillic acid (HVA)
• Vanillylmandelic acid (VMA)

Other lab tests

If neuroblastoma is suspected or has been found, your child’s doctor will probably also order blood tests to check blood cell counts, liver and kidney function, and the balance of salts (electrolytes) in the body. A urinalysis (urine test) may also be done to further check kidney function.

Imaging tests

Imaging tests use x-rays, magnetic fields, sound waves, 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 out whether a suspicious area might be cancerous
• To learn how far cancer may have spread
• To help determine if treatment has been effective

Most patients who have or may have neuroblastoma will have one or more of these tests.

Neuroblastoma patients are generally quite young, so it can be hard to do some of these tests. Parents and medical staff need to be very patient.

Ultrasound

Ultrasound is often one of the first tests done in small children if a tumor is suspected, because it is fairly quick and easy and does not use radiation. This test uses sound wave echoes to create pictures of internal organs or masses. A small wand-like instrument called a transducer gives off sound waves and picks up the echoes as they bounce off body tissues. The echoes are converted by a computer into a black and white image on a computer screen.

For an ultrasound exam, the child simply lies on a table (or the parent holds the child) and a technician moves the transducer across the skin over the part of the body being examined. Usually, the skin is lubricated with gel first.

Ultrasound is used most often to look at masses in the abdomen. (It’s not used in the chest because the ribs block the sound waves.) The pictures from ultrasound aren’t as detailed as those from some other tests, so even if a tumor is found, CT or MRI scans (described below) will likely still be needed.

Ultrasound can also detect if kidneys have become swollen because the outflow of urine has been blocked by enlarged lymph nodes or a mass. Ultrasound can also be used to help guide a biopsy needle into a suspected tumor to get a sample for testing. It is particularly useful in checking to see if tumors in the abdomen are shrinking.

X-rays

The doctor may order an x-ray of the chest or another part of the body as an early test if a child is having symptoms but it’s not clear what might be causing them. But the images may not always be detailed enough to spot tumors.

If neuroblastoma has already been diagnosed, x-rays can be useful to see if cancer has spread to certain bones. An x-ray of the head may be done to see if cancer has spread to the skull bones. An MIBG scan or a bone scan (described below) is usually better for looking at the bones in the rest of the body, but x-rays may be used in infants, where these scans might not be possible. A standard chest x-ray may be done if doctors suspect that the tumor has invaded the lungs, but a CT or MRI scan of the chest can show the area in more detail.

Computed tomography (CT or CAT) scan

CT scans are often the first test used to look for neuroblastoma in the abdomen, pelvis, and chest.

The CT scan is an x-ray test that produces detailed cross-sectional images of parts of the body. Instead of taking one picture, like a regular x-ray, a CT scanner takes many pictures as it rotates around your child while he or she lies on a table. A computer then combines these pictures into images showing slices of the part of the body being studied. Unlike a regular x-ray, a CT scan creates detailed images of the soft tissues in the body.

Your child may be asked to drink a contrast solution and/or receive an IV (intravenous) line through which a contrast dye is injected. This helps better outline structures in the body. The contrast may cause some flushing (a feeling of warmth, especially in the face). Some people are allergic and get hives. Rarely, more serious reactions like trouble breathing or low blood pressure can occur. 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.

CT scans take longer than regular x-rays, but not as long as MRI scans. Your child will need to lie still on a table while they are being done. During the test, the table slides in and out of the scanner, a ring-shaped machine that completely surrounds the table. Some people feel a bit confined by the ring they have to lie in while the pictures are being taken. In some cases, your child may be sedated (given medicine to make them sleepy) before the test to reduce movement and help make sure the pictures come out well. Many medical centers now use spiral CT (also known as helical CT), which uses a faster machine that reduces the dose of radiation and gives more detailed pictures.

CT-guided needle biopsy: CT scans can also be used to help guide a biopsy needle into a tumor. For this procedure, the patient lies 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 fine needle biopsy sample or a larger core needle biopsy sample is then removed and looked at under a microscope. In children, this procedure is always done under general anesthesia (where the child is asleep).

Magnetic resonance imaging (MRI) scan

MRI scans provide detailed images of soft tissues in the body. But MRI scans use radio waves and strong magnets instead of x-rays, so there is no radiation. The energy from the radio waves is absorbed by the body and then released in a pattern formed by the type of body tissue and by certain diseases. A computer translates the pattern into a very detailed image of parts of the body. A contrast material called gadolinium may be injected into a vein before the scan to better see details, but contrast is needed less often than with a CT scan.

MRI scans are most helpful in looking at the brain and spinal cord. MRI may be slightly better than CT at assessing the extent of neuroblastoma, especially around the spine, but this test can be harder to do in children.

MRI scans take longer than CT scans, often up to an hour. For most MRI machines, your child has to lie inside a narrow tube, which is confining and can be distressing. Newer, more open MRI machines may be an option in some cases, but they still require the child to stay still for long periods of time. The MRI machine also makes loud buzzing and clicking noises that may be disturbing. Younger children are often given medicine to help keep them calm or even asleep during the test.

MIBG scan

This scan uses a form of the chemical meta-iodobenzylguanidine (MIBG) that contains a small amount of radioactive iodine. MIBG is similar to norepinephrine, a hormone made by sympathetic nerve cells. It is injected into a vein and travels through the bloodstream, and in most patients it will attach to neuroblastoma cells anywhere in the body. Several hours or days later, the body is scanned with a special camera to look for areas that picked up the radioactivity. This helps doctors tell where the neuroblastoma is and whether it has spread to the bones and/or other parts of the body.

This test is preferred by many doctors as a standard test in children with neuroblastoma. It can be repeated after treatment to see if it has been effective. It is also good to know if the tumor takes up the MIBG because in some cases, this radioactive molecule can be used (at higher doses) to treat the neuroblastoma (see the “Radiation therapy” section).

Positron emission tomography (PET) scan

For a PET scan, a radioactive substance (usually a type of sugar related to glucose, known as FDG) is injected into the blood. The amount of radioactivity used is very low. Because cancer cells in the body are growing quickly, they absorb large amounts of the radioactive 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 as detailed as a CT or MRI scan, but it can provide helpful information about the whole body. Younger children may be given medicine to help keep them calm or even asleep during the test.

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 with the more detailed appearance of that area on the CT.

Bone scan

A bone scan can help show if a cancer has spread to the bones, and can provide a picture of the entire skeleton at once. Neuroblastoma often causes bone damage, which a bone scan can find. This used to be a routine test, but in some centers it has been replaced by use of MIBG or PET scans.

For this test, a small amount of low-level radioactive material (technetium-99) is injected into a vein. The substance settles in areas of damaged bone throughout the entire skeleton over the course of a couple of hours. Your child then lies on a table for about 30 minutes while a special camera detects the radioactivity and creates a picture of the skeleton. Younger children may be given medicine to help keep them calm or even asleep during the test.

Areas of active bone changes attract the radioactivity and appear as “hot spots” on the skeleton. These areas may suggest cancer, but other bone diseases can also cause the same pattern. To distinguish between these conditions, other imaging tests such as plain x-rays or MRI scans, or even a bone biopsy might be needed.

Biopsies

Signs and symptoms, lab tests, and imaging tests may strongly suggest a child has neuroblastoma, but a biopsy (removing some of the tumor for viewing under a microscope and other lab testing) is the only way to be certain.

During a biopsy, the doctor removes a sample of the tumor mass. In adults, biopsies are sometimes done using local anesthetic (numbing medicine), but in children they are more often done while the child is under general anesthesia (asleep). There are 2 main types of biopsies:

• Incisional (open or surgical) biopsy: This type of biopsy is done by cutting away a piece of the tumor through an opening on the skin. For tumors deep in the body this may be done laparoscopically using long, thin surgical tools inserted through small cuts in the skin.
• Needle (closed) biopsy: For this type of biopsy, a hollow needle is placed through the skin and into the tumor. If the tumor is deep within the body, CT scans or ultrasound may be used to help guide the needle into the tumor.

The biopsy samples are then sent to a lab, where they are viewed under a microscope by a pathologist (a doctor with special training in identifying cancer cells).

Some neuroblastomas are easily recognized when looked at by doctors experienced in testing children’s tumor samples. But some cases may be hard to tell apart from other types of children’s cancers. In these situations, special tests such as immunohistochemistry must be done. For this test, a portion of the sample is treated with special proteins (antibodies) that attach to substances in neuroblastoma cells but not in other cancers. Chemicals (stains) are then added so that cells containing these substances change color and can be easily seen under a microscope. This lets the pathologist know that the tumor is a neuroblastoma.

Other types of lab tests may also be done on neuroblastoma samples to help determine how quickly the tumor is likely to grow. Some of these are described in the section, “How is neuroblastoma staged?”

Bone marrow aspiration and biopsy

Neuroblastoma often spreads to the bone marrow (the soft inner parts of certain bones). If blood or urine levels of catecholamines are increased, then finding cancer cells in a bone marrow sample is enough to diagnose neuroblastoma (without getting a biopsy of the main tumor). If neuroblastoma has already been diagnosed by a biopsy done elsewhere in the body, bone marrow testing is done to help determine the extent of the disease.

A bone marrow aspiration and biopsy are usually done at the same time. In most cases the samples are taken from the back of both of the pelvic (hip) bones.

For a bone marrow aspiration, the child lies on a table (on his or her side or belly). After cleaning the skin over the hip, the doctor numbs the area and the surface of the bone with local anesthetic, which may cause a brief stinging or burning sensation. Even with the local anesthetic, most patients still have some brief pain when the marrow is removed. In most cases, the child is also given other medicines to reduce pain or even be asleep during the procedure. 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 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.

Samples from the bone marrow are sent to a lab, where they are looked at and tested for the presence of cancer cells.