Parathyroid tumors are usually benign (not cancer) and are called adenomas. Parathyroid cancer is very rare. Having certain inherited disorders can increase the risk of parathyroid cancer. Explore the links on this page to learn more about parathyroid cancer treatment and clinical trials.
Pheochromocytoma and paraganglioma are rare tumors that come from the same type of tissue.
Pheochromocytoma is a rare tumor that forms in the adrenal medulla (the center of the adrenal gland).
Paragangliomas form outside the adrenal gland.
Some inherited disorders and changes in certain genes increase the risk of pheochromocytoma or paraganglioma.
Signs and symptoms of pheochromocytoma and paraganglioma include high blood pressure and headache.
Signs and symptoms of pheochromocytoma and paraganglioma may occur at any time or be brought on by certain events.
Tests that examine the blood and urine are used to diagnose pheochromocytoma and paraganglioma.
Genetic counseling is part of the treatment plan for patients with pheochromocytoma or paraganglioma.
Certain factors affect prognosis (chance of recovery) and treatment options.
Pheochromocytoma and paraganglioma are rare tumors that come from the same type of tissue.
Paragangliomas form in nerve tissue in the adrenal glands and near certain blood vessels and nerves. Paragangliomas that form in the adrenal glands are called pheochromocytomas. Paragangliomas that form outside the adrenal glands are called extra-adrenal paragangliomas. In this summary, extra-adrenal paragangliomas are called paragangliomas.
Pheochromocytomas and paragangliomas may be benign (not cancer) or cancer.
Pheochromocytoma is a rare tumor that forms in the adrenal medulla (the center of the adrenal gland).
Pheochromocytoma forms in the adrenal glands. There are two adrenal glands, one on top of each kidney in the back of the upper abdomen. Each adrenal gland has two parts. The outer layer of the adrenal gland is the adrenal cortex. The center of the adrenal gland is the adrenal medulla.
Pheochromocytoma is a rare tumor of the adrenal medulla. Usually, pheochromocytoma affects one adrenal gland, but it may affect both adrenal glands. Sometimes there is more than one tumor in one adrenal gland.
The adrenal glands make important hormones called catecholamines. Adrenaline (epinephrine) and noradrenaline (norepinephrine) are two types of catecholamines that help control heart rate, blood pressure, blood sugar, and the way the body reacts to stress. Sometimes a pheochromocytoma will release extra adrenaline and noradrenaline into the blood and cause signs or symptoms of disease.
EnlargeAnatomy of the adrenal gland. There are two adrenal glands, one on top of each kidney. The outer part of each gland is the adrenal cortex and the inner part is the adrenal medulla.
Paragangliomas form outside the adrenal gland.
Paragangliomas are rare tumors that form near the carotid artery, along nerve pathways in the head and neck, and in other parts of the body. Some paragangliomas make extra catecholamines called adrenaline and noradrenaline. The release of these extra catecholamines into the blood may cause signs or symptoms of disease.
EnlargeParaganglioma of the head and neck. A rare tumor that often forms near the carotid artery. It may also form along nerve pathways in the head and neck and in other parts of the body.
Some inherited disorders and changes in certain genes increase the risk of pheochromocytoma or paraganglioma.
Anything that increases your chance of getting a disease is called a risk factor. Having a risk factor doesn’t mean that you will get cancer; not having risk factors doesn’t mean that you will not get cancer. Talk to your doctor if you think you may be at risk.
The following inheritedsyndromes or gene changes increase the risk of pheochromocytoma or paraganglioma:
Signs and symptoms of pheochromocytoma and paraganglioma include high blood pressure and headache.
Some tumors do not make extra adrenaline or noradrenaline and do not cause signs and symptoms. These tumors are sometimes found when a lump forms in the neck or when a test or procedure is done for another reason. Signs and symptoms of pheochromocytoma and paraganglioma occur when too much adrenaline or noradrenaline is released into the blood. These and other signs and symptoms may be caused by pheochromocytoma and paraganglioma or by other conditions. Check with your doctor if you have:
The most common sign is high blood pressure that may be hard to control. Very high blood pressure can cause serious health problems such as irregular heartbeat, heart attack, stroke, or death.
Signs and symptoms of pheochromocytoma and paraganglioma may occur at any time or be brought on by certain events.
Signs and symptoms of pheochromocytoma and paraganglioma may occur when one of the following events happens:
Hard physical activity.
A physical injury or having a lot of emotional stress.
Surgery, including procedures to remove the tumor.
Eating foods high in tyramine (such as red wine, chocolate, and cheese).
Tests that examine the blood and urine are used to diagnose pheochromocytoma and paraganglioma.
In addition to asking about your personal and family health history and doing a physical exam to check for signs of disease, such as high blood pressure, your doctor may perform the following tests and procedures:
Twenty-four-hour urine test: A test in which urine is collected for 24 hours to measure the amounts of catecholamines in the urine. Substances caused by the breakdown of these catecholamines are also measured. An unusual (higher or lower than normal) amount of a substance can be a sign of disease in the organ or tissue that makes it. Higher-than-normal amounts of certain catecholamines may be a sign of pheochromocytoma.
Blood catecholamine studies: A procedure in which a blood sample is checked to measure the amount of certain catecholamines released into the blood. Substances caused by the breakdown of these catecholamines are also measured. An unusual (higher than or lower than normal) amount of a substance can be a sign of disease in the organ or tissue that makes it. Higher-than-normal amounts of certain catecholamines may be a sign of pheochromocytoma.
CT scan (CAT scan): A procedure that makes a series of detailed pictures of areas inside the body, such as the neck, chest, abdomen, and pelvis, taken from different angles. The pictures are made by a computer linked to an x-ray machine. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography.
MRI (magnetic resonance imaging): A procedure that uses a magnet, radio waves, and a computer to make a series of detailed pictures of areas inside the body such as the neck, chest, abdomen, and pelvis. This procedure is also called nuclear magnetic resonance imaging (NMRI).
Genetic counseling is part of the treatment plan for patients with pheochromocytoma or paraganglioma.
All patients who are diagnosed with pheochromocytoma or paraganglioma should have genetic counseling to find out their risk for having an inherited syndrome and other related cancers.
Genetic testing is often recommended by a genetic counselor for patients who:
Have a personal or family history of traits linked with inherited pheochromocytoma or paraganglioma syndrome.
Have tumors in both adrenal glands.
Have more than one tumor in one adrenal gland.
Have signs or symptoms of extra catecholamines being released into the blood or malignant (cancerous) paraganglioma.
Are diagnosed before age 40 years.
Genetic testing is sometimes recommended for patients with pheochromocytoma who:
Are aged 40 to 50 years.
Have a tumor in one adrenal gland.
Do not have a personal or family history of an inherited syndrome.
When certain gene changes are found during genetic testing, the testing is usually offered to family members who are at risk but do not have signs or symptoms.
Genetic testing is not recommended for patients older than 50 years.
Certain factors affect prognosis (chance of recovery) and treatment options.
Whether the tumor is in one area only or has spread to other places in the body.
Whether there are signs or symptoms caused by a higher-than-normal amount of catecholamines.
Whether the tumor has just been diagnosed or has recurred (come back).
Stages of Pheochromocytoma and Paraganglioma
Key Points
After pheochromocytoma and paraganglioma have been diagnosed, tests are done to find out if the tumor has spread to other parts of the body.
There are three ways that cancer spreads in the body.
Cancer may spread from where it began to other parts of the body.
Pheochromocytoma and paraganglioma are described as localized, regional, or metastatic.
Localized pheochromocytoma and paraganglioma
Regional pheochromocytoma and paraganglioma
Metastatic pheochromocytoma and paraganglioma
Pheochromocytoma and paraganglioma can recur (come back) after they have been treated.
After pheochromocytoma and paraganglioma have been diagnosed, tests are done to find out if the tumor has spread to other parts of the body.
The process to find out if cancer has spread to other parts of the body is usually called staging. It is important to know whether the cancer has spread in order to plan treatment. The following tests and procedures may be used to determine if the tumor has spread to other parts of the body:
CT scan (CAT scan): A procedure that makes a series of detailed pictures of areas inside the body, such as the neck, chest, abdomen, and pelvis, taken from different angles. The pictures are made by a computer linked to an x-ray machine. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly. The abdomen and pelvis are imaged to detect tumors that release catecholamine. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography.
MRI (magnetic resonance imaging): A procedure that uses a magnet, radio waves, and a computer to make a series of detailed pictures of areas inside the body such as the neck, chest, abdomen, and pelvis. This procedure is also called nuclear magnetic resonance imaging (NMRI).
MIBG scan: A procedure used to find neuroendocrine tumors, such as pheochromocytoma and paraganglioma. A very small amount of a substance called radioactive MIBG is injected into a vein and travels through the bloodstream. Neuroendocrine tumor cells take up the radioactive MIBG and are detected by a scanner. Scans may be taken over 1-3 days. An iodine solution may be given before or during the test to keep the thyroid gland from absorbing too much of the MIBG.
Octreotide scan: A type of radionuclide scan used to find certain tumors, including tumors that release catecholamine. A very small amount of radioactive octreotide (a hormone that attaches to certain tumors) is injected into a vein and travels through the bloodstream. The radioactive octreotide attaches to the tumor and a special camera that detects radioactivity is used to show where the tumors are in the body.
PET scan (positron emission tomography scan) or FDG-PET scan (fluorodeoxyglucose-positron emission tomography scan): A procedure to find malignant tumor cells in the body. A small amount of FDG, a type of radioactive glucose (sugar), is injected into a vein. The PET scanner rotates around the body and makes a picture of where glucose is being used in the body. Malignant tumor cells show up brighter in the picture because they are more active and take up more glucose than normal cells do. Other substances may be used to attach to the tumor to get a better picture.
There are three ways that cancer spreads in the body.
Tissue. The cancer spreads from where it began by growing into nearby areas.
Lymph system. The cancer spreads from where it began by getting into the lymph system. The cancer travels through the lymph vessels to other parts of the body.
Blood. The cancer spreads from where it began by getting into the blood. The cancer travels through the blood vessels to other parts of the body.
Cancer may spread from where it began to other parts of the body.
When cancer spreads to another part of the body, it is called metastasis. Cancer cells break away from where they began (the primary tumor) and travel through the lymph system or blood.
Lymph system. The cancer gets into the lymph system, travels through the lymph vessels, and forms a tumor (metastatic tumor) in another part of the body.
Blood. The cancer gets into the blood, travels through the blood vessels, and forms a tumor (metastatic tumor) in another part of the body.
The metastatic tumor is the same type of cancer as the primary tumor. For example, if pheochromocytoma spreads to the bone, the cancer cells in the bone are actually pheochromocytoma cells. The disease is metastatic pheochromocytoma, not bone cancer.
Many cancer deaths are caused when cancer moves from the original tumor and spreads to other tissues and organs. This is called metastatic cancer. This animation shows how cancer cells travel from the place in the body where they first formed to other parts of the body.
Pheochromocytoma and paraganglioma are described as localized, regional, or metastatic.
Cancer has spread to lymph nodes or other tissues near where the tumor began.
Metastatic pheochromocytoma and paraganglioma
The cancer has spread to other parts of the body, such as the liver, lungs, bone, or distant lymph nodes.
Pheochromocytoma and paraganglioma can recur (come back) after they have been treated.
The cancer may come back in the same place or in other parts of the body.
Treatment Option Overview
Key Points
There are different types of treatment for patients with pheochromocytoma or paraganglioma.
Patients receive medication to treat the signs and symptoms of pheochromocytoma and paraganglioma.
The following types of treatment are used:
Surgery
Radiation therapy
Chemotherapy
Ablation therapy
Embolization therapy
Targeted therapy
New types of treatment are being tested in clinical trials.
Treatment for pheochromocytoma and paraganglioma may cause side effects.
Follow-up care will be needed.
There are different types of treatment for patients with pheochromocytoma or paraganglioma.
Different types of treatments are available for patients with pheochromocytoma or paraganglioma. Some treatments are standard (the currently used treatment), and some are being tested in clinical trials. A treatment clinical trial is a research study meant to help improve current treatments or obtain information on new treatments for patients with cancer. When clinical trials show that a new treatment is better than the standard treatment, the new treatment may become the standard treatment. Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment
Patients receive medication to treat the signs and symptoms of pheochromocytoma and paraganglioma.
Drug therapy begins when pheochromocytoma or paraganglioma is diagnosed. This may include:
Drugs that keep the blood pressure normal. For example, one type of drug called alpha-blockers stops noradrenaline from making small blood vessels more narrow. Keeping the blood vessels open and relaxed improves blood flow and lowers blood pressure.
Drugs that keep the heart rate normal. For example, one type of drug called beta-blockers stops the effect of too much noradrenaline and slows the heart rate.
Drug therapy is often given for one to three weeks before surgery.
The following types of treatment are used:
Surgery
Surgery to remove pheochromocytoma is usually an adrenalectomy (removal of one or both adrenal glands). During this surgery, the tissues and lymph nodes inside the abdomen will be checked and if the tumor has spread, these tissues may also be removed. Drugs may be given before, during, and after surgery to keep blood pressure and heart rate normal.
After surgery to remove the tumor, catecholamine levels in the blood or urine are checked. Normal catecholamine levels are a sign that all the pheochromocytoma cells were removed.
If both adrenal glands are removed, life-long hormone therapy to replace hormones made by the adrenal glands is needed.
External radiation therapy uses a machine outside the body to send radiation toward the area of the body with cancer.
Metastatic pheochromocytoma is sometimes treated with a radioactive substance called 131I-MIBG. It is given by infusion to deliver radiation directly to tumor cells throughout the body. 131I-MIBG collects in certain kinds of tumor cells, killing them with the radiation that is given off. Not all pheochromocytomas take up 131I-MIBG, so a test is done first to check for this before treatment begins.
The way the radiation therapy is given depends on whether the cancer is localized, regional, metastatic, or recurrent. External radiation therapy and 131I-MIBG therapy are used to treat pheochromocytoma.
Chemotherapy
Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. When chemotherapy is taken by mouth or injected into a vein or muscle, the drugs enter the bloodstream and can reach cancer cells throughout the body (systemic chemotherapy). Combination chemotherapy is treatment using more than one anticancer drug. Systemic chemotherapy is used to treat pheochromocytomas and paragangliomas.
Ablation therapy
Ablation is a treatment to remove or destroy a body part or tissue or its function. Ablation therapies used to help kill cancer cells include:
Radiofrequency ablation: A procedure that uses radio waves to heat and destroy abnormal cells. The radio waves travel through electrodes (small devices that carry electricity). Radiofrequency ablation may be used to treat cancer and other conditions.
Cryoablation: A procedure in which tissue is frozen to destroy abnormal cells. Liquid nitrogen or liquid carbon dioxide is used to freeze the tissue.
Embolization therapy
Embolization therapy is a treatment to block the artery leading to the adrenal gland. Blocking the flow of blood to the adrenal glands helps kill cancer cells growing there.
New types of treatment are being tested in clinical trials.
For some people, joining a clinical trial may be an option. There are different types of clinical trials for people with cancer. For example, a treatment trial tests new treatments or new ways of using current treatments. Supportive care and palliative care trials look at ways to improve quality of life, especially for those who have side effects from cancer and its treatment.
You can use the clinical trial search to find NCI-supported cancer clinical trials accepting participants. The search allows you to filter trials based on the type of cancer, your age, and where the trials are being done. Clinical trials supported by other organizations can be found on the ClinicalTrials.gov website.
Some of the tests that were done to diagnose the cancer or to find out the extent of the cancer may be repeated. Some tests will be repeated to see how well the treatment is working. Decisions about whether to continue, change, or stop treatment will be based on the results of these tests.
Some of the tests will continue to be done after treatment has ended. The results of these tests can show if your condition has changed or if the cancer has recurred (come back). These tests are sometimes called follow-up tests.
For patients with pheochromocytoma or paraganglioma that causes symptoms, catecholamine levels in the blood and urine will be checked on a regular basis. Catecholamine levels that are higher than normal can be a sign that the cancer has come back.
For patients with paraganglioma that does not cause symptoms, follow-up tests, such as CT, MRI, or MIBG scan should be done every year.
For patients with inherited pheochromocytoma or paraganglioma, catecholamine levels in the blood and urine will be checked on a regular basis. Other screening tests will be done to check for other tumors that are linked to the inherited syndrome.
Talk to your doctor about which tests should be done and how often. Patients with pheochromocytoma or paraganglioma need lifelong follow-up.
Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.
Treatment for inherited pheochromocytoma that forms in one adrenal gland is surgery to completely remove the gland.
Treatment for inherited pheochromocytoma that forms in both adrenal glands or later forms in the remaining adrenal gland may be surgery to remove the tumor and as little normal tissue in the adrenal cortex as possible.
Treatment of pheochromocytoma or paraganglioma that has spread to nearby organs or lymph nodes is surgery to completely remove the tumor. Nearby organs that the cancer has spread to, such as the kidney, liver, part of a major blood vessel, and lymph nodes, may also be removed.
Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.
Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.
Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.
Pheochromocytoma During Pregnancy
Key Points
Pregnant women with pheochromocytoma need special care.
Treatment of pregnant women with pheochromocytoma may include surgery.
Pregnant women with pheochromocytoma need special care.
Although it is rarely diagnosed during pregnancy, pheochromocytoma can be very serious for the mother and fetus. Women who have an increased risk of pheochromocytoma should have prenatal testing. Pregnant women with pheochromocytoma should be treated by a team of doctors who are experts in this type of care.
Signs of pheochromocytoma in pregnancy may include:
The diagnosis of pheochromocytoma in pregnant women includes testing for catecholamine levels in blood and urine. See the General Information section for a description of these tests and procedures. An MRI can be done to safely find tumors in pregnant women because it does not expose the fetus to radiation.
Treatment of pregnant women with pheochromocytoma may include surgery.
Treatment of pheochromocytoma during pregnancy may include:
Surgery to completely remove the cancer during the second trimester (the fourth through the sixth month of pregnancy).
Surgery to completely remove the cancer combined with delivery of the baby by cesarean section for patients diagnosed later in pregnancy.
To Learn More About Pheochromocytoma and Paraganglioma
For more information from the National Cancer Institute about pheochromocytoma and paraganglioma, see:
Physician Data Query (PDQ) is the National Cancer Institute’s (NCI’s) comprehensive cancer information database. The PDQ database contains summaries of the latest published information on cancer prevention, detection, genetics, treatment, supportive care, and complementary and alternative medicine. Most summaries come in two versions. The health professional versions have detailed information written in technical language. The patient versions are written in easy-to-understand, nontechnical language. Both versions have cancer information that is accurate and up to date and most versions are also available in Spanish.
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Purpose of This Summary
This PDQ cancer information summary has current information about the treatment of pheochromocytoma and paraganglioma. It is meant to inform and help patients, families, and caregivers. It does not give formal guidelines or recommendations for making decisions about health care.
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Pheochromocytomas and extra-adrenal paragangliomas are rare tumors arising from neural crest tissue that develops into sympathetic and parasympathetic paraganglia throughout the body.
In 2004, the World Health Organization classification used the term pheochromocytoma exclusively for tumors arising from the adrenal medulla, and the term extra-adrenal paraganglioma for similar tumors that arise from other locations.
Incidence and Mortality
The incidence of pheochromocytoma is 2 to 8 per million persons per year.[1,2] Pheochromocytoma is present in 0.1% to 1% of patients with hypertension,[3–5] and it is present in approximately 5% of patients with incidentally discovered adrenal masses.[6] The peak incidence occurs in the third to fifth decades of life. The average age at diagnosis is 24.9 years in hereditary cases and 43.9 years in sporadic cases.[7] The incidence is equal between men and women.[8]
Anatomy
Pheochromocytomas and extra-adrenal paragangliomas arise from neural crest tissue. Neural crest tissue develops into sympathetic and parasympathetic paraganglia.
Sympathetic paraganglia include:
The adrenal medulla.
The organ of Zuckerkandl near the aortic bifurcation.
Other paraganglia along the distribution of the sympathetic nervous system.
Parasympathetic paraganglia include:
The carotid body.
Other paraganglia along the cervical and thoracic branches of the vagus and glossopharyngeal nerves.
Risk Factors
No known environmental, dietary, or lifestyle risk factors have been linked to the development of pheochromocytoma.
Hereditary Predisposition Syndromes
Of all pheochromocytomas and extra-adrenal paragangliomas, 35% occur in patients with a hereditary cancer syndrome.[7–9] Major genetic syndromes that confer an increased risk of pheochromocytoma are included in Table 1.
Table 1. Major Genetic Syndromes or Conditions That Confer an Increased Risk of Pheochromocytoma
Pheochromocytomas and extra-adrenal paragangliomas can also occur in two other very rare syndromes:
The Carney triad of extra-adrenal paraganglioma, gastrointestinal stromal tumor (GIST),[21] and pulmonary chondroma.
The Carney-Stratakis dyad of paraganglioma and GIST.[22]
Genetic counseling and testing
It has been proposed that all patients diagnosed with a pheochromocytoma or paraganglioma should consider genetic testing because the incidence of a hereditary syndrome in apparently sporadic cases is as high as 25%.[7,8,23] Early identification of a hereditary syndrome allows for early screening for other associated tumors and identification of family members who are at risk. In addition, some patients with a hereditary syndrome are more likely to develop multifocal, malignant, or recurrent disease. Knowledge of the specific genetic variant permits increased vigilance during preoperative localization or postoperative surveillance of such patients.
Certain subgroups of patients are at very low risk of having an inherited syndrome (e.g., <2% in patients diagnosed with apparently sporadic pheochromocytoma after age 50 years).[7] Therefore, genetic testing for all patients diagnosed with a pheochromocytoma or paraganglioma may not be practical or cost effective from a population standpoint. It is recommended that every patient diagnosed with a pheochromocytoma or extra-adrenal paraganglioma should first undergo risk evaluation for a hereditary syndrome by a certified genetic counselor.[24]
Genetic testing is often recommended in the following situations:
Patients with a personal or family history of clinical features suggestive of a hereditary pheochromocytoma-paraganglioma syndrome.
Patients with bilateral or multifocal tumors.
Patients with sympathetic or malignant extra-adrenal paragangliomas.
Patients diagnosed before age 40 years.
Genetic testing can be considered when a patient has the following features:
Patient is between the ages of 40 and 50 years.
Patients has a history of a unilateral pheochromocytoma.
Patient does not have a personal or family history suggestive of a hereditary cancer syndrome.
Genetic testing is not recommended in patients who are older than 50 years.
Clinical Features
Patients with pheochromocytomas and sympathetic extra-adrenal paragangliomas may present with symptoms of excess catecholamine production, including:
Hypertension.
Headache.
Perspiration.
Forceful palpitations.
Tremor.
Facial pallor.
These symptoms are often paroxysmal, although sustained hypertension between paroxysmal episodes occurs in 50% to 60% of patients with pheochromocytoma.[25] Episodes of hypertension can be variable in frequency, severity, and duration and are often extremely difficult to manage medically. Hypertensive crisis can lead to cardiac arrhythmias, myocardial infarction, and even death.
Patients are often very symptomatic from excess catecholamine secretion. Symptoms of catecholamine excess can be spontaneous or induced by:
Strenuous physical exertion.
Trauma.
Labor and delivery.
Anesthesia induction.
Surgery or other invasive procedures, including direct instrumentation of the tumor (e.g., fine-needle aspiration).
Eating foods high in tyramine (e.g., red wine, chocolate, and cheese).
Urination (e.g., bladder wall tumor, which is rare).
Phenoxybenzamine (an alpha-adrenergic receptor blocker) is an effective treatment for catecholamine excess and metyrosine (a catecholamine synthesis antagonist) can be added if needed.
Parasympathetic extra-adrenal paragangliomas do not secrete catecholamines. These tumors usually present as a neck mass with symptoms related to compression or are incidentally discovered on an imaging study performed for an unrelated reason. In addition, approximately half of patients with pheochromocytoma are asymptomatic because their neoplasms are discovered in the presymptomatic state by either abdominal imaging for other reasons (e.g., adrenal incidentalomas) or genetic testing in at-risk family members.[17,26–28]
Diagnostics
The diagnosis of pheochromocytoma is usually preceded by the presence of an adrenal mass or is discovered incidentally. Biochemical testing is done to document excess catecholamine secretion. Once the biochemical diagnosis of a catecholamine-secreting tumor is confirmed, localization studies should be performed. Controversy exists as to the optimal single test to make the diagnosis.
Biochemical testing
24-hour urine collection
A 24-hour urine collection for catecholamines (e.g., epinephrine, norepinephrine, and dopamine) and fractionated metanephrines (e.g., metanephrine and normetanephrine) has a relatively low sensitivity (77%–90%) but a high specificity (98%). Pretest probability is also important. The specificity of plasma-free fractionated metanephrines is 82% in patients tested for sporadic pheochromocytoma versus 96% in patients tested for hereditary pheochromocytoma.[29,30]
Plasma-free fractionated metanephrines
Measurement of plasma-free fractionated metanephrines appears to be an ideal case-detection test for patients at higher baseline risk of pheochromocytoma. Examples of these patients might include:
Patients with an incidentally discovered adrenal mass.
Patients with a family history of pheochromocytoma.
Patients with a known inherited predisposition to pheochromocytoma.
The test is associated with a relatively high false-positive rate in patients with a lower baseline risk of pheochromocytoma. Measurement of plasma-free metanephrines (e.g., metanephrine and normetanephrine) has a high sensitivity (97%–99%) but a relatively low specificity (85%).
In general, it is reasonable to use measurement of plasma-free fractionated metanephrines for initial case detection, which is followed by 24-hour measurement of urine-fractionated metanephrines and catecholamines for confirmation. Test results can be difficult to interpret because of the possibility of false-positive results. False-positive results can be caused by:[25,29]
Common medications (e.g., tricyclic antidepressants).
Physical or emotional stress.
Inappropriately low reference ranges based on normal laboratory data rather than clinical data sets.[31]
Common foods (e.g., caffeine and bananas) that interfere with specific assays and medications.
A mildly elevated catecholamine or metanephrine level is usually the result of assay interference caused by drugs or other factors. Patients with symptomatic pheochromocytoma almost always have increases in catecholamines or metanephrines two to three times higher than the upper limits of reference ranges.[25]
Provocative testing (e.g., using glucagon) can be dangerous, adds no value to other current testing methods, and is not recommended.[32]
Imaging studies
Computed tomography (CT) imaging or magnetic resonance imaging (MRI) of the abdomen and pelvis (at least through the level of the aortic bifurcation) are the most commonly used methods for localization.[33] Both have similar sensitivities (90%–100%) and specificities (70%–80%).[33] CT imaging provides superior anatomical detail compared with MRI.
Additional functional imaging may be necessary if CT imaging or MRI fails to localize the tumor. It might also be useful in patients who are at risk for multifocal, malignant, or recurrent disease. Iodine I 123 (123I)-metaiodobenzylguanidine (MIBG) scintigraphy coupled with CT imaging provides anatomical and functional information with good sensitivity (80%–90%) and specificity (95%–100%).[33] 131I-MIBG can be used in the same way, but the image quality is not as high as with 123I-MIBG.[34] Other functional imaging alternatives include gallium Ga 68 (68Ga)-DOTATATE and fluorine F 18-fludeoxyglucose positron emission tomography (PET), both of which can be coupled with CT imaging for improved anatomical detail.[35,36]
It is rare for localization of a catecholamine-secreting tumor to be unsuccessful if currently available imaging methods are used.
Prognosis and Survival
There are no clear data regarding the survival of patients with localized (apparently benign) disease or regional disease. Although patients with localized (apparently benign) disease should experience an overall survival approaching that of age-matched disease-free individuals, 6.5% to 16.5% of these patients will develop a recurrence, usually 5 to 15 years after initial surgery.[37–39]
Approximately 15% to 25% of patients with recurrent disease experience distant metastasis. The 5-year overall survival rates in those with metastatic disease range from 50% to 70%.[40–43] Carriers of SDHB pathogenic variants have an increased risk of developing metastatic disease of approximately 25% to 50%.[44] The most commonly associated gene with metastatic pheochromocytoma and paraganglioma is SDHB (over 40% of cases).[45,46]
Follow-Up Evaluation
Long-term follow-up is essential for all patients with pheochromocytoma or extra-adrenal paraganglioma, even when initial pathology demonstrates no findings that are concerning for malignancy.[5]
After resection of a solitary sporadic pheochromocytoma, patients should undergo baseline postoperative biochemical testing followed by annual lifelong biochemical testing.
Patients who have undergone resection of a noncatecholamine-producing tumor should initially undergo annual imaging with CT or MRI and periodic imaging with radiolabeled MIBG or 68Ga-DOTATATE PET/CT to monitor for recurrence or metastasis.
Patients with a hereditary pheochromocytoma/paraganglioma syndrome who have undergone resection require lifelong annual biochemical screening in addition to routine screening for other component tumors of their specific syndrome.[5]
References
Beard CM, Sheps SG, Kurland LT, et al.: Occurrence of pheochromocytoma in Rochester, Minnesota, 1950 through 1979. Mayo Clin Proc 58 (12): 802-4, 1983. [PUBMED Abstract]
Stenström G, Svärdsudd K: Pheochromocytoma in Sweden 1958-1981. An analysis of the National Cancer Registry Data. Acta Med Scand 220 (3): 225-32, 1986. [PUBMED Abstract]
Sinclair AM, Isles CG, Brown I, et al.: Secondary hypertension in a blood pressure clinic. Arch Intern Med 147 (7): 1289-93, 1987. [PUBMED Abstract]
Anderson GH, Blakeman N, Streeten DH: The effect of age on prevalence of secondary forms of hypertension in 4429 consecutively referred patients. J Hypertens 12 (5): 609-15, 1994. [PUBMED Abstract]
Omura M, Saito J, Yamaguchi K, et al.: Prospective study on the prevalence of secondary hypertension among hypertensive patients visiting a general outpatient clinic in Japan. Hypertens Res 27 (3): 193-202, 2004. [PUBMED Abstract]
Young WF: Management approaches to adrenal incidentalomas. A view from Rochester, Minnesota. Endocrinol Metab Clin North Am 29 (1): 159-85, x, 2000. [PUBMED Abstract]
Neumann HP, Bausch B, McWhinney SR, et al.: Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med 346 (19): 1459-66, 2002. [PUBMED Abstract]
Amar L, Bertherat J, Baudin E, et al.: Genetic testing in pheochromocytoma or functional paraganglioma. J Clin Oncol 23 (34): 8812-8, 2005. [PUBMED Abstract]
Jiménez C, Cote G, Arnold A, et al.: Review: Should patients with apparently sporadic pheochromocytomas or paragangliomas be screened for hereditary syndromes? J Clin Endocrinol Metab 91 (8): 2851-8, 2006. [PUBMED Abstract]
Baysal BE, Ferrell RE, Willett-Brozick JE, et al.: Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science 287 (5454): 848-51, 2000. [PUBMED Abstract]
Hao HX, Khalimonchuk O, Schraders M, et al.: SDH5, a gene required for flavination of succinate dehydrogenase, is mutated in paraganglioma. Science 325 (5944): 1139-42, 2009. [PUBMED Abstract]
Niemann S, Müller U: Mutations in SDHC cause autosomal dominant paraganglioma, type 3. Nat Genet 26 (3): 268-70, 2000. [PUBMED Abstract]
Astuti D, Latif F, Dallol A, et al.: Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Am J Hum Genet 69 (1): 49-54, 2001. [PUBMED Abstract]
Burnichon N, Brière JJ, Libé R, et al.: SDHA is a tumor suppressor gene causing paraganglioma. Hum Mol Genet 19 (15): 3011-20, 2010. [PUBMED Abstract]
Eijkelenkamp K, Olderode-Berends MJW, van der Luijt RB, et al.: Homozygous TMEM127 mutations in 2 patients with bilateral pheochromocytomas. Clin Genet 93 (5): 1049-1056, 2018. [PUBMED Abstract]
Abermil N, Guillaud-Bataille M, Burnichon N, et al.: TMEM127 screening in a large cohort of patients with pheochromocytoma and/or paraganglioma. J Clin Endocrinol Metab 97 (5): E805-9, 2012. [PUBMED Abstract]
Else T, Greenberg S, Fishbein L: Hereditary Paraganglioma-Pheochromocytoma Syndromes. In: Adam MP, Feldman J, Mirzaa GM, et al., eds.: GeneReviews. University of Washington, Seattle, 1993-2024, pp. Available online. Last accessed October 29, 2024.
Letouzé E, Martinelli C, Loriot C, et al.: SDH mutations establish a hypermethylator phenotype in paraganglioma. Cancer Cell 23 (6): 739-52, 2013. [PUBMED Abstract]
Castro-Vega LJ, Buffet A, De Cubas AA, et al.: Germline mutations in FH confer predisposition to malignant pheochromocytomas and paragangliomas. Hum Mol Genet 23 (9): 2440-6, 2014. [PUBMED Abstract]
Clark GR, Sciacovelli M, Gaude E, et al.: Germline FH mutations presenting with pheochromocytoma. J Clin Endocrinol Metab 99 (10): E2046-50, 2014. [PUBMED Abstract]
Carney JA: Gastric stromal sarcoma, pulmonary chondroma, and extra-adrenal paraganglioma (Carney Triad): natural history, adrenocortical component, and possible familial occurrence. Mayo Clin Proc 74 (6): 543-52, 1999. [PUBMED Abstract]
Carney JA, Stratakis CA: Familial paraganglioma and gastric stromal sarcoma: a new syndrome distinct from the Carney triad. Am J Med Genet 108 (2): 132-9, 2002. [PUBMED Abstract]
Neumann HP, Pawlu C, Peczkowska M, et al.: Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. JAMA 292 (8): 943-51, 2004. [PUBMED Abstract]
Lenders JW, Duh QY, Eisenhofer G, et al.: Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 99 (6): 1915-42, 2014. [PUBMED Abstract]
Lenders JW, Eisenhofer G, Mannelli M, et al.: Phaeochromocytoma. Lancet 366 (9486): 665-75, 2005 Aug 20-26. [PUBMED Abstract]
Kopetschke R, Slisko M, Kilisli A, et al.: Frequent incidental discovery of phaeochromocytoma: data from a German cohort of 201 phaeochromocytoma. Eur J Endocrinol 161 (2): 355-61, 2009. [PUBMED Abstract]
Motta-Ramirez GA, Remer EM, Herts BR, et al.: Comparison of CT findings in symptomatic and incidentally discovered pheochromocytomas. AJR Am J Roentgenol 185 (3): 684-8, 2005. [PUBMED Abstract]
Young WF: Clinical practice. The incidentally discovered adrenal mass. N Engl J Med 356 (6): 601-10, 2007. [PUBMED Abstract]
Lenders JW, Pacak K, Walther MM, et al.: Biochemical diagnosis of pheochromocytoma: which test is best? JAMA 287 (11): 1427-34, 2002. [PUBMED Abstract]
Sawka AM, Jaeschke R, Singh RJ, et al.: A comparison of biochemical tests for pheochromocytoma: measurement of fractionated plasma metanephrines compared with the combination of 24-hour urinary metanephrines and catecholamines. J Clin Endocrinol Metab 88 (2): 553-8, 2003. [PUBMED Abstract]
Perry CG, Sawka AM, Singh R, et al.: The diagnostic efficacy of urinary fractionated metanephrines measured by tandem mass spectrometry in detection of pheochromocytoma. Clin Endocrinol (Oxf) 66 (5): 703-8, 2007. [PUBMED Abstract]
Young WF: Phaeochromocytoma: how to catch a moonbeam in your hand. Eur J Endocrinol 136 (1): 28-9, 1997. [PUBMED Abstract]
Ilias I, Pacak K: Current approaches and recommended algorithm for the diagnostic localization of pheochromocytoma. J Clin Endocrinol Metab 89 (2): 479-91, 2004. [PUBMED Abstract]
Furuta N, Kiyota H, Yoshigoe F, et al.: Diagnosis of pheochromocytoma using [123I]-compared with [131I]-metaiodobenzylguanidine scintigraphy. Int J Urol 6 (3): 119-24, 1999. [PUBMED Abstract]
Janssen I, Wolf KI, Chui CH, et al.: Relevant Discordance Between 68Ga-DOTATATE and 68Ga-DOTANOC in SDHB-Related Metastatic Paraganglioma: Is Affinity to Somatostatin Receptor 2 the Key? Clin Nucl Med 42 (3): 211-213, 2017. [PUBMED Abstract]
Janssen I, Chen CC, Millo CM, et al.: PET/CT comparing (68)Ga-DOTATATE and other radiopharmaceuticals and in comparison with CT/MRI for the localization of sporadic metastatic pheochromocytoma and paraganglioma. Eur J Nucl Med Mol Imaging 43 (10): 1784-91, 2016. [PUBMED Abstract]
Plouin PF, Chatellier G, Fofol I, et al.: Tumor recurrence and hypertension persistence after successful pheochromocytoma operation. Hypertension 29 (5): 1133-9, 1997. [PUBMED Abstract]
van Heerden JA, Roland CF, Carney JA, et al.: Long-term evaluation following resection of apparently benign pheochromocytoma(s)/paraganglioma(s). World J Surg 14 (3): 325-9, 1990 May-Jun. [PUBMED Abstract]
Amar L, Servais A, Gimenez-Roqueplo AP, et al.: Year of diagnosis, features at presentation, and risk of recurrence in patients with pheochromocytoma or secreting paraganglioma. J Clin Endocrinol Metab 90 (4): 2110-6, 2005. [PUBMED Abstract]
Ayala-Ramirez M, Feng L, Johnson MM, et al.: Clinical risk factors for malignancy and overall survival in patients with pheochromocytomas and sympathetic paragangliomas: primary tumor size and primary tumor location as prognostic indicators. J Clin Endocrinol Metab 96 (3): 717-25, 2011. [PUBMED Abstract]
Fishbein L, Ben-Maimon S, Keefe S, et al.: SDHB mutation carriers with malignant pheochromocytoma respond better to CVD. Endocr Relat Cancer 24 (8): L51-L55, 2017. [PUBMED Abstract]
Hamidi O, Young WF, Gruber L, et al.: Outcomes of patients with metastatic phaeochromocytoma and paraganglioma: A systematic review and meta-analysis. Clin Endocrinol (Oxf) 87 (5): 440-450, 2017. [PUBMED Abstract]
Asai S, Katabami T, Tsuiki M, et al.: Controlling Tumor Progression with Cyclophosphamide, Vincristine, and Dacarbazine Treatment Improves Survival in Patients with Metastatic and Unresectable Malignant Pheochromocytomas/Paragangliomas. Horm Cancer 8 (2): 108-118, 2017. [PUBMED Abstract]
Andrews KA, Ascher DB, Pires DEV, et al.: Tumour risks and genotype-phenotype correlations associated with germline variants in succinate dehydrogenase subunit genes SDHB, SDHC and SDHD. J Med Genet 55 (6): 384-394, 2018. [PUBMED Abstract]
Fishbein L, Merrill S, Fraker DL, et al.: Inherited mutations in pheochromocytoma and paraganglioma: why all patients should be offered genetic testing. Ann Surg Oncol 20 (5): 1444-50, 2013. [PUBMED Abstract]
Neumann HPH, Young WF, Eng C: Pheochromocytoma and Paraganglioma. N Engl J Med 381 (6): 552-565, 2019. [PUBMED Abstract]
Cellular Classification of Pheochromocytoma and Paraganglioma
Pathological Classification
Pheochromocytoma and paraganglioma characteristically form small nests of uniform polygonal chromaffin cells (“zellballen”). A diagnosis of malignancy can only be made by identifying tumor deposits in tissues that do not normally contain chromaffin cells (e.g., lymph nodes, liver, bone, lung, and other distant metastatic sites).
Regional or distant metastatic disease is documented on initial pathology in only 3% to 8% of patients; thus, an attempt has been made to identify tumor characteristics associated with future malignant behavior. Pathological features associated with malignancy include:
Large tumor size.
Increased number of mitoses.
DNA aneuploidy.
Extensive tumor necrosis.
Vascular or capsular invasion.
In the absence of clearly documented metastases, no combination of clinical, histopathological, or biochemical features has been shown to reliably predict the biological behavior of pheochromocytoma. If no definite malignancy is identified, pathology generally provides insufficient prognostic information regarding the likelihood of recurrence or metastasis. These tumors cannot be considered benign by default; patients require continued lifelong surveillance.[1–7]
References
Plouin PF, Chatellier G, Fofol I, et al.: Tumor recurrence and hypertension persistence after successful pheochromocytoma operation. Hypertension 29 (5): 1133-9, 1997. [PUBMED Abstract]
Thompson LD: Pheochromocytoma of the Adrenal gland Scaled Score (PASS) to separate benign from malignant neoplasms: a clinicopathologic and immunophenotypic study of 100 cases. Am J Surg Pathol 26 (5): 551-66, 2002. [PUBMED Abstract]
Nativ O, Grant CS, Sheps SG, et al.: The clinical significance of nuclear DNA ploidy pattern in 184 patients with pheochromocytoma. Cancer 69 (11): 2683-7, 1992. [PUBMED Abstract]
Wu D, Tischler AS, Lloyd RV, et al.: Observer variation in the application of the Pheochromocytoma of the Adrenal Gland Scaled Score. Am J Surg Pathol 33 (4): 599-608, 2009. [PUBMED Abstract]
Kimura N, Watanabe T, Noshiro T, et al.: Histological grading of adrenal and extra-adrenal pheochromocytomas and relationship to prognosis: a clinicopathological analysis of 116 adrenal pheochromocytomas and 30 extra-adrenal sympathetic paragangliomas including 38 malignant tumors. Endocr Pathol 16 (1): 23-32, 2005. [PUBMED Abstract]
Linnoila RI, Keiser HR, Steinberg SM, et al.: Histopathology of benign versus malignant sympathoadrenal paragangliomas: clinicopathologic study of 120 cases including unusual histologic features. Hum Pathol 21 (11): 1168-80, 1990. [PUBMED Abstract]
Tischler AS: Pheochromocytoma and extra-adrenal paraganglioma: updates. Arch Pathol Lab Med 132 (8): 1272-84, 2008. [PUBMED Abstract]
Stage Information for Pheochromocytoma and Paraganglioma
AJCC Stage Groupings and TNM Definitions
The American Joint Committee on Cancer (AJCC) has designated staging by TNM (tumor, node, metastasis) classification to define pheochromocytoma and paraganglioma.[1] Although the AJCC staging system does not account for the unique characteristics of these tumors, it could increase the understanding of prognostic indicators for survival.
Definitions of TNM Stage Ia,b
Stage
TNM
Description
T = primary tumor; N = regional lymph nodes; M = distant metastasis; PH = pheochromocytoma.
aReprinted with permission from AJCC: Adrenal – Neuroendocrine tumors. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp. 919–27.
bPH: within adrenal gland; PG sympathetic: functional; PG parasympathetic: nonfunctional, usually in the head and neck region; Note: parasympathetic paraganglioma are not staged because they are largely benign.
I
T1, N0, M0
T1 = PH <5 cm in greatest dimension, no extra-adrenal invasion.
N0 = No lymph node metastasis.
M0 = No distant metastasis.
Definitions of TNM Stage IIa,b
Stage
TNM
Description
T = primary tumor; N = regional lymph nodes; M = distant metastasis; PG = paraganglioma; PH = pheochromocytoma.
aReprinted with permission from AJCC: Adrenal – Neuroendocrine tumors. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp. 919–27.
bPH: within adrenal gland; PG sympathetic: functional; PG parasympathetic: nonfunctional, usually in the head and neck region; Note: parasympathetic paraganglioma are not staged because they are largely benign.
II
T2, N0, M0
T2 = PH ≥5 cm or PG-sympathetic of any size, no extra-adrenal invasion.
N0 = No lymph node metastasis.
M0 = No distant metastasis.
Definitions of TNM Stage IIIa,b
Stage
TNM
Description
T = primary tumor; N = regional lymph nodes; M = distant metastasis; PG = paraganglioma; PH = pheochromocytoma.
aReprinted with permission from AJCC: Adrenal – Neuroendocrine tumors. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp. 919–27.
bPH: within adrenal gland; PG sympathetic: functional; PG parasympathetic: nonfunctional, usually in the head and neck region; Note: parasympathetic paraganglioma are not staged because they are largely benign.
III
T1, N1, M0
T1 = PH <5 cm in greatest dimension, no extra-adrenal invasion.
N1 = Regional lymph node metastasis.
M0 = No distant metastasis.
T2, N1, M0
T2 = PH ≥5 cm or PG-sympathetic of any size, no extra-adrenal invasion.
N1 = Regional lymph node metastasis.
M0 = No distant metastasis.
T3, Any N, M0
T3 = Tumor of any size with invasion into surrounding tissues (e.g., liver, pancreas, spleen, kidneys).
NX = Regional lymph nodes cannot be assessed.
N0 = No lymph node metastasis.
N1 = Regional lymph node metastasis.
M0 = No distant metastasis.
Definitions of TNM Stage IVa,b
Stage
TNM
Description
T = primary tumor; N = regional lymph nodes; M = distant metastasis; PG = paraganglioma; PH = pheochromocytoma.
aReprinted with permission from AJCC: Adrenal – Neuroendocrine tumors. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp. 919–27.
bPH: within adrenal gland; PG sympathetic: functional; PG parasympathetic: nonfunctional, usually in the head and neck region; Note: parasympathetic paraganglioma are not staged because they are largely benign.
IV
Any T, Any N, M1
TX = Primary tumor cannot be assessed.
T1 = PH <5 cm in greatest dimension, no extra-adrenal invasion.
T2 = PH ≥5 cm or PG-sympathetic of any size, no extra-adrenal invasion.
T3 = Tumor of any size with invasion into surrounding tissues (e.g., liver, pancreas, spleen, kidneys).
NX = Regional lymph nodes cannot be assessed.
N0 = No lymph node metastasis.
N1 = Regional lymph node metastasis.
M1 = Distant metastasis.
–M1a = Distant metastasis to only bone.
–M1b = Distant metastasis to only distant lymph nodes/liver or lung.
–M1c = Distant metastasis to bone plus multiple other sites.
References
Adrenal – Neuroendocrine tumors. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp. 919–27.
Treatment Option Overview for Pheochromocytoma and Paraganglioma
Limited data are available from phase II clinical trials to guide the management of patients diagnosed with pheochromocytoma or paraganglioma. There are no phase III trials. Everything is based on case series, and the impact on survival is not known.
Localized and Regional Pheochromocytoma
Definitive treatment for localized and regional pheochromocytoma, including localized disease recurrence, consists of alpha- and beta-adrenergic blockade followed by surgery.
Metastatic Pheochromocytoma
For patients with unresectable or metastatic pheochromocytoma, treatment may include a combination of:
Catecholamine blockade.
Surgery.
Chemotherapy.
Radiofrequency ablation.
Cryoablation.
Radiation therapy.
Treatment for patients with localized, regional, metastatic, or recurrent pheochromocytoma is summarized in Table 2.
Table 2. Treatment Options for Patients With Pheochromocytoma
Surgery is the mainstay of treatment for most patients; however, preoperative medical preparation is critical. Alpha-adrenergic blockade should be initiated at the time of diagnosis and maximized preoperatively to prevent potentially life-threatening cardiovascular complications, which can occur as a result of excess catecholamine secretion during surgery. Complications may include:
Hypertensive crisis.
Arrhythmia.
Myocardial infarction.
Pulmonary edema.
Phenoxybenzamine (a nonselective alpha-antagonist) is the usual drug of choice; prazosin, terazosin, and doxazosin (selective alpha-1-antagonists) are alternative choices.[1,2] Prazosin, terazosin, and doxazosin are shorter acting than phenoxybenzamine, and therefore, the duration of postoperative hypotension is theoretically less than with phenoxybenzamine; however, there is less overall experience with selective alpha-1-antagonists than with phenoxybenzamine.
A preoperative treatment period of 1 to 3 weeks is usually sufficient; resolution of spells and a target low normal blood pressure for age indicate that alpha-adrenergic blockade is adequate. During alpha-adrenergic blockade, liberal salt and fluid intake should be encouraged because volume loading reduces excessive orthostatic hypotension both preoperatively and postoperatively. If tachycardia develops or if blood pressure control is not optimal with alpha-adrenergic blockade, a beta-adrenergic blocker (e.g., metoprolol or propranolol) can be added, but only after alpha-blockade. Beta-adrenergic blockade must never be initiated before alpha-adrenergic blockade; doing so blocks beta-adrenergic receptor-mediated vasodilation and results in unopposed alpha-adrenergic receptor-mediated vasoconstriction, which can lead to a life-threatening crisis.
References
Cubeddu LX, Zarate NA, Rosales CB, et al.: Prazosin and propranolol in preoperative management of pheochromocytoma. Clin Pharmacol Ther 32 (2): 156-60, 1982. [PUBMED Abstract]
Prys-Roberts C, Farndon JR: Efficacy and safety of doxazosin for perioperative management of patients with pheochromocytoma. World J Surg 26 (8): 1037-42, 2002. [PUBMED Abstract]
Treatment of Localized Pheochromocytoma
Treatment Options for Localized Pheochromocytoma
Treatment options for localized pheochromocytoma include:
Surgical resection (i.e., adrenalectomy) is the definitive treatment for patients with localized pheochromocytoma. A minimally invasive adrenalectomy is generally the preferred approach if the following conditions can be met:
Preoperative imaging reveals an adrenal pheochromocytoma that is approximately 6 cm or smaller in diameter.
No radiographic evidence of invasion into adjacent structures or evidence of regional or metastatic disease (i.e., presumably a benign tumor).
Normal contralateral adrenal gland.
Both anterior transabdominal laparoscopic adrenalectomy and posterior retroperitoneoscopic adrenalectomy have been demonstrated to be safe for most patients with a modestly sized, radiographically benign pheochromocytoma.[1,2] If preoperative imaging suggests malignancy, or if the patient has an extra-adrenal paraganglioma or multifocal disease, an open approach is generally preferred.
Intraoperative hypertension can be controlled with intravenous infusion of phentolamine, sodium nitroprusside, or a short-acting calcium-channel blocker (e.g., nicardipine). Tumor removal may be followed by a sudden drop in blood pressure that may require rapid volume replacement and intravenous vasoconstrictors (e.g., norepinephrine or phenylephrine). Postoperatively, patients should remain in a monitored environment for 24 hours. Postoperative hypotension is managed primarily by volume expansion, and postoperative hypertension usually responds to diuretics.
Treatment Options for Inherited Pheochromocytoma
Treatment options for inherited pheochromocytoma include:
The surgical management of pheochromocytoma in patients with the hereditary syndromes multiple endocrine neoplasia type 2 (MEN2) or von Hippel-Lindau (VHL) disease has been controversial. In both of these syndromes, pheochromocytoma is bilateral in at least 50% of patients; however, malignancy is very uncommon. Bilateral total adrenalectomy commits all patients to lifelong steroid dependence, and up to 25% of patients will experience Addisonian crisis (acute adrenal insufficiency).[3,4]
Recommendations generally favor preservation of adrenal cortical tissue in patients with MEN2 or VHL when possible. Patients who initially present with unilateral pheochromocytoma should undergo unilateral adrenalectomy, and patients who present with bilateral pheochromocytomas or who develop pheochromocytoma in their remaining adrenal gland should undergo cortical-sparing adrenalectomy, when technically feasible.[3]
Evidence (surgery):
A single-institution study included 56 patients with adrenal pheochromocytomas.[5]
Of the 30 patients who underwent one or more cortical-sparing adrenalectomies, 17 (57%) avoided the need for routine steroid replacement.
The clinical recurrence rate was low (3 of 30 patients) and none of the patients developed metastatic disease.[5][Level of evidence C2]
A similar approach may be reasonable in other hereditary pheochromocytoma-paraganglioma syndromes that are characterized by benign disease, but there are insufficient data upon which to base unequivocal recommendations. For more information, see Genetics of Endocrine and Neuroendocrine Neoplasias.
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References
Walz MK, Alesina PF, Wenger FA, et al.: Posterior retroperitoneoscopic adrenalectomy–results of 560 procedures in 520 patients. Surgery 140 (6): 943-8; discussion 948-50, 2006. [PUBMED Abstract]
Gagner M, Breton G, Pharand D, et al.: Is laparoscopic adrenalectomy indicated for pheochromocytomas? Surgery 120 (6): 1076-9; discussion 1079-80, 1996. [PUBMED Abstract]
Lee JE, Curley SA, Gagel RF, et al.: Cortical-sparing adrenalectomy for patients with bilateral pheochromocytoma. Surgery 120 (6): 1064-70; discussion 1070-1, 1996. [PUBMED Abstract]
de Graaf JS, Dullaart RP, Zwierstra RP: Complications after bilateral adrenalectomy for phaeochromocytoma in multiple endocrine neoplasia type 2–a plea to conserve adrenal function. Eur J Surg 165 (9): 843-6, 1999. [PUBMED Abstract]
Yip L, Lee JE, Shapiro SE, et al.: Surgical management of hereditary pheochromocytoma. J Am Coll Surg 198 (4): 525-34; discussion 534-5, 2004. [PUBMED Abstract]
Treatment of Regional Pheochromocytoma
Treatment Options for Regional Pheochromocytoma
Treatment options for regional pheochromocytoma include:
Surgical resection is the definitive treatment for pheochromocytoma or extra-adrenal paraganglioma that is regionally advanced (e.g., from direct tumor extension into adjacent organs or because of regional lymph node involvement). Data to guide management are limited because regional disease is diagnosed in very few patients who present with pheochromocytoma.[1] However, aggressive surgical resection to remove all existing disease can render patients symptom free.[2] Surgical management of these patients may require en bloc resection of all or part of adjacent organs (e.g., kidney, liver, inferior vena cava) along with extended lymph node dissection. Patients who have undergone complete resection of regional pheochromocytoma require lifelong monitoring for disease recurrence.
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References
Amar L, Servais A, Gimenez-Roqueplo AP, et al.: Year of diagnosis, features at presentation, and risk of recurrence in patients with pheochromocytoma or secreting paraganglioma. J Clin Endocrinol Metab 90 (4): 2110-6, 2005. [PUBMED Abstract]
Zarnegar R, Kebebew E, Duh QY, et al.: Malignant pheochromocytoma. Surg Oncol Clin N Am 15 (3): 555-71, 2006. [PUBMED Abstract]
Treatment of Metastatic Pheochromocytoma
Treatment Options for Metastatic Pheochromocytoma
Treatment options for metastatic pheochromocytoma include:
The most common sites of metastasis for pheochromocytoma or extra-adrenal paraganglioma are lymph nodes, bones, lungs, and liver. Patients with known or suspected malignancy should undergo staging with computed tomography or magnetic resonance imaging as well as functional imaging (e.g., with iodine I 123-metaiodobenzylguanidine [MIBG]) to determine the extent and location of disease. Patients are often very symptomatic from excess catecholamine secretion. Phenoxybenzamine is effective, and metyrosine, which is a drug that blocks catecholamine synthesis, can be added if needed.
Surgery
If all identifiable disease is resectable, including a limited number of distant metastases, surgery can provide occasional long-term remission. If disease is unresectable, surgical debulking will not improve survival; however, it is occasionally indicated for symptom palliation.
Palliative therapy
Chemotherapy
Chemotherapy has not been shown to improve survival in patients with metastatic pheochromocytoma; however, chemotherapy may be useful for symptom palliation.
The best-established chemotherapy regimen is a combination of cyclophosphamide, vincristine, and dacarbazine (the Averbuch protocol).[1]
Evidence (chemotherapy):
A nonrandomized single-arm trial included 18 patients with metastatic malignant pheochromocytoma or paraganglioma. Patients were treated with a combination of cyclophosphamide, vincristine, and dacarbazine.[2]
After 22 years of follow-up, the complete response rate was 11%, the partial response rate was 44%, the biochemical response rate was 72%, and the median survival was 3.3 years.[2][Level of evidence C3]
A retrospective study showed a therapeutic benefit of temozolomide in patients with metastatic pheochromocytoma or paraganglioma. Fifteen consecutive patients with metastatic pheochromocytoma or paraganglioma were enrolled; 10 (67%) had an SDHB variant. The mean dose intensity of temozolomide was 172 mg/m2 daily for 5 days every 28 days.[3]
The median progression-free survival was 13.3 months after a median follow-up of 35 months. Of the 15 patients, 5 (33%) had a partial response, 7 (47%) had stable disease, and 3 (20%) had progressive disease.[3][Level of evidence C3]
Several other chemotherapy regimens have been used in small numbers of patients, but the overall results were disappointing.[4,5]
Targeted therapy
Novel targeted therapies are emerging as potential treatment strategies for metastatic pheochromocytoma. Disappointing initial results were reported with the mammalian target of rapamycin (mTOR) inhibitor everolimus,[6] but results from a very small number of patients treated with the tyrosine kinase inhibitors sunitinib, axitinib, and cabozantinib have been more promising.[7,8][Level of evidence C3]
Radiation therapy
Iodine I 131 (131I)-MIBG radiation therapy has been used for the treatment of patients with MIBG-avid metastases.[9,10] Approximately 60% of metastatic pheochromocytoma or paraganglioma sites are MIBG-avid;[11] protocol-based treatment with other experimental radiolabeled agents, such as radiolabeled somatostatin, can be considered for metastases that do not take up MIBG.
Evidence (radiation therapy):
A phase II study of high-dose 131I-MIBG radiation therapy included 49 patients with metastatic pheochromocytoma or paraganglioma.[11]
Eight percent of patients had a complete response, 14% had a partial response, and the estimated 5-year survival rate was 64%.[11][Level of evidence C3]
Iobenguane I 131 is a high-specific-activity 131I-MIBG agent made of labeled MIBG molecules that allows lower mass doses of MIBG to be given for adult and pediatric patients (age >12 years) with advanced unresectable disease. It has been shown to be safe and generally well tolerated and was approved by the U.S. Food and Drug Administration via fast track designation in 2018.
A phase II, open-label, multicenter trial included 68 patients with pheochromocytoma or paraganglioma. The primary end point was a greater than 50% reduction of all antihypertensive medications lasting for at least 6 months.[12][Level of evidence C3]
Twenty-five percent of evaluable patients experienced a 50% or greater reduction of all antihypertensive medication for at least 6 months.
Overall tumor response was achieved in 22% of patients and, of those patients, 53% experienced durable tumor responses lasting 6 months or longer.
Other therapy
Other palliative treatment modalities include external-beam radiation therapy (e.g., for palliation of bone metastases) and embolization, radiofrequency ablation, or cryoablation (e.g., for palliation of bulky hepatic metastases or isolated bony metastases).
Pheochromocytoma and paraganglioma often express the somatostatin receptor proteins SSTR2 and SSTR3 which may allow for targeted treatment with somatostatin receptor agonists.[13,14] A meta-analysis of studies involving advanced or metastatic pheochromocytoma and paraganglioma patients treated with peptide receptor radionuclide therapy showed that 89.8% of pooled patients had achieved disease stabilization or a partial response.[15][Level of evidence C3]
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References
Averbuch SD, Steakley CS, Young RC, et al.: Malignant pheochromocytoma: effective treatment with a combination of cyclophosphamide, vincristine, and dacarbazine. Ann Intern Med 109 (4): 267-73, 1988. [PUBMED Abstract]
Huang H, Abraham J, Hung E, et al.: Treatment of malignant pheochromocytoma/paraganglioma with cyclophosphamide, vincristine, and dacarbazine: recommendation from a 22-year follow-up of 18 patients. Cancer 113 (8): 2020-8, 2008. [PUBMED Abstract]
Hadoux J, Favier J, Scoazec JY, et al.: SDHB mutations are associated with response to temozolomide in patients with metastatic pheochromocytoma or paraganglioma. Int J Cancer 135 (11): 2711-20, 2014. [PUBMED Abstract]
Nakane M, Takahashi S, Sekine I, et al.: Successful treatment of malignant pheochromocytoma with combination chemotherapy containing anthracycline. Ann Oncol 14 (9): 1449-51, 2003. [PUBMED Abstract]
Kulke MH, Stuart K, Enzinger PC, et al.: Phase II study of temozolomide and thalidomide in patients with metastatic neuroendocrine tumors. J Clin Oncol 24 (3): 401-6, 2006. [PUBMED Abstract]
Druce MR, Kaltsas GA, Fraenkel M, et al.: Novel and evolving therapies in the treatment of malignant phaeochromocytoma: experience with the mTOR inhibitor everolimus (RAD001). Horm Metab Res 41 (9): 697-702, 2009. [PUBMED Abstract]
Jimenez C, Cabanillas ME, Santarpia L, et al.: Use of the tyrosine kinase inhibitor sunitinib in a patient with von Hippel-Lindau disease: targeting angiogenic factors in pheochromocytoma and other von Hippel-Lindau disease-related tumors. J Clin Endocrinol Metab 94 (2): 386-91, 2009. [PUBMED Abstract]
Joshua AM, Ezzat S, Asa SL, et al.: Rationale and evidence for sunitinib in the treatment of malignant paraganglioma/pheochromocytoma. J Clin Endocrinol Metab 94 (1): 5-9, 2009. [PUBMED Abstract]
Buscombe JR, Cwikla JB, Caplin ME, et al.: Long-term efficacy of low activity meta-[131I]iodobenzylguanidine therapy in patients with disseminated neuroendocrine tumours depends on initial response. Nucl Med Commun 26 (11): 969-76, 2005. [PUBMED Abstract]
Scholz T, Eisenhofer G, Pacak K, et al.: Clinical review: Current treatment of malignant pheochromocytoma. J Clin Endocrinol Metab 92 (4): 1217-25, 2007. [PUBMED Abstract]
Gonias S, Goldsby R, Matthay KK, et al.: Phase II study of high-dose [131I]metaiodobenzylguanidine therapy for patients with metastatic pheochromocytoma and paraganglioma. J Clin Oncol 27 (25): 4162-8, 2009. [PUBMED Abstract]
FDA Approves AZEDRA Specified Use in Pheochromocytomas/Paragangliomas. J Nucl Med 59 (10): 17N, 2018. [PUBMED Abstract]
Reubi JC, Waser B, Schaer JC, et al.: Somatostatin receptor sst1-sst5 expression in normal and neoplastic human tissues using receptor autoradiography with subtype-selective ligands. Eur J Nucl Med 28 (7): 836-46, 2001. [PUBMED Abstract]
Mundschenk J, Unger N, Schulz S, et al.: Somatostatin receptor subtypes in human pheochromocytoma: subcellular expression pattern and functional relevance for octreotide scintigraphy. J Clin Endocrinol Metab 88 (11): 5150-7, 2003. [PUBMED Abstract]
Taïeb D, Jha A, Treglia G, et al.: Molecular imaging and radionuclide therapy of pheochromocytoma and paraganglioma in the era of genomic characterization of disease subgroups. Endocr Relat Cancer 26 (11): R627-R652, 2019. [PUBMED Abstract]
Treatment of Recurrent Pheochromocytoma
Treatment Options for Recurrent Pheochromocytoma
Treatment options for recurrent pheochromocytoma include:
After resection of a localized pheochromocytoma presumed to represent a benign tumor and documented normal postoperative biochemical testing, disease recurrence occurs in 6.5% to 16.5% of patients, and 50% of patients with disease recurrence develop metastatic disease.[1–3] Insufficient data exist to determine recurrence rates after complete surgical resection of regional or metastatic disease.
Surgery
Treatment for recurrent disease involves appropriate medical management (i.e., alpha-adrenergic blockade) followed by complete surgical resection, when possible.
Palliative therapy
Palliation of symptoms, including those related to catecholamine excess and local mass effect, is the primary focus of treatment for disease that is not resectable.
Options for patients with local-regional or metastatic disease who are not considered candidates for surgical resection include:
Chemotherapy.
Targeted therapies.
High-dose iodine I 131-metaiodobenzylguanidine radiation therapy.
Treatment Options for Inherited Pheochromocytoma or Paraganglioma
Patients with inherited pheochromocytoma or paraganglioma are at risk of recurrent disease in the form of additional primary tumors. Follow-up evaluation and management of additional primary tumors in such patients is essential. For more information, see the Treatment of Localized Pheochromocytoma section.
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References
Plouin PF, Chatellier G, Fofol I, et al.: Tumor recurrence and hypertension persistence after successful pheochromocytoma operation. Hypertension 29 (5): 1133-9, 1997. [PUBMED Abstract]
van Heerden JA, Roland CF, Carney JA, et al.: Long-term evaluation following resection of apparently benign pheochromocytoma(s)/paraganglioma(s). World J Surg 14 (3): 325-9, 1990 May-Jun. [PUBMED Abstract]
Amar L, Servais A, Gimenez-Roqueplo AP, et al.: Year of diagnosis, features at presentation, and risk of recurrence in patients with pheochromocytoma or secreting paraganglioma. J Clin Endocrinol Metab 90 (4): 2110-6, 2005. [PUBMED Abstract]
Treatment of Pheochromocytoma During Pregnancy
Pheochromocytoma diagnosed during pregnancy is extremely rare (0.007% of all pregnancies).[1,2] However, women with hereditary conditions that increase the risk of developing pheochromocytoma are often also of childbearing age, and the outcome of undiagnosed pheochromocytoma during pregnancy can be catastrophic.
Diagnosis
Prenatal diagnosis clearly results in decreased mortality for both mother and fetus.[3] Prior to 1970, a prenatal diagnosis of pheochromocytoma was made in only approximately 25% of cases, and the mortality rate for both mother and fetus was around 50%.[4,5] The prenatal diagnosis rate rose to greater than 80% through the 1980s and 1990s, and decreased maternal and fetal mortality rates were 6% and 15%, respectively.[4,6]
The diagnosis of pheochromocytoma should be suspected in any pregnant woman who develops hypertension in the first trimester, paroxysmal hypertension, or hypertension that is unusually difficult to treat.[2,7] Normal pregnancy does not affect catecholamine levels.[8] Thus, the usual biochemical tests are valid. Magnetic resonance imaging is the localization method of choice because it does not expose the fetus to ionizing radiation.
Treatment Options for Pheochromocytoma During Pregnancy
Phenoxybenzamine use is safe in pregnancy, but beta-adrenergic blockers should be initiated only if needed because their use has been associated with intrauterine growth restriction.[9,10] Resection of the tumor can often be performed safely during the second trimester, or tumor resection can be combined with cesarean delivery for patients diagnosed later in pregnancy.[2] Case reports have documented successful outcomes in the rare circumstance when surgical resection was delayed until a short time after vaginal delivery.[11] The successful management of pheochromocytoma in pregnancy depends on careful monitoring and the availability of an experienced team of specialists.
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References
Harrington JL, Farley DR, van Heerden JA, et al.: Adrenal tumors and pregnancy. World J Surg 23 (2): 182-6, 1999. [PUBMED Abstract]
Sarathi V, Lila AR, Bandgar TR, et al.: Pheochromocytoma and pregnancy: a rare but dangerous combination. Endocr Pract 16 (2): 300-9, 2010 Mar-Apr. [PUBMED Abstract]
Freier DT, Thompson NW: Pheochromocytoma and pregnancy: the epitome of high risk. Surgery 114 (6): 1148-52, 1993. [PUBMED Abstract]
Mannelli M, Bemporad D: Diagnosis and management of pheochromocytoma during pregnancy. J Endocrinol Invest 25 (6): 567-71, 2002. [PUBMED Abstract]
Schenker JG, Granat M: Phaeochromocytoma and pregnancy–an updated appraisal. Aust N Z J Obstet Gynaecol 22 (1): 1-10, 1982. [PUBMED Abstract]
Ahlawat SK, Jain S, Kumari S, et al.: Pheochromocytoma associated with pregnancy: case report and review of the literature. Obstet Gynecol Surv 54 (11): 728-37, 1999. [PUBMED Abstract]
Keely E: Endocrine causes of hypertension in pregnancy–when to start looking for zebras. Semin Perinatol 22 (6): 471-84, 1998. [PUBMED Abstract]
Jaffe RB, Harrison TS, Cerny JC: Localization of metastatic pheochromocytoma in pregnancy by caval catheterization. Including urinary catecholamine values in uncomplicated pregnancies. Am J Obstet Gynecol 104 (7): 939-44, 1969. [PUBMED Abstract]
Butters L, Kennedy S, Rubin PC: Atenolol in essential hypertension during pregnancy. BMJ 301 (6752): 587-9, 1990. [PUBMED Abstract]
Montan S, Ingemarsson I, Marsál K, et al.: Randomised controlled trial of atenolol and pindolol in human pregnancy: effects on fetal haemodynamics. BMJ 304 (6832): 946-9, 1992. [PUBMED Abstract]
Junglee N, Harries SE, Davies N, et al.: Pheochromocytoma in Pregnancy: When is Operative Intervention Indicated? J Womens Health (Larchmt) 16 (9): 1362-5, 2007. [PUBMED Abstract]
Latest Updates to This Summary (12/12/2024)
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Editorial changes were made to this summary.
This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.
About This PDQ Summary
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of pheochromocytoma and paraganglioma. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
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Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewer for Pheochromocytoma and Paraganglioma Treatment is:
Jaydira del Rivero, MD (National Cancer Institute)
Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website’s Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
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PDQ® Adult Treatment Editorial Board. PDQ Pheochromocytoma and Paraganglioma Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/pheochromocytoma/hp/pheochromocytoma-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389312]
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Pheochromocytoma and paraganglioma are rare tumors that can be benign (not cancer) or malignant. Pheochromocytomas form in the adrenal glands, and paragangliomas usually along nerve pathways in the head, neck, and spine. Explore the links on this page to learn more about these tumors, their treatment, research, and clinical trials.
Screening, usually at age 6 months, for urine vanillylmandelic acid and homovanillic acid, which are metabolites of the hormones, norepinephrine and dopamine.
Benefits
Based on solid evidence, screening for neuroblastoma does not lead to decreased mortality.
Description of the Evidence
Study Design: Evidence obtained from nonrandomized controlled trials.
Internal Validity: Good.
Consistency: Good.
Magnitude of Effects on Health Outcomes: No effect on mortality.
External Validity: Fair.
Harms
Based on solid evidence, screening infants for neuroblastoma leads to an increase in incidence of early-stage neuroblastoma. There is no concurrent decrease in incidence in children who are screened for advanced-stage disease, which typically has a poor outcome, or in children older than 1 year. The cases identified by screening almost exclusively have biologically favorable properties.
Based on solid evidence, screening infants for neuroblastoma results in overdiagnosis (diagnosis of some neuroblastomas detectable by mass screening that would not have been clinically diagnosed later). This leads to unnecessary diagnostic and therapeutic procedures with consequent physical and psychological morbidity, including death from treatment complications.
Description of the Evidence
Study Design: Evidence obtained from nonrandomized controlled trials.
Internal Validity: Good.
Consistency: Good.
Magnitude of Effects on Health Outcomes: No effect on mortality. Screening may overdiagnose as many as seven cases per 100,000 infants screened.
External Validity: Fair.
Significance
Incidence and Mortality
About 7% of all malignancies in children younger than 15 years are neuroblastomas. About one-quarter of cancers in the first year of life are neuroblastomas, making this the most frequent histological type of infant cancer.[1,2] The incidence rate of the disease in children younger than 1 year is about 35 per million but declines rapidly with age to about 1 per million between ages 10 and 14 years.[3] Males appear to be affected slightly more commonly than females, with about five cases occurring in boys to every four occurring in girls.
Screening Method and Sensitivity
The risk factors for and causes of neuroblastoma have not been established, and therefore it is not possible to provide information or advice for the primary prevention of this disease. It is generally thought that many neuroblastomas are present and detectable at birth, thereby allowing for detection of tumors by a single, once-in-a-lifetime screening test, such as those used for neonatal screening for noncancerous conditions (e.g., phenylketonuria). Screening is performed through biochemical tests for metabolites of norepinephrine and dopamine (i.e., vanillylmandelic acid [VMA], and homovanillic acid [HVA]). Seventy-five percent to 90% of cases of neuroblastoma excrete these substances into the urine, which can be measured in urine specimens.[4] There is no known optimal age for screening, but the most commonly discussed and studied age for a one-time screen has been 6 months. Screening at 12 months has also been evaluated in a population-based study in Germany.[5] Approximately 65% of cases are present before 6 months.[6] Furthermore, the clinical significance of screen-detected neuroblastomas is in question since stage I and II localized tumors less than 5 cm have been observed to regress without treatment in an observational study.[7]
Testing of liquid urine samples or of samples collected on filter paper for VMA and HVA is possible.[8] The first attempts to conduct mass screening through urinary testing occurred in Japan in the early 1970s.[9] The VMA and HVA levels are usually measured by gas chromatography, thin layer chromatography, and/or high performance liquid chromatography.
There are no standard cutoff levels between positive and negative VMA and HVA tests. One recommendation is to use a VMA cutoff level of 25 μg/mg creatinine and an HVA cutoff level of 32 μg/mg creatinine. Alternatively, individual laboratories use a level of two standard deviations above that laboratory’s age-specific mean to identify specimens for reanalysis. On reanalysis, a level of three standard deviations above the mean is used to determine the need for diagnostic evaluation.[10]
The sensitivity of the screening procedure used in different studies ranges from 40% to 80%.[10–13] False-positives results can be caused by dietary agents such as bananas and vanilla [14] but are rare with quantitative assays such as gas chromatography (specificity approximates 99.9%).[12,15] Because of the low prevalence of the disease, even in the Quebec Neuroblastoma Screening Project in which the specificity of the test was extremely high, the positive-predictive value was only 52%,[11] i.e., for every two children identified by screening as being likely to have neuroblastoma, only one was actually affected. In the German Neuroblastoma Screening Project, the positive-predictive value has been reported as only 8.4%.[5] False-positive cases are generally followed for prolonged periods with serial noninvasive testing before a definitive diagnosis excluding cancer can be offered to the parents.[16]
References
Gurney JG, Severson RK, Davis S, et al.: Incidence of cancer in children in the United States. Sex-, race-, and 1-year age-specific rates by histologic type. Cancer 75 (8): 2186-95, 1995. [PUBMED Abstract]
Gao RN, Levy IG, Woods WG, et al.: Incidence and mortality of neuroblastoma in Canada compared with other childhood cancers. Cancer Causes Control 8 (5): 745-54, 1997. [PUBMED Abstract]
Stiller CA, Parkin DM: International variations in the incidence of neuroblastoma. Int J Cancer 52 (4): 538-43, 1992. [PUBMED Abstract]
Williams CM, Greer M: Homovanillic acid and vanilmandelic acid in diagnosis of neuroblastoma. JAMA 183: 836-40, 1963. [PUBMED Abstract]
Schilling FH, Spix C, Berthold F, et al.: Children may not benefit from neuroblastoma screening at 1 year of age. Updated results of the population based controlled trial in Germany. Cancer Lett 197 (1-2): 19-28, 2003. [PUBMED Abstract]
Parker L, Craft AW: Neuroblastoma screening: more questions than answers? Eur J Cancer 27 (6): 682-3, 1991. [PUBMED Abstract]
Yamamoto K, Hanada R, Kikuchi A, et al.: Spontaneous regression of localized neuroblastoma detected by mass screening. J Clin Oncol 16 (4): 1265-9, 1998. [PUBMED Abstract]
Tuchman M, Auray-Blais C, Ramnaraine ML, et al.: Determination of urinary homovanillic and vanillylmandelic acids from dried filter paper samples: assessment of potential methods for neuroblastoma screening. Clin Biochem 20 (3): 173-7, 1987. [PUBMED Abstract]
Sawada T: Past and future of neuroblastoma screening in Japan. Am J Pediatr Hematol Oncol 14 (4): 320-6, 1992. [PUBMED Abstract]
Chamberlain J: Screening for neuroblastoma: a review of the evidence. J Med Screen 1 (3): 169-75, 1994. [PUBMED Abstract]
Woods WG, Tuchman M, Robison LL, et al.: A population-based study of the usefulness of screening for neuroblastoma. Lancet 348 (9043): 1682-7, 1996 Dec 21-28. [PUBMED Abstract]
Nishi M, Miyake H, Takeda T, et al.: Mass screening for neuroblastoma and estimation of costs. Acta Paediatr Scand 80 (8-9): 812-7, 1991 Aug-Sep. [PUBMED Abstract]
Chamberlain J: Neuroblastoma. In: Chamberlain J, Moss S, eds.: Evaluation of Cancer Screening. Springer, 1996, pp 145-149.
Woods WG, Tuchman M: Neuroblastoma: the case for screening infants in North America. Pediatrics 79 (6): 869-73, 1987. [PUBMED Abstract]
Scriver CR, Gregory D, Bernstein M, et al.: Feasibility of chemical screening of urine for neuroblastoma case finding in infancy in Quebec. CMAJ 136 (9): 952-6, 1987. [PUBMED Abstract]
Bernstein ML, Woods WG: Screening for neuroblastoma. In: Miller AB, ed.: Advances in Cancer Screening. Kluwer Academic Publishers, 1996, pp 149-163.
Evidence of Benefit
Evidence of screening effect derives from descriptive studies of local and national programs in Japan, uncontrolled pilot experiences at a number of sites in Europe and the United States, and population-based studies in Canada and Germany.[1–7]
An increase in survival rates among screen-detected cases would be expected if screening was detecting neuroblastoma at an earlier and more curable stage. While improved survival rates after initiation of screening have been reported,[8,9] these observations should be viewed cautiously because improvements could be caused by lead-time bias, length bias, and identification of cases through screening that would have spontaneously regressed.
Screening results in an increased incidence of early-stage disease. The cases detected by screening almost exclusively have biologically favorable properties (unamplified N-myc oncogene, near triploidy, and favorable histology), and this type of favorable neuroblastoma has a high survival rate, whether detected by screening or detected clinically.[1,6,7,10–17] There is evidence that some tumors regress spontaneously in the absence of treatment.[18–21]
Some authors have argued that the Japanese experience shows that the number of children older than 1 year, who are diagnosed with neuroblastoma, may have decreased since the inception of screening [22] and that overall mortality has declined during this period.[12,23] A true reduction in neuroblastoma mortality may reflect improvements in treatment efficacy as much as a benefit of treating earlier-stage disease. Mortality has decreased in other countries where screening does not occur.[24] In another study of regional comparisons, disease rates were compared between Osaka, Japan, where screenings were initiated in 1985, and Great Britain, where screening was not done.[25] There was little change during this time in the cumulative mortality rates in either region; 52 versus 57.5 per million between 1970 and 1979 versus 1991 and 1994 in Osaka, compared with 78.6 versus 70.1 in the corresponding periods in Great Britain. In any case, the majority of cases detected by screening at 6 months appear to have biologically favorable prognoses independent of stage.[1,26–29] Furthermore, despite the shift in stage distribution of cases detected by screening compared with those that are routinely detected, the evidence of reduction in the incidence of advanced-stage cancers in the Japanese experience has been disputed;[3,11,30] in the Quebec Project, as noted below, no such reduction is observed.[1]
A study of mortality trends before and after the national mass screening program in Japan for neuroblastoma analyzed age-specific mortality rates from 1980 through 2006. Screening began in the mid-1980s and was halted in 2003. Mortality rates were either stable through the entire period for age groups 5 years to 9 years and 10 years to 14 years, or were declining before the initiation of screening and continued to do so through 2006 for age groups younger than 1 year and 1 year to 4 years. Because the most recent year of death analyzed was 2006, any increase in age-specific mortality associated with the cessation of mass screening in 2003 would have been expected to occur among children younger than 1 year or 1 year to 4 years. No such increase was observed. This is the first postscreening analysis to provide evidence that screening had no impact on mortality rates and that stopping screening had no adverse effect.[31]
A study compared neuroblastoma incidence and mortality rates in Japan in three cohorts: children born before screening between 1980 and 1983, and those born during screening between 1986 and 1989, and between 1990 and 1998.[32] Cumulative incidence was higher in the screened cohorts (21.56–29.80 cases per 100,000 births) compared with the prescreening cohort (11.56 cases). Cumulative mortality was lower in the screened cohorts compared with the prescreening cohort (2.83–3.90 vs. 5.38 deaths per 100,000 births). The impact of changes in treatment on these rates is unclear.
Before and after the cessation of the Japanese mass screening program in 2003, another study of neuroblastoma incidence and mortality was conducted in five prefectures (incidence) and nationwide (mortality). This study extended follow-up after cessation of screening several years beyond that reported in previous publications.[33] The incidence rate for infants younger than 1 year, the screened age-group, dropped markedly after the cessation of screening, while the rate for older children remained similar. The mortality rate in each age group was very similar over the entire time period studied (1993–2014). In addition, children were divided into two birth cohorts, those born before the cessation of screening (2003 or earlier) and those born 2004 or later. Cumulative incidence up to 5 years was lower after the cessation of screening, but there was no substantial change in mortality. Results of the mass screening program in Japan are consistent with no effect on neuroblastoma mortality and document that the program caused substantial overdiagnosis with no counterbalancing benefit.[33]
The Quebec Neuroblastoma Screening Project compared neuroblastoma incidence and mortality in a 5-year birth cohort (n = 476,603) from Quebec (where urinary screening was offered at 3 weeks and 6 months [overall compliance, 92%]) with various North American birth cohorts in which no screening took place. In this study, the incidence of early-stage disease in children younger than 1 year, in the screened population, more than doubled that expected; while in the control population, it approximated that expected (standardized incidence ratio, 3.03; 95% confidence interval [CI], 2.30–3.86) in Quebec versus 0.82 in Minnesota (95% CI, 0.41–1.38) and Ontario (95% CI, 0.53–1.17).[1] The incidence of advanced-stage disease (stage III and stage IV) in older children in Quebec showed a statistically nonsignificant increase over that which would have been expected (standard incidence ratio, 1.52; 95% CI, 0.95–2.23).[1] After approximately 8 years of follow-up (range 6–11 years) the neuroblastoma death rate in the screened population was not significantly different from rates in unscreened populations (standardized mortality ratio, 1.11 [95% CI, 0.64–1.92] for the Quebec cohort compared with Ontario children).[7] Similar findings were observed in the German neuroblastoma study.[34] Although final mortality rates are expected in 2008, an interim analysis shows that the death rate from neuroblastoma is similar in screened and control populations (1.6 vs. 1.9 deaths per 100,000 children). A study in Austria yielded a similar conclusion, though screening was performed at age 7 to 12 months. In the screening cohort, neuroblastoma incidence was statistically significantly higher than in children who were not screened (18.2 vs. 11.2 per 100,000 births), while mortality was not statistically significantly different (0.96 vs. 1.57 per 100,000 births).[35]
There is no evidence from controlled studies or randomized trials of decreases in mortality associated with screening.
References
Woods WG, Tuchman M, Robison LL, et al.: A population-based study of the usefulness of screening for neuroblastoma. Lancet 348 (9043): 1682-7, 1996 Dec 21-28. [PUBMED Abstract]
Parker L, Craft AW, Dale G, et al.: Screening for neuroblastoma in the north of England. BMJ 305 (6864): 1260-3, 1992. [PUBMED Abstract]
Bessho F, Hashizume K, Nakajo T, et al.: Mass screening in Japan increased the detection of infants with neuroblastoma without a decrease in cases in older children. J Pediatr 119 (2): 237-41, 1991. [PUBMED Abstract]
Takeda T: History and current status of neuroblastoma screening in Japan. Med Pediatr Oncol 17 (5): 361-3, 1989. [PUBMED Abstract]
Chauvin F, Mathieu P, Frappaz D, et al.: Screening for neuroblastoma in France: methodological aspects and preliminary observations. Med Pediatr Oncol 28 (2): 81-91, 1997. [PUBMED Abstract]
Schilling FH, Spix C, Berthold F, et al.: Neuroblastoma screening at one year of age. N Engl J Med 346 (14): 1047-53, 2002. [PUBMED Abstract]
Woods WG, Gao RN, Shuster JJ, et al.: Screening of infants and mortality due to neuroblastoma. N Engl J Med 346 (14): 1041-6, 2002. [PUBMED Abstract]
Sawada T, Matsumura T, Kawakatsu H, et al.: Long-term effects of mass screening for neuroblastoma in infancy. Am J Pediatr Hematol Oncol 13 (1): 3-7, 1991 Spring. [PUBMED Abstract]
Nishi M, Miyake H, Takeda T, et al.: Effects of the mass screening of neuroblastoma in Sapporo City. Cancer 60 (3): 433-6, 1987. [PUBMED Abstract]
Bernstein ML, Woods WG: Screening for neuroblastoma. In: Miller AB, ed.: Advances in Cancer Screening. Kluwer Academic Publishers, 1996, pp 149-163.
Yamamoto K, Hayashi Y, Hanada R, et al.: Mass screening and age-specific incidence of neuroblastoma in Saitama Prefecture, Japan. J Clin Oncol 13 (8): 2033-8, 1995. [PUBMED Abstract]
Asami T, Otabe N, Wakabayashi M, et al.: Screening for neuroblastoma: a 9-year birth cohort-based study in Niigata, Japan. Acta Paediatr 84 (10): 1173-6, 1995. [PUBMED Abstract]
Naito H, Sasaki M, Yamashiro K, et al.: Improvement in prognosis of neuroblastoma through mass population screening. J Pediatr Surg 25 (2): 245-8, 1990. [PUBMED Abstract]
Takeuchi LA, Hachitanda Y, Woods WG, et al.: Screening for neuroblastoma in North America. Preliminary results of a pathology review from the Quebec Project. Cancer 76 (11): 2363-71, 1995. [PUBMED Abstract]
Look AT, Hayes FA, Shuster JJ, et al.: Clinical relevance of tumor cell ploidy and N-myc gene amplification in childhood neuroblastoma: a Pediatric Oncology Group study. J Clin Oncol 9 (4): 581-91, 1991. [PUBMED Abstract]
Bowman LC, Castleberry RP, Cantor A, et al.: Genetic staging of unresectable or metastatic neuroblastoma in infants: a Pediatric Oncology Group study. J Natl Cancer Inst 89 (5): 373-80, 1997. [PUBMED Abstract]
Brodeur GM, Look AT, Shimada H, et al.: Biological aspects of neuroblastomas identified by mass screening in Quebec. Med Pediatr Oncol 36 (1): 157-9, 2001. [PUBMED Abstract]
Yamamoto K, Hanada R, Kikuchi A, et al.: Spontaneous regression of localized neuroblastoma detected by mass screening. J Clin Oncol 16 (4): 1265-9, 1998. [PUBMED Abstract]
Nishihira H, Toyoda Y, Tanaka Y, et al.: Natural course of neuroblastoma detected by mass screening: s 5-year prospective study at a single institution. J Clin Oncol 18 (16): 3012-7, 2000. [PUBMED Abstract]
Tanaka T, Matsumura T, Iehara T, et al.: Risk of unfavorable character among neuroblastomas detected through mass screening. The Japanese Infantile Neuroblastoma Cooperative Study. Med Pediatr Oncol 35 (6): 705-7, 2000. [PUBMED Abstract]
Yoneda A, Oue T, Imura K, et al.: Observation of untreated patients with neuroblastoma detected by mass screening: a “wait and see” pilot study. Med Pediatr Oncol 36 (1): 160-2, 2001. [PUBMED Abstract]
Sawada T: Past and future of neuroblastoma screening in Japan. Am J Pediatr Hematol Oncol 14 (4): 320-6, 1992. [PUBMED Abstract]
Hanawa Y, Sawada T, Tsunoda A: Decrease in childhood neuroblastoma death in Japan. Med Pediatr Oncol 18 (6): 472-5, 1990. [PUBMED Abstract]
Cole M, Parker L, Craft A: “Decrease in childhood neuroblastoma death in Japan,” Hanawa et al. (1990) Med Pediatr Oncol 20 (1): 84-5, 1992. [PUBMED Abstract]
Honjo S, Doran HE, Stiller CA, et al.: Neuroblastoma trends in Osaka, Japan, and Great Britain 1970-1994, in relation to screening. Int J Cancer 103 (4): 538-43, 2003. [PUBMED Abstract]
Hachitanda Y, Ishimoto K, Hata J, et al.: One hundred neuroblastomas detected through a mass screening system in Japan. Cancer 74 (12): 3223-6, 1994. [PUBMED Abstract]
Hayashi Y, Hanada R, Yamamoto K: Biology of neuroblastomas in Japan found by screening. Am J Pediatr Hematol Oncol 14 (4): 342-7, 1992. [PUBMED Abstract]
Nakagawara A, Zaizen Y, Ikeda K, et al.: Different genomic and metabolic patterns between mass screening-positive and mass screening-negative later-presenting neuroblastomas. Cancer 68 (9): 2037-44, 1991. [PUBMED Abstract]
Kaneko Y, Kanda N, Maseki N, et al.: Current urinary mass screening for catecholamine metabolites at 6 months of age may be detecting only a small portion of high-risk neuroblastomas: a chromosome and N-myc amplification study. J Clin Oncol 8 (12): 2005-13, 1990. [PUBMED Abstract]
Bessho F: Effects of mass screening on age-specific incidence of neuroblastoma. Int J Cancer 67 (4): 520-2, 1996. [PUBMED Abstract]
Katanoda K, Hayashi K, Yamamoto K, et al.: Secular trends in neuroblastoma mortality before and after the cessation of national mass screening in Japan. J Epidemiol 19 (5): 266-70, 2009. [PUBMED Abstract]
Hiyama E, Iehara T, Sugimoto T, et al.: Effectiveness of screening for neuroblastoma at 6 months of age: a retrospective population-based cohort study. Lancet 371 (9619): 1173-80, 2008. [PUBMED Abstract]
Shinagawa T, Kitamura T, Katanoda K, et al.: The incidence and mortality rates of neuroblastoma cases before and after the cessation of the mass screening program in Japan: A descriptive study. Int J Cancer 140 (3): 618-625, 2017. [PUBMED Abstract]
Schilling FH, Spix C, Berthold F, et al.: Children may not benefit from neuroblastoma screening at 1 year of age. Updated results of the population based controlled trial in Germany. Cancer Lett 197 (1-2): 19-28, 2003. [PUBMED Abstract]
Kerbl R, Urban CE, Ambros IM, et al.: Neuroblastoma mass screening in late infancy: insights into the biology of neuroblastic tumors. J Clin Oncol 21 (22): 4228-34, 2003. [PUBMED Abstract]
Latest Updates to This Summary (06/15/2023)
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Added text to state that the Summary of Evidence section summarizes the published evidence on the topic of neuroblastoma screening. The rest of the summary describes the evidence in more detail.
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About This PDQ Summary
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about neuroblastoma screening. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.
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EnlargeNeuroblastoma may be found in the adrenal glands and paraspinal nerve tissue from the neck to the pelvis.
Neuroblastoma most often begins in infancy. It is usually diagnosed between the first month of life and age 5 years. The tumor is found when it begins to grow and cause signs or symptoms. Sometimes it forms before birth and is found during an ultrasound of the baby.
Certain genetic conditions affect the risk of having neuroblastoma.
Neuroblastoma is caused by certain changes to the way neuroblast cells function, especially how they grow and divide into new cells. There are many risk factors for neuroblastoma, but many do not directly cause cancer. Instead, they increase the chance of DNA damage in cells that may lead to neuroblastoma. Learn more about how cancer develops at What Is Cancer?
A risk factor is anything that increases the chance of getting a disease. Some risk factors can be changed. Risk factors also include things people cannot change, like family history. It’s important to learn about risk factors for neuroblastoma because it can help you make choices about screening for cancer.
ROHHAD syndromes (rapid-onset obesity, hypothalamic dysfunction, hypoventilation, and autonomic dysfunction)
having a strong family history of neuroblastoma
Genetic testing can determine whether a child has an inherited form of neuroblastoma.
Gene mutations that increase the risk of neuroblastoma are sometimes inherited (passed from the parent to the child). In children with a gene mutation, neuroblastoma usually occurs at a younger age, and more than one tumor may form in the adrenal glands or in the nerve tissue in the neck, chest, abdomen, or pelvis.
It is not always clear from the family medical history whether a condition is inherited. Certain families may benefit from genetic counseling and genetic testing. Genetic counselors and other specially trained health professionals can discuss a child’s diagnosis and the family’s medical history to understand:
the options for ALK or PHOX2B gene testing
the risk of neuroblastoma for your child and your child’s siblings
the risks and benefits of learning genetic information
Genetic counselors can also help parents cope with their child’s genetic testing results, including how to discuss the results with family members.
Once it is known that your child has an inherited form of neuroblastoma, other family members can be screened for the ALK or PHOX2B mutation.
Sometimes children with certain gene mutations should be checked for signs of neuroblastoma.
Children with certain gene mutations or hereditary (inherited) syndromes should be checked for signs of neuroblastoma until they are 10 years old. The following tests may be used:
Abdominal ultrasound: A test in which high-energy sound waves (ultrasound) are bounced off the abdomen and make echoes. The echoes form a picture of the abdomen called a sonogram.
Urine catecholamine studies: A test in which a urine sample is checked to measure the amounts of certain substances, vanillylmandelic acid (VMA) and homovanillic acid (HVA), that are made when catecholamines break down and are released into the urine. A higher-than-normal amount of VMA or HVA can be a sign of neuroblastoma.
Chest x-ray: An x-ray of the organs and bones inside the chest. An x-ray is a type of energy beam that can go through the body and onto film, making a picture of areas inside the body.
Talk to your child’s doctor about how often these tests need to be done.
Signs and symptoms of neuroblastoma include bone pain or a lump in the abdomen, neck, or chest.
The most common signs and symptoms of neuroblastoma are caused by the tumor pressing on nearby tissues as it grows or by cancer spreading to the bone.
Check with your child’s doctor if your child has:
a lump in the abdomen, neck, or chest
bone pain
a swollen stomach and trouble breathing (in infants)
bulging eyes
dark circles around the eyes (“black eyes”)
painless, bluish lumps under the skin (in infants)
weakness or paralysis (loss of ability to move a body part)
Less common signs and symptoms of neuroblastoma include:
Horner syndrome (droopy eyelid, smaller pupil, and less sweating on one side of the face)
jerky muscle movements
uncontrolled eye movements
These and other signs and symptoms may be caused by neuroblastoma or by other conditions. The only way to know is to see your child’s doctor.
Tests that examine many different body tissues and fluids are used to diagnose neuroblastoma.
If your child has symptoms that suggest neuroblastoma, the doctor will need to find out if these are due to cancer or another condition. The doctor will ask when the symptoms started and how often your child has been having them. They will also ask about your child’s personal and family medical history and do a physical exam.
Depending on your child’s symptoms and medical history and the results of their physical and neurological exam, the doctor may recommend more tests to find out if your child has neuroblastoma, and if so, its extent (stage). If neuroblastoma is diagnosed, the results of these tests and procedures will help you and your child’s doctor make decisions about treatment.
The following tests and procedures may be used:
Urine catecholamine studies: A test in which a urine sample is checked to measure the amounts of certain substances, vanillylmandelic acid (VMA) and homovanillic acid (HVA), that are made when catecholamines break down and are released into the urine. A higher-than-normal amount of VMA or HVA can be a sign of neuroblastoma.
Blood chemistry studies: A test in which a blood sample is checked to measure the amounts of certain substances released into the blood by organs and tissues in the body. A higher-than-normal amount of lactate dehydrogenase (LDH) can be a sign of disease.
Ferritin level: A test in which a blood sample is checked to measure the amount of ferritin (a protein that stores iron in cells). A higher-than-normal amount may be a sign of disease.
MIBG scan: A procedure used to find neuroendocrine tumors, such as neuroblastoma. A very small amount of a substance called radioactive MIBG is injected into a vein and travels through the bloodstream. Neuroendocrine tumor cells take up the radioactive MIBG and are detected by a scanner. Scans may be taken over 1–3 days. An iodine solution may be given before or during the test to keep the thyroid gland from absorbing too much of the MIBG. This test is also used to find out how well the tumor is responding to treatment. MIBG is also used in high doses to treat neuroblastoma.
CT scan (CAT scan): A procedure that makes a series of detailed pictures of areas inside the body, taken from different angles. The pictures are made by a computer linked to an x-ray machine. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography. Learn more about Computed Tomography (CT) Scans and Cancer. EnlargeComputed tomography (CT) scan. The child lies on a table that slides through the CT scanner, which takes a series of detailed x-ray pictures of areas inside the body.
MRI (magnetic resonance imaging) with gadolinium: A procedure that uses a magnet, radio waves, and a computer to make a series of detailed pictures of areas inside the body. A substance called gadolinium is injected into a vein. The gadolinium collects around the cancer cells so they show up brighter in the picture. This procedure is also called nuclear magnetic resonance imaging (NMRI). EnlargeMagnetic resonance imaging (MRI) scan. The child lies on a table that slides into the MRI machine, which takes a series of detailed pictures of areas inside the body. The positioning of the child on the table depends on the part of the body being imaged.
PET scan (positron emission tomography scan): A procedure to find malignant tumor cells in the body. A small amount of radioactive glucose (sugar) is injected into a vein. The PET scanner rotates around the body and makes a picture of where glucose is being used in the body. Malignant tumor cells show up brighter in the picture because they are more active and take up more glucose than normal cells do. This test will usually only be done if the tumor does not take up MIBG.
X-ray of the chest or bone: An x-ray is a type of energy beam that can go through the body and onto film, making a picture of areas inside the body.
Ultrasound exam: A procedure in which high-energy sound waves (ultrasound) are bounced off internal tissues or organs and make echoes. The echoes form a picture of body tissues called a sonogram. An ultrasound exam is not done if a CT/MRI has been done. EnlargeAbdominal ultrasound. An ultrasound transducer connected to a computer is pressed against the skin of the abdomen. The transducer bounces sound waves off internal organs and tissues to make echoes that form a sonogram (computer picture).
Tumor biopsy: Cells and tissues are removed during a biopsy so they can be viewed under a microscope by a pathologist to check for signs of cancer. The way the biopsy is done depends on where the tumor is in the body. Sometimes the whole tumor is removed at the same time the biopsy is done. The doctor who reviews the tumor biopsy will determine if the tumor appears to have more favorable or unfavorable features. These features may affect treatment and survival.
Children up to age 6 months may not need a biopsy or surgery to remove the tumor because the tumor may disappear without treatment.
Bone marrow aspiration and biopsy: The removal of bone marrow, blood, and a small piece of bone by inserting a hollow needle into the hipbone or breastbone. A pathologist views the bone marrow, blood, and bone under a microscope to look for signs of cancer. This test is also used to stage the tumor. EnlargeBone marrow aspiration and biopsy. After a small area of skin is numbed, a bone marrow needle is inserted into the child’s hip bone. Samples of blood, bone, and bone marrow are removed for examination under a microscope.
Lymph node biopsy: The removal of all or part of a lymph node. A pathologist views the lymph node tissue under a microscope to check for cancer cells. This test is used to diagnose and stage the tumor. One of the following types of biopsies may be done:
Light microscopy: A laboratory test in which cells in a sample of tissue are viewed under regular and high-powered microscopes to look for certain changes in the cells.
Immunohistochemistry: A laboratory test that uses antibodies to check for certain antigens (markers) in a sample of a patient’s tissue. The antibodies are usually linked to an enzyme or a fluorescent dye. After the antibodies bind to a specific antigen in the tissue sample, the enzyme or dye is activated, and the antigen can then be seen under a microscope. This type of test is used to help diagnose cancer and to help tell one type of cancer from another type of cancer.
Molecular testing: A molecular test checks for certain genes, proteins, or other molecules in a sample of tissue, blood, or bone marrow. Molecular tests also check for certain changes in a gene or chromosome that may cause or affect the chance of developing neuroblastoma. A molecular test may be used to help plan treatment, find out how well treatment is working, or make a prognosis.
Children with newly diagnosed high-risk neuroblastoma may be eligible for molecular testing through the Molecular Characterization Initiative.
The Molecular Characterization Initiative offers free molecular testing to children, adolescents, and young adults with certain types of newly diagnosed cancer. The program is offered through NCI’s Childhood Cancer Data Initiative. To learn more, visit About the Molecular Characterization Initiative.
Biomarker testing: Biomarker testing is a way to look for genes, proteins, and other substances (called biomarkers or tumor markers) that can provide information about cancer. Some biomarkers affect how certain cancers behave and how certain treatments work. Biomarker testing may help your doctor choose a cancer treatment.
To check for these biomarkers, samples of tissue containing neuroblastoma cells are removed during a biopsy or surgery and tested in a laboratory.
Neuroblastoma biomarker testing includes:
MYCN amplification study: A laboratory study in which cells in a sample of tumor or bone marrow are checked to see how many copies of the MYCN gene are in the tumor DNA. MYCN is important for cell growth. Having more than 10 copies of the gene is called MYCN amplification. Neuroblastoma with MYCN amplification is more likely to spread in the body and more likely to show rapid growth.
ALK: The tumor cells may be checked in the laboratory for mutations or amplification (checking the number) of the ALK gene. These changes may increase the growth of cancer cells. Finding changes in the ALK gene in tumor tissue may lead to changes in the cancer treatment plan.
Cytogenetic analysis: A laboratory test in which the number and structure of chromosomes of cells in a sample of tissue are counted and checked for any changes, such as broken, missing, rearranged, or extra chromosomes. Changes in certain chromosomes may be a sign of cancer. Cytogenetic analysis is used to help diagnose cancer, plan treatment, or find out how well treatment is working.
ALK or PHOX2B genetic tests: A laboratory test in which a sample of blood or tissue is tested for a change in the ALK gene or PHOX2B gene in normal cells.
Getting a second opinion.
You may want to get a second opinion to confirm their child’s neuroblastoma diagnosis and treatment plan. If you seek a second opinion, you will need to get medical test results and reports from the first doctor to share with the second doctor. The second doctor will review the genetic test results, pathology report, slides, and scans. This doctor may agree with the first doctor, suggest changes to the treatment plan, or provide more information about your child’s cancer.
To learn more about choosing a doctor and getting a second opinion, see Finding Cancer Care. You can contact NCI’s Cancer Information Service via chat, email, or phone (both in English and Spanish) for help finding a doctor or hospital that can provide a second opinion. For questions you might want to ask at your child’s appointments, see Questions to Ask Your Doctor About Cancer.
Certain factors affect prognosis (chance of recovery) and treatment options.
If your child has been diagnosed with neuroblastoma, you may have questions about how serious the cancer is and your child’s chances of survival. The likely outcome or course of a disease is called prognosis.
Prognosis and treatment options for neuroblastoma are also affected by tumor histology, which includes:
the patterns of the tumor cells
how different the tumor cells are from normal cells
how fast the tumor cells are growing
The tumor histology is said to be favorable or unfavorable, depending on these factors. A child with favorable tumor histology has a better chance of recovery.
In some children up to age 6 months, neuroblastoma may disappear without treatment. This is called spontaneous regression. The child is closely watched for signs or symptoms of neuroblastoma. If signs or symptoms occur, treatment may be needed.
Stages of Neuroblastoma
Key Points
After neuroblastoma has been diagnosed, tests are done to find out if cancer has spread from where it started to other parts of the body.
The International Neuroblastoma Risk Group Staging System (INRGSS) is used to determine the stage of neuroblastoma.
Stage L1
Stage L2
Stage M
Stage MS
Treatment of neuroblastoma is based on risk groups.
Sometimes neuroblastoma does not respond to treatment or comes back after treatment.
After neuroblastoma has been diagnosed, tests are done to find out if cancer has spread from where it started to other parts of the body.
The process used to find out the extent or spread of cancer is called staging. The information gathered from the staging process helps determine the stage of the disease. For neuroblastoma, the stage of disease affects whether the cancer is low risk, intermediate risk, or high risk. It also affects the treatment plan. The results of some tests and procedures used to diagnose neuroblastoma may be used for staging. See the General Information section for a description of these tests and procedures.
The International Neuroblastoma Risk Group Staging System (INRGSS) is used to determine the stage of neuroblastoma.
Stage L1
In stage L1, the cancer is in only one area, and there are no image-defined risk factors (IDRFs). IDRFs are found on MRI or CT scans done during diagnosis. IDRFs are used to determine the risk of surgery and the chance of completely removing the tumor.
Stage L2
In stage L2, the cancer is in one area, has not spread beyond nearby tissue, and there are one or more IDRFs.
Stage M
In stage M, neuroblastoma has spread to areas far from the tumor. This does not include stage MS.
Stage MS
In stage MS, children younger than 18 months have cancer that has spread to the skin, liver, or bone marrow.
Treatment of neuroblastoma is based on risk groups.
For many types of cancer, stages are used to plan treatment. For neuroblastoma, treatment depends on the patient’s risk group. The risk group is determined by the following factors:
the stage of the cancer
the child’s age at diagnosis
the International Neuroblastoma Pathologic Classification (INPC) (tumor histology)
whether the tumors are diploid or hyperdiploid (DNA index)
whether the cancer gene MYCN is found in the tumor cells
how much of the cancer could be removed by surgery
There are three risk groups: low risk, intermediate risk, and high risk.
Low-risk and intermediate-risk neuroblastoma have a good chance of being cured.
Sometimes neuroblastoma does not respond to treatment or comes back after treatment.
Refractory neuroblastoma is a tumor that does not respond to treatment.
Recurrent neuroblastoma is cancer that has recurred (come back) after it has been treated. The tumor may come back in the site where it began or in the central nervous system.
Treatment Option Overview
Key Points
There are different types of treatment for children with neuroblastoma.
Children with neuroblastoma should have their treatment planned by a team of doctors who are experts in treating childhood cancer, especially neuroblastoma.
The following types of treatment may be used:
Observation
Surgery
Chemotherapy
Radiation therapy
High-dose chemotherapy and radiation therapy with stem cell rescue
Iodine 131-MIBG therapy
Targeted therapy
Other drug therapy
Immunotherapy
New types of treatment are being tested in clinical trials.
Treatment for neuroblastoma causes side effects and late effects.
Follow-up care may be needed.
There are different types of treatment for children with neuroblastoma.
There are different types of treatment for children and adolescents with neuroblastoma. You and your child’s cancer team will work together to decide treatment. Many factors will be considered, such as your child’s overall health and whether the cancer is newly diagnosed or has come back.
Children with neuroblastoma should have their treatment planned by a team of doctors who are experts in treating childhood cancer, especially neuroblastoma.
A pediatric oncologist, a doctor who specializes in treating children with cancer, will oversee treatment. The pediatric oncologist works with other pediatric health care professionals who are experts in treating children with cancer and who specialize in certain areas of medicine. These may include the following specialists and others:
Your child’s treatment plan will include information about the cancer, the goals of treatment, treatment options, and the possible side effects. It will be helpful to talk with your child’s cancer care team before treatment begins about what to expect. For help every step of the way, see our downloadable booklet, Children with Cancer: A Guide for Parents.
The following types of treatment may be used:
Observation
Observation is closely monitoring a patient’s condition without giving any treatment until signs or symptoms appear or change.
Surgery
Surgery is used to treat neuroblastoma that has not spread to other parts of the body. As much of the tumor as is safely possible is removed. Lymph nodes are also removed and checked for signs of cancer.
If the tumor cannot be removed, a biopsy may be done instead.
Chemotherapy (also called chemo) uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. When chemotherapy is taken by mouth or injected into a vein or muscle, the drugs enter the bloodstream and can reach cancer cells throughout the body (systemic chemotherapy).
Radiation therapy is a cancer treatment that uses high-energy x-rays or other types of radiation to kill cancer cells or keep them from growing. There are different types of radiation therapy:
External radiation therapy uses a machine outside the body to send radiation toward the area of the body with cancer. This treatment is used for patients with high-risk neuroblastoma or for patients whose tumor grew while being treated with chemotherapy.
Radioimmunotherapy is a type of radiation therapy in which a radioactive substance is linked to a monoclonal antibody and injected into the body. The monoclonal antibody can bind to substances in the body, including cancer cells. The radioactive substance gives off radiation, which may help kill cancer cells.
High-dose chemotherapy and radiation therapy with stem cell rescue
High-dose chemotherapy and radiation therapy are given to kill any cancer cells that may regrow and cause the cancer to come back. Healthy cells, including blood-forming cells, are also destroyed by the cancer treatment. Stem cell rescue is a treatment to replace the blood-forming cells. Stem cells (immature blood cells) are removed from the blood or bone marrow of the patient and are frozen and stored. After the completion of chemotherapy and radiation therapy, the stored stem cells are thawed and given back to the patient through an infusion. These reinfused stem cells grow into (and restore) the body’s blood cells.
Iodine 131-MIBG therapy
Iodine 131-MIBGtherapy is a treatment with radioactive iodine. The radioactive iodine is given through an intravenous (IV) line and enters the bloodstream, which carries radiation directly to tumor cells. Radioactive iodine collects in neuroblastoma cells and kills them with the radiation that is given off. Iodine 131-MIBG therapy is sometimes used to treat high-risk neuroblastoma that comes back after initial treatment.
Targeted therapy
Targeted therapy uses drugs or other substances to block the action of specific enzymes, proteins, or other molecules involved in the growth and spread of cancer cells.
Monoclonal antibody therapy: Monoclonal antibodies are immune system proteins made in the laboratory to treat many diseases, including cancer. As a cancer treatment, these antibodies can attach to a specific target on cancer cells or other cells that may help cancer cells grow. The antibodies are able to then kill the cancer cells, block their growth, or keep them from spreading. Monoclonal antibodies are given by infusion. They may be used alone or to carry drugs, toxins, or radioactive material directly to cancer cells.
Dinutuximab is used to treat patients with high-risk neuroblastoma and neuroblastoma that has come back after treatment or has not responded to treatment.
How do monoclonal antibodies work to treat cancer? This video shows how monoclonal antibodies, such as trastuzumab, pembrolizumab, and rituximab, block molecules cancer cells need to grow, flag cancer cells for destruction by the body’s immune system, or deliver harmful substances to cancer cells.
Ornithine decarboxylase inhibitor therapy slows the growth and division of cancer cells.
Eflornithine may be given for two years after maintenance therapy for high-risk neuroblastoma.
Other drugs used in combination to treat neuroblastoma include:
Isotretinoin: A vitamin-like drug that slows the cancer’s ability to make more cancer cells and changes how these cells look and act. This drug is taken by mouth.
Immunotherapy
Immunotherapy helps a child’s immune system fight cancer.
CAR T-cell therapy: The patient’s T cells (a type of immune system cell) are changed so that they will attack certain proteins on the surface of cancer cells. T cells are taken from the patient, and special receptors are added to their surface in the laboratory. The changed cells are called chimeric antigen receptor (CAR) T cells. The CAR T cells are grown in the laboratory and given to the patient by infusion. The CAR T cells multiply in the patient’s blood and attack cancer cells. EnlargeCAR T-cell therapy. A type of treatment in which a patient’s T cells (a type of immune cell) are changed in the laboratory so they will bind to cancer cells and kill them. Blood from a vein in the patient’s arm flows through a tube to an apheresis machine (not shown), which removes the white blood cells, including the T cells, and sends the rest of the blood back to the patient. Then, the gene for a special receptor called a chimeric antigen receptor (CAR) is inserted into the T cells in the laboratory. Millions of the CAR T cells are grown in the laboratory and then given to the patient by infusion. The CAR T cells are able to bind to an antigen on the cancer cells and kill them.
CAR T-cell therapy is being studied to treat neuroblastoma that has come back after treatment or has not responded to treatment.
New types of treatment are being tested in clinical trials.
A treatment clinical trial is a research study meant to help improve current treatments or obtain information on new treatments for people with cancer. For some patients, taking part in a clinical trial may be an option. Because cancer in children is rare, taking part in a clinical trial should be considered.
Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. Some clinical trials are open only to patients who have not started treatment. Clinical trials supported by other organizations can be found on the ClinicalTrials.gov website.
Side effects from cancer treatment that begin after treatment and continue for months or years are called late effects. Late effects of cancer treatment may include:
Some late effects may be treated or controlled. It is important to talk with your child’s doctors about the effects cancer treatment can have on your child. Learn more about Late Effects of Treatment for Childhood Cancer.
Follow-up care may be needed.
As your child goes through treatment, they will have follow-up tests or check-ups. Some tests that were done to diagnose or stage the cancer may be repeated to see how well the treatment is working. Decisions about whether to continue, change, or stop treatment may be based on the results of these tests.
Some of the tests will continue to be done from time to time after treatment has ended. The results of these tests can show if your child’s condition has changed or if the cancer has recurred (come back).
Follow-up care for children with neuroblastoma may include:
observation alone for infants younger than 6 months who have small adrenaltumors or for infants who do not have signs or symptoms of neuroblastoma
observation with biopsy for infants younger than age 1 year who have favorable histology and meet other low-risk criteria
chemotherapy with or without surgery, for children with symptoms or children whose tumor has continued to grow and cannot be removed by surgery
chemotherapy, for certain patients
radiation therapy to treat tumors that are causing serious problems and do not respond quickly to chemotherapy or surgery
Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.
Radiation therapy to treat tumors that have continued to grow during treatment with chemotherapy or tumors that cannot be removed by surgery and have continued to grow after treatment with chemotherapy.
Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.
Treatment after maintenance may include eflornithine.
Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.
Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.
Treatment for neuroblastoma that recurs (comes back) in the central nervous system (CNS; brain and spinal cord) may include:
surgery to remove the tumor in the CNS followed by radiation therapy
chemotherapy, surgery, and radiation therapy
Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.
Physician Data Query (PDQ) is the National Cancer Institute’s (NCI’s) comprehensive cancer information database. The PDQ database contains summaries of the latest published information on cancer prevention, detection, genetics, treatment, supportive care, and complementary and alternative medicine. Most summaries come in two versions. The health professional versions have detailed information written in technical language. The patient versions are written in easy-to-understand, nontechnical language. Both versions have cancer information that is accurate and up to date and most versions are also available in Spanish.
PDQ is a service of the NCI. The NCI is part of the National Institutes of Health (NIH). NIH is the federal government’s center of biomedical research. The PDQ summaries are based on an independent review of the medical literature. They are not policy statements of the NCI or the NIH.
Purpose of This Summary
This PDQ cancer information summary has current information about the treatment of neuroblastoma. It is meant to inform and help patients, families, and caregivers. It does not give formal guidelines or recommendations for making decisions about health care.
Reviewers and Updates
Editorial Boards write the PDQ cancer information summaries and keep them up to date. These Boards are made up of experts in cancer treatment and other specialties related to cancer. The summaries are reviewed regularly and changes are made when there is new information. The date on each summary (“Updated”) is the date of the most recent change.
The information in this patient summary was taken from the health professional version, which is reviewed regularly and updated as needed, by the PDQ Pediatric Treatment Editorial Board.
Clinical Trial Information
A clinical trial is a study to answer a scientific question, such as whether one treatment is better than another. Trials are based on past studies and what has been learned in the laboratory. Each trial answers certain scientific questions in order to find new and better ways to help cancer patients. During treatment clinical trials, information is collected about the effects of a new treatment and how well it works. If a clinical trial shows that a new treatment is better than one currently being used, the new treatment may become “standard.” Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.
Clinical trials can be found online at NCI’s website. For more information, call the Cancer Information Service (CIS), NCI’s contact center, at 1-800-4-CANCER (1-800-422-6237).
Permission to Use This Summary
PDQ is a registered trademark. The content of PDQ documents can be used freely as text. It cannot be identified as an NCI PDQ cancer information summary unless the whole summary is shown and it is updated regularly. However, a user would be allowed to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks in the following way: [include excerpt from the summary].”
The best way to cite this PDQ summary is:
PDQ® Pediatric Treatment Editorial Board. PDQ Neuroblastoma Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/neuroblastoma/patient/neuroblastoma-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389278]
Images in this summary are used with permission of the author(s), artist, and/or publisher for use in the PDQ summaries only. If you want to use an image from a PDQ summary and you are not using the whole summary, you must get permission from the owner. It cannot be given by the National Cancer Institute. Information about using the images in this summary, along with many other images related to cancer can be found in Visuals Online. Visuals Online is a collection of more than 3,000 scientific images.
Disclaimer
The information in these summaries should not be used to make decisions about insurance reimbursement. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.
Contact Us
More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s E-mail Us.
Screening is looking for cancer before a person has any symptoms. This can help find cancer at an early stage. When abnormaltissue or cancer is found early, it may be easier to treat. By the time symptoms appear, cancer may have begun to spread.
Scientists are trying to better understand which people are more likely to get certain types of cancer. They also study the things we do and the things around us to see if they cause cancer. This information helps doctors recommend who should be screened for cancer, which screening tests should be used, and how often the tests should be done.
It is important to remember that your doctor does not necessarily think you have cancer if he or she suggests a screening test. Screening tests are given when you have no cancer symptoms.
If a screening test result is abnormal, you may need to have more tests done to find out if you have cancer. These are called diagnostic tests.
General Information About Neuroblastoma Cancer
Key Points
Neuroblastoma is a disease in which malignant (cancer) cells form in nerve tissue.
Most cases of neuroblastoma are diagnosed before 1 year of age.
The risk factors for neuroblastoma are not known.
Neuroblastoma is a disease in which malignant (cancer) cells form in nerve tissue.
Most cases of neuroblastoma are diagnosed before 1 year of age.
Neuroblastoma is the most common type of cancer in infants. The number of new cases of neuroblastoma is greatest among children under 1 year of age. As children get older, the number of new cases decreases. Neuroblastoma is slightly more common in males than females.
Neuroblastoma sometimes forms before birth but is usually found later, when the tumor begins to grow and cause symptoms. In rare cases, neuroblastoma may be found before birth by fetalultrasound.
The risk factors for neuroblastoma are not known.
Neuroblastoma Screening
Key Points
Tests are used to screen for different types of cancer when a person does not have symptoms.
There is no standard or routine screening test for neuroblastoma.
Screening for neuroblastoma may not help the child live longer.
Screening tests for neuroblastoma are being studied in clinical trials.
Tests are used to screen for different types of cancer when a person does not have symptoms.
Scientists study screening tests to find those with the fewest harms and most benefits. Cancer screening trials also are meant to show whether early detection (finding cancer before it causes symptoms) helps a person live longer or decreases a person’s chance of dying from the disease. For some types of cancer, the chance of recovery is better if the disease is found and treated at an early stage.
There is no standard or routine screening test for neuroblastoma.
There is no standard or routine screening test used to find neuroblastoma. A urine test is sometimes used to check for neuroblastoma, usually when the child is 6 months old. This is a test in which urine is collected for 24 hours to measure the amounts of certain substances. An unusual (higher or lower than normal) amount of a substance can be a sign of disease in the organ or tissue that makes it. A higher than normal amount of homovanillic acid (HMA) and vanillyl mandelic acid (VMA) may be a sign of neuroblastoma.
Screening for neuroblastoma may not help the child live longer.
Studies have shown that screening for neuroblastoma does not decrease the chance of dying from the disease. Almost all neuroblastomas that are found by screening children at 6 months of age are the type that have a good prognosis (chance of recovery).
Screening tests for neuroblastoma are being studied in clinical trials.
The risks of neuroblastoma screening include the following:
Neuroblastoma may be overdiagnosed.
False-negative test results can occur.
False-positive test results can occur.
Screening tests have risks.
Decisions about screening tests can be difficult. Not all screening tests are helpful and most have risks. Before having any screening test, you may want to discuss the test with your doctor. It is important to know the risks of the test and whether it has been proven to reduce the risk of dying from cancer.
The risks of neuroblastoma screening include the following:
Neuroblastoma may be overdiagnosed.
When a screening test result leads to the diagnosis and treatment of a disease that may never have caused symptoms or become life-threatening, it is called overdiagnosis. For example, when a urine test result shows a higher than normal amount of homovanillic acid (HMA) or vanillyl mandelic acid (VMA), tests and treatments for neuroblastoma are likely to be done, but may not be needed. At this time, it is not possible to know which neuroblastomas found by a screening test will cause symptoms and which neuroblastomas will not. Diagnostic tests (such as biopsies) and cancer treatments (such as surgery, radiation therapy, and chemotherapy) can have serious risks, including physical and emotional problems.
False-negative test results can occur.
Screening test results may appear to be normal even though neuroblastoma is present. A person who receives a false-negative test result (one that shows there is no cancer when there really is) may delay seeking medical care even if there are symptoms.
False-positive test results can occur.
Screening test results may appear to be abnormal even though no cancer is present. A false-positive test result (one that shows there is cancer when there really isn’t) can cause anxiety and is usually followed by more tests and procedures, which also have risks.
About This PDQ Summary
About PDQ
Physician Data Query (PDQ) is the National Cancer Institute’s (NCI’s) comprehensive cancer information database. The PDQ database contains summaries of the latest published information on cancer prevention, detection, genetics, treatment, supportive care, and complementary and alternative medicine. Most summaries come in two versions. The health professional versions have detailed information written in technical language. The patient versions are written in easy-to-understand, nontechnical language. Both versions have cancer information that is accurate and up to date and most versions are also available in Spanish.
PDQ is a service of the NCI. The NCI is part of the National Institutes of Health (NIH). NIH is the federal government’s center of biomedical research. The PDQ summaries are based on an independent review of the medical literature. They are not policy statements of the NCI or the NIH.
Purpose of This Summary
This PDQ cancer information summary has current information about neuroblastoma screening. It is meant to inform and help patients, families, and caregivers. It does not give formal guidelines or recommendations for making decisions about health care.
Reviewers and Updates
Editorial Boards write the PDQ cancer information summaries and keep them up to date. These Boards are made up of experts in cancer treatment and other specialties related to cancer. The summaries are reviewed regularly and changes are made when there is new information. The date on each summary (“Updated”) is the date of the most recent change.
The information in this patient summary was taken from the health professional version, which is reviewed regularly and updated as needed, by the PDQ Screening and Prevention Editorial Board.
Clinical Trial Information
A clinical trial is a study to answer a scientific question, such as whether one treatment is better than another. Trials are based on past studies and what has been learned in the laboratory. Each trial answers certain scientific questions in order to find new and better ways to help cancer patients. During treatment clinical trials, information is collected about the effects of a new treatment and how well it works. If a clinical trial shows that a new treatment is better than one currently being used, the new treatment may become “standard.” Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.
Clinical trials can be found online at NCI’s website. For more information, call the Cancer Information Service (CIS), NCI’s contact center, at 1-800-4-CANCER (1-800-422-6237).
Permission to Use This Summary
PDQ is a registered trademark. The content of PDQ documents can be used freely as text. It cannot be identified as an NCI PDQ cancer information summary unless the whole summary is shown and it is updated regularly. However, a user would be allowed to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks in the following way: [include excerpt from the summary].”
The best way to cite this PDQ summary is:
PDQ® Screening and Prevention Editorial Board. PDQ Neuroblastoma Screening. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/neuroblastoma/patient/neuroblastoma-screening-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389302]
Images in this summary are used with permission of the author(s), artist, and/or publisher for use in the PDQ summaries only. If you want to use an image from a PDQ summary and you are not using the whole summary, you must get permission from the owner. It cannot be given by the National Cancer Institute. Information about using the images in this summary, along with many other images related to cancer can be found in Visuals Online. Visuals Online is a collection of more than 3,000 scientific images.
Disclaimer
The information in these summaries should not be used to make decisions about insurance reimbursement. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.
Contact Us
More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s E-mail Us.
Dramatic improvements in survival have been achieved for children and adolescents with cancer.[1,2] Between 1975 and 2020, childhood cancer mortality decreased by more than 50%.[1–5] Between 1975 and 2020, the 5-year survival rate for patients with neuroblastoma increased, from 86% to 93% for children younger than 1 year and from 34% to 83% for children aged 1 to 14 years.[2,3]
Childhood and adolescent cancer survivors require close monitoring because cancer therapy side effects may persist or develop months or years after treatment. For specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors, see Late Effects of Treatment for Childhood Cancer.
Incidence and Epidemiology
Neuroblastoma is the most common extracranial solid tumor in childhood. More than 650 cases are diagnosed each year in the United States.[2,6–8] The prevalence is about 1 case per 7,000 live births. The incidence is 8.3 cases per 1 million per year in children younger than 15 years. The overall incidence of neuroblastoma cases in the United States has remained stable.[9] About 37% of patients are diagnosed as infants, and 90% are younger than 5 years at diagnosis, with a median age at diagnosis of 17 months.[8,10] The data on age at diagnosis show that this is a disease of infancy, with the highest rate of diagnosis in the first month of life.[6,10,11]
Population-based studies (of screening for infants with neuroblastoma) have demonstrated that spontaneous regression of neuroblastoma without clinical detection in the first year of life is at least as prevalent as clinically detected neuroblastoma.[12–14]
The United States Cancer Statistics database and the National Program of Cancer Registries survival database were used to describe epidemiological trends in incidence and outcomes in patients with neuroblastoma between 2003 and 2019. Non-Hispanic White patients have a higher risk of developing neuroblastoma than all other race and ethnicity groups. Compared with non-Hispanic White patients, the relative risks were 0.54 for Hispanic patients, 0.64 for non-Hispanic Asian or Pacific Islander patients, 0.69 for non-Hispanic American Indian and Alaska Native patients, and 0.73 for non-Hispanic Black patients.[9] The 5-year relative survival rates were higher for non-Hispanic White patients (80.7%) and Hispanic patients (80.8%), compared with non-Hispanic Black patients (72.6%).[9]
Findings from epidemiological studies have not unequivocally linked environmental or other exposures to increased or decreased incidences of neuroblastoma.[15]
Anatomy
Neuroblastoma originates in the adrenal medulla and paraspinal or periaortic regions where sympathetic nervous system tissue is present (see Figure 1).
EnlargeFigure 1. Neuroblastoma may be found in the adrenal glands and paraspinal nerve tissue from the neck to the pelvis.
Neuroblastoma Screening
Familial neuroblastoma and genetic predisposition
Studies analyzing constitutional DNA in rare cohorts of patients with familial neuroblastoma have provided insight into the complex genetic basis for tumor initiation. About 1% to 2% of patients with neuroblastoma have a family history of the disease. These children are, on average, younger (9 months at diagnosis) than patients without a family history, and about 20% of these patients have multifocal primary neuroblastoma.
Germline variants. Several germline variants have been associated with a genetic predisposition to neuroblastoma, including the following:
ALK gene variant. The primary cause of familial neuroblastoma (about 75% of familial cases) is aberrant activation of the germline ALK signaling pathway, which results from single nucleotide variants in the tyrosine kinase domain of the ALK gene.[16] Somatic activating single nucleotide variants in ALK are also seen in about 9% of sporadic neuroblastoma cases. In addition, in a small proportion of neuroblastoma cases with MYCN amplification, ALK is co-amplified (ALK is near MYCN on chromosome 2), which may also result in ALK activation. ALK is a tyrosine kinase receptor. For more information about ALK variants, see the Genomic and Biological Features of Neuroblastoma section.
PHOX2B gene variant. Rarely, familial neuroblastoma may be associated with congenital central hypoventilation syndrome (Ondine curse), which is caused by a germline variant of the PHOX2B gene.[17] Most PHOX2B variants causing Ondine curse or Hirschsprung disease are polyalanine repeats and are not associated with familial neuroblastoma. However, germline loss-of-function PHOX2B variants have been identified in rare patients with sporadic neuroblastoma and Ondine curse and/or Hirschsprung disease.[18] This aberration has not been seen in patients with sporadic neuroblastoma without associated Ondine curse or Hirschsprung disease. Additionally, somatic PHOX2B variants occur in about 2% of sporadic cases of neuroblastoma.[19,20]
Deletion at the 1p36 or 11q14-23 locus. In case studies, germline deletion at the 1p36 or 11q14-23 locus has been associated with familial neuroblastoma. The same deletions are found somatically in some sporadic neuroblastoma cases.[21,22] More generally, large germline structural variants appear to be enriched in male patients with neuroblastoma, compared with controls. Some of these variants disrupt known neuroblastoma predisposition genes, such as PHOX2B or BARD1.[23]
Other cancer predisposition syndromes. Children with gene aberrations associated with other cancer predisposition syndromes may be at increased risk of developing neuroblastoma and other malignancies. The following syndromes primarily involve genes in the canonical RAS pathway:
With increased availability of sequencing techniques, the spectrum of germline alterations seen in patients with neuroblastoma is expanding. For example, one study identified a series of 11 patients with germline pathogenic variants in SMARCA4.[30] In another study of 786 patients with neuroblastoma, 13.9% had pathogenic or likely pathogenic germline variants in cancer predisposition genes. BARD1, ERCC2, CHEK2, and MSH3 were the genes in which germline pathogenic variants were most commonly observed. Germline pathogenic variants in BARD1, EZH2, ALK, PTCH1, and MSH3 were specifically enriched in patients with neuroblastoma, compared with controls. Patients with these alterations had inferior survival, compared with patients without these alterations.[31] Another study replicated the findings that germline alterations in cancer predisposition genes are associated with inferior outcomes. In addition, the researchers showed that the burden of germline functional variants beyond conventional cancer predisposition genes was also prognostic.[32] For more information about SMARCA4, visit Rhabdoid Tumor Predisposition Syndrome Type 2.
Sporadic neuroblastoma may also have an increased incidence resulting from less potent germline predispositions. Genome-wide association studies have identified several common genomic variants (single nucleotide polymorphisms) with modest effect size that are associated with increased risk of developing neuroblastoma. Most of these genomic risk variants are significantly associated with distinct neuroblastoma phenotypes (i.e., high-risk vs. low-risk disease).[33]
Neuroblastoma predisposition and surveillance
Screening recommendations from the American Association for Cancer Research (AACR) came from the 2016 Childhood Cancer Predisposition Workshop. The AACR recommends that the following individuals undergo biochemical and radiographic surveillance for early detection of tumors in the first 10 years of life:[27]
Individuals with highly penetrant, heritable ALK or PHOX2B pathogenic variants (45%–50% risk of developing one or more tumors).
Individuals with Li-Fraumeni syndrome and germline TP53 p.R337H pathogenic variants.
Individuals with Beckwith-Wiedemann syndrome and germline CDKN1C pathogenic variants.
Individuals with Costello syndrome and HRAS pathogenic variants.
Individuals with neuroblastoma and a strong family history of neuroblastoma or clearly bilateral/multifocal neuroblastoma.
Quantitative, normalized assessment of urinary catecholamines,[34] such as urine vanillylmandelic acid (VMA) and homovanillic acid (HVA), by gas chromatography and mass spectroscopy (can be a random urine collection normalized for urine creatinine, because this approach appears to have similar sensitivity to a 24-hour collection).
Chest x-ray.
Surveillance begins at birth or at diagnosis of neuroblastoma predisposition and continues every 3 months until age 6 years, then every 6 months until age 10 years. Patients with Costello syndrome may have elevated urinary catecholamines in the absence of a catecholamine-secreting tumor, so only high or significantly rising levels should prompt investigation beyond ultrasonography and chest x-ray.[35] Patients with Li-Fraumeni syndrome should not undergo chest x-rays.[27]
About 5% of children with Beckwith-Wiedemann syndrome have variants that cause decreased activity of CDKN1C. A review of all large studies of genetically subtyped Beckwith-Wiedemann syndrome found 70 children with the CDKN1C variant, 4.6% of whom developed neuroblastoma. There were no cases of Wilms tumor or hepatoblastoma. There is little experience with screening these children for neuroblastoma, so there are no generally accepted guidelines. However, the authors of the study suggest screening with urinary VMA/HVA every 4 to 6 months. Patients with other genetic subtypes of Beckwith-Wiedemann syndrome have a prevalence of neuroblastoma of less than 1%. No neuroblastic tumors were found among 123 children with the genotype gain of methylation at imprinting control region 1.[36]
General population
Current data do not support neuroblastoma screening in the general public. Screening at the ages of 3 weeks, 6 months, or 1 year did not lead to a reduced incidence of advanced-stage neuroblastoma with unfavorable biological characteristics in older children, nor did it reduce overall mortality from neuroblastoma.[13,14] No public health benefits have been shown from screening infants for neuroblastoma at these ages.
Evidence (against neuroblastoma screening):
In a large population-based North American study, most infants in Quebec, Canada, were screened at the ages of 3 weeks and 6 months.[12,13]
Screening detected many neuroblastomas with favorable characteristics that would never have been detected clinically because of spontaneous regression of the tumors.
Another study of infants screened at the age of 1 year showed similar results.[14]
Clinical Presentation
The most frequent signs and symptoms of neuroblastoma in children are caused by tumor mass and metastases and include the following:
Abdominal mass: The most common presentation of neuroblastoma.
Proptosis and periorbital ecchymosis: Common in high-risk patients; arise from retrobulbar metastasis.
Abdominal distention: May occur with respiratory compromise in infants because of massive liver metastases.
Bone pain: Occurs in association with metastatic disease.
Pancytopenia: May result from extensive bone marrow metastasis.
Fever, hypertension, and anemia: Occasionally found in patients without metastasis.
Paralysis: Neuroblastoma originating in paraspinal ganglia may invade through neural foramina and compress the spinal cord extradurally. Immediate treatment is given for symptomatic spinal cord compression. For more information, see the Treatment of Spinal Cord Compression section.
Watery diarrhea: On rare occasions, children may have severe, watery diarrhea caused by the secretion of vasoactive intestinal peptide by the tumor, or they may have protein-losing enteropathy with intestinal lymphangiectasia.[37] Vasoactive intestinal peptide secretion may occur at presentation (with diarrhea being the first symptom of neuroblastoma), may appear with the initiation of chemotherapy, or occasionally may become evident later in the course of treatment. Tumor resection reduces vasoactive intestinal peptide secretion.[38]
Presence of Horner syndrome: Characterized by miosis, ptosis, and anhidrosis. It may be caused by neuroblastoma in the stellate ganglion. Horner syndrome without other apparent causes may be a symptom of neuroblastoma and other tumors.[39]
Subcutaneous skin nodules: Subcutaneous metastases of neuroblastoma often have bluish discoloration of the overlying skin; usually seen only in infants.
The clinical presentation of neuroblastoma in adolescents is similar to that in children. The only exception is that bone marrow involvement occurs less frequently in adolescents, and there is a greater frequency of metastases in unusual sites such as lung or brain.[40]
Opsoclonus/myoclonus syndrome
Paraneoplastic neurological findings, including cerebellar ataxia or opsoclonus/myoclonus, occur rarely in children with neuroblastoma.[41] Of young children presenting with opsoclonus/myoclonus syndrome, about one-half are found to have neuroblastoma.[42,43] The incidence in the United Kingdom is estimated at 0.18 cases per 1 million children per year. The average age at diagnosis is 1.5 to 2 years.[44]
The usual presentation is the onset of progressive neurological dysfunction over a few days before a neuroblastoma is discovered. However, on occasion, neurological symptoms arise long after removal of the primary tumor.[42,45,46] Patients with neuroblastoma who present with opsoclonus/myoclonus syndrome often have neuroblastoma with favorable biological features and have excellent survival rates, although tumor-related deaths have been reported.[42]
The opsoclonus/myoclonus syndrome appears to be caused by an immunologic mechanism that is not yet fully characterized.[42] The primary tumor is typically diffusely infiltrated with lymphocytes.[47] Cerebrospinal fluid shows an increased number of B cells, and oligoclonal immunoglobulin bands are often seen. Steroid-responsive elevations of B-cell–related cytokines are also often seen.[48]
Genomic copy number profiles were analyzed in 44 cases of neuroblastoma associated with opsoclonus/myoclonus syndrome. Because there were no tumor relapses or disease-related deaths, the overall genomic profile was not prognostically significant.[49]
Some patients may rapidly respond neurologically to immune interventions or simply to removal of the neuroblastoma, but in many cases, improvement may be slow and partial. While immunological therapy has improved acutely presenting motor deficits and ataxia, its benefit on long-term neuropsychological disability, which primarily consists of cognitive and behavioral deficits, is not clear. The long-term benefits of rapid improvement resulting from treatment, whether of symptoms or of the underlying neuroblastoma, are unclear, but rapid improvement appears to be worthwhile.[46,50]
Treatment with adrenocorticotropic hormones or corticosteroids can be effective for acute symptoms, but some patients do not respond to corticosteroids.[45,51] Other therapy with various immunomodulatory drugs, plasmapheresis, intravenous gamma globulin, and rituximab have been reported to be effective in select cases.[45,52–55] Combination immunosuppressive therapy has been explored, with improved short-term results.[56] The short-term neurological outcomes may be superior in patients treated with chemotherapy, possibly because of its immunosuppressive effects.[41]
The Children’s Oncology Group (COG) completed the first randomized, open-label, phase III study of patients with opsoclonus/myoclonus ataxia syndrome.[57] Patients with newly diagnosed neuroblastoma and opsoclonus/myoclonus ataxia syndrome who were younger than 8 years were randomly assigned to receive either intravenous immunoglobulin (IVIG) or no IVIG in addition to prednisone and risk-adapted treatment of the tumor.[57]
Of the 53 patients who participated, 21 of 26 patients (81%) in the IVIG group had an opsoclonus/myoclonus ataxia syndrome response over a period of weeks to months, compared with 11 of 27 patients (41%) in the non-IVIG group (odds ratio [OR], 6.1; P = .0029).
This study demonstrated that short-term neurological response is improved in patients treated with chemotherapy, corticosteroids, and immunoglobulin, compared with patients treated with chemotherapy and corticosteroids without immunoglobulin.
Patients on the trial were monitored to track adaptive (n = 25) and cognitive functioning (n = 15) over time. Both adaptive and cognitive functioning remained grossly stable during the first 2 years after diagnosis. Assessments beyond 2 years were limited by small sample sizes.[58] Additional data are needed to assess long-term neurodevelopmental and learning problems in this population.
Diagnosis
Diagnostic evaluation of neuroblastoma includes the following:
Tumor imaging: Imaging of the primary tumor mass is generally accomplished by computed tomography or magnetic resonance imaging (MRI) with contrast. Paraspinal tumors that might threaten spinal cord compression are imaged using MRI.
Metaiodobenzylguanidine (MIBG) scanning is a critical part of the standard diagnostic evaluation of neuroblastoma, for both the primary tumor and sites of metastases.[59,60] MIBG scanning is also critical to assess response to therapy.[60] About 90% of neuroblastoma cases are MIBG avid. Fluorine F 18-fludeoxyglucose positron emission tomography (PET) scans are used to evaluate extent of disease in patients with tumors that are not MIBG avid.[61] For more information about imaging of neuroblastoma, see the Evaluation of Primary Tumor and Metastatic Disease section.
Urine catecholamine metabolites: Urinary excretion of the catecholamine metabolites VMA and HVA per milligram of excreted creatinine is measured before therapy. Collection of urine for 24 hours is not needed. If they remain elevated, these markers can be used to suggest the persistence of disease.
In contrast to urine, serum catecholamines are not routinely used in the diagnosis of neuroblastoma except in unusual circumstances.
Biopsy: Tumor tissue is often needed to obtain all the biological data required for risk-group assignment and subsequent treatment stratification in current COG clinical trials. There is an absolute requirement for tissue biopsy to determine the International Neuroblastoma Pathology Classification (INPC). Additionally, a significant number of tumor cells are needed to determine MYCN copy number, DNA index, and the presence of segmental chromosomal aberrations. Tissue from several core biopsies, or approximately 1 cm3 of tissue from an open biopsy, is needed for adequate biological staging. A systematic review of eight retrospective studies showed that both surgical biopsy and core-needle biopsy produced similar rates of obtaining adequate tissue for histopathological diagnosis and molecular characterization. Core-needle biopsy was associated with lower complication rates and reduced transfusion requirements.[62] Core-needle biopsy also appears to yield sufficient material for assessment of ALK status. In one single-center report of patients with neuroblastoma who were newly diagnosed using core-needle biopsy, ALK status was determined in 88% of cases.[63]
For patients older than 18 months with stage 4 disease, bone marrow with extensive tumor involvement combined with elevated catecholamine metabolites may be adequate for diagnosis and assigning the risk and treatment group. However, INPC cannot be determined from tumor metastatic to bone marrow. Testing for MYCN amplification may be successfully performed on involved bone marrow if there is at least 30% tumor involvement. However, every attempt should be made to obtain an adequate biopsy from the primary tumor.
The diagnosis of neuroblastoma requires the involvement of pathologists who are familiar with childhood tumors. Some neuroblastomas cannot be differentiated morphologically, via conventional light microscopy with hematoxylin and eosin staining alone, from other small round blue cell tumors of childhood, such as lymphomas, Ewing sarcoma, and rhabdomyosarcomas. In such cases, immunohistochemical and cytogenetic analysis may be needed to diagnose a specific small round blue cell tumor.
The minimum criterion for a diagnosis of neuroblastoma, as established by international agreement, is that diagnosis must be based on one of the following:[64]
An unequivocal pathological diagnosis made from tumor tissue by light microscopy (with or without immunohistology or electron microscopy).
The combination of bone marrow aspirate or trephine biopsy containing unequivocal tumor cells (e.g., syncytia or immunocytologically positive clumps of cells) and increased levels of urinary catecholamine metabolites.
Observation and Spontaneous Regression of Fetal/Neonatal Neuroblastoma
The phenomenon of spontaneous regression has been well described in infants with neuroblastoma, especially in infants with the INSS 4S/INRG MS pattern of metastatic spread.[65] In rare cases, fetal ultrasonography can show suspected neuroblastoma prenatally.[66] Management recommendations are evolving regarding the need for immediate diagnostic biopsy in infants aged 6 months and younger with suspected neuroblastoma tumors that are likely to spontaneously regress. For more information about INSS 4S/INRG MS disease, see the Evaluation of Primary Tumor and Metastatic Disease section.
Spontaneous regression generally occurs in tumors with the following features:[67–69]
Near triploid number of chromosomes.
No MYCN amplification.
No loss of chromosome 1p.
Additional features associated with spontaneous regression include the lack of telomerase expression,[67,70] the expression of the H-Ras protein,[71] and the expression of the neurotrophin receptor TrkA, a nerve growth factor receptor.[72]
Studies have suggested that selected infants who appear to have asymptomatic, small, low-stage adrenal neuroblastoma (detected by screening or during prenatal or incidental ultrasonography) often have tumors that spontaneously regress. These patients may be observed safely without surgical intervention or tissue diagnosis.[73–75]
Evidence (observation [spontaneous regression]):
In a COG study, 83 highly selected infants younger than 6 months with stage 1 small adrenal masses (3.1 cm or less), as defined by imaging studies, were observed without biopsy. Surgical intervention was reserved for those with growth or progression of the mass or increasing concentrations of urinary catecholamine metabolites.[76]
Eighty-one percent of patients did not undergo surgery, and all patients were alive after 2 years of follow-up. For more information, see the Principles of Surgery section.
Therefore, prenatally and neonatally identified adrenal masses approximately 3.1 cm or less can be safely observed if no metastatic disease is identified and there is no involvement of large vessels or organs.
A German clinical trial reported on 340 infants with localized neuroblastoma without MYCN amplification. Of these patients, 190 underwent resection, 57 were treated with chemotherapy, and 93 were observed with gross residual tumor.[77]
Of the 93 observed patients with gross residual tumor, spontaneous regression and/or lack of progression occurred in 44 asymptomatic infants originally diagnosed at age 12 months or younger with stage 1, 2, or 3 tumors without MYCN amplification.
Complete regression was seen in 17 of the 44 patients with tumor regression.
In 15 of 44 patients with tumor regression, regression did not occur until more than 1 year after diagnosis.
In neuroblastoma screening trials in Quebec, Canada, and Germany, the incidence of neuroblastoma was twice that reported in nonscreened populations, suggesting that many neuroblastomas are never diagnosed clinically and spontaneously regress.[12–14]
Prognostic Factors
The prognosis for patients with neuroblastoma is related to the following:
The effect of age at diagnosis on 5-year survival is profound. In the COG ANBL00B1 (NCT00904241) study of 4,832 patients with newly diagnosed neuroblastoma, those younger than 18 months had a 5-year EFS rate of 82% and an OS rate of 91%. In comparison, patients aged 18 months or older had a 5-year EFS rate of 64% and an OS rate of 74%.[78]
According to the National Childhood Cancer Registry (NCCR), the 5-year relative survival rates from 2014 to 2020 were as follows:[2]
Aged younger than 1 year: 93%.
Aged 1 to 4 years: 78%.
Aged 5 to 9 years: 83%.
Aged 10 to 14 years: 86%.
The effect of patient age on prognosis is strongly influenced by clinical and pathobiological factors, as evidenced by the following:
Since 2000, nonrandomized studies of low-risk and intermediate-risk patients have demonstrated that patient age has no effect on outcome of INSS stage 1 or stage 2A disease. However, stage 2B patients younger than 18 months had a 5-year OS rate of 99% (± 1%), compared with 90% (± 4%) for children aged 18 months and older.[79]
In the COG intermediate-risk study A3961 (NCT00003093) that included only MYCN-nonamplified tumors, infants with INSS stage 3 tumors were compared with children with INSS stage 3 favorable-histology tumors. When INSS stage 3 infants with any histology were compared with stage 3 children with favorable histology, only EFS rates, not OS rates, were significantly different (3-year EFS rate, 95% ± 2% vs. 87% ± 3%; OS rate, 98% ± 1% vs. 99% ± 1%).[80]
Infants younger than 12 months with INSS stage 4 disease and MYCN amplification are categorized as high risk and have a 5-year EFS rate of 37% and an OS rate of 45%.[78] Toddlers aged 12 months to younger than 18 months with stage 4 disease and MYCN-amplified tumors had a 5-year EFS rate of 53% and an OS rate of 54%.[78]
Adolescents and young adults
Adolescents and adults rarely develop neuroblastoma, accounting for less than 5% of all cases. When neuroblastoma occurs in this age range, it shows a more indolent clinical course than neuroblastoma in younger patients, and it often shows de novo chemotherapy resistance.[81] Neuroblastoma in adolescents and young adults may also exhibit unusual clinicopathological characteristics such as large tumors, bilateral adrenal disease, and pheochromocytoma-like features.[82][Level of evidence C1] Neuroblastoma has a worse long-term prognosis in adolescents older than 10 years or in adults, regardless of stage or site.
Although adolescent and young adult patients have infrequent MYCN amplification (9% in patients aged 10–21 years), older children with advanced disease have a poor rate of survival. Tumors from the adolescent and young adult population commonly have segmental chromosomal aberrations, and ALK and ATRX variants are much more frequent.[83–85] In adolescents, approximately 40% of the tumors have loss-of-function variants in ATRX, compared with less than 20% in younger children and 0% in infants younger than 1 year.[81] Complex DNA microarray findings and novel variants have been reported in some patients.[82][Level of evidence C1]
The 5-year OS rate for adolescent and young adult patients (aged 15–39 years) is 38%.[86][Level of evidence C1] The 5-year EFS rate is 32% for patients between the ages of 10 years and 21 years, and the OS rate is 46%. For patients with stage 4 disease, the 10-year EFS rate is 3%, and the OS rate is 5%.[87] Aggressive chemotherapy and surgery have been shown to achieve a minimal disease state in more than 50% of these patients.[40,88] Other modalities, such as local radiation therapy, autologous stem cell transplant, and the use of agents with confirmed activity, may improve the poor prognosis for adolescents and adults.[87,88]
Adults
The biology of adult-onset neuroblastoma appears to differ from the biology of pediatric or adolescent neuroblastoma based on a single-institution series of 44 patients (aged 18–71 years).[89]
Genetic abnormalities in adult patients included somatic ATRX (58%) and ALK variants (42%) but no MYCN amplification.
Germline testing was performed in four patients, two of whom had aberrations (one patient with a BRCA1 pathogenic variant, the other patient with TP53 and NF1 pathogenic variants).
In the 11 patients with locoregional disease, the 10-year progression-free survival (PFS) rate was 35%, and the OS rate was 61%.
Among 33 adults with stage 4 neuroblastoma, 7 patients (21%) achieved a complete response (CR) after induction chemotherapy and/or surgery. In patients with stage 4 disease at diagnosis, the 5-year PFS rate was 10%, and most patients who were alive with disease at 5 years died of neuroblastoma over the next 5 years. The 10-year OS rate was 19%. CR after induction was the only prognostic factor for PFS and OS.
Anti-GD2 immunotherapy (m3F8 or hu3F8) was well tolerated in adults.
As noted above, adult-onset neuroblastoma is enriched for activating ALK variants. In a single-institution retrospective study, 13 adults (median age, 34 years; range, 16–71 years) with relapsed, ALK-altered neuroblastoma were treated with lorlatinib. Nine patients (69%) had a complete or partial response, five of whom were previously treated with other ALK inhibitors. Lorlatinib was associated with significant adverse events requiring dose reduction. However, responses were seen using doses below the recommended adult dose.[90] In another multicenter trial, 15 adults (aged 18 years or older; median age, 24 years) with relapsed or refractory ALK-altered neuroblastoma were treated with lorlatinib. The response rate (complete, partial, and minor response) was 67%.[91]
Stage of disease
Several image-based and surgery-based systems were used for assigning disease stage of neuroblastoma before the 1990s. In an effort to compare results obtained throughout the world, a surgical pathological staging system, termed the International Neuroblastoma Staging System (INSS), was developed.[64] The INSS predicted outcome based on stage at diagnosis, although important interactions with biological variables were also found.[3,4,11,64,79,80,92–94] However, because surgical approaches differ from one institution to another, INSS stage for patients with locoregional disease may also vary considerably. To define extent of disease at diagnosis in a uniform manner, a presurgical International Neuroblastoma Risk Group staging system (INRGSS) was developed for the International Neuroblastoma Risk Group Classification System.[95,96] The INRGSS is currently used in North American and European cooperative group studies. This staging system is not affected by locoregional lymph node involvement.
For the patients with newly diagnosed neuroblastoma enrolled in the ANBL00B1 (NCT00904241) study, the 5-year EFS and OS rates, according to INRGSS stage, were the following:[78]
In the ANBL00B1 (NCT00904241) study of 4,832 patients with newly diagnosed neuroblastoma, 52% of tumors were classified as favorable and 48% as unfavorable, according to the International Neuroblastoma Pathology Classification (INPC). For patients with tumors classified as favorable, the 5-year EFS rate was 88%, and the 5-year OS rate was 96%. For patients with tumors classified as unfavorable, the 5-year EFS rate was 55%, and the 5-year OS rate was 66% (P < .0001).[78]
Histological characteristics considered prognostically favorable include the following:
Cellular differentiation/maturation. Higher degrees of neuroblastic maturation confer improved prognosis for stage 4 patients with segmental chromosome changes without MYCN amplification. Neuroblastoma tumors containing many differentiating cells, termed ganglioneuroblastoma, can have diffuse differentiation conferring a very favorable prognosis or can have nodules of undifferentiated cells, termed nodular ganglioneuroblastoma, whose histology, along with MYCN status, determine prognosis.[97,98]
Schwannian stroma.
Cystic neuroblastoma. About 25% of reported neuroblastomas diagnosed in the fetus and neonate are cystic. Patients with cystic neuroblastomas have tumors with lower disease stages and a higher incidence of favorable biology.[99]
High mitosis/karyorrhexis index and undifferentiated tumor cells are considered prognostically unfavorable histological characteristics, but the prognostic value is age dependent.[100,101]
A COG study (P9641 [NCT00003119]) investigated the effect of histology, among other factors, on outcome. Of 915 children with stage 1 and stage 2 neuroblastoma without MYCN amplification, 87% were treated with initial surgery and observation. Patients (13%) who had or were at risk of developing symptomatic disease, or who had less than 50% tumor resection at diagnosis, or who had unresectable progressive disease after surgery alone, were treated with chemotherapy and surgery. Those with favorable histological features reported a 5-year EFS rate of 90% to 94% and an OS rate of 99% to 100%. Those with unfavorable histology had an EFS rate of 80% to 86% and an OS rate of 89% to 93%.[79]
In the COG ANBL0531 (NCT00499616) study for intermediate-risk patients with neuroblastoma, treatment was assigned using a biology-based and response-based algorithm, which included allelic status of 1p36 and 11q23. Patients with MYCN-amplified tumors were excluded.[102]
EFS was statistically significantly better for infants with stage 4 disease with favorable tumor biology (n = 61) (3-year EFS rate, 86.9%; 95% CI, 78.3%–95.4%), compared with those with confirmed unfavorable tumor biology (n = 47) (3-year EFS rate, 66.8%; 95% CI, 53.1%–80.6%; P = .02). With longer follow-up, the 10-year EFS rates were 86.9% for infants with stage 4 tumors that had favorable biology versus 66.8% (P = .02) for infants with tumors that had unfavorable biology.[103]
OS for infants with stage 4 disease and favorable tumor biology showed a trend toward OS advantage (3-year OS rate, 95.0%; 95% CI, 89.5%–100% vs. 86.7%; 95% CI, 76.6%–96.7%; P = .08). However, with longer follow-up, the 10-year OS rates were not significantly different between infants with stage 4 tumors that had favorable biology and those with tumors that had unfavorable biology (95.0% vs. 84.4%; P = .08).[103]
Among the group 4 infants (n = 24) with stage 4 disease with confirmed diploid or unfavorable histology tumors, with or without 1p36/11q23 loss of heterozygosity, the 3-year EFS rate estimate was 63.9% (95% CI, 43.8%–84.0%), and the 3-year OS rate estimate was 77.3% (95% CI, 59.2%–95.3%).
For infants with stage 4 hyperdiploid favorable-histology tumors assigned to group 4 because of 1p36/11q23 loss of heterozygosity or unknown allelic status (n = 32), the 3-year EFS and OS rate estimates were 68.6% (95% CI, 52.2%–85.1%) and 93.8% (95% CI, 85.2%–100%), respectively.
The EFS and OS rate estimates for the eight toddlers (aged 12–18 months) with stage 4 hyperdiploid favorable-histology tumors were 62.5% (95% CI, 28.9%–96.1%) and 100%, respectively.
Patients with favorable biology and localized disease had a 100% survival rate.
A study using data from the INRG Data Commons evaluated the prognostic strength of the underlying INPC histological criteria. The independent prognostic ability of age, histological category, mitosis-karyorrhexis index (MKI), and grade was demonstrated. Four age-related, histological prognostic groups were identified (aged <18 months with low vs. high MKI, and aged ≥18 months with differentiated vs. undifferentiated/poorly differentiated tumors). Compared with survival trees generated with established COG risk criteria, an additional prognostic subgroup was identified and validated when individual histological features were analyzed in lieu of INPC.[104] The INPC is described in the Histological Classification of Neuroblastic Tumors section.
Clinical and biological features of neuroblastoma differ by primary tumor site. In a study of data on 8,389 patients in clinical trials and compiled by the International Risk Group Project, the following results were observed, confirming the results from much smaller, previous studies with less complete clinical and biological data:[105]
Adrenal tumors. Adrenal primary tumors were more likely than tumors originating in other sites to be associated with unfavorable prognostic features, including MYCN amplification, even after researchers controlled for age, stage, and histological grade. Adrenal neuroblastomas were also associated with a higher incidence of stage 4 tumors, segmental chromosomal aberrations, diploidy, unfavorable INPC histology, age younger than 18 months, and elevated levels of LDH and ferritin. The relative risks of MYCN amplification, compared with adrenal tumors, were 0.7 in abdominal nonadrenal tumors and about 0.1 in nonabdominal paraspinal tumors.
Thoracic tumors. Thoracic tumors were compared with nonthoracic tumors. After researchers controlled for age, stage, and histological grade, results showed patients with thoracic tumors had fewer deaths and recurrences (hazard ratio, 0.79; 95% CI, 0.67–0.92), and thoracic tumors had a lower incidence of MYCN amplification (adjusted OR, 0.20; 95% CI, 0.11–0.39).
Using the Therapeutically Applicable Research to Generate Effect Treatments (TARGET) and genome-wide association study data sets, a study compared the genomic and epigenomic data of primary diagnostic neuroblastomas originating in the adrenal gland (n = 646) with that of neuroblastomas originating in the thoracic sympathetic ganglia (n = 118). Neuroblastomas arising in the adrenal gland were more likely to harbor structural DNA aberrations such as MYCN amplification, whereas thoracic tumors showed defects in mitotic checkpoints resulting in hyperdiploidy. Thoracic tumors were more likely to harbor gain-of-function ALK aberrations than were adrenal tumors among all cases (OR, 1.89; P = .04), and among cases without MYCN amplification (OR, 2.86; P = .003). Because 16% of thoracic tumors harbor ALK variants, routine sequencing for these variants in this setting should be considered.[106]
In the TARGET cohort, 70% of patients with adrenal primary tumors and 51% of patients with thoracic primary tumors had stage 4 disease. In the genome-wide association study without MYCN amplification, 43% of patients with adrenal primary tumors and 17% of patients with thoracic primary tumors had stage 4 disease. By multivariate analysis, adrenal site was an independent predictor of worse outcome in the genome-wide association study cohort but not in the TARGET cohort after adjusting for MYCN amplification status, disease stage, and age of at least 18 months. Adrenal neuroblastoma was not an independent predictor of worse EFS by similar multivariable analysis for either the genome-wide association study or TARGET cohorts.[106]
It is not clear whether the effect of primary neuroblastoma tumor site on prognosis is entirely dependent on the differences in tumor biology associated with tumor site.
Multifocal neuroblastoma occurs rarely, usually in infants, and generally has a good prognosis.[107] Familial neuroblastoma and germline ALK gene pathogenic variants should be considered in patients with multiple primary neuroblastomas.
Response to treatment
Response to treatment has been associated with outcome. In patients with intermediate-risk disease who had a poor response to initial therapy in the COG ANBL0531 (NCT00499616) study, 6 of 20 patients subsequently developed progressive or recurrent disease, and one patient died.[102]
In patients with high-risk disease, the persistence of neuroblastoma cells in bone marrow after induction chemotherapy is associated with a poor prognosis. Sensitive techniques that detect minimal residual disease may be used to assess prognosis.[108–110] For example, detection of RNA transcripts expressed by neuroblastoma cells (in the bone marrow) after initial induction chemotherapy in children with high-risk neuroblastoma has been associated with significantly inferior EFS and OS.[111]
Similarly, the persistence of MIBG-avid tumor, measured as Curie score greater than 2 after completion of induction therapy, predicts a poor prognosis for patients with MYCN-nonamplified high-risk tumors. A Curie score greater than 0 after induction therapy is associated with a worse outcome for high-risk patients with MYCN-amplified disease.[112,113] An analysis of North American patients who went on to receive tandem transplants showed that patients with Curie scores greater than 0 at the end of induction therapy had inferior EFS rates.[114] For more information about Curie scoring, see the Curie and SIOPEN scoring methods section.
In an analysis of patients from four consecutive COG high-risk trials, an end-induction response of partial response (PR) or better, according to the 1993 International Neuroblastoma Response Criteria,[64] was significantly associated with higher EFS and OS. On multivariable analysis (n = 407), the absence of 11q loss of heterozygosity (LOH) was the only factor that remained significantly associated with PR or better (OR, 1.962 vs. 11q LOH; 95% CI, 1.104–3.487; P = .0216).[115]
A treatment-associated decrease in mitosis and an increase in histological differentiation of the primary tumor are also prognostic of response.[116]
The accuracy of prognostication based on decrease in primary tumor size is less clear. In a study conducted by seven large international centers, 229 high-risk patients were treated in a variety of ways. Treatment included chemotherapy, surgical removal of the primary tumor, radiation to the tumor bed, high-dose myeloablative therapy plus stem cell transplant, and, in most cases, isotretinoin and anti-GD2 antibody immunotherapy enhanced by cytokines. Primary tumor response was measured after induction chemotherapy in three ways: as 30% or greater reduction in the longest dimension, 50% or greater reduction in tumor volume, or 65% or greater reduction in tumor volume (calculated from three tumor dimensions, a conventional radiological technique). The measurements were performed at diagnosis and after induction chemotherapy before primary tumor resection. None of the methods of measuring primary tumor response at end of induction chemotherapy predicted survival.[117]
Levels of LDH and ferritin
Higher serum LDH and ferritin values conferred worse 5-year EFS and OS rates in a large international cohort of patients diagnosed with neuroblastoma (n > 8,575) from 1990 to 2016. Higher serum values for LDH and ferritin also conferred worse 3-year EFS and OS rates in patients with high-risk neuroblastoma after 2009. In a multivariate analysis that adjusted for age at diagnosis, MYCN status, and INSS stage 4 disease, LDH and ferritin maintained independent prognostic ability (P < .0001).[118][Level of evidence C1]
Although not critically evaluated in the original INRG classification system, subsequent analysis of the INRG Data Commons has clearly demonstrated independent statistical significance of the levels of serum ferritin and LDH on prognosis in all patients and in high-risk patients, including in the time period between 2010 and 2016. Therefore, it was suggested that these two easily obtainable lab values be incorporated into the prognostic classification system of the INRG.[118]
Treatment era
Between 1975 and 2020, the 5-year survival rate for neuroblastoma in the United States increased from 86% to 93% for children younger than 1 year and from 34% to 83% for children aged 1 to 14 years.[2,3] The 5-year relative survival rate for all infants and children with neuroblastoma increased from 46% when diagnosed between 1974 and 1989 to 71% when diagnosed between 1999 and 2005.[119] More recent estimates from 2014 to 2020 show an even higher 5-year relative survival rate of approximately 85% for infants and children younger than 15 years.[2] These statistics can be misleading because of the extremely heterogeneous prognosis based on the patient’s age, stage, and biology. However, studies demonstrate a significant improvement in survival for high-risk patients diagnosed and treated between 2000 and 2019, compared with patients diagnosed from 1990 to 1999.[120,121] For more information, see Table 1. Similarly, the COG ANBL0531 (NCT00499616) study found equivalent outcomes for many subsets of intermediate-risk children who were treated with substantially reduced chemotherapy, compared with the earlier COG-A3961 (NCT00003093) study.[102]
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Hero B, Simon T, Spitz R, et al.: Localized infant neuroblastomas often show spontaneous regression: results of the prospective trials NB95-S and NB97. J Clin Oncol 26 (9): 1504-10, 2008. [PUBMED Abstract]
Irwin MS, Naranjo A, Zhang FF, et al.: Revised Neuroblastoma Risk Classification System: A Report From the Children’s Oncology Group. J Clin Oncol 39 (29): 3229-3241, 2021. [PUBMED Abstract]
Strother DR, London WB, Schmidt ML, et al.: Outcome after surgery alone or with restricted use of chemotherapy for patients with low-risk neuroblastoma: results of Children’s Oncology Group study P9641. J Clin Oncol 30 (15): 1842-8, 2012. [PUBMED Abstract]
Baker DL, Schmidt ML, Cohn SL, et al.: Outcome after reduced chemotherapy for intermediate-risk neuroblastoma. N Engl J Med 363 (14): 1313-23, 2010. [PUBMED Abstract]
Cheung NK, Zhang J, Lu C, et al.: Association of age at diagnosis and genetic mutations in patients with neuroblastoma. JAMA 307 (10): 1062-71, 2012. [PUBMED Abstract]
McCarthy LC, Chastain K, Flatt TG, et al.: Neuroblastoma in Adolescents and Children Older than 10 Years: Unusual Clinicopathologic and Biologic Features. J Pediatr Hematol Oncol 41 (8): 586-595, 2019. [PUBMED Abstract]
Mazzocco K, Defferrari R, Sementa AR, et al.: Genetic abnormalities in adolescents and young adults with neuroblastoma: A report from the Italian Neuroblastoma group. Pediatr Blood Cancer 62 (10): 1725-32, 2015. [PUBMED Abstract]
Defferrari R, Mazzocco K, Ambros IM, et al.: Influence of segmental chromosome abnormalities on survival in children over the age of 12 months with unresectable localised peripheral neuroblastic tumours without MYCN amplification. Br J Cancer 112 (2): 290-5, 2015. [PUBMED Abstract]
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Chen I, Pasalic D, Fischer-Valuck B, et al.: Disparity in Outcomes for Adolescent and Young Adult Patients Diagnosed With Pediatric Solid Tumors Across 4 Decades. Am J Clin Oncol 41 (5): 471-475, 2018. [PUBMED Abstract]
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Stiefel J, Kushner BH, Roberts SS, et al.: Anaplastic Lymphoma Kinase Inhibitors for Therapy of Neuroblastoma in Adults. JCO Precis Oncol 7: e2300138, 2023. [PUBMED Abstract]
Goldsmith KC, Park JR, Kayser K, et al.: Lorlatinib with or without chemotherapy in ALK-driven refractory/relapsed neuroblastoma: phase 1 trial results. Nat Med 29 (5): 1092-1102, 2023. [PUBMED Abstract]
Ward E, DeSantis C, Robbins A, et al.: Childhood and adolescent cancer statistics, 2014. CA Cancer J Clin 64 (2): 83-103, 2014 Mar-Apr. [PUBMED Abstract]
Bagatell R, Beck-Popovic M, London WB, et al.: Significance of MYCN amplification in international neuroblastoma staging system stage 1 and 2 neuroblastoma: a report from the International Neuroblastoma Risk Group database. J Clin Oncol 27 (3): 365-70, 2009. [PUBMED Abstract]
Campbell K, Gastier-Foster JM, Mann M, et al.: Association of MYCN copy number with clinical features, tumor biology, and outcomes in neuroblastoma: A report from the Children’s Oncology Group. Cancer 123 (21): 4224-4235, 2017. [PUBMED Abstract]
Cohn SL, Pearson AD, London WB, et al.: The International Neuroblastoma Risk Group (INRG) classification system: an INRG Task Force report. J Clin Oncol 27 (2): 289-97, 2009. [PUBMED Abstract]
Monclair T, Brodeur GM, Ambros PF, et al.: The International Neuroblastoma Risk Group (INRG) staging system: an INRG Task Force report. J Clin Oncol 27 (2): 298-303, 2009. [PUBMED Abstract]
Kubota M, Suita S, Tajiri T, et al.: Analysis of the prognostic factors relating to better clinical outcome in ganglioneuroblastoma. J Pediatr Surg 35 (1): 92-5, 2000. [PUBMED Abstract]
Peuchmaur M, d’Amore ES, Joshi VV, et al.: Revision of the International Neuroblastoma Pathology Classification: confirmation of favorable and unfavorable prognostic subsets in ganglioneuroblastoma, nodular. Cancer 98 (10): 2274-81, 2003. [PUBMED Abstract]
Ikeda H, Iehara T, Tsuchida Y, et al.: Experience with International Neuroblastoma Staging System and Pathology Classification. Br J Cancer 86 (7): 1110-6, 2002. [PUBMED Abstract]
Teshiba R, Kawano S, Wang LL, et al.: Age-dependent prognostic effect by Mitosis-Karyorrhexis Index in neuroblastoma: a report from the Children’s Oncology Group. Pediatr Dev Pathol 17 (6): 441-9, 2014 Nov-Dec. [PUBMED Abstract]
Twist CJ, Schmidt ML, Naranjo A, et al.: Maintaining Outstanding Outcomes Using Response- and Biology-Based Therapy for Intermediate-Risk Neuroblastoma: A Report From the Children’s Oncology Group Study ANBL0531. J Clin Oncol 37 (34): 3243-3255, 2019. [PUBMED Abstract]
Barr EK, Naranjo A, Twist CJ, et al.: Long-term follow-up of patients with intermediate-risk neuroblastoma treated with response- and biology-based therapy: A report from the Children’s Oncology Group study ANBL0531. Pediatr Blood Cancer 71 (8): e31089, 2024. [PUBMED Abstract]
Sokol E, Desai AV, Applebaum MA, et al.: Age, Diagnostic Category, Tumor Grade, and Mitosis-Karyorrhexis Index Are Independently Prognostic in Neuroblastoma: An INRG Project. J Clin Oncol 38 (17): 1906-1918, 2020. [PUBMED Abstract]
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Burchill SA, Lewis IJ, Abrams KR, et al.: Circulating neuroblastoma cells detected by reverse transcriptase polymerase chain reaction for tyrosine hydroxylase mRNA are an independent poor prognostic indicator in stage 4 neuroblastoma in children over 1 year. J Clin Oncol 19 (6): 1795-801, 2001. [PUBMED Abstract]
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Histological Classification of Neuroblastic Tumors
Neuroblastomas are classified as one of the small round blue cell tumors of childhood. They are a heterogenous group of tumors composed of cellular aggregates with varying degrees of differentiation, from mature ganglioneuromas to less-mature ganglioneuroblastomas to immature neuroblastomas. These differences reflect the varying malignant potential of these tumors.[1]
International Neuroblastoma Pathology Classification (INPC) System
The INPC system was derived from the experience with the original Shimada classification, and the two systems are compared in Table 1. The INPC involves histological evaluation of tumor specimens obtained before therapy for the following morphological features:[2–6]
Amount of Schwannian stroma.
Degree of neuroblastic maturation.
Mitosis-karyorrhexis index (MKI) of the neuroblastic cells.
Favorable and unfavorable prognoses are defined based on these histological parameters and patient age. The prognostic significance of this classification system, and of related systems using similar criteria, has been confirmed in several studies (see Table 1).[2–4,6]
Table 1. Prognostic Evaluation of Neuroblastic Tumors According to the International Neuroblastoma Pathology Classification (Shimada System)a
International Neuroblastoma Pathology Classification
bSubtypes of neuroblastoma are described in detail elsewhere.[7]
cRare subtype, especially diagnosed in this age group. Further investigation and analysis required.
dPrognostic grouping for these tumor categories is not related to patient age.
Neuroblastoma:
(Schwannian stroma-poor)b
Stroma-poor
Favorable:
Favorable
Favorable
<1.5 y
Poorly differentiated or differentiating & low or intermediate MKI tumor
1.5–5 y
Differentiating & low MKI tumor
Unfavorable:
Unfavorable
Unfavorable
<1.5 y
a) undifferentiated tumorc
b) high MKI tumor
1.5–5 y
a) undifferentiated or poorly differentiated tumor
b) intermediate or high MKI tumor
≥5 y
All tumors
Ganglioneuroblastoma, intermixed
(Schwannian stroma-rich)
Stroma-rich intermixed (favorable)
Favorabled
Ganglioneuroma:
(Schwannian stroma-dominant)
Maturing
Well differentiated (favorable)
Favorabled
Mature
Ganglioneuroma
Ganglioneuroblastoma, nodular
(composite Schwannian stroma-rich/stroma-dominate and stroma-poor)
Stroma-rich nodular (unfavorable)
Unfavorabled
Most neuroblastomas with MYCN amplification have unfavorable INPC histology, but about 7% of tumors have favorable histology. The tumors generally do not express MYCN, even with the gene being amplified, and these patients have a more favorable prognosis than patients whose tumors are MYCN amplified and overexpress MYCN.[8]
The individual components of INPC data from the INRG Data Commons (18,865 patients) were analyzed, and the analysis validated the independent prognostic ability of age at diagnosis, histological category, MKI, and grade of differentiation. Four histological prognostic groups of patients were identified (aged <18 months with low vs. high MKI; aged >18 months with differentiating vs. undifferentiating/poorly differentiating tumors). Also, by using a risk schema devoid of the confounding of age and INPC, this analysis identified a novel and unfavorable subgroup of patients older than 547 days with stage 1 or 2, MYCN-nonamplified, intermediate or high MKI diploid tumors who had a very poor event-free survival (EFS) rate of 46%.[9][Level of evidence C1]
In some cases, biopsy may not be fully representative of the type of neuroblastic tumor present. For example, in one study of 125 patients with a biopsy diagnosis of ganglioneuroma or ganglioneuroblastoma, intermixed went on to undergo surgical resections. The pathological diagnosis changed in 39% of the cases, including 14 cases (12%) in which pathology changed to neuroblastoma or ganglioneuroblastoma, nodular.[10]
Shimada H, Ambros IM, Dehner LP, et al.: The International Neuroblastoma Pathology Classification (the Shimada system). Cancer 86 (2): 364-72, 1999. [PUBMED Abstract]
Shimada H, Umehara S, Monobe Y, et al.: International neuroblastoma pathology classification for prognostic evaluation of patients with peripheral neuroblastic tumors: a report from the Children’s Cancer Group. Cancer 92 (9): 2451-61, 2001. [PUBMED Abstract]
Goto S, Umehara S, Gerbing RB, et al.: Histopathology (International Neuroblastoma Pathology Classification) and MYCN status in patients with peripheral neuroblastic tumors: a report from the Children’s Cancer Group. Cancer 92 (10): 2699-708, 2001. [PUBMED Abstract]
Peuchmaur M, d’Amore ES, Joshi VV, et al.: Revision of the International Neuroblastoma Pathology Classification: confirmation of favorable and unfavorable prognostic subsets in ganglioneuroblastoma, nodular. Cancer 98 (10): 2274-81, 2003. [PUBMED Abstract]
Teshiba R, Kawano S, Wang LL, et al.: Age-dependent prognostic effect by Mitosis-Karyorrhexis Index in neuroblastoma: a report from the Children’s Oncology Group. Pediatr Dev Pathol 17 (6): 441-9, 2014 Nov-Dec. [PUBMED Abstract]
Shimada H, Ambros IM, Dehner LP, et al.: Terminology and morphologic criteria of neuroblastic tumors: recommendations by the International Neuroblastoma Pathology Committee. Cancer 86 (2): 349-63, 1999. [PUBMED Abstract]
Suganuma R, Wang LL, Sano H, et al.: Peripheral neuroblastic tumors with genotype-phenotype discordance: a report from the Children’s Oncology Group and the International Neuroblastoma Pathology Committee. Pediatr Blood Cancer 60 (3): 363-70, 2013. [PUBMED Abstract]
Sokol E, Desai AV, Applebaum MA, et al.: Age, Diagnostic Category, Tumor Grade, and Mitosis-Karyorrhexis Index Are Independently Prognostic in Neuroblastoma: An INRG Project. J Clin Oncol 38 (17): 1906-1918, 2020. [PUBMED Abstract]
Burnand KM, Neville J, Budzanowski A, et al.: Management of Ganglioneuroma and Ganglioneuroblastoma Intermixed: A United Kingdom Children’s Cancer and Leukaemia Group (UK CCLG) Nationwide Study Report. Pediatr Blood Cancer 72 (2): e31445, 2025. [PUBMED Abstract]
Neuroblastoma Staging and Risk Classification Systems
International Neuroblastoma Staging System (INSS)
The INSS was developed and adopted by the Children’s Oncology Group (COG) in 1986 and by cooperative groups in Europe and Japan in 1993. The INSS is a postsurgical staging system that uses tumor location with respect to midline structures, lymph node status, and, importantly, extent of upfront surgical resection to determine whether a locoregional tumor is INSS stage 1, 2A, 2B, or 3.[1,2] This system represented the first step in harmonizing disease staging and risk stratification worldwide. As a result of further advances in the understanding of neuroblastoma biology and genetics, a risk classification system was developed that incorporates clinical and biological factors in addition to INSS stage to facilitate risk group and treatment assignment for COG studies.[1–4] The final use of the INSS by the COG was for the intermediate-risk ANBL0531 (NCT00499616) study, which was closed in 2014.
International Neuroblastoma Risk Group Staging System (INRGSS)
To create a staging system independent of surgical resection extent, the INRGSS was developed in 2005 using image-defined risk factors (IDRFs) to categorize locoregional tumors as L1 (IDRFs absent), L2 (IDRFs present), M (metastatic), or MS (the equivalent of 4S in the INSS). For example, in the case of spinal cord compression, an IDRF is present when more than one-third of the spinal canal in the axial plane is invaded, when the leptomeningeal spaces are not visible, or when the spinal cord magnetic resonance signal intensity is abnormal. For more information about the INRGSS, see Table 2 and the lists of IDRFs (original IDRFs and COG IDRFs).
Presence of IDRFs has been associated with an increase in intraoperative complications, incomplete tumor resection, and worse survival in numerous studies.[5–7] Since 2014, COG and International Society of Paediatric Oncology Europe Neuroblastoma (SIOPEN) clinical trials have used the INRGSS, a preoperative staging system that was developed specifically for the International Neuroblastoma Risk Group (INRG) classification system (see Table 2), in place of the INSS.
Table 2. International Neuroblastoma Risk Group Staging Systema
Localized tumor not involving vital structures as defined by the list of IDRFsa and confined to one body compartment.
L2
Locoregional tumor with presence of one or more IDRFs.a
M
Distant metastatic disease (except stage MS).
MS
Metastatic disease in children younger than 18 months with metastases confined to skin, liver, and/or bone marrow. The primary tumor can be INSS stage 1, 2, or 3.
IDRFs, as defined in the original literature, include the following:[5,7]
Ipsilateral tumor extension within two body compartments: neck and chest; chest and abdomen; abdomen and pelvis.
Encasement of major vessels by tumor: vertebral artery, internal jugular vein, subclavian vessels, carotid artery, aorta, vena cava, major thoracic vessels, branches of the superior mesenteric artery at its root and the celiac axis, iliac vessels.
Compression of trachea or central bronchi.
Encasement of brachial plexus.
Infiltration of portohepatic or hepatoduodenal ligament.
Infiltration of the costovertebral junction between T9 and T12.
Tumor crossing the sciatic notch.
Tumor invading renal pedicle.
Extension of tumor to base of skull.
Intraspinal tumor extension such that more than one-third of the spinal canal is invaded, leptomeningeal space is obliterated, or spinal cord MRI signal is abnormal.
COG IDRFs, using an anatomical localization approach, include the following:[6,8]; [7][Level of evidence C1]
Neck/cervicothoracic junction: Tumor involving/encasing brachial plexus, subclavian vessels and/or vertebral and/or carotid artery, internal jugular vein, base of skull; tumor compressing the trachea.
Thorax: Tumor involving/encasing the aorta and/or major branches; tumor compressing the trachea and/or principal bronchi; lower mediastinal tumor, infiltrating the costovertebral junction between T9 and T12.
Thoracoabdominal: Tumor involving/encasing the aorta and/or vena cava.
Abdomen/pelvis: Tumor involving/encasing the porta hepatis and/or hepatoduodenal ligament, superior mesenteric artery at the root, the origin of the celiac axis, and/or of the superior mesenteric artery; tumor involving/encasing one or both renal pedicles, aorta and/or vena cava; tumor involving/encasing the iliac vessels; pelvic tumor involving/encasing the sciatic notch.
Intra-spinal tumor extension: Invading more than one-third of axial plane and/or perimedullary leptomeningeal spaces are not visible, abnormal spinal cord signal; dumbbell tumors with symptoms of spinal cord compression.
Any localization involvement/infiltration of adjacent organs/structures: Pericardium, diaphragm, kidney, liver, duodenopancreatic block, mesentery, and others.
Tumor involving two body compartments: Neck and chest; chest and abdomen; abdomen and pelvis.
Assessment of surgical resectability must include IDRFs. The more IDRFs present, the higher the morbidity of the operation and the lower the chance of complete resection. The presence of two or more IDRFs should prompt a discussion regarding up-front chemotherapy rather than surgical resection at diagnosis. To decrease morbidity, it is critical to avoid up-front surgical resection with invasive tumors. An international analysis demonstrated that specific IDRFs present at diagnosis or before surgery may be associated with a lower likelihood of achieving a greater than 90% resection of the primary tumor.[9] Concordance in assessing IDRFs between local investigators and central reviewers was assessed in the context of a COG intermediate-risk trial and showed agreement in only 51.9% of cases.[10]
Neoadjuvant chemotherapy is not always effective in eliminating IDRFs. A retrospective study in the European Unresectable Neuroblastoma trial from 2001 to 2006 examined data from 143 patients with INSS stage 3 neuroblastoma who were older than 1 year without MYCN amplification. All patients had surgical risk factors that deemed the tumors unresectable. In a centrally reviewed subset, unfavorable histology by International Neuroblastoma Pathology Classification was found in 53% of patients. At diagnosis, 228 IDRFs were identified.[8]; [11][Level of evidence C1]
After four cycles of chemotherapy with carboplatin/etoposide alternating with vincristine/cyclophosphamide/doxorubicin, only 32.2% of patients demonstrated resolution of the IDRFs, 49% of patients showed no change in IDRFs, and 18.8% of patients developed new IDRFs.
Complete resection was possible in 71.2% of patients in whom the IDRFs were reduced or disappeared. Complete or near-complete resection was achieved in 84% of patients (37 of 44) whose IDRFs decreased or disappeared. Complete or near-complete resection was achieved in 70% of patients (39 of 56) who had stable IDRFs and in 52% of patients (13 of 25) who had new IDRFs appear.
No significant differences were observed in event-free survival (EFS) or overall survival (OS) based on the response of the IDRF to chemotherapy and surgical outcomes. There was no association between type of IDRF before surgery and extent of resection.
When the tumor was wrapped around the superior mesenteric artery and/or celiac axis, disease-free survival (DFS) and OS were impacted (perhaps because of the difficulty in achieving a complete resection in these areas).
Prolonged chemotherapy beyond five courses did not lead to further reduction of IDRFs and was associated with a lower DFS and OS.
The INRGSS staging system is one of the prognostic markers included in the INRG Classification System.[12] For more information, see Table 4.
The INRGSS includes four disease stages: L1, L2, M, or MS. Localized tumors are classified as stage L1 or L2 disease based on whether one or more of the 20 IDRFs are present.[5]
The INRG Task Force has also reported consensus techniques for detecting and quantifying neuroblastoma in bone marrow, both at diagnosis and after treatment. Quantification of bone marrow metastatic disease may result in more accurate assessment of response to treatment,[13] and it is now incorporated into the International Neuroblastoma Response Criteria, which assess response to therapy.[14]
The decision by the INRG Task Force to define MS disease differently from 4S disease was based on reports in which small numbers of infants with L2 primary tumors and 4S metastatic patterns, including those aged 12 to 18 months, had favorable outcomes.[5,15] A subsequent study analyzing INRG data demonstrated that a number of biological characteristics predicted poor outcome for patients with MS disease who were aged 12 to 18 months at diagnosis. However, long-term outcomes of toddlers, aged 12 to 18 months, with favorable-biology MS disease were similar to those of infants younger than 12 months with INSS stage 4S neuroblastoma.[15]
By combining the INRGSS, age, and biological factors, each patient is assigned an INRG risk group that is prognostic of outcome and guides the appropriate risk-based treatment approach. The validity of the INRGSS was explored in the following retrospective studies of localized neuroblastoma with previously defined INSS stage without MYCN amplification:
In the first study, using data from a SIOPEN trial, patients with INSS stage 1 (21%), stage 2 (45%), and stage 3 (94%) disease were classified as having L2 tumors according to the INRGSS. The INRGSS had predictive value for outcomes, with patients with stage L1 having a 5-year EFS rate of 90% and an OS rate of 96%, versus an EFS rate of 79% and an OS rate of 89% for patients with L2 tumors.[5]
In the second study, data was used from the European multicenter study LNESG1, a trial of primary surgery followed by observation, performed between 1995 and 1999. In this study, 291 children had L1 tumors and all underwent primary surgery. Of the patients with L2 tumors, 118 had primary surgery and 125 had no surgery (106 of the latter group received neoadjuvant chemotherapy).[16]
The 5-year EFS and OS rates were 92% and 98% for the L1 group, 86% and 95% for the L2 with primary surgery group, and 73% and 83% for the L2 without primary surgery group.
It should be noted that many children with L2 tumors underwent primary surgery and had an outcome significantly superior to that of children who underwent biopsy only as the initial operative procedure (5-year OS rate of 93% vs. 83%). The patients with L2 tumors who underwent primary resection may have been selected for less-risky resectability. However, these children also had a 17% rate of operative complications (vs. 5% in L1 resections).
In patients who underwent primary surgery, those with operative complications had a lower OS rate (92% vs. 97%, P = .05), but this effect on outcome was statistically significant only in patients with L1 tumors.
For patients with L2 tumors, the operative complications were not statistically related to the IDRFs.
Most international protocols have begun to incorporate the collection and use of IDRFs to define INRG stage, which is used in risk stratification and assignment of therapy.[17,18] The COG has been collecting and evaluating INRGSS data since 2006. A COG trial that opened in 2014 uses the INRGSS along with input from the surgeon to determine therapy for subsets of patients not at high risk, including those with L1, L2, and MS disease (ANBL1232 [NCT02176967], closed to accrual). Note that the INSS allows patients up to age 12 months to be classified as stage 4S, while the INRGSS allows patients up to age 18 months to be staged as MS. The primary tumor in INSS stage 4S must be INSS stage 1 or 2, while the primary tumor in MS can be L1 or L2, which includes INSS stages 1, 2, or 3. The INRGSS is used in ongoing COG studies and does not depend on a resection variable, but rather on pretreatment imaging combined with age and biological variables. It is anticipated that the use of standardized nomenclature will contribute substantially to more uniform staging and facilitate comparisons of clinical trials conducted in different parts of the world.
Children’s Oncology Group (COG) Neuroblastoma Risk Grouping
The COG ANBL00B1 (NCT00904241) biology study served as the infrastructure for rapid and reliable acquisition of the clinical and biological prognostic markers used for risk classification and clinical trial eligibility between 2000 and 2023. The APEC14B1 trial is currently used to facilitate risk group. For more information about the COG risk categories, see Table 3.
Based on data from 4,832 patients who were enrolled from 2007 to 2017 in the ANBL00B1 study, the COG has updated the risk classification.[19] Patients are defined as having low-, intermediate-, or high-risk disease based on clinical and biological factors (see Table 3).
Table 3. Risk Groups Used by the Children’s Oncology Group Committee
High-Risk Disease
1. Stage M, aged ≥18 months, regardless of other features
2. Stage M, aged <18 months with MYCN-amplified disease
3. Stage MS or L2 with MYCN-amplified disease
4. Stage L2 with unfavorable histology, aged ≥18 months
5. Stage M or MS 12–18 months with at least one unfavorable feature:
—Unfavorable histology
— Segmental chromosomal aberrations
—Diploid tumor
6. Stage L1 incompletely resected tumor with MYCN amplification
Low-Risk Disease
1. Stage L1 with MYCN-nonamplified disease regardless of other features
2. Stage L1 completely resected with MYCN-amplified disease
3. Stage MS, aged <12 months with all favorable features:
—Asymptomatic
—Favorable histology
—No segmental chromosomal aberrations
—Hyperdiploid tumor
Intermediate-Risk Disease
All other groups not meeting the definition of high-risk or low-risk disease.a
aFor complete classification, see Irwin MS et al.[19]
International Neuroblastoma Risk Group (INRG)
Combinations of prognostic factors (clinical and biological features) have been used for decades to risk-stratify patients and inform treatment assignment.[12] Schema differ across international cooperative groups. The INRG Task Force has led efforts to develop uniform approaches for staging and pretreatment risk classification, as outlined below.[20] The algorithms that use these factors to determine risk are complex and change slightly based on new knowledge. The INRG Classification System was designed based on survival-tree analyses of 35 prognostic factors in more than 8,800 patients with neuroblastoma from a variety of clinical trials. The underlying histological features in the INPC (Shimada system) were included in the analysis:[20,21]
Diagnostic category.
Grade of differentiation.
Mitosis-karyorrhexis index (MKI).
The INRG classification schema assigns neuroblastoma patients to one of 16 pretreatment risk groups based on INRG stage, age, histological category, grade of tumor differentiation, MYCN amplification, 11q aberration (the only segmental chromosomal aberration studied), and ploidy. Four levels of risk were defined according to outcomes among 8,800 patients with high-quality data, as they had been entered in clinical trials (see Table 4).
In the overall risk grouping, histological category is an important risk determinant for all stage L1 and L2 tumors, and grade of differentiation is prognostic in neuroblastomas and nodular ganglioneuroblastomas in patients older than 18 months. The goals of the INRG are to increase international collaboration and classify patients uniformly so that the results of clinical trials conducted around the world can be compared.[20]
Table 4. International Neuroblastoma Risk Group (INRG) Pretreatment Classification Schemaa
INRG Stage
Histological Category
Grade of Tumor Differentiation
MYCN
11q Aberration
Ploidy
Pretreatment Risk Group
GN = ganglioneuroma; GNB = ganglioneuroblastoma; NA = not amplified.
Because patient age is used in all risk stratification systems, a cellular classification system that did not employ patient age was desirable, and underlying histological criteria, rather than INPC or Shimada Classification, was used in the survival-tree analyses to select prognostic criteria for the INRG Classification System. Histological findings discriminated prognostic groups most clearly in two subsets of patients, as shown in Table 5.
Table 5. Histological Discrimination of International Neuroblastoma Risk Group Subsets of Neuroblastoma Patientsa
INSS Stage/Histological Subtype
Number of Cases
EFS (%)
OS (%)
EFS = event-free survival; GN = ganglioneuroma; GNB = ganglioneuroblastoma; INSS = International Neuroblastoma Staging System; NB = neuroblastoma; OS = overall survival.
The INRG histological subsets are incorporated into the INRG Risk Classification Schema.
Evaluation of Primary Tumor and Metastatic Disease
Approximately 70% of patients with neuroblastoma have metastatic disease at diagnosis. A thorough evaluation for metastatic disease is performed before therapy initiation. The studies described below are typically performed.[1]
Computed tomography (CT) and magnetic resonance imaging (MRI) scan
Three-dimensional (3-D) imaging of the primary tumor and potential lymph node drainage sites is done using CT scans and/or MRI scans of the chest, abdomen, and pelvis. Ultrasonography is generally considered suboptimal for accurate 3-D measurements.
Paraspinal tumors may extend through neural foramina to compress the spinal cord. Therefore, MRI of the spine adjacent to any paraspinal tumor is part of the staging evaluation.
A brain/orbit CT and/or MRI is performed if clinically indicated by examination and/or uptake on metaiodobenzylguanidine (MIBG) scan.
One study of 50 children with neuroblastoma (all with primary tumors in the abdomen or pelvis) evaluated the role of gadolinium contrast as part of MRI scans. Assessment of tumor size and IDRFs appeared similar regardless of whether gadolinium was used.[22]
Metaiodobenzylguanidine (MIBG) scan
The extent of metastatic disease is assessed by MIBG scan, which is applicable to all sites of disease, including soft tissue, bone marrow, and cortical bone. Approximately 90% of neuroblastomas will be MIBG avid. The MIBG scan has a sensitivity and specificity of 90% to 99%, and MIBG avidity is equally distributed between primary and metastatic sites.[23] Although iodine I 123 (123I) has a shorter half-life, it is preferred over 131I because of its lower radiation dose, better quality images, reduced thyroid toxicity, and lower cost.
Imaging with 123I-MIBG is optimal for identifying soft tissue and bony metastases. It was shown to be superior to positron emission tomography–computed tomography (PET-CT) in one prospective comparison.[24] In a retrospective review of 132 children with neuroblastoma, technetium Tc 99m-methylene diphosphonate (99mTc-MDP) bone scintigraphy failed to identify unique sites of metastatic disease that would change the disease stage or clinical management determined using 123I-MIBG or PET scanning. Bone scans are not used as part of standard staging for neuroblastoma.[25]
Baseline MIBG scans performed at diagnosis are excellent for monitoring disease response and performing posttherapy surveillance.[26] A retrospective analysis of paired 123I-MIBG and PET scans in 60 patients with newly diagnosed neuroblastoma demonstrated that for patients with INSS stage 1 and stage disease, PET was superior at determining the extent of primary disease and more sensitive in detecting residual masses. In contrast, for stage 4 disease, 123I-MIBG imaging was superior in detecting bone marrow and bony metastases.[27]
Curie and SIOPEN scoring methods
Multiple groups have investigated a semiquantitative scoring method to evaluate disease extent and prognostic value. The most common scoring methods in use for evaluation of disease extent and response are the Curie and the SIOPEN methods.
Curie scoring method: The Curie score is a semiquantitative scoring system developed to predict the extent and severity of MIBG-avid disease. The use of the Curie scoring system was assessed as a prognostic marker for response and survival in patients with MIBG-avid, stage 4, newly diagnosed, high-risk neuroblastoma (N = 280), treated on the COG protocol COG-A3973 (NCT00004188). For patients with MYCN-nonamplified neuroblastoma, a postinduction chemotherapy Curie score greater than 2 was associated with a higher risk of an event, independent of other known neuroblastoma clinical and biological factors, including age, MYCN status, ploidy, MKI, and histological grade.[28] For patients with MYCN-amplified tumors, a postinduction Curie score greater than 0 was associated with worse outcomes.
The prognostic significance of postinduction Curie scores has been validated in an independent cohort of patients.[29] A retrospective study of Curie scoring was performed on 123I-MIBG scans obtained from high-risk patients who had been prospectively enrolled in the SIOPEN/HR-NBL1 (NCT00030719) trial. Scans of nine anatomical regions were evaluated for bone metastases and a tenth region for all sites of soft tissue disease. Each region was scored 0 to 3 based on disease extent, and a cumulative Curie score was generated. The optimal prognostic cut point for Curie score at diagnosis was 12 in the SIOPEN/HR-NBL1 trial, with a significant outcome difference by Curie score noted (5-year EFS rate, 43.0% ± 5.7% [Curie score ≤12] vs. 21.4% ± 3.6% [Curie score >12], P < .0001). The optimal Curie score cut point after induction chemotherapy was 2 in the SIOPEN/HR-NBL1 trial, with a postinduction Curie score of greater than 2 being associated with an inferior outcome (5-year EFS rate, 39.2% ± 4.7% [Curie score ≤2] vs. 16.4% ± 4.2% [Curie score >2], P < .0001). The postinduction Curie score maintained independent statistical significance in Cox models when adjusted for the covariates of age and MYCN gene copy number.[29]
SIOPEN scoring method: SIOPEN independently developed an MIBG scan scoring system. Compared with the Curie scoring system, the SIOPEN method divided the body into 12 segments, rather than 10 segments, and assigned six degrees, rather than four degrees, of MIBG uptake in bone metastases only within each segment.[30] Subsequently, the SIOPEN scoring system was independently validated using data from a second large clinical trial.[31]
The German Pediatric Oncology Group compared the prognostic value of the Curie and SIOPEN scoring methods in a retrospective study of 58 patients with stage 4 neuroblastoma who were older than 1 year. The study found concordance in prognostic value (of these two methods) at diagnosis and after induction chemotherapy. At diagnosis, a Curie score of 2 or lower and a SIOPEN score of 4 or lower (best cutoff) correlated with significantly better EFS and overall survival (OS) rates, compared with higher scores. After four cycles of induction chemotherapy, patients with a complete response by SIOPEN and Curie scoring had a better outcome than patients with residual uptake in metastases. However, subsequent resolution of MIBG-positive metastases occurring between the fourth and sixth cycles of chemotherapy did not affect prognosis.[32]
The cited clinical trials did not include postinduction-phase assessments of Curie or SIOPEN scores after transplant and immunotherapy. Cutoffs and outcomes associated with those assessments may differ from the preinduction and postinduction scores.
PET scan
Fluorine F 18-fludeoxyglucose PET scans are used to evaluate extent of disease in patients with tumors that are not MIBG avid.[27]
Bone marrow aspiration and biopsy
Bone marrow is assessed by bilateral iliac crest marrow aspirates and trephine (core) bone marrow biopsies to exclude bone marrow involvement. To be considered adequate, core biopsy specimens must contain at least 1 cm of marrow, excluding cartilage. Many COG studies require two core biopsies and two aspirates. Bone marrow sampling may not be necessary for tumors that are otherwise stage 1.[33]
Other staging tests and procedures
Other tests and procedures used to stage neuroblastoma include the following:
Lymph node assessment: Palpable lymph nodes are clinically examined and histologically confirmed if INSS staging is used to evaluate extent of disease.[1] CT, MRI, or both are used to assess lymph nodes in regions that are not readily identified by physical examination. The INRG staging system does not require lymph node assessment, although lymph node masses can affect IDRFs. For more information, see the lists of IDRFs (original IDRFs and COG IDRFs).
Lumbar puncture is avoided because central nervous system (CNS) metastasis at diagnosis is rare,[34] and lumbar puncture may be associated with an increased incidence of subsequent development of CNS metastasis.[35]
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Taggart DR, London WB, Schmidt ML, et al.: Prognostic value of the stage 4S metastatic pattern and tumor biology in patients with metastatic neuroblastoma diagnosed between birth and 18 months of age. J Clin Oncol 29 (33): 4358-64, 2011. [PUBMED Abstract]
Monclair T, Mosseri V, Cecchetto G, et al.: Influence of image-defined risk factors on the outcome of patients with localised neuroblastoma. A report from the LNESG1 study of the European International Society of Paediatric Oncology Neuroblastoma Group. Pediatr Blood Cancer 62 (9): 1536-42, 2015. [PUBMED Abstract]
Cecchetto G, Mosseri V, De Bernardi B, et al.: Surgical risk factors in primary surgery for localized neuroblastoma: the LNESG1 study of the European International Society of Pediatric Oncology Neuroblastoma Group. J Clin Oncol 23 (33): 8483-9, 2005. [PUBMED Abstract]
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Irwin MS, Naranjo A, Zhang FF, et al.: Revised Neuroblastoma Risk Classification System: A Report From the Children’s Oncology Group. J Clin Oncol 39 (29): 3229-3241, 2021. [PUBMED Abstract]
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Genomic and Biological Features of Neuroblastoma
Molecular features of neuroblastoma
Children with neuroblastoma can be divided into subsets with different predicted risks of relapse based on clinical factors and biological markers at the time of diagnosis.
Low-risk or intermediate-risk neuroblastoma patients. Patients classified as low risk or intermediate risk have a favorable prognosis, with survival rates exceeding 95%. Low-risk and intermediate-risk neuroblastoma usually occur in children younger than 18 months. These tumors commonly have gains of whole chromosomes and are hyperdiploid when examined by flow cytometry.[1,2]
High-risk neuroblastoma patients. The prognosis is more guarded for patients with high-risk neuroblastoma, with a long-term survival rate of less than 50%. High-risk neuroblastoma generally occurs in children older than 18 months and is often metastatic to bone and bone marrow. Segmental chromosome abnormalities (gains or losses) and/or MYCN gene amplification are usually detected in these tumors. They are near diploid or near tetraploid by flow cytometric measurement.[1–7] High-risk tumors generally harbor few exonic variants in cancer-related genes (see the Exonic Variants in Neuroblastoma section).
Biological subtypes of high-risk neuroblastoma can be defined by the mostly nonoverlapping genomic alterations listed below:
MYCN amplification.
Structural variants up- or down-stream of TERT, resulting in TERT expression.
ATRX alterations leading to activation of the alternative lengthening of telomere (ALT) pathway.
FOXR2 expression resulting in MYCN stabilization.
CDK4 and MDM2 co-amplification.
The subtypes listed have specific clinical characteristics, as discussed below. Variants in ALK, which occur across the different subtypes of high-risk neuroblastoma, are observed in approximately 15% of cases and are discussed separately.
Key genomic characteristics of high-risk neuroblastoma that are present in most cases of high-risk neuroblastoma are discussed below.
Segmental chromosomal aberrations (SCAs)
The SCAs frequently observed in neuroblastoma and used when assigning SCA status include losses of or at chromosome arms 1p, 3p, 4p, and 11q and gains of or at chromosome arms 1q, 2p, and 17q.[8] These alterations can be detected by multiple methods, including fluorescence in situ hybridization (FISH), array comparative genomic hybridization (aCGH), and next-generation sequencing (NGS) assays. SCAs are present in most high-risk and/or stage 4 neuroblastoma tumors.[3,4,6,7,9] Among all patients with neuroblastoma, a higher number of chromosome breakpoints (i.e., a higher number of SCAs) correlated with the following:[3–7][Level of evidence C2]
Advanced age at diagnosis.
Advanced stage of disease.
Higher risk of relapse.
Poorer outcome.
Determining the presence of SCAs is potentially clinically useful. Detecting SCAs can help distinguish patients with clinically favorable presentation who are at higher risk of treatment failure. Examples are provided below.
In an analysis of localized, resectable, non-MYCN amplified neuroblastoma, cases from two consecutive European studies and a North American cohort (including International Neuroblastoma Staging System [INSS] stages 1, 2A, and 2B) were analyzed for selected SCAs (namely loss of 1p, 3p, 4p, and 11q and gain of 1q, 2p, and 17q). The study revealed a different prognostic impact of tumor genomics depending on patient age (<18 months vs. >18 months) and stage (1 vs. 2). Patients were treated with surgery alone regardless of a tumor residuum.[10][Level of evidence C1]
For patients with stage 1 disease, presence of SCAs was not predictive of relapse and overall survival (OS).
For patients younger than 18 months with stage 2 disease:
Chromosome 1p loss was a risk factor for relapse but not for diminished OS.
Patients with numerical chromosomal aberrations (NCA) and patients with SCAs had similar outcomes.
For patients older than 18 months with stage 2 disease:
SCAs were observed in approximately 50% of patients.
SCAs (especially 11q loss) were independent risk factors for reduced event-free survival (EFS) and OS. The 5-year EFS rate was 48%, compared with 85% (P = .033), respectively, for patients with or without chromosome 11q loss. The 5-year OS rate was 46%, compared with 92% (P = .038), respectively, for patients with or without chromosome 11q loss.
In a study of children older than 12 months who had unresectable primary neuroblastomas without metastases, SCAs were found in most patients. Older children were more likely to have them and to have more SCAs per tumor cell. In children aged 12 to 18 months, the presence of SCAs had a significant effect on EFS but not on OS. However, in children older than 18 months, there was a significant difference in OS between children with SCAs (67%) and children without SCAs (100%), regardless of tumor histology.[7]
SCAs were also found to be predictive of recurrence in infants with localized unresectable or metastatic neuroblastoma without MYCN gene amplification.[1,2] An analysis of 133 patients (aged ≥18 months) with INSS stage 3 tumors without MYCN amplification demonstrated that SCAs were associated with inferior EFS, and chromosome 11q loss was independently associated with worse OS.[11]
Chromosome 11q loss occurs in approximately 30% of high-risk neuroblastoma cases, but it is uncommonly observed in tumors with MYCN amplification.[3] Chromosome 11q loss is frequently observed in high-risk neuroblastoma cases with either TERT rearrangements or with ALT pathway activation.[12,13] Chromosome 11q loss has also been associated with inferior EFS and poor response to induction therapy in patients with high-risk neuroblastoma, as described below:
In an analysis of intermediate-risk patients in a Children’s Oncology Group (COG) study, 11q loss, but not 1p loss, was associated with reduced EFS but not OS (11q loss and no 11q loss: 3-year EFS rates, 68% and 85%, respectively; P = .022; 3-year OS rates, 88% and 94%, respectively; P = .09).[14][Level of evidence B4]
In a multivariable analysis of 407 patients from four consecutive COG high-risk trials, 11q loss was shown to be a significant predictor of progressive disease, and was associated with both lower rates of end-induction complete response and lower end-induction partial response.[15][Level of evidence C1]
Distal chromosome 6q losses have also been associated with poor outcome. An international collaboration studied 556 patients with high-risk neuroblastoma. Distal 6q losses were found in 6% of patients and were associated with a 10-year survival rate of only 3.4%.[16] A second study confirmed the very poor prognosis of patients with high-risk neuroblastoma who have distal 6q loss. Pooling across both studies, MYCN amplification occurred in only 20% of cases with distal chromosome 6q loss.[17]
The same study of 556 patients with high-risk neuroblastoma that identified poor prognosis for patients with distal 6q loss also evaluated amplifications of regions not encompassing the MYCN locus. Regions of non-MYCN amplification were detected in 18% of the patients and were associated with a 10-year survival rate of 5.8%.[16]
MYCN gene amplification
MYCN amplification is detected in 16% to 25% of neuroblastoma tumors.[18] Among patients with high-risk neuroblastoma, 40% to 50% of cases show MYCN amplification.[19]
In all stages of disease, amplification of the MYCN gene strongly predicts a poorer prognosis, in both time to tumor progression and OS, in almost all multivariate regression analyses of prognostic factors.[1,2] In the ANBL00B1 (NCT00904241) study of 4,832 newly diagnosed patients enrolled between 2007 to 2017, the 5-year EFS and OS rates were 77% and 87%, respectively, for patients whose tumors were MYCN nonamplified (n = 3,647; 81%). In comparison, the 5-year EFS and OS rates were 51% and 57%, respectively, for patients whose tumors were MYCN amplified (n = 827; 19%).[9]
Within the localized-tumor MYCN-amplified cohort, patients with hyperdiploid tumors have better outcomes than patients with diploid tumors.[20] However, patients with hyperdiploid tumors with MYCN amplification or any SCAs do relatively poorly, compared with patients with hyperdiploid tumors without MYCN amplification.[3]
Most unfavorable clinical and pathobiological features are associated, to some degree, with MYCN amplification. In a multivariable logistic regression analysis of 7,102 patients in the International Neuroblastoma Risk Group (INRG) study, pooled SCAs and gains of 17q were poor prognostic features, even when not associated with MYCN amplification. However, another poor prognostic feature, SCAs at 11q, are almost entirely mutually exclusive of MYCN amplification.[21,22]
In a cohort of 6,223 patients from the INRG database with known MYCN status, the OS hazard ratio (HR) associated with MYCN amplification was 6.3 (95% confidence interval [CI], 5.7–7.0; P < .001). The greatest adverse prognostic impact of MYCN amplification for OS was in the youngest patients (aged <18 months: HR, 19.6; aged ≥18 months: HR, 3.0). Patients whose outcome was most impacted by MYCN status were those with otherwise favorable features, including age younger than 18 months, high mitosis-karyorrhexis index, and low ferritin.[23][Level of evidence C1]
Intratumoral heterogeneous MYCN amplification (hetMNA) refers to the coexistence of MYCN-amplified cells (as a cluster or as single scattered cells) and non–MYCN-amplified tumor cells. HetMNA has been reported infrequently. It can occur spatially within the tumor as well as between the tumor and the metastasis at the same time or temporally during the disease course. The International Society of Paediatric Oncology Europe Neuroblastoma (SIOPEN) biology group investigated the prognostic significance of this neuroblastoma subtype. Tumor tissue from 99 patients identified as having hetMNA and diagnosed between 1991 and 2015 was analyzed to elucidate the prognostic significance of MYCN-amplified clones in otherwise non-MYCN–amplified neuroblastomas. Patients younger than 18 months showed a better outcome in all stages compared with older patients. The genomic background correlated significantly with relapse frequency and OS. No relapses occurred in cases of only numerical chromosomal aberrations. This study suggests that hetMNA tumors be evaluated in the context of the genomic tumor background in combination with the clinical pattern, including the patient’s age and disease stage. Future studies are needed in patients younger than 18 months who have localized disease with hetMNA.[24]
Lengthening of telomeres, the tips of chromosomes, promotes cell survival. Telomeres otherwise shorten with each cell replication, eventually resulting in the cell’s inability to replicate. Patients whose tumors lack telomere maintenance mechanisms have an excellent prognosis, while patients whose tumors harbored telomere maintenance mechanisms have a substantially worse prognosis.[25] Low-risk neuroblastoma tumors, as defined by clinical/biological features, have little telomere lengthening activity. Aberrant genetic mechanisms for telomere lengthening have been identified in high-risk neuroblastoma tumors.[25–28] Thus far, the following three mechanisms, which appear to be mutually exclusive, have been described:
MYCN amplification, which is associated with approximately 40% to 50% of high-risk neuroblastoma cases, is sufficient to drive TERT overexpression.[25,26,29]
TERT gene rearrangements are a second method for neuroblastoma to achieve TERT expression. Chromosomal rearrangements, either proximal or distal to the TERT gene, which encodes the catalytic unit of telomerase, occur in approximately 20% to 25% of high-risk neuroblastoma cases and are mutually exclusive with MYCN amplifications and ALT activation.[13,26–28] The rearrangements induce transcriptional upregulation of TERT by juxtaposing the TERT coding sequence with strong enhancer elements. Rearrangements distal to the TERT gene occur less commonly and also lead to TERT expression.
Children whose tumors have TERT rearrangements have a poor prognosis, which is comparable to the prognosis of children whose tumors have MYCN amplification.[28]
Chromosome 11q loss and chromosome 1q gain are common in patients with TERT rearrangements.
NGS or FISH using break-apart probes may be used to identify TERT rearrangements.[13]
ALT pathway activation is an additional mechanism of telomere maintenance that is used by neuroblastoma tumors. Approximately 55% to 60% of ALT-positive cases are characterized by deleterious ATRX variants.[30–32] Cases lacking ATRX variants often show low ATRX protein expression.[31]
ALT activation is present in approximately 20% to 25% of newly diagnosed high-risk cases, compared with approximately 5% to 12% of low-risk and intermediate-risk cases.[28,31,32]
Compared with newly diagnosed cases, the proportion of neuroblastoma cases with ALT-positive tumors was higher in a cohort of patients who relapsed (10% vs. 48%, respectively). This finding may reflect the relatively indolent course of tumors with ALT activation after relapse (see below), compared with the clinical course of other tumors after relapse.[31]
Like cases with TERT rearrangements, chromosome 11q loss is commonly observed in ALT-positive neuroblastoma. Unique to ALT-positive cases is deletion at chromosome 1q42.2.[12,31]
Neuroblastoma cases with ALT activation have low TERT expression and can be identified by immunohistochemistry for the ALT-associated promyelocytic nuclear body, by FISH with a telomere probe to visualize telomere ultrabright spots, and by the C-circle assay.[31–33]
ALT-positive tumors in pediatric populations rarely present before the age of 18 months and occur almost exclusively in older children (median age at diagnosis, approximately 8 years).[28,31] The proportion of neuroblastoma cases with ATRX variants increases with age into the adolescent and young adult populations.[30]
The prognosis for high-risk patients with ALT activation is as poor as that for patients with MYCN amplification for EFS.[28,31] However, OS is more favorable for patients with ALT activation. The more favorable OS appears to result from a more protracted disease course after relapse, but with long-term survival at 10 to 15 years being as low as that for other patients with high-risk neuroblastoma.[28,31] In one report, EFS and OS for low-risk and intermediate-risk patients with ALT activation were similar to those observed for ALT-positive patients with high-risk disease.[31]
FOXR2 activation
FOXR2 gene expression is observed in approximately 8% of neuroblastoma cases. FOXR2 gene expression is normally absent postnatally, with the exception of male reproductive tissues.[34] FOXR2 expression is also observed in a subset of central nervous system (CNS) primitive neuroectodermal tumors, termed CNS NB-FOXR2.[35] FOXR2 overexpression was virtually mutually exclusive in neuroblastoma tumors with both elevated MYC and MYCN expression. Although MYCN gene expression was not elevated in neuroblastoma with FOXR2 activation, the gene expression profile for the FOXR2 expressing cases closely resembled that of MYCN-amplified neuroblastoma. FOXR2 binds MYCN and appears to stabilize the MYCN protein, leading to high levels of MYCN protein in neuroblastoma with FOXR2 activation. This finding provides an explanation for the similar gene expression profiles for neuroblastoma with FOXR2 activation and neuroblastoma with MYCN amplification.
Neuroblastoma with FOXR2 activation is observed at comparable rates in high-risk and non–high-risk cases.[34] Among high-risk cases, outcomes for patients whose tumors showed FOXR2 activation were similar to those for cases with MYCN amplification. In a multivariable analysis, FOXR2 activation was significantly associated with inferior OS, along with INSS stage 4, age 18 months or older, and MYCN amplification.
CDK4 and MDM2 amplification
CDK4 and MDM2 amplification are observed together in 1% to 2% of neuroblastoma cases, and these cases have distinctive biological and clinical features:[36,37]
Neuroblastoma with chromosome 12q amplification typically has discrete amplicons involving 12q13–14, which includes CDK4, and 12q15, which includes MDM2 and FRS2 (encoding the gene for fibroblast growth factor receptor substrate 2).
The primary tumors of most cases with CDK4 or MDM2 amplification were associated with the adrenal gland, although some renal primary tumors were also observed.
Lung metastases, which are infrequent in neuroblastoma, were observed in 9 of 13 cases with CDK4 or MDM2 amplification that presented with metastatic disease.
Most patients with CDK4 or MDM2 amplification did not have MYCN amplification, although MYCN amplification was present in approximately 25% of cases.
Outcome for patients with CDK4 or MDM2 amplification is poor. In one experience, only two of six patients with localized disease showed long-term survival, and nine of ten patients with metastatic disease died.[37] Another report described only one of eight patients with CDK4 or MDM2 amplification as a long-term survivor.[36] A third report described three patients with localized disease, all of whom subsequently died of their disease.[38]
Exonic variants in neuroblastoma (including ALK variants and amplification)
Compared with adult cancers, pediatric neuroblastoma tumors show a low number of variants per genome that affect protein sequence (10–20 per genome).[39] The most common gene variant is ALK, which is altered in approximately 10% of patients (see below). Other genes with even lower frequencies of variants include ATRX, PTPN11, ARID1A, and ARID1B.[26,27,30,40–43] As shown in Figure 2, most neuroblastoma cases lack variants in genes that are altered in a recurrent manner.
EnlargeFigure 2. Data tracks (rows) facilitate the comparison of clinical and genomic data across cases with neuroblastoma (columns). The data sources and sequencing technology used were whole-exome sequencing (WES) from whole-genome amplification (WGA) (light purple), WES from native DNA (dark purple), Illumina WGS (green), and Complete Genomics WGS (yellow). Striped blocks indicate cases analyzed using two approaches. The clinical variables included were sex (male, blue; female, pink) and age (brown spectrum). Copy number alterations indicates ploidy measured by flow cytometry (with hyperdiploid meaning DNA index >1) and clinically relevant copy number alterations derived from sequence data. Significantly mutated genes are those with statistically significant mutation counts given the background mutation rate, gene size, and expression in neuroblastoma. Germline indicates genes with significant numbers of germline ClinVar variants or loss-of-function cancer gene variants in our cohort. DNA repair indicates genes that may be associated with an increased mutation frequency in two apparently hypermutated tumors. Predicted effects of somatic mutations are color coded according to the legend. Reprinted by permission from Macmillan Publishers Ltd: Nature Genetics (Pugh TJ, Morozova O, Attiyeh EF, et al.: The genetic landscape of high-risk neuroblastoma. Nat Genet 45 (3): 279-84, 2013), copyright (2013).
The ALK gene provides instructions for making a cell surface receptor tyrosine kinase, expressed at significant levels only in developing embryonic and neonatal brains. ALK is the exonic variant found most commonly in neuroblastoma. Germline pathogenic variants in ALK have been identified as the major cause of hereditary neuroblastoma. Somatically acquired ALK-activating exonic variants are also found as oncogenic drivers in neuroblastoma.[42]
Two large cohort studies examined the clinical correlates and prognostic significance of ALK alterations. One study from the COG examined ALK status in 1,596 diagnostic neuroblastoma samples across all risk groups.[42] Another study from SIOPEN evaluated 1,092 patients with high-risk neuroblastoma.[44]
ALK tyrosine kinase domain variants occurred primarily at three hot spots (F1174, R1275, and F1245 positions), with 10% to 15% of variants occurring at other kinase domain positions.
In the COG cohort, the frequency of ALK variants was 10% in the high-risk neuroblastoma group, 8% in the intermediate-risk neuroblastoma group, and 6% in the low-risk neuroblastoma group.
In the SIOPEN high-risk population, ALK variants were divided into clonal (>20% variant allele frequency [VAF]) and subclonal (0.1%–20% VAF). Clonal ALK variants were detected in 10% of cases, and subclonal variants were found in 3.9% of patients. A total of 13.9% of the cases had an ALK variant.
ALK variants were found at higher rates in patients with MYCN-amplified tumors compared with those without MYCN amplification: 10.9% versus 7.2%, respectively, for the COG cohort and 14% versus 6.5%, respectively, for the SIOPEN cohort (for clonal ALK variants).
For patients with high-risk neuroblastoma, the ALK amplification was observed in approximately 4% of cases in both the COG and the SIOPEN cohorts. ALK amplification occurred almost exclusively in cases that also had MYCN amplification.
ALK alterations were associated with inferior prognoses for patients with high-risk neuroblastoma in both the COG and the SIOPEN studies:
In the SIOPEN cohort, a statistically significant difference in OS was observed between cases with ALK amplification (ALKa) or clonal ALK variant (ALKm) versus subclonal ALKm or no ALK alterations (5-year OS rate: ALKa, 26% [95% CI, 10%–47%]; clonal ALKm, 33% [95% CI, 21%–44%]; subclonal ALKm, 48% [95% CI, 26%–67%]; and no alteration, 51% [95% CI, 46%–55%], respectively; P = .001). In a multivariate model, ALK amplification (HR, 2.38; P = .004) and clonal ALK variant (HR, 1.77; P = .001) were independent predictors of poor outcome.
In the COG high-risk neuroblastoma population, inferior prognoses, similar to those seen in the SIOPEN cohort, were observed for cases with ALK variants and ALK amplifications.
In a study that compared the genomic data of primary diagnostic neuroblastomas originating in the adrenal gland (n = 646) with that of neuroblastomas originating in the thoracic sympathetic ganglia (n = 118), 16% of thoracic tumors harbored ALK variants.[45]
Small-molecule ALK kinase inhibitors such as lorlatinib (added to conventional therapy) are being tested in patients with recurrent ALK-altered neuroblastoma (NCT03107988) and in patients with newly diagnosed high-risk neuroblastoma with activated ALK (COG ANBL1531).[42] For more information, see the sections on Treatment of High-Risk Neuroblastoma and Treatment of Recurrent or Refractory Neuroblastoma in Neuroblastoma Treatment.
Genomic evolution of exonic variants
There are limited data regarding the genomic evolution of exonic variants from diagnosis to relapse for neuroblastoma. Whole-genome sequencing was applied to 23 paired diagnostic and relapsed neuroblastoma tumor samples to define somatic genetic alterations associated with relapse,[46] while a second study evaluated 16 paired diagnostic and relapsed specimens.[47] Both studies identified an increased number of variants in the relapsed samples compared with the samples at diagnosis. This has been confirmed in a study of neuroblastoma tumor samples sent for NGS.[48]
In the first study, an increased incidence of variants in genes associated with RAS-MAPK signaling was found in tumors at relapse compared with tumors from the same patient at diagnosis; 15 of 23 relapse samples contained somatic variants in genes involved in this pathway, and each variant was consistent with pathway activation.[46]
In addition, three relapse samples showed structural alterations involving MAPK pathway genes consistent with pathway activation, so aberrations in this pathway were detected in 18 of 23 (78%) relapse samples. Aberrations were found in ALK (n = 10), NF1 (n = 2), and one each in NRAS, KRAS, HRAS, BRAF, PTPN11, and FGFR1. Even with deep sequencing, 7 of the 18 alterations were not detectable in the primary tumor, highlighting the evolution of variants presumably leading to relapse and the importance of genomic evaluations of tissues obtained at relapse.
In the second study, ALK variants were not observed in either diagnostic or relapse specimens, but relapse-specific recurrent single-nucleotide variants were observed in 11 genes, including the putative CHD5 neuroblastoma tumor suppressor gene located at chromosome 1p36.[47]
A third retrospective variant-sequencing study used data from Foundation Medicine to compare tumor samples from patients with newly diagnosed neuroblastoma with tumor samples from patients with refractory and relapsed neuroblastoma. The study found a higher percentage of variants that were targetable with current drugs in the relapsed and refractory group.[48]
A fourth study evaluated the frequency of ALK alterations at diagnosis and relapse. There were significantly higher rates of ALK variants at relapse than at diagnosis (17.7% at relapse vs. 10.5% at diagnosis). The rate of ALK amplifications did not differ between diagnosis and relapse.[49]
Given the widespread metastatic nature of high-risk and relapsed neuroblastoma, use of circulating tumor DNA (ctDNA) technologies may reveal additional genomic alterations not found in conventional tumor biopsies. Moreover, these approaches have demonstrated the ability to detect resistant variants in patients with neuroblastoma who were treated with ALK inhibitors.[50][Level of evidence C1] In one analysis of serial ctDNA samples from patients treated with lorlatinib, ALK VAF tracked with disease burden in most but not all patients.[51] In subsets of patients who progressed while taking lorlatinib, second compound variants in ALK or variants in other genes, including RAS pathway genes and TP53, have been reported.[51,52]
In a deep-sequencing study, 276 neuroblastoma samples (comprised of all stages and from patients of all ages at diagnosis) underwent very deep (33,000X) sequencing of just two amplified ALK variant hot spots, which revealed 4.8% clonal variants and an additional 5% subclonal variants. This finding suggests that subclonal ALK gene variants are common.[53] Thus, deep sequencing can reveal the presence of variants in tiny subsets of neuroblastoma tumor cells that may be able to survive during treatment and grow to constitute a relapse.
Additional biological factors associated with prognosis
MYC and MYCN expression
Immunostaining for MYC and MYCN proteins on a restricted subset of 357 undifferentiated/poorly differentiated neuroblastoma tumors demonstrated that elevated MYC/MYCN protein expression is prognostically significant.[54] Sixty-eight tumors (19%) highly expressed the MYCN protein, and 81 were MYCN amplified. Thirty-nine tumors (10.9%) expressed MYC highly and were mutually exclusive of high MYCN expression. In the MYC-expressing tumors, MYC or MYCN gene amplification was not seen. SCAs were not examined in this study.[54]
Patients with favorable-histology tumors without high MYC/MYCN expression had favorable survival (3-year EFS rate, 89.7% ± 5.5%; 3-year OS rate, 97% ± 3.2%).
Patients with undifferentiated or poorly differentiated histology tumors without MYC/MYCN expression had a 3-year EFS rate of 63.1% (± 13.6%) and a 3-year OS rate of 83.5% (± 9.4%).
The 3-year EFS rates in patients with MYCN amplification, high MYCN expression, and high MYC expression were 48.1% (± 11.5%), 46.2% (± 12%), and 43.4% (± 23.1%), respectively. OS rates were 65.8% (± 11.1%), 63.2% (± 12.1%), and 63.5% (± 19.2%), respectively.
Additionally, when high expression of MYC and MYCN proteins underwent multivariate analysis with other prognostic factors, including MYC/MYCN gene amplification, high MYC and MYCN protein expression was independent of other prognostic markers.
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Rosswog C, Fassunke J, Ernst A, et al.: Genomic ALK alterations in primary and relapsed neuroblastoma. Br J Cancer 128 (8): 1559-1571, 2023. [PUBMED Abstract]
Bosse KR, Giudice AM, Lane MV, et al.: Serial Profiling of Circulating Tumor DNA Identifies Dynamic Evolution of Clinically Actionable Genomic Alterations in High-Risk Neuroblastoma. Cancer Discov 12 (12): 2800-2819, 2022. [PUBMED Abstract]
Berko ER, Witek GM, Matkar S, et al.: Circulating tumor DNA reveals mechanisms of lorlatinib resistance in patients with relapsed/refractory ALK-driven neuroblastoma. Nat Commun 14 (1): 2601, 2023. [PUBMED Abstract]
Bobin C, Iddir Y, Butterworth C, et al.: Sequential Analysis of cfDNA Reveals Clonal Evolution in Patients with Neuroblastoma Receiving ALK-Targeted Therapy. Clin Cancer Res 30 (15): 3316-3328, 2024. [PUBMED Abstract]
Bellini A, Bernard V, Leroy Q, et al.: Deep Sequencing Reveals Occurrence of Subclonal ALK Mutations in Neuroblastoma at Diagnosis. Clin Cancer Res 21 (21): 4913-21, 2015. [PUBMED Abstract]
Wang LL, Teshiba R, Ikegaki N, et al.: Augmented expression of MYC and/or MYCN protein defines highly aggressive MYC-driven neuroblastoma: a Children’s Oncology Group study. Br J Cancer 113 (1): 57-63, 2015. [PUBMED Abstract]
Special Considerations for the Treatment of Children With Cancer
Cancer in children and adolescents is rare, although the overall incidence has slowly increased since 1975.[1] Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the following pediatric specialists and others to ensure that children receive treatment, supportive care, and rehabilitation to achieve optimal survival and quality of life:
Primary care physicians.
Pediatric surgeons.
Transplant surgeons.
Pathologists.
Pediatric radiation oncologists.
Pediatric medical oncologists and hematologists.
Ophthalmologists.
Rehabilitation specialists.
Pediatric oncology nurses.
Social workers.
Child-life professionals.
Psychologists.
Nutritionists.
For specific information about supportive care for children and adolescents with cancer, see the summaries on Supportive and Palliative Care.
The American Academy of Pediatrics has outlined guidelines for pediatric cancer centers and their role in the treatment of children and adolescents with cancer.[2] At these centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate is offered to most patients and their families. Clinical trials for children and adolescents diagnosed with cancer are generally designed to compare potentially better therapy with current standard therapy. Other types of clinical trials test novel therapies when there is no standard therapy for a cancer diagnosis. Most of the progress in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI website.
References
Smith MA, Seibel NL, Altekruse SF, et al.: Outcomes for children and adolescents with cancer: challenges for the twenty-first century. J Clin Oncol 28 (15): 2625-34, 2010. [PUBMED Abstract]
American Academy of Pediatrics: Standards for pediatric cancer centers. Pediatrics 134 (2): 410-4, 2014. Also available online. Last accessed February 25, 2025.
Treatment Option Overview for Neuroblastoma
Generally, treatment of neuroblastoma is based on whether the tumor is classified as non-high risk (low or intermediate risk) or high risk. Because 5-year survival rates are generally 90% or higher, the goal of treatment for non–high-risk disease is to cure the disease with minimal toxicity. Outcomes for patients with high-risk disease have improved over time with the use of increasingly intensive multimodal therapy, but they remain suboptimal.
Low risk. For patients with low-risk tumors, the approach is either observation or resection, with chemotherapy restricted to symptomatic patients with low-risk biology. The 5-year overall survival (OS) rate was 98% for the low-risk patients among more than 5,000 patients enrolled in the Children’s Oncology Group (COG) ANBL00B1 (NCT00904241) biology study.[1]
Intermediate risk. For patients with intermediate-risk tumors, chemotherapy is often given before definitive resection. Multiagent chemotherapy consisting of doxorubicin, cyclophosphamide, a platinum drug, and etoposide is used. The number of chemotherapy cycles is based on clinical and tumor biological risk factors and response to therapy.[2] The goal of chemotherapy is to deliver a sufficient duration of chemotherapy (with or without surgery) to achieve at least a partial response (at least 50% reduction of soft tissue masses) and resolution of metastatic disease.[2] In some studies, select patients have been observed without undergoing chemotherapy or attempted resection. The 5-year OS rate was about 95% for the intermediate-risk patients among more than 5,000 patients enrolled in the COG ANBL00B1 (NCT00904241) biology study.[1] In the COG ANBL0531 (NCT00499616) study, the duration and intensity of chemotherapy was decreased in several subsets of intermediate-risk children to further diminish side effects; no declines in outcomes were seen.[2,3]
High risk. For high-risk patients, treatment has intensified to include chemotherapy, surgery, radiation therapy, myeloablative therapy and hematopoietic stem cell transplant (HSCT), isotretinoin, and immunotherapy, resulting in 5-year survival rates of 62%.[1] Statistically significant improvement in event-free survival (EFS) was observed in a randomized phase III COG study (ANBL0532 [NCT00567567]) with tandem cycles of myeloablative therapy and HSCT, compared with a single cycle of myeloablative therapy and HSCT. The 3-year EFS rate for patients who received tandem transplants was superior (P = .006) to the EFS rate for patients who received single transplants, although OS was not statistically different. In this study, a large proportion of patients were not randomized.[4][Level of evidence A1] For more information, see the Consolidation phase section.
Table 6 summarizes the treatment options for patients with low-risk, intermediate-risk, and high-risk disease.
Chemotherapy (for symptomatic patients, those with unfavorable tumor biology, and infants aged <3 months).
Surgery (rarely, for patients with hepatomegaly that compromises the kidney or other abdominal organs).
Radiation therapy (rarely, for patients with symptoms related to hepatomegaly from metastatic disease).
Principles of Surgery
In patients without metastatic disease, the standard of care is to perform an initial surgery. This surgery aims to accomplish the following, based on the disease stage and the risk group:
Obtain tissue for diagnosis. Incisional or core biopsy only is recommended for patients with L2 disease,[5][Level of evidence C1] and an up-front resection should generally not be attempted. For more information about image-defined risk factors (IDRFs), see the International Neuroblastoma Risk Group Staging System (INRGSS) section.
Either incisional biopsy or percutaneous core needle biopsy are acceptable for patients with L2 disease. In a multi-institutional retrospective study, there was no significant difference in the ability to accurately obtain a primary diagnosis by percutaneous core needle biopsy compared with incisional biopsy (95.7% vs. 98.9%, P = .314) or determine MYCN copy number (92.4% vs. 97.8%; P = .111). The yield for loss of heterozygosity and tumor ploidy was lower with percutaneous core needle biopsy (dependent on the number of cores/volume of tissue obtained) than with incisional biopsy (56.1% vs. 90.9%, P < .05; and 58.0% vs. 88.5%, P < .05). Complications did not differ between the groups.[6][Level of evidence C1]
Near-total or total resection (80%–90%) of the primary tumor is recommended based on stage.
This is standard for patients with low-risk (excluding prenatally diagnosed infants who are candidates for observation) and intermediate-risk disease. In patients with L1 tumors (defined as having no image-defined surgical risk factors), the tumors are resectable with low risk of nephrectomy or life-threatening complications. Unilateral adrenal gland primary tumors, thoracic L1 disease, or neck L1 disease should be resected up front (per the surgeons’ discretion).[5][Level of evidence C1]
Minimally invasive surgery may be considered in highly selected patients with neuroblastoma if it is performed by a pediatric surgical oncologist who has expertise using this technique.[7][Level of evidence C1]; [8,9]
The COG reported that expectant observation in infants younger than 6 months with small (L1) adrenal masses resulted in an excellent EFS and OS while avoiding surgical intervention in a large majority of patients.[10] According to the surgical guidelines described in the intermediate-risk neuroblastoma clinical trial (ANBL0531 [NCT00499616]), the primary tumor is not routinely resected in patients with 4S neuroblastoma. German studies of selected groups of patients have biopsied tissue and observed infants with both L1 and L2 tumors without MYCN amplification, avoiding additional surgery and chemotherapy in most patients.[11]
Whether there is any advantage to gross-total resection (>90%) of the primary tumor mass after chemotherapy in patients older than 18 months with stage 4 disease remains controversial.[12–17] A meta-analysis of patients with stage 3 versus stage 4 neuroblastoma, at all ages combined, found an advantage for gross-total resection (>90%) over subtotal resection in stage 3 neuroblastoma only.[18] A small study suggested that after neoadjuvant chemotherapy, completeness of resection was affected by the number of IDRFs remaining.[19] When an experienced surgeon performed the procedure, a 90% or greater resection of the primary tumor in stage 4 neuroblastoma resulted in a higher local control rate, but it did not have a statistically significant impact on OS.[20]
In the current treatment paradigm, radiation therapy for patients with low-risk or intermediate-risk neuroblastoma is reserved for symptomatic life-threatening or organ-threatening tumor bulk that did not respond rapidly enough to chemotherapy. Common situations in which radiation therapy is used in these patients include the following:
Infants aged 60 days and younger with stage 4S and marked respiratory compromise from liver metastases that has not responded to chemotherapy.[21]
For patients with spinal cord compression. However, most patients are treated with chemotherapy or neurosurgical intervention because of the responsiveness of neuroblastoma to chemotherapy and the potentially devastating late effects of radiation therapy in young children.[22]
Radiation therapy has become part of the standard of care for patients with high-risk disease and is usually delivered after high-dose chemotherapy and stem cell rescue. For more information, see the Treatment of High-Risk Neuroblastoma section.
Limiting the use of radiation therapy in infants with neuroblastoma (who generally have non–high-risk disease) is supported by long-term follow-up data from the Childhood Cancer Survivor Study. This study demonstrated higher rates of second malignant neoplasms and significant chronic health conditions in infants who were treated with radiation therapy.[23][Level of evidence C1]
Treatment of Spinal Cord Compression
Spinal cord compression is considered a medical emergency. Patients receive immediate treatment because neurological recovery is more likely when symptoms are present for a relatively short time before diagnosis and treatment. Recovery also depends on the severity of neurological defects (weakness vs. paralysis). Neurological outcome appears to be similar whether cord compression is treated with chemotherapy, radiation therapy, or surgery, although radiation therapy is used less frequently than in the past.
The completed COG neuroblastoma clinical trials recommended immediate chemotherapy for cord compression in low-risk or intermediate-risk patients.[22,24,25] In a single study in this setting looking at the effect of glucocorticoids on neurological outcome, treatment was associated with improved early symptom relief. However, glucocorticoids did not prevent late residual impairment.[25]
Children with severe spinal cord compression that does not promptly improve or those with worsening symptoms may benefit from neurosurgical intervention. Laminectomy may result in later kyphoscoliosis and may not eliminate the need for chemotherapy.[22,24,25] Osteoplastic laminotomy, a procedure that does not remove bone, was thought to lessen spinal deformity. Osteoplastic laminotomy may be associated with a lower incidence of progressive spinal deformity requiring fusion, but there is no evidence that functional neurological deficit is improved with laminoplasty.[26]
The burden of long-term health problems in survivors of neuroblastoma with intraspinal extension is high. In a systematic review of 28 studies of treatment and outcome of patients with intraspinal extension, the severity of the symptoms at diagnosis and the treatment modalities were most associated with the presence of long-term health problems. In particular, the severity of neurological motor deficits was most likely to predict neurological outcome.[27] The severity of motor deficits at diagnosis is associated with spinal deformity and sphincter dysfunction at the end of follow-up, while sphincter dysfunction at diagnosis was correlated with long-term sphincter problems.[28] This supports the initiation of treatment before symptoms have deteriorated to complete loss of neurological function.
In a series of 34 infants with symptomatic epidural spinal cord compression, both surgery and chemotherapy provided unsatisfactory results once paraplegia had been established. The frequency of grade 3 motor deficits and bowel dysfunction increased with a longer symptom duration interval. Most infants with symptomatic epidural spinal cord compression developed sequelae, which were severe in about one-half of patients.[29]
An analysis of patients with intermediate-risk disease treated in the COG ANBL0531 [NCT00499616] study included 92 patients with intraspinal disease.[30] Of these patients, 42 (46%) were symptomatic. Among patients who were symptomatic, motor symptoms and bowel/bladder symptoms resolved completely in 73% and 88% of patients, respectively. Laminectomy or laminoplasty was performed in 22 of 42 symptomatic patients and was not significantly associated with improvements in symptoms.
Surveillance During and After Treatment
Although the role of surveillance imaging for detection of neuroblastoma relapse has not been well studied, most patients will undergo regular imaging tests after completing therapy. Many patients who relapse are asymptomatic, and relapse is detected on surveillance evaluations. Factors such as risk stratification, disease sites, biomolecular markers, and cumulative radiation dose may be considered in surveillance after treatment.[31–33]
One series included 154 patients with high-risk neuroblastoma who had a complete or very good partial response and subsequently had relapsed disease. The study found that 113 of the patients (73%) had asymptomatic relapse, while only 41 (27%) presented with symptoms. Metaiodobenzylguanidine (MIBG) scans were the most reliable study to detect asymptomatic relapse.[32]
In another series of 183 patients diagnosed with neuroblastoma, 50 patients experienced recurrence or progression. Relapsed disease was detected in most patients by symptoms/examination, MIBG scan, urinary catecholamines, and/or x-rays or ultrasonography.[33]
Of the 50 patients, 37 had clinically evident or measurable disease detected by x-ray, ultrasonography, or urinary catecholamines. The addition of MIBG scanning identified eight additional recurrences.
The cross-sectional imaging (computed tomography [CT]/magnetic resonance imaging) was only required to identify 10% of cases (5 of 50).
Thirty-two of the 50 relapses (64%) were detected by scheduled surveillance investigations, and 18 of the 50 relapses (36%) were detected because of new symptoms and/or history.
Twenty-three of 50 relapses were associated with new concerning symptoms and/or examination. As a result, 18 of 50 patients had earlier-than-planned imaging performed, 17 of whom had new lesions that corresponded to the symptoms or examination. Seventeen of the 18 patients were high risk at diagnosis.
Cross-sectional imaging with CT scans is controversial because of the amount of radiation received and the low proportion of relapses detected with this modality.[33]
Evaluation of Disease Response
Evaluation of response is critical for the management of individual patients, but it is also necessary for comparing results of clinical trials. Given the complexities of a disease with propensity for bone and bone marrow metastasis, international consensus criteria have been developed and refined over the last several decades. The current version of these International Neuroblastoma Response Criteria (INRC) is presented below.
Revised International Neuroblastoma Response Criteria (INRC)
INRC is used to assess response to treatment.[34–36] Overall response in the revised INRC integrates tumor response in three components: primary tumor, soft tissue and bone metastases, and bone marrow. Primary and metastatic soft tissue sites are assessed using Response Evaluation Criteria in Solid Tumors (RECIST) and iodine I 123 (123I) MIBG scans or fluorine F 18-fludeoxyglucose (18F-FDG) positron emission tomography (PET) scans if the tumor is MIBG nonavid. 123I-MIBG scans, or 18F-FDG PET scans for MIBG-nonavid disease, replaced Technetium Tc 99m (99mTc) diphosphonate bone scintigraphy for osteomedullary metastasis assessment. Bone marrow is assessed by histology with or without immunohistochemistry and cytology or immunocytology. Bone marrow with 5% or less tumor involvement is classified as minimal disease. Urinary catecholamine levels are not included in response assessment. Overall response is defined as complete response, partial response, minor response, stable disease, or progressive disease.[36]
The overall INRC response criteria are defined as follows:[34,35]
Complete Response: No evidence of disease, including resolution of MIBG uptake (or PET scan positivity in MIBG non-avid disease) in any location of soft tissue or bone, with less than 10 mm remaining on 3-D imaging of primary tumor; target lymph nodes less than 15 mm in short dimension; and no histological tumor in two bone marrow biopsies and two bone marrow aspirates sampled at one time point.
Partial Response: 30% or more decrease in longest diameter of primary site and at least 30% decrease in sum of diameters of nonprimary soft tissue metastases (soft tissue sites may still be avid); and at least a 50% reduction in absolute MIBG bone score or a 50% or greater reduction in number of 18F-FDG PET-avid bone lesions; and bone marrow with 0% to 5% tumor; and no new lesions.
Minor Response: Partial response or complete response of at least one component of disease, but at least one other component with stable disease and no component with progressive disease.
Progressive Disease: Any new lesion; increase in longest diameter in any measurable soft tissue lesion by 20% with at least 5 mm absolute increase; previous negative bone marrow now positive for at least 5% tumor or previous positive bone marrow that increases twofold in tumor percentage and increases to more than 20% tumor; any new soft tissue lesion that is MIBG (or 18F-FDG PET) avid or positive by biopsy; a new avid bone site; or increase in relative MIBG score to at least 1.2.
Stable Disease: Stable disease in one component with no better than stable disease or no involvement at other two components. No components meet criteria for progressive disease or partial response.
Care should be taken in interpreting the development of metastatic disease in an infant who was initially considered to have stage 1 or 2 disease. If the pattern of metastases in such a patient is consistent with a 4S pattern of disease (involvement of skin, liver, and/or bone marrow, the latter less than 10% involved), these patients are not classified as having progressive/metastatic disease, which would typically be a criterion for removal from protocol therapy. Instead, these patients are managed as stage 4S patients.
Controversy exists regarding the necessity of measuring the primary tumor response in all three dimensions or whether the single longest dimension, as in RECIST tumor response determination, is equally useful.[37] The latter has been adopted for use in the INRC.
References
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Twist CJ, Schmidt ML, Naranjo A, et al.: Maintaining Outstanding Outcomes Using Response- and Biology-Based Therapy for Intermediate-Risk Neuroblastoma: A Report From the Children’s Oncology Group Study ANBL0531. J Clin Oncol 37 (34): 3243-3255, 2019. [PUBMED Abstract]
Barr EK, Naranjo A, Twist CJ, et al.: Long-term follow-up of patients with intermediate-risk neuroblastoma treated with response- and biology-based therapy: A report from the Children’s Oncology Group study ANBL0531. Pediatr Blood Cancer 71 (8): e31089, 2024. [PUBMED Abstract]
Park JR, Kreissman SG, London WB, et al.: Effect of Tandem Autologous Stem Cell Transplant vs Single Transplant on Event-Free Survival in Patients With High-Risk Neuroblastoma: A Randomized Clinical Trial. JAMA 322 (8): 746-755, 2019. [PUBMED Abstract]
Newman EA, Nuchtern JG: Recent biologic and genetic advances in neuroblastoma: Implications for diagnostic, risk stratification, and treatment strategies. Semin Pediatr Surg 25 (5): 257-264, 2016. [PUBMED Abstract]
Overman RE, Kartal TT, Cunningham AJ, et al.: Optimization of percutaneous biopsy for diagnosis and pretreatment risk assessment of neuroblastoma. Pediatr Blood Cancer 67 (5): e28153, 2020. [PUBMED Abstract]
Gabra HO, Irtan S, Cross K, et al.: Minimally invasive surgery for neuroblastic tumours: A SIOPEN multicentre study: Proposal for guidelines. Eur J Surg Oncol 48 (1): 283-291, 2022. [PUBMED Abstract]
Zenitani M, Yoshida M, Matsumoto S, et al.: Feasibility and safety of laparoscopic tumor resection in children with abdominal neuroblastomas. Pediatr Surg Int 39 (1): 91, 2023. [PUBMED Abstract]
Chang S, Lin Y, Yang S, et al.: Safety and feasibility of laparoscopic resection of abdominal neuroblastoma without image-defined risk factors: a single-center experience. World J Surg Oncol 21 (1): 113, 2023. [PUBMED Abstract]
Nuchtern JG, London WB, Barnewolt CE, et al.: A prospective study of expectant observation as primary therapy for neuroblastoma in young infants: a Children’s Oncology Group study. Ann Surg 256 (4): 573-80, 2012. [PUBMED Abstract]
Hero B, Simon T, Spitz R, et al.: Localized infant neuroblastomas often show spontaneous regression: results of the prospective trials NB95-S and NB97. J Clin Oncol 26 (9): 1504-10, 2008. [PUBMED Abstract]
Adkins ES, Sawin R, Gerbing RB, et al.: Efficacy of complete resection for high-risk neuroblastoma: a Children’s Cancer Group study. J Pediatr Surg 39 (6): 931-6, 2004. [PUBMED Abstract]
Castel V, Tovar JA, Costa E, et al.: The role of surgery in stage IV neuroblastoma. J Pediatr Surg 37 (11): 1574-8, 2002. [PUBMED Abstract]
La Quaglia MP, Kushner BH, Su W, et al.: The impact of gross total resection on local control and survival in high-risk neuroblastoma. J Pediatr Surg 39 (3): 412-7; discussion 412-7, 2004. [PUBMED Abstract]
Simon T, Häberle B, Hero B, et al.: Role of surgery in the treatment of patients with stage 4 neuroblastoma age 18 months or older at diagnosis. J Clin Oncol 31 (6): 752-8, 2013. [PUBMED Abstract]
Englum BR, Rialon KL, Speicher PJ, et al.: Value of surgical resection in children with high-risk neuroblastoma. Pediatr Blood Cancer 62 (9): 1529-35, 2015. [PUBMED Abstract]
von Allmen D, Davidoff AM, London WB, et al.: Impact of Extent of Resection on Local Control and Survival in Patients From the COG A3973 Study With High-Risk Neuroblastoma. J Clin Oncol 35 (2): 208-216, 2017. [PUBMED Abstract]
Mullassery D, Farrelly P, Losty PD: Does aggressive surgical resection improve survival in advanced stage 3 and 4 neuroblastoma? A systematic review and meta-analysis. Pediatr Hematol Oncol 31 (8): 703-16, 2014. [PUBMED Abstract]
Irtan S, Brisse HJ, Minard-Colin V, et al.: Image-defined risk factor assessment of neurogenic tumors after neoadjuvant chemotherapy is useful for predicting intra-operative risk factors and the completeness of resection. Pediatr Blood Cancer 62 (9): 1543-9, 2015. [PUBMED Abstract]
Wolden SL, Gollamudi SV, Kushner BH, et al.: Local control with multimodality therapy for stage 4 neuroblastoma. Int J Radiat Oncol Biol Phys 46 (4): 969-74, 2000. [PUBMED Abstract]
Hsu LL, Evans AE, D’Angio GJ: Hepatomegaly in neuroblastoma stage 4s: criteria for treatment of the vulnerable neonate. Med Pediatr Oncol 27 (6): 521-8, 1996. [PUBMED Abstract]
Katzenstein HM, Kent PM, London WB, et al.: Treatment and outcome of 83 children with intraspinal neuroblastoma: the Pediatric Oncology Group experience. J Clin Oncol 19 (4): 1047-55, 2001. [PUBMED Abstract]
Friedman DN, Goodman PJ, Leisenring WM, et al.: Long-Term Morbidity and Mortality Among Survivors of Neuroblastoma Diagnosed During Infancy: A Report From the Childhood Cancer Survivor Study. J Clin Oncol 41 (8): 1565-1576, 2023. [PUBMED Abstract]
De Bernardi B, Pianca C, Pistamiglio P, et al.: Neuroblastoma with symptomatic spinal cord compression at diagnosis: treatment and results with 76 cases. J Clin Oncol 19 (1): 183-90, 2001. [PUBMED Abstract]
Simon T, Niemann CA, Hero B, et al.: Short- and long-term outcome of patients with symptoms of spinal cord compression by neuroblastoma. Dev Med Child Neurol 54 (4): 347-52, 2012. [PUBMED Abstract]
McGirt MJ, Chaichana KL, Atiba A, et al.: Incidence of spinal deformity after resection of intramedullary spinal cord tumors in children who underwent laminectomy compared with laminoplasty. J Neurosurg Pediatr 1 (1): 57-62, 2008. [PUBMED Abstract]
Kraal K, Blom T, van Noesel M, et al.: Treatment and outcome of neuroblastoma with intraspinal extension: A systematic review. Pediatr Blood Cancer 64 (8): , 2017. [PUBMED Abstract]
Angelini P, Plantaz D, De Bernardi B, et al.: Late sequelae of symptomatic epidural compression in children with localized neuroblastoma. Pediatr Blood Cancer 57 (3): 473-80, 2011. [PUBMED Abstract]
De Bernardi B, Quaglietta L, Haupt R, et al.: Neuroblastoma with symptomatic epidural compression in the infant: the AIEOP experience. Pediatr Blood Cancer 61 (8): 1369-75, 2014. [PUBMED Abstract]
Voeller J, Katzenstein HM, Naranjo A, et al.: Outcomes of patients with intermediate-risk neuroblastoma presenting with motor deficits relating to intraspinal tumor extension: A report from the Children’s Oncology Group study ANBL0531. Pediatr Blood Cancer 72 (1): e31407, 2025. [PUBMED Abstract]
Papathanasiou ND, Gaze MN, Sullivan K, et al.: 18F-FDG PET/CT and 123I-metaiodobenzylguanidine imaging in high-risk neuroblastoma: diagnostic comparison and survival analysis. J Nucl Med 52 (4): 519-25, 2011. [PUBMED Abstract]
Kushner BH, Kramer K, Modak S, et al.: Sensitivity of surveillance studies for detecting asymptomatic and unsuspected relapse of high-risk neuroblastoma. J Clin Oncol 27 (7): 1041-6, 2009. [PUBMED Abstract]
Owens C, Li BK, Thomas KE, et al.: Surveillance imaging and radiation exposure in the detection of relapsed neuroblastoma. Pediatr Blood Cancer 63 (10): 1786-93, 2016. [PUBMED Abstract]
Brodeur GM, Pritchard J, Berthold F, et al.: Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. J Clin Oncol 11 (8): 1466-77, 1993. [PUBMED Abstract]
Brodeur GM, Seeger RC, Barrett A, et al.: International criteria for diagnosis, staging, and response to treatment in patients with neuroblastoma. J Clin Oncol 6 (12): 1874-81, 1988. [PUBMED Abstract]
Park JR, Bagatell R, Cohn SL, et al.: Revisions to the International Neuroblastoma Response Criteria: A Consensus Statement From the National Cancer Institute Clinical Trials Planning Meeting. J Clin Oncol 35 (22): 2580-2587, 2017. [PUBMED Abstract]
Bagatell R, McHugh K, Naranjo A, et al.: Assessment of Primary Site Response in Children With High-Risk Neuroblastoma: An International Multicenter Study. J Clin Oncol 34 (7): 740-6, 2016. [PUBMED Abstract]
Treatment of Non–High-Risk Neuroblastoma
Approximately one-half of all newly diagnosed patients with neuroblastoma have non–high-risk disease (i.e., low and intermediate risk).[1] Since these patients have excellent survival, with 5-year survival rates higher than 95% for patients with low-risk disease and between 90% and 95% for patients with intermediate-risk disease, the goal of therapy for these patients is to cure the disease with minimal toxicity.
The staging system, risk classification system, and response criteria definitions for neuroblastoma have evolved over the past 20 years. As a result, published results from clinical trials for patients with non–high-risk neuroblastoma from the past used different staging systems (International Neuroblastoma Staging System) and response criteria or protocol-specific response criteria, making it difficult to compare trial results.
Low-Risk Neuroblastoma
The success of previous Children’s Oncology Group (COG) clinical trials has contributed to the continued reduction in therapy for select patients with neuroblastoma. According to the COG risk categorization, patients with low-risk disease generally have low-stage disease (International Neuroblastoma Risk Group [INRG] stage L1) and the tumors are MYCN-nonamplified, hyperdiploid, and have favorable histology (FH). For more information about the COG risk categories, see Table 3.
Surgery, by an experienced surgeon, is the treatment of choice for patients with low-risk, INRG stage L1 tumors. The exception is for patients who are younger than 6 months with isolated adrenal masses with maximum diameter smaller than 3.1 cm if solid, or 5 cm if at least 25% of the mass is cystic. For these patients, observation without biopsy is the recommended approach. If the biology is confirmed to be favorable, residual disease after surgery is not considered a risk factor for relapse and chemotherapy is not indicated. Several studies have shown that patients with favorable biology and residual disease have excellent outcomes, with event-free survival (EFS) rates exceeding 90% and overall survival (OS) rates ranging from 99% to 100%.[2,3]
In patients with INRG stage MS disease who are asymptomatic and have tumors with favorable biology, observation is the preferred approach.
Some patients with presumed neuroblastoma have been observed without biopsy. The COG is studying this strategy further in the ANBL1232 (NCT02176967) trial (closed to accrual).[4,5]
Treatment options for low-risk neuroblastoma include the following:
Observation without biopsy (for perinatal neuroblastoma with small adrenal tumors). The COG experience with observation of apparent neuroblastoma without diagnostic biopsy is limited and under investigation.
Observation with biopsy (for infants aged <12 months with INRG stage MS disease without hepatomegaly and MYCN-nonamplified tumors; infants aged <12 months with localized disease, favorable histology and genomics, and MYCN-nonamplified tumors with no segmental chromosomal aberrations).
Treatment for patients categorized as low risk may be surgery alone. For more information, see Table 3.
Evidence (surgery followed by observation):
Results from the COG-P9641 (NCT00003119) study showed that surgery alone, even without complete resection, can cure nearly all patients with stage 1 neuroblastoma and the vast majority of patients with asymptomatic, favorable-biology, and International Neuroblastoma Staging System (INSS) stage 2A or stage 2B disease.[3]
Similar outcomes were seen in a nonrandomized clinical trial in Japan.[6]
Observation with or without biopsy
Observation without biopsy has been used to treat perinatal neuroblastoma with small adrenal tumors.
A COG study determined that selected small INSS stage 1 or stage 2 adrenal masses, presumed to be neuroblastoma, detected in infants younger than 6 months by screening or incidental ultrasonography, may safely be observed without obtaining a definitive histological diagnosis and without surgical intervention. This technique avoids potential complications of surgery in newborn patients.[4] Patients are observed frequently to detect any tumor growth or spread, indicating a need for intervention. Additional studies, including an expansion of criteria allowing observation without surgery, are under way in the COG ANBL1232 (NCT02176967) study (closed to accrual).
Evidence (observation without biopsy):
The COG-ANBL00P2 (NCT00445718) study reported that expectant observation is safe in patients younger than 6 months with solid adrenal tumors smaller than 3.1 cm (or cystic tumors smaller than 5 cm) and INSS stage 1 disease.[4]
Sixty-seven of 83 patients (81%) demonstrated spontaneous regression and avoided surgical intervention.
Eighty-three of 87 eligible patients were observed without biopsy or resection; only 16 patients (19%) ultimately underwent surgery.
The 3-year EFS rate for a neuroblastoma event was 97.7%, and the OS rate was 100%.
Controversy exists about the need to attempt resection, at the time of diagnosis or later, in asymptomatic infants aged 12 months or younger with apparent stage 2B and stage 3 MYCN-nonamplified and favorable-biology disease. In a German clinical trial, some of these patients were observed after biopsy or partial resection without chemotherapy or radiation therapy. Many patients did not progress locally and never underwent a first or additional resection.[5] In the COG ANBL1232 (NCT02176967) study (closed to accrual), infants younger than 18 months who have L2 tumors with favorable biology are being observed after tumor biopsy.
Chemotherapy with or without surgery
Chemotherapy with or without surgery is used to treat the following:
Symptomatic disease. The chemotherapy regimen consists of carboplatin, cyclophosphamide, doxorubicin, and etoposide. The cumulative chemotherapy dose of each agent is kept low to minimize long-term effects.[3]
Unresectable progressive disease after surgery.
Evidence (for removal of chemotherapy):
The COG-P9641 study was one of the first COG studies to test risk stratification based on consensus-derived factors. In this phase III nonrandomized trial, 915 infants and children with INSS stage 2A and 2B disease underwent an initial operation to obtain tissue for diagnosis and biology studies and for maximal safe primary tumor resection. Chemotherapy was reserved for patients with, or at risk of, symptomatic disease, with less than 50% tumor resection at diagnosis, or with unresectable progressive disease after surgery alone.[3]
Stage 1:
Patients with stage 1 disease achieved a 5-year EFS rate of 93% and a 5-year OS rate of 99%.
Stage 2A and 2B:
Asymptomatic patients with stage 2A and 2B disease (n = 306) who were observed after initial operation had a 5-year EFS rate of 87% and an OS rate of 96%.
The EFS rate was significantly better for patients with stage 2A than for patients with stage 2B neuroblastoma (92% vs. 85%; P = .0321), but OS did not differ significantly (98% vs. 96%; P = .2867).
The primary study objective (to achieve a 3-year OS rate of 95% for asymptomatic patients with stage 2A and 2B disease) was met.
Patients with stage 2B disease had a lower EFS and OS if they had an unfavorable histology (EFS rate, 72%; OS rate, 86%) or diploid tumors (EFS rate, 75%; OS rate, 84%) or were older than 18 months.
Outcomes for patients with stage 2B, diploid tumors, and unfavorable histology were particularly poor (EFS rate, 54%; OS rate, 70%), with no survivors among the few patients who had additional 1p loss of heterozygosity.
All the deaths occurred in children older than 18 months.
Outcome of asymptomatic patients at diagnosis who were observed after initial operation and patients treated with chemotherapy postoperatively: Of the initial 915 patients, 800 were asymptomatic at diagnosis and observed after their initial operations. Within this group, 11% of patients experienced recurrent or progressive disease. Of the 115 patients who underwent surgery followed by immediate chemotherapy (median, 4 cycles; range, 1–8 cycles), 81% of the patients had a very good partial response or better. After chemotherapy, 10% of the patients had disease recurrence or progression.
For patients treated with surgery alone, the 5-year EFS rate was 89%, and the OS estimate was 97%.
For patients treated with surgery and immediate chemotherapy, the 5-year EFS rate was 91%, and the OS estimate was 98%.
MYCN amplification: The impact of MYCN-amplified tumors was analyzed in patients with stage 1 disease.
For patients with MYCN-nonamplified tumors, the 5-year EFS rate was 93%, and the OS rate was 99%.
For patients with MYCN-amplified tumors, the 5-year EFS rate was 70% (P = .0042), and the OS rate was 80% (P < .001).
Treatment options under clinical evaluation
Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website.
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
Intermediate-Risk Neuroblastoma
According to the 2021 COG risk classifier, intermediate risk includes the following for localized, INRG stage L2 tumors (no MYCN amplification):[1]
Children younger than 5 years with favorable biology.
Children older than 5 years with favorable biology and differentiating tumors (International Neuroblastoma Pathology Classification [INPC]).
Children younger than 365 days with unfavorable histology (UH), DNA Index (DI) higher than 1, no segmental chromosomal alterations (SCAs).
Children younger than 365 days with FH, DI is 1, no SCAs.
Children younger than 365 days with UH, DI is 1, no SCAs.
Children younger than 365 days with FH, DI higher than 1, and SCAs.
Children older than 365 days with FH and SCAs.
Children younger than 365 days with SCAs (with either UH or DI = 1).
Children aged 365 days to younger than 547 days with UH.
Children younger than 3 months with evolving hepatomegaly or symptomatic with all favorable biology.
Symptomatic children with unfavorable biology.
Children aged 365 days to younger than 18 months, FH, and no SCAs (DI > 1).
For infants with stage MS tumors who are too unstable to undergo biopsy before starting treatment, chemotherapy is initiated, and a biopsy is obtained when safe.
For more information about the COG risk categories, see Table 3.
Patients categorized as intermediate risk have been successfully treated with complete surgical resection and two, four, or eight cycles of neoadjuvant chemotherapy. The chemotherapy regimen consists of carboplatin, cyclophosphamide, doxorubicin, and etoposide. The cumulative dose of each agent is kept low to minimize long-term effects from the chemotherapy regimen (ANBL0531 [NCT00499616]). As a rule, patients whose tumors had unfavorable biology received eight cycles of chemotherapy, and patients whose tumors had favorable biology received either two or four cycles of chemotherapy. Favorable biological features include FH, DI higher than 1, and no SCAs.
Tumor response assessment is measured with a single dimension, as per Response Evaluation Criteria in Solid Tumors (RECIST). After the number of assigned cycles of chemotherapy (based on disease stage, age, and biological features), if greater than a partial response has not been obtained, then a multidisciplinary discussion should occur to discuss the role of surgery versus additional chemotherapy. Patients who achieve a partial response or greater will enter surveillance. Surgical resection should be considered if chemotherapy has resulted in less than 50% reduction in tumor size. For patients unable to undergo surgical resection, and additional chemotherapy is given, response should be re-evaluated after every two cycles of therapy. Another biopsy to look for histological differentiation may be necessary to assess a residual mass that did not shrink sufficiently with chemotherapy.[7]
In cases of abdominal neuroblastoma thought to involve a kidney, nephrectomy is not undertaken before a course of chemotherapy has been given.[8] Nephrectomy should be avoided in all cases.
Cyclophosphamide and topotecan were used in the ANBL0531 (NCT00499616) study as additional treatment in patients who had received eight cycles of intermediate-risk chemotherapy and did not achieve the targeted response.[9,10]
Whether initial chemotherapy is indicated for all intermediate-risk infants with localized neuroblastoma requires further study.
Evidence (chemotherapy with or without surgery):
The goal of the ANBL0531 (NCT00499616) study was to reduce therapy for subsets of patients with intermediate-risk neuroblastoma (MYCN-nonamplified, age and stage defined). Treatment duration (two, four, or eight cycles of moderate-dose neoadjuvant chemotherapy) was assigned according to clinical features and a tumor biology (including allelic status of 1p36 and 11q23) and response-based algorithm. The 10-year EFS and OS rates for the entire study cohort (N = 404) were 82.0% and 94.7%, respectively.[10] Treatment duration and intensity was reduced for several subsets of patients. The study added stage 4 patients with favorable biology who were aged 12 to 18 months.[9]
In the legacy (A3961 [NCT00003093]) study, the administration of neoadjuvant chemotherapy facilitated at least a partial resection of 99.6% of previously unresectable tumors. No significant difference was noted in OS according to the degree of resection accomplished (complete vs. incomplete) in either study.[9,11]
Less than 3% of patients in the ANBL0531 study received local radiation therapy, and only the patients with progressive hepatic enlargement or spinal cord compression received radiation therapy.[9]
Inferior EFS, but not OS, was observed among patients who had tumors with 11q loss of heterozygosity (n = 26) compared with those who had tumors without 11q loss of heterozygosity (n = 314) (10-year EFS rates, 68.4% vs. 83.9%; P = .03; 10-year OS rates, 88.0% vs. 95.7%; P = .09).[10]
The 3-year EFS rate was 92% for patients with stage 3 disease with favorable histopathology (n = 269); 90% for patients with stage 4S disease and unfavorable biology, including diploidy or unfavorable histology (n = 31); and 81% for infants with stage 4 disease (n = 176) (P < .001 for stages 3 and 4S vs. stage 4).
Infants with stage 4 disease with favorable biology (n = 61) had a superior 10-year EFS, compared with those with confirmed unfavorable biology tumors (n = 47) (10-year EFS rate, 86.9% vs. 66.8%; P = .02), although OS was not significantly different (10-year OS rate, 95.0% vs. 84.4%; P = .08).[10]
Only infants were stratified by ploidy. Those with diploid tumors received eight versus four cycles of chemotherapy. The 3-year OS rate estimates were 98% for stage 3 disease, 97% for stage 4S disease, and 93% for stage 4 disease (P = .002 for stages 3 and 4S vs. stage 4). Infants with diploidy had a poorer outcome (P = .03), as did all patients with diploidy studied, when combined (P = .03).
In patients with favorable biological features, there was no difference in OS between those who received eight cycles of chemotherapy (100%) for persistent disease and those who received four cycles (96%).
There was no unexpected toxicity.
Patients who had not achieved a PR (n = 27) (after completing therapy with eight cycles of carboplatin, cyclophosphamide, doxorubicin, and etoposide) were then treated with cyclophosphamide and topotecan to reach a PR. These patients had an inferior EFS than those who did not require cyclophosphamide and topotecan to reach a PR.
During long-term follow-up beyond 3 years, there were only three patients who experienced disease relapse, suggesting that ongoing surveillance beyond that time point may not be useful.[10]
A German prospective clinical trial enrolled 340 infants aged 1 year or younger whose tumors were stage 1, 2, or 3; histologically verified; and lacked MYCN amplification. Chemotherapy was given at diagnosis to 57 infants with organs threatened by the tumor. The tumor was completely resected or nearly so in 190 infants who underwent low-risk surgery. A total of 93 infants whose tumors were not resectable without high-risk surgery because of age or organ involvement were observed without chemotherapy.[5]
The 3-year OS rate was excellent (95%) for infants who received chemotherapy.
Further surgery was avoided in 33 infants, and chemotherapy was avoided in 72 infants.
The 3-year OS rate for the infants who were observed without treatment was 99%. The metastases-free survival rate was 94% for infants with unresected tumors and did not differ from the rate for infants treated with surgery or chemotherapy (median follow-up, 58 months).
Forty-four of 93 infants with unresected tumors experienced spontaneous regression (17 were complete regressions), and 39 infants experienced progression.
The investigators suggested that a wait-and-see strategy is appropriate for infants with localized neuroblastoma because regressions have been observed after the first year of life.
Moderate-dose chemotherapy has been shown to be effective in the prospective Infant Neuroblastoma European Study (EURO-INF-NB-STUDY-1999-99.1). About one-half of the infants with unresectable, nonmetastatic neuroblastoma and no MYCN amplification underwent a safe surgical resection and avoided long-term adverse effects.[12][Level of evidence C1]
The 5-year OS rate was 99%, and the EFS rate was 90% (median follow-up, 6 years).
In this study, infants who underwent surgical resection had a better EFS than did those who did not have surgery.
In two European prospective trials of infants with disseminated neuroblastoma without MYCN gene amplification, infants with INSS stage 3 primary or positive skeletal scintigraphy without radiological bone metastasis (identified mostly by MIBG scan, but a few with just technetium Tc 99m bone scan) were not administered chemotherapy unless life-threatening or organ-threatening symptoms developed. When given, chemotherapy consisted of short and standard doses.[13]
The OS rate was 100% in the 41 patients who did not have INSS stage 4S, regardless of initial chemotherapy.
In infants with overt metastases to the skeleton, lung, and central nervous system (by radionuclide scan, but not by plain x-ray or computed tomography [CT] scan), the 2-year OS rate was 96% (n = 45).
No patients died of surgery-related or chemotherapy-related complications on either protocol.
A retrospective analysis from the COG evaluated patients aged 12 to 18 months with metastatic disease and favorable biological features. In legacy trials, these patients were treated with high-risk disease regimens.[14]
This analysis demonstrated that this group of patients had similar excellent outcomes with intermediate-risk therapy, compared with high-risk therapy. These patients are now treated with intermediate-risk therapy in current clinical trials.
A prospective International Society of Paediatric Oncology Europe Neuroblastoma (SIOPEN) trial treated infants with MYCN-nonamplified, stage 2 or stage 3 unresectable neuroblastoma, as well as those aged 12 to 18 months who had favorable INPC.[15][Level of evidence C2]
The EFS rate was 98% with conventional chemotherapy.
These results are similar to results from the COG-A3961 trial.
Surgery and observation (in infants)
The need for chemotherapy in all asymptomatic infants with stage 3 or stage 4 disease is controversial, as some European studies have shown favorable outcomes with surgery and observation.[13]
Evidence (surgery and observation in infants):
A French study classified infants as stage 4 because of a primary tumor infiltrating across the midline (INSS stage 3 primary with metastases limited to 4S category) or positive bone scintigraphy not associated with changes in the cortical bone documented on plain radiographs and/or CT.[16]
Infants with this classification were reported to have a better outcome with less aggressive chemotherapy than were other stage 4 infants (EFS rate, 90% vs. 27%).
However, a much higher proportion of those with radiologically demonstrated cortical bone lesions also had tumors with MYCN amplification.
Building on the French study, SIOPEN conducted a prospective trial of 125 infants (n = 41 with INSS 3 primary tumors or positive scintigraphy) with disseminated neuroblastoma without MYCN amplification to determine whether these patients could be observed in the absence of symptoms. However, treating physicians did not always follow the wait-and-see strategy.[13]
There was no significant difference in 2-year OS rates between patients with unresectable primary tumors and patients with resectable primary tumors (97% vs. 100%) and between patients with negative and positive skeletal scintigraphy without radiological abnormalities (100% vs. 97%).
A German prospective clinical trial enrolled 340 infants aged 1 year or younger whose tumors were stage 1, 2, or 3; verified histologically; and lacked MYCN amplification. Of the 190 infants who underwent resection, 8 had stage 3 disease. A total of 93 infants whose tumors were not resectable without high-risk surgery, because of age or organ involvement, were observed without chemotherapy, which included 21 patients with stage 3 disease. Fifty-seven infants, including 41 with stage 3 disease, were treated with chemotherapy to control threatening symptoms.[5]
The 3-year OS rate was excellent for the entire group of infants with unresected tumors (99%), infants who received chemotherapy (95%), and infants with resected tumors (98%) (P = .45).
Radiation therapy
Radiation therapy for children with intermediate-risk disease is reserved for patients with progressive disease during treatment with chemotherapy or progressive unresectable disease after treatment with chemotherapy.
In a prospective randomized COG trial that tested reduced-intensity chemotherapy for patients with intermediate-risk neuroblastoma, only 12 of 479 patients (2.5%) received local radiation therapy (21 Gy). One patient had stage 4S disease, five patients had stage 3 disease, and six patients had stage 4 disease. Radiation therapy was administered for clinical deterioration despite initial therapy (eight patients), residual macroscopic disease and unfavorable biological features (three patients), or relapse after therapy (one patient).[2,11,17]
Treatment options under clinical evaluation
Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website.
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References
Irwin MS, Naranjo A, Zhang FF, et al.: Revised Neuroblastoma Risk Classification System: A Report From the Children’s Oncology Group. J Clin Oncol 39 (29): 3229-3241, 2021. [PUBMED Abstract]
Matthay KK, Perez C, Seeger RC, et al.: Successful treatment of stage III neuroblastoma based on prospective biologic staging: a Children’s Cancer Group study. J Clin Oncol 16 (4): 1256-64, 1998. [PUBMED Abstract]
Strother DR, London WB, Schmidt ML, et al.: Outcome after surgery alone or with restricted use of chemotherapy for patients with low-risk neuroblastoma: results of Children’s Oncology Group study P9641. J Clin Oncol 30 (15): 1842-8, 2012. [PUBMED Abstract]
Nuchtern JG, London WB, Barnewolt CE, et al.: A prospective study of expectant observation as primary therapy for neuroblastoma in young infants: a Children’s Oncology Group study. Ann Surg 256 (4): 573-80, 2012. [PUBMED Abstract]
Hero B, Simon T, Spitz R, et al.: Localized infant neuroblastomas often show spontaneous regression: results of the prospective trials NB95-S and NB97. J Clin Oncol 26 (9): 1504-10, 2008. [PUBMED Abstract]
Iehara T, Hamazaki M, Tajiri T, et al.: Successful treatment of infants with localized neuroblastoma based on their MYCN status. Int J Clin Oncol 18 (3): 389-95, 2013. [PUBMED Abstract]
Bagatell R, Park JR, Acharya S, et al.: Neuroblastoma, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 22 (6): 413-433, 2024. [PUBMED Abstract]
Shamberger RC, Smith EI, Joshi VV, et al.: The risk of nephrectomy during local control in abdominal neuroblastoma. J Pediatr Surg 33 (2): 161-4, 1998. [PUBMED Abstract]
Twist CJ, Schmidt ML, Naranjo A, et al.: Maintaining Outstanding Outcomes Using Response- and Biology-Based Therapy for Intermediate-Risk Neuroblastoma: A Report From the Children’s Oncology Group Study ANBL0531. J Clin Oncol 37 (34): 3243-3255, 2019. [PUBMED Abstract]
Barr EK, Naranjo A, Twist CJ, et al.: Long-term follow-up of patients with intermediate-risk neuroblastoma treated with response- and biology-based therapy: A report from the Children’s Oncology Group study ANBL0531. Pediatr Blood Cancer 71 (8): e31089, 2024. [PUBMED Abstract]
Baker DL, Schmidt ML, Cohn SL, et al.: Outcome after reduced chemotherapy for intermediate-risk neuroblastoma. N Engl J Med 363 (14): 1313-23, 2010. [PUBMED Abstract]
Rubie H, De Bernardi B, Gerrard M, et al.: Excellent outcome with reduced treatment in infants with nonmetastatic and unresectable neuroblastoma without MYCN amplification: results of the prospective INES 99.1. J Clin Oncol 29 (4): 449-55, 2011. [PUBMED Abstract]
De Bernardi B, Gerrard M, Boni L, et al.: Excellent outcome with reduced treatment for infants with disseminated neuroblastoma without MYCN gene amplification. J Clin Oncol 27 (7): 1034-40, 2009. [PUBMED Abstract]
Bender HG, Irwin MS, Hogarty MD, et al.: Survival of Patients With Neuroblastoma After Assignment to Reduced Therapy Because of the 12- to 18-Month Change in Age Cutoff in Children’s Oncology Group Risk Stratification. J Clin Oncol 41 (17): 3149-3159, 2023. [PUBMED Abstract]
Kohler JA, Rubie H, Castel V, et al.: Treatment of children over the age of one year with unresectable localised neuroblastoma without MYCN amplification: results of the SIOPEN study. Eur J Cancer 49 (17): 3671-9, 2013. [PUBMED Abstract]
Minard V, Hartmann O, Peyroulet MC, et al.: Adverse outcome of infants with metastatic neuroblastoma, MYCN amplification and/or bone lesions: results of the French society of pediatric oncology. Br J Cancer 83 (8): 973-9, 2000. [PUBMED Abstract]
Kim C, Choi YB, Lee JW, et al.: Excellent treatment outcomes in children younger than 18 months with stage 4 MYCN nonamplified neuroblastoma. Korean J Pediatr 61 (2): 53-58, 2018. [PUBMED Abstract]
Treatment of High-Risk Neuroblastoma
Patients most at risk for disease progression and mortality are older than 18 months, have metastatic disease or localized disease with unfavorable biology such as MYCN amplification, or have unfavorable histology. For more information about the Children’s Oncology Group (COG) risk categories, see Table 3.
Approximately 8% to 10% of infants with stage MS disease have MYCN-amplified tumors and are usually treated using high-risk protocols. The 5-year event-free survival (EFS) and overall survival (OS) rates were 60% and 64%, respectively, for the infants with stage MS disease and MYCN amplification (n = 23), among the 5,000 patients enrolled in the COG ANBL00B1 (NCT00904241) trial.[1]
For children with high-risk neuroblastoma who received current treatments, the 5-year OS rate was about 60% for patients diagnosed between 2007 and 2017.[1] Children with aggressively treated, high-risk neuroblastoma may develop late recurrences, some more than 5 years after completion of therapy.[2,3]
A study from the International Neuroblastoma Risk Group (INRG) database found 146 patients with distant metastases limited to lymph nodes, termed stage 4N, who tended to have favorable-biology disease and a good outcome (5-year OS rate, 85%). This finding suggests that for this very rare, special subgroup of high-risk, stage 4 patients, less-intensive therapy might be considered.[4] These more favorable outcomes were confirmed in a single-institution study of 51 patients.[5]
Treatment Options for High-Risk Neuroblastoma
Outcomes for patients with high-risk neuroblastoma remain poor despite recent improvements in survival in randomized trials.
Treatment options for high-risk neuroblastoma typically include the following:
Chemotherapy, surgery, tandem cycles of myeloablative therapy and HSCT, radiation therapy, and dinutuximab, with GM-CSF and isotretinoin
Treatment for patients with high-risk disease is generally divided into the following three phases:
Induction (includes chemotherapy and surgical resection).
Consolidation (tandem cycles of myeloablative therapy and HSCT and radiation therapy to the site of the primary tumor and residual metastatic sites).
Postconsolidation (immunotherapy with GM-CSF and isotretinoin therapy).
Induction phase
The backbone of the most commonly used induction therapy includes dose-intensive cycles of cisplatin and etoposide alternating with vincristine, cyclophosphamide, and doxorubicin.[6] Topotecan and cyclophosphamide were added to this regimen based on the antineuroblastoma activity seen in patients with relapsed disease.[7] Response to therapy after four cycles of chemotherapy or at the end of induction chemotherapy correlates with EFS at the completion of high-risk therapy.[8–10]
Evidence (induction chemotherapy with or without additional treatments):
In one study, the addition of anti-GD2 antibody therapy with GM-CSF and low-dose interleukin-2 (IL-2), given with each induction chemotherapy course, had encouraging outcomes in 42 children with newly diagnosed stage 4 disease.[11]
This induction therapy, followed by standard consolidation and postconsolidation therapy, produced early partial responses or better in most patients, reduced tumor volumes, and an encouraging 3-year EFS rate of 73.7%.
A European prospective randomized controlled trial investigated extended induction therapy in 422 patients with newly diagnosed high-risk neuroblastoma. Patients were randomly assigned to receive either standard induction chemotherapy with six chemotherapy courses or experimental induction chemotherapy that began with two additional courses of topotecan, cyclophosphamide, and etoposide, followed by standard induction chemotherapy.[12][Level of evidence B3]
The 3-year EFS rate was 34% for patients who received the experimental induction regimen and 32% for patients who received the standard induction regimen.
The addition of two topotecan-containing chemotherapy courses did not improve the EFS of patients with high-risk neuroblastoma and resulted in more toxicity per patient.
European investigators completed another randomized study of induction regimens for patients with high-risk neuroblastoma. A total of 630 patients were randomly assigned to receive either cisplatin, vincristine, carboplatin, etoposide, and cyclophosphamide (rCOJEC regimen; n = 313) or the Memorial Sloan Kettering Cancer Center N5 induction regimens (MSKCC-N5; n = 317).[13][Level of evidence B1]
There were no significant differences in metastatic complete response rates between the two regimens (32% for rCOJEC vs. 35% for MSKCC-N5; P = .368) or 3-year EFS rates (44% for rCOJEC vs. 47% for MSKCC-N5; P = .527).
Patients who received the rCOJEC regimen experienced less acute toxicity.
The rCOJEC regimen has been selected as the standard induction regimen for the current International Society of Pediatric Oncology European Neuroblastoma (SIOPEN) trial.
After a response to induction chemotherapy, resection of the primary tumor is recommended by most treatment protocols. Whether a gross-total resection is beneficial is controversial.[14]
Evidence (extent of resection of the primary tumor):
The COG A3973 (NCT00004188) study had central surgical review of 220 patients who underwent attempted gross-total resection after induction chemotherapy. By the surgeon’s estimate, the degree of resection was determined to be 90% or greater versus less than 90%, but only 63% concordance with central review of imaging was found.[15][Level of evidence C1]
Nevertheless, the surgeon’s assessment of 90% or greater resection versus less than 90% resection predicted an EFS rate of 46% versus 38% (P = .01), respectively, and a cumulative incidence of local relapse rate of 8.5% versus 20%, respectively.
OS rates were not significantly different between the two groups (57% vs. 49%, P = .3).
The authors’ conclusion supports continued efforts to achieve greater than 90% resection to decrease local recurrence.
A single-center retrospective study of 87 children with high-risk neuroblastoma demonstrated no significant benefit of gross-total resection compared with near-total (>90%) resection.[16][Level of evidence C2]
However, the results suggest that greater than 90% resection is associated with improved OS compared with less than 90% resection.
The potential benefit of aggressive surgical approaches in high-risk patients with metastatic disease to achieve complete tumor resection, either at the time of diagnosis or after chemotherapy, has not been unequivocally demonstrated. Several studies have reported that complete resection of the primary tumor at diagnosis improved survival. However, the outcome in these patients may be more dependent on the biology of the tumor, which itself may determine resectability, than on the extent of surgical resection.[17–19]
In patients older than 18 months with stage 4 neuroblastoma, controversy exists about whether there is any advantage to gross-total resection of the primary tumor after chemotherapy.[15,18–20] In some studies, patients who underwent incomplete resections fared less well than those who underwent complete resections.[21] These outcomes could have resulted from either the biology of unresectable tumors or reduction of tumor bulk.[22][Level of evidence B1] Complete resection that requires nephrectomy is not recommended because of the nephrotoxic nature of standard chemotherapy and unproven effect of complete resection on outcome.
In most group studies, surgical resection of the primary tumor is performed during the induction phase. However, the JN-H-11 trial evaluated the feasibility of delayed resection after high-dose chemotherapy with stem cell rescue, with the goal of prioritizing systemic therapy.[23] Rates of complete or greater-than-90% resection were similar to those seen in a previous trial, in which surgery was performed during induction. The rate of nephrectomy was nominally lower (5.8% vs. 17%), and the 3-year cumulative incidence of local failure rate was nominally higher (17.3% vs. 11.6%), compared with the rates found in the previous trial.
At the end of induction therapy, patients with high-risk disease typically undergo a full disease evaluation. Management of patients with residual disease at the end of conventional induction therapy is not standardized. A retrospective study analyzed 201 patients with high-risk disease who had a partial response or less at the end of induction therapy. Patients were selected to immediately receive either high-dose chemotherapy (cohort 1), bridging therapy (usually chemoimmunotherapy or iodine I 131-metaiodobenzylguanidine [MIBG]) followed by high-dose chemotherapy (cohort 2), or additional therapy but not high-dose chemotherapy (cohort 3).[24]
Despite having less-favorable features, patients in cohort 2 had similar EFS compared with patients in cohort 1, while patients in cohort 3 had inferior EFS.
Among patients with stable disease in metastatic sites at the end of induction therapy, patients in cohort 2 had superior EFS compared with patients in cohort 1.
These retrospective data suggest a role for bridging therapy in patients with incomplete response to conventional induction therapy.
Consolidation phase
The consolidation phase of high-risk regimens involves myeloablative chemotherapy and HSCT, which attempts to eradicate minimal residual disease (MRD) using otherwise lethal doses of ablative chemotherapy rescued by autologous stem cells (collected during induction chemotherapy) to repopulate the bone marrow. Several large randomized controlled studies showed improved 3-year EFS rates for treatment with HSCT (31%–47%) versus conventional chemotherapy (22%–31%).[25–27] Previously, total-body irradiation had been used in HSCT conditioning regimens. Most current protocols in North America use tandem cycles of chemotherapy and HSCT with cyclophosphamide/thiotepa and carboplatin/etoposide/melphalan.[28][Level of evidence C1] In Europe, clinical trials have also evaluated busulfan/melphalan and HSCT.
Evidence (myeloablative chemotherapy and stem cell rescue):
A large European multicenter trial of consolidation therapy randomly assigned patients who had completed a multidrug induction regimen (cisplatin, carboplatin, cyclophosphamide, vincristine, and etoposide with or without topotecan, vincristine, and doxorubicin) and achieved an adequate response to receive either busulfan/melphalan or carboplatin/etoposide/melphalan.[29][Level of evidence A1]
Induction therapy with cisplatin, carboplatin, cyclophosphamide, vincristine, and etoposide, and consolidation for HSCT with busulfan/melphalan resulted in an improved EFS, without an effect on OS or severe adverse events.
A randomized clinical study (COG-ANBL0532) tested the efficacy of two cycles versus one cycle of myeloablative chemotherapy with stem cell rescue.[30][Level of evidence A1] Children older than 18 months with stage 4 neuroblastoma who had received six cycles of induction chemotherapy were then randomly assigned to receive a single autologous HSCT with carboplatin/etoposide/melphalan or tandem transplants with cyclophosphamide/thiotepa followed by reduced-dose carboplatin/etoposide/melphalan. After tumor bed radiation therapy, most patients were randomly assigned to a second separate trial to receive isotretinoin alone or isotretinoin with dinutuximab and immune enhancement.
The 3-year EFS rate from the time of randomization was 62% for tandem transplants and 48% for single HSCT (P = .006). The 3-year OS rate was 74% for tandem autologous HSCTs and 69% for single autologous HSCT (P = .25).
For randomized patients who subsequently received dinutuximab and immune enhancement, the 3-year EFS rate was 73% for tandem HSCTs and 55% for single HSCT (P = .004), while the OS rate was 84% and 74%, respectively.[30][Level of evidence B1]
These study results have an important limitation: a substantial portion of the patients were not randomly assigned to therapy (because of patient and provider preference), introducing a potential selection bias.
An updated Cochrane review evaluated three randomized clinical trials comparing autologous bone marrow transplant (BMT) with standard chemotherapy.[25–27,31,32]
EFS was significantly better for autologous BMT, but there was no statistically significant difference in OS.
A review of 147 allogeneic transplant cases submitted to the Center for International Blood and Marrow Transplant Research found no advantage for allogeneic transplant over autologous transplant, even if the allogeneic transplant recipient had received a previous autologous transplant.[33]
In a separate prospective randomized study, there was no advantage to purging harvested autologous stem cells of neuroblastoma cells before transplant.[34]
Radiation to the primary tumor site (whether or not a complete excision was obtained) is indicated after myeloablative therapy.[35,36]; [37][Level of evidence C1] Boost radiation therapy for gross-residual disease did not show improved local control when studied prospectively in the ANBL0532 (NCT00567567) trial.[38][Level of evidence C1] The optimal dose of radiation therapy has not been determined.[39]
Evidence (radiation therapy with a boost vs. radiation therapy without a boost for incomplete resection):
Because of the high rates of local recurrence after incomplete surgical resection, the COG ANBL0532 (NCT00567567) trial prospectively evaluated the potential benefit of boost radiation therapy for patients with gross-residual tumor and compared the results with the preceding COG clinical trial for high-risk neuroblastoma (A3973 [NCT00004188]), in which patients did not receive boost radiation therapy. All patients on the ANBL0532 trial received 21.6 Gy of radiation to the preoperative primary tumor volume after induction chemotherapy.[38][Level of evidence C1]
There were no differences in outcomes between the patients in the ANBL0532 trial who received a single HSCT and boost radiation therapy (n = 74) and the patients in the A3973 trial who underwent an incomplete resection and received no boost radiation therapy (n = 47).
The 5-year cumulative incidence of local progression was 16.3% for patients in the ANBL0532 trial versus 10.6% for patients in the A3973 trial (P = .4126).
The EFS rate was 50.9% for patients in the ANBL0532 trial versus 48.9% for patients in the A3973 trial (P = .5084).
The OS rate was 68.1% for patients in the ANBL0532 trial versus 56.9% for patients in the A3973 trial (P = .2835).
Boost radiation therapy administered to gross residual tumor that was present at the end of induction did not significantly improve the 5-year cumulative incidence of local progression; therefore, it is not recommended.[38]
Extensive lymph node irradiation, regardless of the extent of surgical resection preceding HSCT, did not benefit patients for local progression or OS.[40][Level of evidence C1]
A detailed retrospective multicenter review of locoregional recurrences demonstrated that 48.4% were in-field recurrences and another 19.4% were marginal recurrences.[41] These findings suggest that additional optimization of radiation therapy approaches are still needed.
Treatment of bony metastatic disease, delivered at the time of primary tumor bed irradiation, is also considered to maximize disease control. Radiation therapy to metastatic disease sites is determined on an individual basis or according to protocol guidelines for patients enrolled in studies. Many children present with widespread bony metastases. Because it is not feasible to irradiate all initial sites, the current practice is to treat the sites that have not responded, as assessed by MIBG before HSCT.[42–44] Metastatic sites identified at diagnosis that did not receive radiation during frontline therapy appeared to have a higher risk of involvement at first relapse relative to previously irradiated metastatic sites.[42] In one single-institution study, 17 of 24 patients with residual MIBG-avid skeletal uptake at the end of front-line therapy without metastatic-site radiation therapy had disease recurrence. Of the 17 patients, 13 (76.5%) had disease recurrence at sites of prior skeletal disease.[45]
In a retrospective series of 159 children with high-risk stage M neuroblastoma, focal irradiation was delivered to all metastatic sites, regardless of response to chemotherapy, unless metastases were too numerous.[46]
The 5-year control rate of irradiated metastatic sites was 81%.
Metastases that became MIBG negative after chemotherapy were significantly less likely to recur than the sites that remained MIBG positive.
Patients whose disease did not relapse in their irradiated metastatic sites had improved OS.
When feasible to deliver radiation therapy, including to sites that resolved with induction chemotherapy, radiation therapy was more than 90% effective in providing disease control in those metastatic sites.
These observations support the current paradigm of irradiating metastases that persist by MIBG uptake after induction chemotherapy in high-risk patients. Irradiation of more than 50% of the bone marrow is not advised.[46]
In cases where diffuse bone metastases remain after induction chemotherapy, high-dose chemotherapy is followed by reassessment before deciding on consolidative radiation therapy.
Preliminary outcomes of proton radiation therapy to treat patients with high-risk neuroblastoma primary tumors have been published, demonstrating acceptable efficacy and toxicity.[47]
Postconsolidation phase
Postconsolidation therapy is designed to treat potential MRD after HSCT.[31] For high-risk patients in remission after HSCT, dinutuximab combined with GM-CSF given together with isotretinoin demonstrated improved EFS.[48,49]
Evidence (all treatments):
A randomized study compared high-dose therapy and purged autologous BMT with three cycles of intensive consolidation chemotherapy. In addition, after the completion of either chemotherapy or autologous BMT, patients were randomly assigned to stop therapy or to receive 6 months of isotretinoin. The EFS and OS results described below reflect outcome from the time of each randomization.[25]; [31][Level of evidence A1]
The 5-year EFS rate was significantly better in the autologous BMT arm (30%), than in the consolidation chemotherapy arm (19%; P = .04). There was no significant difference in 5-year OS rates between the two arms (39% vs. 30%; P = .08).
Patients who received isotretinoin had a higher 5-year EFS rate than patients who received no maintenance therapy (42% vs. 31%), although the difference was not significant (P = .12).
The OS rate was higher for patients randomly assigned to receive isotretinoin (50%) than for those who stopped therapy (39%), but this difference was not significant (P = .10).
A retrospective, single-institution, nonrandomized trial compared patients who received GM-CSF and 3F8 anti-GD2 antibody therapy after either autologous HSCT or conventional chemotherapy.[50] The patients were a mixture of those referred for initial treatment or further therapy, and included patients with refractory and relapsed disease, some of whom had received autologous HSCT at referring institutions. In the autologous HSCT group, there was a significantly longer time from first chemotherapy or from autologous HSCT to initiation of GM-CSF and 3F8 anti-GD2 antibody treatment. The autologous HSCT group also had significantly more ultra–high-risk patients.
A trend for better EFS with GM-CSF and 3F8 anti-GD2 antibody therapy and autologous HSCT was observed (65% vs. 51%, P = .128), but there was no statistically significant difference in OS between patients who were treated with chemotherapy alone and those who were treated with autologous HSCT.
In a COG phase III trial (ANBL0032 [NCT00026312]), participants who had previously undergone HSCT were randomly assigned to receive dinutuximab administered with GM-CSF and IL-2 in conjunction with isotretinoin, versus isotretinoin alone.[48]
Immunotherapy together with isotretinoin (EFS rate, 66%) was superior to standard isotretinoin maintenance therapy (EFS rate, 46%). As a result, immunotherapy post-HSCT is considered the standard of care in COG trials for high-risk disease.
As a result of the COG studies, the U.S. Food and Drug Administration (FDA) approved dinutuximab.
Long-term follow-up (median follow-up time, 9.97 years; range, 0.7–15.3 years) was available for 226 eligible patients. The 5-year EFS rate was 56.6% (± 4.7%) for patients randomly assigned to receive immunotherapy (n = 114) versus 46.1% (± 5.1%) for those randomly assigned to receive isotretinoin only (n = 112) (P = .042). The 5-year OS rate was 73.2% (± 4.2%) for patients who received immunotherapy, versus 56.6% (± 5.1%) for patients who received isotretinoin (P = .045). Thirteen of 122 patients who received dinutuximab developed human anti-chimeric antibodies (HACA). Plasma levels of dinutuximab, HACA, and soluble IL-2 receptor-alpha did not correlate with EFS, OS, or clinically significant toxicity.[51][Level of evidence B1]
After randomization was stopped for ANBL0032, all patients were assigned to receive immunotherapy. With longer follow-up data available for 1,183 patients, survival and toxicity results were similar to previous reports. For patients older than 18 months at diagnosis with International Neuroblastoma Staging System stage 4 disease (n = 662), the 5-year EFS rate was 57%, and the OS rate was 70.9%. Toxicities were similar to those reported for the randomized cohort. Among patients with available data, higher dinutuximab levels and Fc gamma receptor 3A (FCGR3A) genotype were associated with superior EFS.[52]
Anti-GD2 antibodies, along with modulation of the immune system to enhance the antibody’s antineuroblastoma activity, are often used to help treat patients with neuroblastoma. The clinical effectiveness of one such antibody led to the FDA approval of dinutuximab. The patient’s response to immunotherapy may be caused, in part, by variation in immune function among patients. One anti-GD2 antibody, termed 3F8, used for treating neuroblastoma exclusively at one institution, directs natural killer cells to kill the neuroblastoma cells. However, the natural killer cells can be inhibited by the interaction of HLA antigens and killer immunoglobulin receptor (KIR) subtypes.[53,54] This finding was confirmed and expanded by an analysis of outcomes for patients treated in the national randomized COG-ANBL0032 (NCT00026312) study with the anti-GD2 antibody dinutuximab combined with GM-CSF and IL-2. The study found that certain KIR/KIR-ligand genotypes were associated with better outcomes for patients who were treated with immunotherapy.[55][Level of evidence A2] The presence of inhibitory KIR/KIR ligands was associated with a decreased effect of immunotherapy. Thus, the patient’s immune system genes help determine response to immunotherapy for neuroblastoma. Additional studies are needed to determine whether this immune system genotyping can guide patient selection for certain immunotherapies.
A European study compared dinutuximab-beta (dinutuximab manufactured in hamster cells instead of mouse cells) to dinutuximab-beta plus subcutaneous (SQ) IL-2 administered as maintenance therapy after high-dose chemotherapy with autologous HSCT. All patients additionally received isotretinoin.[56]
The addition of SQ IL-2 did not improve outcome. The 3-year EFS rate was 56% for patients treated with dinutuximab-beta and 60% for patients treated with dinutuximab-beta and SQ IL-2 (P = .76).
There was also no difference in incidence of relapse/progression or 5-year OS.
Patients treated with IL-2 had higher rates of fever, pain, allergic reaction, capillary leak syndrome, neurotoxicity, and gastrointestinal toxicity. In this study, only 62% of patients randomly assigned to the IL-2 arm received the planned therapy because of toxicity.
Response rates and 2-year EFS and OS rates did not differ for patients treated with IL-2 versus no IL-2.
SIOPEN subsequently eliminated IL-2 from standard postconsolidation therapy.
A third randomized, phase II, SIOPEN trial compared treatment with IL-2 to treatment without IL-2.[57]
Response, EFS, and OS rates were not significantly different with IL-2 versus without IL-2, but toxicity was higher in the IL-2 arm.
Based on the SIOPEN data, the COG removed IL-2 from standard postconsolidation immunotherapy.
Radioactive MIBG therapy has been used to treat recurrent neuroblastoma with some success. This therapy has been shown to be safe and feasible to incorporate into the treatment regimen for children with newly diagnosed high-risk neuroblastoma.[58] A randomized trial (ANBL1531 [NCT03126916]) incorporating radioactive MIBG therapy into the complex therapy for newly diagnosed high-risk neuroblastoma has completed accrual.
A multi-institution, phase II clinical trial of children with high-risk neuroblastoma evaluated 2 years of continuation therapy using eflornithine (previously known as difluoromethylornithine [DFMO]), an oral ornithine decarboxylase inhibitor.[59] Although the study concluded that survival was improved compared with a subset of patients who were previously treated in the ANBL0032 (NCT00026312) trial, the historical comparison and potential patient selection bias limit the validity of this finding. An updated report describes the results of a propensity matching analysis that compared patients who were treated with eflornithine with patients in the ANBL0032 trial who were not treated with eflornithine.[60] Propensity matching generally balanced differences in available patient characteristics. In the matched analysis, patients in the eflornithine cohort had statistically significantly higher EFS and OS, compared with patients in the non-eflornithine cohort (4-year EFS rates, 84% vs. 73% and 4-year OS rates, 96% vs. 84%). The authors noted that uncontrolled confounders may exist in this nonrandomized comparison. Based on these results, the FDA approved the use of eflornithine as continuation therapy in December 2023.
A GD2/GD3 ganglioside vaccine has been studied for patients in first remission after completion of standard therapy. In a randomized trial that mainly included patients in first remission, early introduction of beta-glucan along with a GD2/GD3 vaccine increased GD2/GD3 antibody titers without increasing toxicity. Progression-free survival (PFS) rates were similar for patients in both randomized treatment arms. However, patients with higher titers had more favorable PFS rates, regardless of the treatment arm.[61][Level of evidence B1]
Treatment Options Under Clinical Evaluation
Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website.
The following is an example of a national and/or institutional clinical trial that is currently being conducted:
ANBL2131 (NCT06172296) (Dinutuximab with Chemotherapy, Surgery, and Stem Cell Transplant for the Treatment of Children With Newly Diagnosed High-Risk Neuroblastoma): This phase III randomized study seeks to determine if the early addition of dinutuximab (an anti-GD2 monoclonal antibody) plus GM-CSF to standard COG induction therapy improves EFS for patients with newly diagnosed high-risk neuroblastoma. All patients will receive the same induction cycle 1 while their tumors undergo centralized molecular testing as part of APEC14B1 Molecular Characterization Initiative. Patients will then be randomly assigned to receive either standard induction therapy or standard induction therapy with the addition of dinutuximab and GM-CSF.
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References
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Yoneda A, Shichino H, Hishiki T, et al.: A nationwide phase II study of delayed local treatment for children with high-risk neuroblastoma: The Japan Children’s Cancer Group Neuroblastoma Committee Trial JN-H-11. Pediatr Blood Cancer 71 (6): e30976, 2024. [PUBMED Abstract]
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Matthay KK, Villablanca JG, Seeger RC, et al.: Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. Children’s Cancer Group. N Engl J Med 341 (16): 1165-73, 1999. [PUBMED Abstract]
Berthold F, Boos J, Burdach S, et al.: Myeloablative megatherapy with autologous stem-cell rescue versus oral maintenance chemotherapy as consolidation treatment in patients with high-risk neuroblastoma: a randomised controlled trial. Lancet Oncol 6 (9): 649-58, 2005. [PUBMED Abstract]
Pritchard J, Cotterill SJ, Germond SM, et al.: High dose melphalan in the treatment of advanced neuroblastoma: results of a randomised trial (ENSG-1) by the European Neuroblastoma Study Group. Pediatr Blood Cancer 44 (4): 348-57, 2005. [PUBMED Abstract]
Elborai Y, Hafez H, Moussa EA, et al.: Comparison of toxicity following different conditioning regimens (busulfan/melphalan and carboplatin/etoposide/melphalan) for advanced stage neuroblastoma: Experience of two transplant centers. Pediatr Transplant 20 (2): 284-9, 2016. [PUBMED Abstract]
Ladenstein R, Pötschger U, Pearson ADJ, et al.: Busulfan and melphalan versus carboplatin, etoposide, and melphalan as high-dose chemotherapy for high-risk neuroblastoma (HR-NBL1/SIOPEN): an international, randomised, multi-arm, open-label, phase 3 trial. Lancet Oncol 18 (4): 500-514, 2017. [PUBMED Abstract]
Park JR, Kreissman SG, London WB, et al.: Effect of Tandem Autologous Stem Cell Transplant vs Single Transplant on Event-Free Survival in Patients With High-Risk Neuroblastoma: A Randomized Clinical Trial. JAMA 322 (8): 746-755, 2019. [PUBMED Abstract]
Matthay KK, Reynolds CP, Seeger RC, et al.: Long-term results for children with high-risk neuroblastoma treated on a randomized trial of myeloablative therapy followed by 13-cis-retinoic acid: a children’s oncology group study. J Clin Oncol 27 (7): 1007-13, 2009. [PUBMED Abstract]
Yalçin B, Kremer LC, Caron HN, et al.: High-dose chemotherapy and autologous haematopoietic stem cell rescue for children with high-risk neuroblastoma. Cochrane Database Syst Rev 8: CD006301, 2013. [PUBMED Abstract]
Hale GA, Arora M, Ahn KW, et al.: Allogeneic hematopoietic cell transplantation for neuroblastoma: the CIBMTR experience. Bone Marrow Transplant 48 (8): 1056-64, 2013. [PUBMED Abstract]
Kreissman SG, Seeger RC, Matthay KK, et al.: Purged versus non-purged peripheral blood stem-cell transplantation for high-risk neuroblastoma (COG A3973): a randomised phase 3 trial. Lancet Oncol 14 (10): 999-1008, 2013. [PUBMED Abstract]
Haas-Kogan DA, Swift PS, Selch M, et al.: Impact of radiotherapy for high-risk neuroblastoma: a Children’s Cancer Group study. Int J Radiat Oncol Biol Phys 56 (1): 28-39, 2003. [PUBMED Abstract]
Casey DL, Kushner BH, Cheung NK, et al.: Local Control With 21-Gy Radiation Therapy for High-Risk Neuroblastoma. Int J Radiat Oncol Biol Phys 96 (2): 393-400, 2016. [PUBMED Abstract]
Gatcombe HG, Marcus RB, Katzenstein HM, et al.: Excellent local control from radiation therapy for high-risk neuroblastoma. Int J Radiat Oncol Biol Phys 74 (5): 1549-54, 2009. [PUBMED Abstract]
Liu KX, Naranjo A, Zhang FF, et al.: Prospective Evaluation of Radiation Dose Escalation in Patients With High-Risk Neuroblastoma and Gross Residual Disease After Surgery: A Report From the Children’s Oncology Group ANBL0532 Study. J Clin Oncol 38 (24): 2741-2752, 2020. [PUBMED Abstract]
Casey DL, Kushner BH, Cheung NV, et al.: Dose-escalation is needed for gross disease in high-risk neuroblastoma. Pediatr Blood Cancer 65 (7): e27009, 2018. [PUBMED Abstract]
Braunstein SE, London WB, Kreissman SG, et al.: Role of the extent of prophylactic regional lymph node radiotherapy on survival in high-risk neuroblastoma: A report from the COG A3973 study. Pediatr Blood Cancer 66 (7): e27736, 2019. [PUBMED Abstract]
Liu KX, Shaaban SG, Chen JJ, et al.: Patterns of recurrence after radiotherapy for high-risk neuroblastoma: Implications for radiation dose and field. Radiother Oncol 198: 110384, 2024. [PUBMED Abstract]
Polishchuk AL, Li R, Hill-Kayser C, et al.: Likelihood of bone recurrence in prior sites of metastasis in patients with high-risk neuroblastoma. Int J Radiat Oncol Biol Phys 89 (4): 839-45, 2014. [PUBMED Abstract]
Li R, Polishchuk A, DuBois S, et al.: Patterns of Relapse in High-Risk Neuroblastoma Patients Treated With and Without Total Body Irradiation. Int J Radiat Oncol Biol Phys 97 (2): 270-277, 2017. [PUBMED Abstract]
Mazloom A, Louis CU, Nuchtern J, et al.: Radiation therapy to the primary and postinduction chemotherapy MIBG-avid sites in high-risk neuroblastoma. Int J Radiat Oncol Biol Phys 90 (4): 858-62, 2014. [PUBMED Abstract]
Rossillon L, Edeline V, Agrigoroaie L, et al.: Rationale for irradiation of persisting oligo-skeletal metastases to improve survival of metastatic neuroblastoma patients with a poor response to chemotherapy: A retrospective study. Pediatr Blood Cancer 72 (1): e31350, 2025. [PUBMED Abstract]
Casey DL, Pitter KL, Kushner BH, et al.: Radiation Therapy to Sites of Metastatic Disease as Part of Consolidation in High-Risk Neuroblastoma: Can Long-term Control Be Achieved? Int J Radiat Oncol Biol Phys 100 (5): 1204-1209, 2018. [PUBMED Abstract]
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Cheung NK, Cheung IY, Kushner BH, et al.: Murine anti-GD2 monoclonal antibody 3F8 combined with granulocyte-macrophage colony-stimulating factor and 13-cis-retinoic acid in high-risk patients with stage 4 neuroblastoma in first remission. J Clin Oncol 30 (26): 3264-70, 2012. [PUBMED Abstract]
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Yu AL, Gilman AL, Ozkaynak MF, et al.: Long-Term Follow-up of a Phase III Study of ch14.18 (Dinutuximab) + Cytokine Immunotherapy in Children with High-Risk Neuroblastoma: COG Study ANBL0032. Clin Cancer Res 27 (8): 2179-2189, 2021. [PUBMED Abstract]
Desai AV, Gilman AL, Ozkaynak MF, et al.: Outcomes Following GD2-Directed Postconsolidation Therapy for Neuroblastoma After Cessation of Random Assignment on ANBL0032: A Report From the Children’s Oncology Group. J Clin Oncol 40 (35): 4107-4118, 2022. [PUBMED Abstract]
Forlenza CJ, Boudreau JE, Zheng J, et al.: KIR3DL1 Allelic Polymorphism and HLA-B Epitopes Modulate Response to Anti-GD2 Monoclonal Antibody in Patients With Neuroblastoma. J Clin Oncol 34 (21): 2443-51, 2016. [PUBMED Abstract]
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Erbe AK, Wang W, Carmichael L, et al.: Neuroblastoma Patients’ KIR and KIR-Ligand Genotypes Influence Clinical Outcome for Dinutuximab-based Immunotherapy: A Report from the Children’s Oncology Group. Clin Cancer Res 24 (1): 189-196, 2018. [PUBMED Abstract]
Ladenstein R, Pötschger U, Valteau-Couanet D, et al.: Interleukin 2 with anti-GD2 antibody ch14.18/CHO (dinutuximab beta) in patients with high-risk neuroblastoma (HR-NBL1/SIOPEN): a multicentre, randomised, phase 3 trial. Lancet Oncol 19 (12): 1617-1629, 2018. [PUBMED Abstract]
Ladenstein RL, Poetschger U, Valteau-Couanet D, et al.: Randomization of dose-reduced subcutaneous interleukin-2 (scIL2) in maintenance immunotherapy (IT) with anti-GD2 antibody dinutuximab beta (DB) long-term infusion (LTI) in front–line high-risk neuroblastoma patients: Early results from the HR-NBL1/SIOPEN trial. [Abstract] J Clin Oncol 37 (suppl 15): A-10013, 2019. Also available online. Last accessed August 21, 2023.
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Treatment of INSS Stage 4S and INRG Stage MS Neuroblastoma
International Neuroblastoma Staging System (INSS) stage 4S patients are younger than 12 months and have an INSS stage 1 or stage 2 primary tumor. International Neuroblastoma Risk Group (INRG) stage MS patients are younger than 18 months with any stage of primary tumor. Both staging systems have the same definition of limited pattern of metastases.
The decision by the INRG Task Force to replace the category of 4S disease with that of the new MS definition was based on reports in which small numbers of infants with L2 primary tumors and 4S metastatic patterns, including patients aged 12 to 18 months, had favorable outcomes.[1,2] A subsequent study of the actual INRG data found that a number of biological characteristics predicted poor outcome of patients aged 12 to 18 months with stage MS disease, and that only those infants with favorable biology had long-term outcomes similar to those with the traditional 4S diagnosis.[2]
Infants with INRG stage MS disease have more favorable biology and superior outcomes despite receiving less aggressive therapy. The 5-year event-free survival (EFS) rate was 86%, and the overall survival (OS) rate was 95%. For patients with MYCN-amplified tumors, the 5-year EFS rate was 60%, and the OS rate was 65%.[3]
Many patients with stage 4S/MS neuroblastoma do not require therapy. However, tumors with unfavorable biology or patients who are symptomatic because of evolving hepatomegaly and organ compromise are at increased risk of death and are treated with low-dose to moderate-dose chemotherapy. Eight percent to 10% of these patients will have MYCN amplification and are treated with high-risk treatment regimens.[4]
For more information about the Children’s Oncology Group (COG) classification schema for stage 4S/MS neuroblastoma, see Table 3.
Treatment Options for Stage 4S/MS Neuroblastoma
There is no standard approach for the treatment of stage 4S/MS neuroblastoma.
Treatment options for stage 4S/MS neuroblastoma include the following:
Chemotherapy (for symptomatic patients or patients with unfavorable tumor biology).
Surgery (rarely, for patients with hepatomegaly that compromises the kidney or other abdominal organs).
Radiation therapy (rarely, for patients with symptoms related to hepatomegaly from metastatic disease).
Resection of the primary tumor is not associated with improved outcome.[5–7] Rarely, infants with massive hepatic 4S/MS neuroblastoma develop cirrhosis from the chemotherapy and/or radiation therapy that is used to control the disease and may benefit from orthotopic liver transplant.[8]
Observation with supportive care
Observation with supportive care is used to treat asymptomatic patients with favorable tumor biology.
The treatment of children with stage 4S/MS disease depends on clinical presentation.[5,6] Most patients do not require therapy unless bulky disease causes organ compromise and risk of death.
Chemotherapy
Chemotherapy is used to treat symptomatic patients or patients with unfavorable tumor biology. Patients with evidence of rapid tumor growth in the first several weeks of life require immediate intervention with chemotherapy to avoid potentially irreversible abdominal compartment syndrome and hepatic and/or renal failure.[9]
Infants diagnosed with INSS stage 4S/MS neuroblastoma, particularly those with hepatomegaly or those younger than 2 months with high-risk features or hepatomegaly, have the potential for rapid clinical deterioration and may benefit from early initiation of therapy.[9] It has been difficult to identify infants with stage 4S disease who will benefit from chemotherapy.
A scoring system to measure signs and symptoms of deterioration or compromise was developed to better assess this group of stage 4S patients.[10] This scoring system has been evaluated retrospectively, was predictive of the clinical course, and has been applied prospectively to guide the management of patients with INSS stage 4S disease.[10,11] The scoring system has been modified based on the ANBL0531 (NCT00499616) study results in the youngest infants discussed above to guide chemotherapeutic intervention for 4S/MS in infants.[9]
Various chemotherapy regimens (cyclophosphamide alone, carboplatin/etoposide, cyclophosphamide/doxorubicin/vincristine) have been used to treat symptomatic patients. The approach is to administer the chemotherapy only as long as symptoms persist to avoid toxicity, which contributes to poorer survival. Additionally, lower doses of chemotherapy are often recommended for very young or low-weight infants, along with granulocyte colony-stimulating factors after each cycle of chemotherapy.
Evidence (chemotherapy for 4S/MS disease):
The COG ANBL0531 (NCT00499616) trial prospectively studied a subset of 4S patients who had MYCN-nonamplified tumors with impaired or impending organ dysfunction or unfavorable biology (unfavorable histology and/or diploid DNA index [DI]). Forty-nine patients were enrolled, 41 of whom were symptomatic and 28 of whom had unfavorable biology. Patients were assigned to receive two, four, or eight cycles of chemotherapy based on the tumor biology, age of the patient, and symptoms.[9][Level of evidence C1]
The 3-year OS rate was 81.4%.
Eight of the nine deaths occurred in patients younger than 2 months at diagnosis. Five deaths were related to acute complications of rapidly progressing hepatomegaly (i.e., abdominal compartment syndrome, renal failure, respiratory failure, coagulopathy, and infection). Patients younger than 40 days at diagnosis had more than 13 times the risk of dying compared with patients older than 47 days. The study was amended after the five deaths to mandate immediate chemotherapy for patients with 4S disease younger than 2 months at diagnosis with evolving hepatomegaly. No deaths related to complications of hepatomegaly occurred in the subsequent infants enrolled, including 18 infants who were younger than 2 months.
This study confirmed the inferior outcome of patients with unfavorable biology (DI = 1, segmental chromosome aberrations [1p and/or 11p loss of heterozygosity, unfavorable histology] without MYCN amplification) compared with symptomatic patients with favorable biology.
Both of the patients with late death died of metastatic disease and had unfavorable biology.
Eighty patients with stage 4S disease were enrolled on the COG-P9641 (NCT00003119) trial. Forty-one patients with asymptomatic stage 4S neuroblastoma were treated with surgery or biopsy alone, and 39 patients were treated with surgery and chemotherapy.[12]
Overall, the 5-year EFS rate was 77%, and the OS rate was 91%.
The 5-year EFS rate was 63% for patients treated with surgery or biopsy alone and 95% for patients treated with surgery and chemotherapy (P = .0016).
The 5-year OS rate was 84% for patients treated with surgery or biopsy alone and 97% for patients treated with surgery and chemotherapy (P = .1302).
Previously, chemotherapy toxicity was thought to be responsible for the poorer survival of patients with stage 4S disease. However, the use of chemotherapy on the COG-P9641 trial was restricted to specific clinical situations with a recommended number of cycles.
Also, on the COG-P9641 trial, asymptomatic infants with biologically favorable (MYCN-nonamplified) INSS stage 4S disease did not receive chemotherapy until the development of progressive disease or clinical symptoms.[12]
Infants who became symptomatic had disease-related organ failure and infectious complications, resulting in an inferior OS compared with those who received immediate chemotherapy (4–8 cycles of therapy). The 3-year OS rate was 84% for infants who did not receive chemotherapy versus 97% for infants who received chemotherapy (P = .1321).
For the COG-ANBL0531 trial, treatment was allocated based on symptoms, patient age, and tumor biology.[9]
The 2-year OS rate was 81% for patients with INSS stage 4S disease, which is lower than that reported in other cooperative trials such as COG-P9641.
Many patients enrolled in the ANBL0531 study were more ill than patients entered in previous trials, in part because tumor biopsy was not required in symptomatic infants. Previous trials mainly included asymptomatic patients, most with favorable tumor biology.
A prospective study was performed in 125 infants with stage 4S MYCN-nonamplified tumors or INSS stage 3 primary tumors and/or positive bone scintigraphy not associated with changes in the cortical bone (documented on plain radiographs and/or computed tomography).[11] A pretreatment symptom score was used to determine initial treatment. Observation was recommended for infants with low symptom scores (n = 86), and chemotherapy was recommended for infants with high symptom scores (n = 37).
The chemotherapy for patients with high symptom scores included two to four 3-day courses of carboplatin and etoposide. If symptoms persisted or progressive disease developed, up to four 5-day courses of cyclophosphamide, doxorubicin, and vincristine were administered. One-half of the patients underwent complete or partial resection of the primary tumor.
There was no difference in the 2-year EFS and OS between asymptomatic and symptomatic patients (EFS rate, 87% vs. 88%; OS rate, 98% vs. 97%), although many of the investigators preferred to give chemotherapy in the presence of a low symptom score.
For infants with low symptom scores, there was no difference in the outcome between the initially untreated infants (n = 56; OS rate, 93%) and treated infants (n = 30; OS rate, 86%).
The OS rate was 90% for infants presenting with high symptom scores.
There was no significant difference in 2-year OS rates between patients with unresectable primary tumors and patients with resectable primary tumors (97% vs. 100%) and between patients with negative and positive skeletal scintigraphy without radiological abnormalities (100% vs. 97%).
Surgery
Occasionally, if the liver becomes too large and is compromising the kidney and other abdominal organs, a decompressive laparotomy may be necessary,[13,14] although this would typically be an indication for chemotherapy as well. Likewise, emergent surgical abdominal decompression can be used to avoid respiratory deterioration and improve ventilation.[13,14]
Radiation therapy
In rare cases of marked hepatomegaly in symptomatic MS (4S) infants with neuroblastoma who were unresponsive to chemotherapy, very low-dose radiation therapy has been used. In a series of 41 symptomatic infants with MS disease, radiation therapy was administered to five infants, three of whom died.[9]
Treatment Options Under Clinical Evaluation
Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website.
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References
Monclair T, Brodeur GM, Ambros PF, et al.: The International Neuroblastoma Risk Group (INRG) staging system: an INRG Task Force report. J Clin Oncol 27 (2): 298-303, 2009. [PUBMED Abstract]
Taggart DR, London WB, Schmidt ML, et al.: Prognostic value of the stage 4S metastatic pattern and tumor biology in patients with metastatic neuroblastoma diagnosed between birth and 18 months of age. J Clin Oncol 29 (33): 4358-64, 2011. [PUBMED Abstract]
Irwin MS, Naranjo A, Zhang FF, et al.: Revised Neuroblastoma Risk Classification System: A Report From the Children’s Oncology Group. J Clin Oncol 39 (29): 3229-3241, 2021. [PUBMED Abstract]
Canete A, Gerrard M, Rubie H, et al.: Poor survival for infants with MYCN-amplified metastatic neuroblastoma despite intensified treatment: the International Society of Paediatric Oncology European Neuroblastoma Experience. J Clin Oncol 27 (7): 1014-9, 2009. [PUBMED Abstract]
Guglielmi M, De Bernardi B, Rizzo A, et al.: Resection of primary tumor at diagnosis in stage IV-S neuroblastoma: does it affect the clinical course? J Clin Oncol 14 (5): 1537-44, 1996. [PUBMED Abstract]
Katzenstein HM, Bowman LC, Brodeur GM, et al.: Prognostic significance of age, MYCN oncogene amplification, tumor cell ploidy, and histology in 110 infants with stage D(S) neuroblastoma: the pediatric oncology group experience–a pediatric oncology group study. J Clin Oncol 16 (6): 2007-17, 1998. [PUBMED Abstract]
Nickerson HJ, Matthay KK, Seeger RC, et al.: Favorable biology and outcome of stage IV-S neuroblastoma with supportive care or minimal therapy: a Children’s Cancer Group study. J Clin Oncol 18 (3): 477-86, 2000. [PUBMED Abstract]
Steele M, Jones NL, Ng V, et al.: Successful liver transplantation in an infant with stage 4S(M) neuroblastoma. Pediatr Blood Cancer 60 (3): 515-7, 2013. [PUBMED Abstract]
Twist CJ, Naranjo A, Schmidt ML, et al.: Defining Risk Factors for Chemotherapeutic Intervention in Infants With Stage 4S Neuroblastoma: A Report From Children’s Oncology Group Study ANBL0531. J Clin Oncol 37 (2): 115-124, 2019. [PUBMED Abstract]
Hsu LL, Evans AE, D’Angio GJ: Hepatomegaly in neuroblastoma stage 4s: criteria for treatment of the vulnerable neonate. Med Pediatr Oncol 27 (6): 521-8, 1996. [PUBMED Abstract]
De Bernardi B, Gerrard M, Boni L, et al.: Excellent outcome with reduced treatment for infants with disseminated neuroblastoma without MYCN gene amplification. J Clin Oncol 27 (7): 1034-40, 2009. [PUBMED Abstract]
Strother DR, London WB, Schmidt ML, et al.: Outcome after surgery alone or with restricted use of chemotherapy for patients with low-risk neuroblastoma: results of Children’s Oncology Group study P9641. J Clin Oncol 30 (15): 1842-8, 2012. [PUBMED Abstract]
Harper L, Perel Y, Lavrand F, et al.: Surgical management of neuroblastoma-related hepatomegaly: do material and method really count? Pediatr Hematol Oncol 25 (4): 313-7, 2008. [PUBMED Abstract]
Treatment of Recurrent or Refractory Neuroblastoma
Tumor growth resulting from maturation should be differentiated from tumor progression by performing a biopsy and reviewing histology. Patients may have persistent maturing disease with metaiodobenzylguanidine (MIBG) uptake that does not affect outcome, particularly patients with low-risk and intermediate-risk disease.[1] An analysis of 23 paired MIBG and positron emission tomography (PET) scans in 14 patients with refractory or recurrent high-risk neuroblastoma treated with iodine I 131-MIBG (131I-MIBG) found that the MIBG scan was more sensitive than fluorine F 18-fludeoxyglucose (18F-FDG) PET for detecting metastatic bone lesions, although there was a trend for 18F-FDG PET to be more sensitive for soft tissue lesions.[2]
Subclonal ALK variants or other MAPK pathway lesions may be present at diagnosis, with subsequent clonal expansion at relapse. Consequently, serial sampling of progressive tumors may lead to the identification of potentially actionable variants.[3,4] Modern comprehensive molecular analysis comparing primary and relapsed neuroblastoma from the same patients revealed extensive clonal enrichment and several newly discovered variants, with many tumors showing new or clonal-enriched variants in the RAS-MAPK pathway. This was true for patients with both high-risk and low-risk tumors at diagnosis.[5,6] For more information, see the Genomic and Biological Features of Neuroblastoma section.
Sequencing of recurrent and refractory neuroblastoma tumors from pediatric (n = 59) and young adult patients (n = 1) enrolled in the NCI-COG Pediatric MATCH trial revealed genomic alterations that were considered actionable for treatment in MATCH study arms in 27 of 60 tumors (45%).[7] Hotspot variants in ALK were most frequent, reported in 19 of 60 tumors (31.7%). MAPK pathway variants (NF1, NRAS) were detected in 4 of 60 tumors (6.7%), and FGFR1 variants were detected in 3 of 60 tumors (5%).
If neuroblastoma recurs in a child originally diagnosed with high-risk disease, the prognosis is usually poor despite additional intensive therapy.[8–11] However, it is often possible to gain many additional months of life for these patients with alternative chemotherapy regimens.[12,13] Clinical trials are appropriate for these patients and may be offered. Information about ongoing clinical trials is available from the NCI website.
Prognostic Factors in Patients With Recurrent Neuroblastoma
A comprehensive analysis of the patterns of relapse was conducted using the International Neuroblastoma Risk Group (INRG) database on patients diagnosed/enrolled between 1989 and 2017.[14][Level of evidence C1]
For 1,833 children, the pattern of first relapse included isolated local (19%), distant only (65%), and combined sites (16%).
Patients with isolated local failure had more favorable prognostic features.
Patients with stage 3 disease were more likely to have isolated local failure than patients with all other stages (49% vs. 16%, P < .001).
The 5-year overall survival (OS) rates significantly differed by relapse pattern, with a rate of 64% for isolated local, 23% for distant only, and 26% for combined sites (P < .001).
After controlling for age, stage, and MYCN status, patients with isolated local failure (adjusted hazard ratio [HR], 0.46; P < .001) and distant-only failure (adjusted HR, 0.57; P < .001) remained at decreased risk of death, compared with patients with combined failure.
The INRG database was used to examine clinical and biological features that are prognostic of survival after relapse or progression of INRG Staging System (INRGSS) stage MS pattern neuroblastoma. Of the 1,511 patients diagnosed between 1984 and 2021 who met the eligibility criteria, 209 patients were identified as having an event. Eligibility criteria included patients younger than 365 days at initial diagnosis with INRGSS stage MS disease or with International Neuroblastoma Staging System (INSS) stage 4S, or patients aged 365 to 546 days with INSS stage 4 disease and metastasis limited to the liver, skin, and/or bone marrow.[15][Level of evidence C1]
In this group, the median time to first event was 8.16 months.
Most relapses had a component of metastatic failure. These metastases more commonly occurred at sites outside of the liver, skin, and bone marrow.
The 5-year OS rate was 62% for patients treated in 2001 and later.
The International Neuroblastoma Risk Group Project performed a survival-tree analysis of clinical and biological characteristics (defined at diagnosis) associated with survival after relapse in 2,266 patients with neuroblastoma entered in large clinical trials in well-established clinical trials groups around the world.[8] The survival-tree analysis revealed the following:
The OS rate was 20% in the entire population with relapsed disease.
Among patients with all stages of disease at diagnosis, MYCN amplification predicted a poorer prognosis, measured as 5-year OS.
Among patients diagnosed with INSS stage 4 without MYCN amplification, age older than 18 months and high lactate dehydrogenase (LDH) level predicted poor prognosis.
Among patients with MYCN amplification, those diagnosed with stage 1 and stage 2 disease had a better prognosis than those diagnosed with stage 3 and stage 4 disease.
Among patients with MYCN-nonamplified tumors who were not stage 4, patients with hyperdiploidy had a better prognosis than patients with diploidy in those younger than 18 months. Among those older than 18 months, patients with differentiating tumors fared much better than patients with undifferentiated and poorly differentiated tumors.
Significant prognostic factors determined at diagnosis for postrelapse survival include the following:[8]
Age.
INSS stage.
MYCN status.
Time from diagnosis to first relapse.
LDH level, ploidy, and histological grade of tumor differentiation (to a lesser extent).
The Children’s Oncology Group (COG) experience with recurrence in patients with low-risk and intermediate-risk neuroblastoma showed that most patients can be salvaged. The COG reported a 3-year event free survival (EFS) rate of 88% and an OS rate of 96% in intermediate-risk patients and a 5-year EFS rate of 89% and OS rate of 97% in low-risk patients.[16,17] Moreover, in most patients originally diagnosed with low-risk or intermediate-risk disease, local recurrence or recurrence in the 4S pattern may be treated successfully with observation alone, surgery alone, or with moderate-dose chemotherapy, without myeloablative therapy and stem cell transplant.
The OS after recurrence in children presenting with high-risk neuroblastoma is generally extremely poor. However, such patients at first relapse after complete remission or minimal residual disease (MRD) in whom relapse was a single site of soft tissue mass (a few children also had bone marrow or bone disease at relapse) had a 5-year OS rate of 35% in one single-institution study. All patients underwent surgical resection of the soft tissue disease. MYCN amplification and multifocal soft tissue disease were associated with a worse postprogression survival.[18] Older children with local recurrence, with either unfavorable International Neuroblastoma Pathology Classification at diagnosis or MYCN gene amplification, have a poor prognosis and may be treated with surgery or aggressive combination chemotherapy, or they may be offered entry into a clinical trial.
Table 7 summarizes the treatment options for recurrent neuroblastoma by INSS-based risk group.
Table 7. Treatment Options for Recurrent Neuroblastoma
COG Risk-Group Assignment
Treatment Options
COG = Children’s Oncology Group; 131I-MIBG = iodine I 131-metaiodobenzylguanidine.
Locoregional recurrence in patients initially classified as low risk
Recurrent Neuroblastoma in Patients Initially Classified as Low Risk
Locoregional recurrence
Treatment options for locoregional recurrent neuroblastoma initially classified as low risk include the following:
Surgery followed by observation or chemotherapy.
Chemotherapy that may be followed by surgery.
Local or regional recurrent cancer is resected if possible.
Patients with favorable biology and regional recurrence more than 3 months after completion of planned treatment are observed if resection of the recurrence is total or near total (≥90% resection). Those with favorable biology and a less-than-near-total resection are treated with chemotherapy.[16,17,19]
Infants younger than 1 year at the time of locoregional recurrence whose tumors have any unfavorable biological properties are observed if resection is total or near total. If the resection is less than near total, these infants are treated with chemotherapy. Chemotherapy may consist of moderate doses of carboplatin, cyclophosphamide, doxorubicin, and etoposide, or cyclophosphamide and topotecan. The cumulative dose of each agent is kept low to minimize long-term effects, as used in previous COG trials (COG-P9641 and COG-A3961).[16,17,19]
Evidence (surgery followed by observation or chemotherapy):
A COG study of low-risk patients with stages 1, 2A, 2B, and 4S neuroblastoma enrolled 915 patients, 800 of whom were asymptomatic and treated with surgery alone followed by observation. The other patients received chemotherapy with or without surgery.[17]
About 10% of patients developed progressive or recurrent tumors.
Most recurrences were treated during the study with surgery alone or moderate chemotherapy with or without surgery.
Most patients’ disease was salvaged, as demonstrated by the EFS (89%) and OS (97%) rates at 5 years.
Metastatic recurrence or disease refractory to standard treatment
Treatment options for metastatic recurrent neuroblastoma initially classified as low risk include the following:
Observation.
Chemotherapy (based on age of patient, tumor biology, and prior treatment; treatment may include intermediate-risk or high-risk therapies, as used at initial diagnosis).
Surgery followed by chemotherapy.
Metastatic recurrent or progressive neuroblastoma in an infant initially categorized as low risk and younger than 1 year at recurrence may be treated according to tumor biology, as defined in the previous COG trials (COG-P9641 and COG-A3961):
If the biology is completely favorable, metastasis is in a 4S pattern, and the recurrence or progression is within 3 months of diagnosis, the patient is observed symptomatically.
If the metastatic progression or recurrence occurs more than 3 months after diagnosis or not in a 4S pattern, then the primary tumor is resected, if possible, and chemotherapy is given.
Chemotherapy may consist of moderate doses of carboplatin, cyclophosphamide, doxorubicin, and etoposide. The cumulative dose of each agent is kept low to minimize long-term effects, as used in previous COG trials (COG-P9641 and COG-A3961).
Any child initially categorized as low risk who is older than 18 months at the time of metastatic recurrent or progressive disease and whose recurrence is not in the stage 4S pattern usually has a poor prognosis and is treated as follows:
High-risk therapy.
Patients with metastatic recurrent neuroblastoma are treated like patients with newly diagnosed high-risk neuroblastoma. For more information, see the Treatment Options for High-Risk Neuroblastoma section.
Recurrent Neuroblastoma in Patients Initially Classified as Intermediate Risk
The COG ANBL0531 (NCT00499616) study treated patients with newly diagnosed intermediate-risk neuroblastoma with chemotherapy consisting of carboplatin, etoposide, cyclophosphamide, and doxorubicin. Retrieval therapy was included in the protocol for patients who developed progressive nonmetastatic disease within 3 years of study enrollment. Up to six cycles of cyclophosphamide and topotecan could be given to patients. Of 29 patients who received cyclophosphamide and topotecan, 18 remained event free, 9 experienced relapse, and 2 died. Twenty patients who experienced an inadequate initial response to eight cycles of chemotherapy were treated with cyclophosphamide and topotecan. Of those 20 patients, 9 patients achieved a very good partial response or better; however, 6 patients developed progressive disease or experienced relapse, and 1 patient died. This suggests that more aggressive therapy is needed for patients who do not achieve the defined treatment end point after eight cycles of chemotherapy.[19]
A COG study for intermediate-risk neuroblastoma (COG-A3961) enrolled 479 patients, 42 of whom developed disease progression. The recurrence rate was 10% for those with favorable biology and 17% for those with unfavorable biology. Thirty patients had locoregional recurrences, 11 had metastatic recurrences, and 1 had both types of recurrent disease. Six of the 42 patients died of disease, while 36 patients responded to therapy. Thus, most patients with intermediate-risk neuroblastoma and disease progression may be salvaged.[16] It is not feasible to compare these results with the results of the other COG intermediate-risk study (ANBL0531) because of differences between the classification of patients for eligibility in the two studies.[19]
Locoregional recurrence
Treatment options for locoregional recurrent neuroblastoma initially classified as intermediate risk include the following:
Surgery (complete resection).
Surgery (incomplete resection) followed by chemotherapy.
Radiation therapy. Radiation therapy is considered only for patients with disease progression after chemotherapy and second-look surgery.[16]
Locoregional recurrence of neuroblastoma with favorable biology that occurs more than 3 months after completion of chemotherapy may be treated surgically. If resection is less than near total, then additional chemotherapy may be given. Chemotherapy should be selected based on the previous chemotherapy received.[16]
Metastatic recurrence
Treatment options for metastatic recurrent neuroblastoma initially classified as intermediate risk include the following:
High-risk therapy.
Patients with metastatic recurrent neuroblastoma are treated like patients with newly diagnosed high-risk neuroblastoma. For more information, see the Treatment Options for High-Risk Neuroblastoma section.
Recurrent or Refractory Neuroblastoma in Patients Initially Classified as High Risk
Any recurrence in patients initially classified as high risk signifies a very poor prognosis.[8] Clinical trials may be considered. Palliative care should also be considered as part of the patient’s treatment plan.
An analysis of several trials included 383 patients with neuroblastoma whose tumor recurred or progressed in COG modern-era, early-phase trials. The 1-year progression-free survival (PFS) rate was 21%, and the 4-year PFS rate was 6%. The OS rates were 57% at 1 year and 20% at 4 years. Less than 10% of patients experienced no subsequent recurrence or progression. MYCN amplification predicted worse PFS and OS rates.[20] Although the OS after recurrence in children presenting with high-risk neuroblastoma is generally extremely poor, patients with high-risk neuroblastoma at first relapse after complete remission or MRD in whom relapse was a single site of soft tissue mass (a few children also had bone marrow or bone disease at relapse) had a 5-year OS rate of 35% in one single-institution study.[18]
Treatment options for recurrent or refractory neuroblastoma in patients initially classified as high risk include the following:
131I-MIBG. 131I-MIBG alone, in combination with other therapy, followed by stem cell rescue.
Novel therapies.
ALK inhibitors for patients with ALK variants. In a trial of 20 patients with ALK aberrations treated with crizotinib, the response rate was 15%. Two patients had partial responses, and one patient had a complete response. All three patients had a somatic ALK Arg1275Gln variant.[22][Level of evidence C3] Lorlatinib has shown activity in patients with ALK-aberrant, relapsed neuroblastoma. The response rates were 13% in patients younger than 18 years and 47% in patients aged 18 years or older.[23] Additional patients in each cohort had minor responses, resulting in modified response rates of 30% and 67%, respectively. A single-institution series reported that 9 of 13 adult patients with relapsed, ALK-aberrant neuroblastoma responded to lorlatinib.[24]
WEE1 inhibitors. A phase II trial of adavosertib plus irinotecan reported that 3 of 20 patients with relapsed neuroblastoma had objective responses, which met the primary efficacy end point.[25]
Bevacizumab. The BEACON trial was a multiarm randomized trial with a factorial design for patients with relapsed or refractory high-risk neuroblastoma. Eighty patients were assigned to receive chemotherapy with the addition of bevacizumab and 80 patients were assigned to receive chemotherapy alone.[26] Patients randomly assigned to receive bevacizumab had a higher response rate (26% vs. 18%) that met a prespecified threshold for success. The 1-year PFS rate was nominally higher for patients who received bevacizumab (46% with bevacizumab vs. 38% for those who did not receive bevacizumab; HR, 0.89; 95% confidence interval [CI], 0.63–1.27). There was evidence for an interaction with the chemotherapy randomization (see below), such that patients randomly assigned to bevacizumab, irinotecan, and temozolomide had the most favorable 1-year PFS rates (67%).
RIST regimen. A randomized phase II trial included 129 patients with relapsed or refractory neuroblastoma. The study compared the combination of dasatinib and rapamycin added to irinotecan and temozolomide (RIST regimen) with irinotecan and temozolomide alone. In the full cohort, the median PFS was significantly longer in the RIST group (11 months) than in the chemotherapy-alone group (5 months; HR, 0.62; P = .019). On subgroup analysis, the benefit was largely seen in patients with MYCN-amplified disease (median PFS, 6 months with RIST vs. 2 months with control; HR, 0.45; P = .012) and not in patients with MYCN wild-type disease (median PFS, 14 months with RIST vs. 8 months with control; HR, 0.84; P = .49).[27]
Chemotherapy (phase I/II studies).
Topotecan in combination with cyclophosphamide or etoposide.[28]
Temozolomide with irinotecan.
Immunotherapy. Novel anti-GD2 drugs have been evaluated in patients with recurrent or refractory neuroblastoma. Hu14.18 anti-GD2 has been chemically linked with IL-2 and combined with granulocyte-macrophage colony-stimulating factor (GM-CSF), and a phase II trial of this regimen reported a few durable responses.[29]
Chemotherapy combined with immunotherapy produces the best response rate and response duration of treatments for high-risk patients with disease progression.
Evidence (chemotherapy combined with immunotherapy):
The ANBL1221 (NCT01767194) trial was the first multicenter trial to evaluate anti-GD2 therapy combined with chemotherapy in a cohort of patients with relapsed or refractory neuroblastoma. Patients in first relapse or progression were randomly assigned to receive either irinotecan/temozolomide/dinutuximab/GM-CSF (I/T/DIN/GM-CSF) or temozolomide/irinotecan/temsirolimus.[21]; [30][Level of evidence C3]
Of the 17 patients treated with the combination that included dinutuximab, 9 patients (53%) had objective responses, compared with 1 of 18 patients treated with the regimen that contained temsirolimus.
In an expansion cohort consisting of 36 additional patients nonrandomly assigned to receive I/T/DIN/GM-CSF, objective responses were seen in 13 patients (36.1%). For all 53 patients enrolled on the study and treated with I/T/DIN/GM-CSF, there were 22 objective responses (41.5%).[30][Level of evidence C3] This outcome is superior to any other published outcome for patients with refractory or relapsed high-risk neuroblastoma.
In a retrospective cohort study of 146 patients with high-risk neuroblastoma who received chemoimmunotherapy with I/T/DIN/GM-CSF in first relapse, the following results were reported:[31][Level of evidence C2]
A total of 49% of patients had an objective response, similar to the response rate seen in the ANBL1221 trial.
Of the patients with stable disease or better at first disease evaluation after chemoimmunotherapy, 22% had an improved response (per International Neuroblastoma Response Criteria) on subsequent evaluation. Only 13% of patients with stable disease at first disease evaluation eventually had an objective response, whereas approximately 40% of patients with initial minimal response or partial response status achieved complete response after subsequent cycles. Patients who received more than six cycles of therapy and had continued stable disease were unlikely to achieve an objective response.
The median PFS was 13.1 months from initiation of therapy. The 1-year PFS rate was 50%, and the 2-year PFS rate was 28%.
The median duration of response was 15.9 months.
The median PFS after discontinuation of all anticancer therapy, including I/T/DIN/GM-CSF, was 10.4 months.
Limited data are available about the use of chemotherapy backbones other than irinotecan/temozolomide as part of a chemoimmunotherapy strategy. A registry study included 24 patients with relapsed or progressive high-risk neuroblastoma who were treated with topotecan/cyclophosphamide and dinutuximab.[32]
The objective response rate was 42%.
Evidence (131I-MIBG alone or in combination with other therapies):
For children with recurrent or refractory neuroblastoma, 131I-MIBG is an effective palliative agent and may be considered alone or in combination with chemotherapy and stem cell support in a clinical research trial.[33–38]; [39,40][Level of evidence C1]
A North American retrospective study of more than 200 patients treated with 131I-MIBG therapy compared children who had recurrence or progression of disease with children who had stable or persistent disease since diagnosis.[41]
The rate of immediate progression after 131I-MIBG therapy was lower, and the OS rate at 2 years was better (65% vs. 39%) in patients with stable, persistent disease.
Tandem consolidation using 131I-MIBG, vincristine, and irinotecan with autologous hematopoietic stem cell transplant (HSCT) followed by busulfan/melphalan with autologous HSCT was retrospectively reported in eight patients.[40]
This treatment resulted in three complete responses, two partial responses, and one minor response.
Single autologous HSCT with 131I-MIBG and carboplatin/etoposide/melphalan was studied in additional patients. Patients were treated after completing induction chemotherapy.[42]
Response to induction therapy included refractory disease in 27 patients and progressive disease in 15 patients. Four of 41 evaluable patients had complete or partial responses after transplant. Eight patients with partial responses to induction therapy were treated, resulting in three responses.
There was a 12% incidence of sinusoidal obstructive syndrome.
A randomized phase II trial included 105 evaluable patients who were treated with either 131I-MIBG alone, 131I-MIBG with irinotecan and vincristine, or 131I-MIBG with vorinostat.[43]
Patients enrolled in the vorinostat arm had the highest response rate (32%).
Patients treated with MIBG alone or with irinotecan/vincristine had response rates of 14%.
A single-arm, phase II trial included 30 patients with relapsed or refractory neuroblastoma who were treated with 131I-MIBG and topotecan.[44]
A 13% response rate was reported.
131I-MIBG is associated with risk of second malignancy. In one report of 563 5-year survivors of neuroblastoma, 15.5% had received prior 131I-MIBG therapy.[45]
The risk of a second malignant neoplasm was higher for patients treated with prior 131I-MIBG, compared with survivors who were not treated with 131I-MIBG (sub-hazard ratio, 5.7; 95% CI, 1.8–17.8).
Evidence (chemotherapy):
Irinotecan and temozolomide.
The combination of irinotecan and temozolomide had a 15% response rate in one study.[46][Level of evidence B4]
In the BEACON trial, patients were randomly assigned to receive either temozolomide or irinotecan and temozolomide, with or without bevacizumab, in a factorial trial design.[26]
Response rates were similar in the two treatment groups (21% with temozolomide vs. 20% with irinotecan and temozolomide).
The 1-year PFS rate was superior for patients who were treated with irinotecan and temozolomide (53%), compared with temozolomide (30%; HR, 0.59; 95% CI, 0.39–0.90).
A retrospective study reported on 74 patients who received 92 cycles of ifosfamide, carboplatin, and etoposide. The study included 37 patients who received peripheral blood stem cell rescue after responding to this drug combination.[47]
Disease regressions (major and minor responses) were achieved in 14 of 17 patients (82%) with a new relapse, 13 of 26 patients (50%) with refractory neuroblastoma, and 12 of 34 patients (35%) who were treated for progressive disease during chemotherapy (P = .005).
Grade 3 toxicities were rare.
Topotecan in combination with cyclophosphamide alone or with etoposide has been used in patients with recurrent disease who did not receive topotecan initially.[28][Level of evidence A2]
The response rates were 32% (18 of 57) for patients who received topotecan and cyclophosphamide and 19% (11 of 59) for patients who received topotecan alone.
In the BEACON trial, patients were randomly assigned to receive either temozolomide or topotecan and temozolomide, with or without bevacizumab.[26]
Response rates were similar in the two treatment groups (23% with temozolomide vs. 27% with topotecan and temozolomide).
The 1-year PFS rate was nominally higher in patients who received topotecan and temozolomide (47%) than in patients who received temozolomide (23%; HR, 0.59; 95% CI, 0.33–1.08).
High-dose carboplatin, irinotecan, and/or temozolomide has been used to treat patients with refractory disease or new relapses (after treatment that included topotecan) occurring off therapy (68% objective response rate). However, this regimen is not used to treat patients whose disease progresses while on therapy.[48]
A range of other immunotherapy approaches have been used in patients with relapsed neuroblastoma. Single-agent anti-GD2 monoclonal antibody therapy has shown activity in this setting. For example, a phase II trial evaluated a 10-day, long-term infusion of dinutuximab in 40 children with relapsed or refractory high-risk neuroblastoma. The study reported an objective response rate of 26%. This approach was tolerable, with no grade 4 or grade 5 events.[49]
Allogeneic transplant has a historically low success rate in recurrent or progressive neuroblastoma. In a retrospective registry study, allogeneic HSCT after a previous autologous HSCT appeared to offer no benefit. Disease recurrence remains the most common cause of treatment failure.[50] A similar conclusion was reached in a multicenter phase II trial of reduced-intensity conditioning allogeneic HSCT in 51 patients, 44 of whom had relapsed or refractory high-risk neuroblastoma. The 5-year disease-free survival (DFS) rate was 11.8%.[51]
The use of GD2-directed therapy after haploidentical transplant may be a more promising strategy. In one trial of 68 patients with relapsed neuroblastoma, the use of dinutuximab and subcutaneous interleukin-2 after haploidentical transplant was feasible, with a low rate of graft-versus-host disease. The 5-year EFS rate was 43%. Superior outcomes were obtained for patients who had complete or partial responses at the start of dinutuximab therapy. Among patients with disease after transplant, the complete response rate to anti-GD2 immunotherapy was 35%.[52]
Clinical trials of vaccines designed to induce host antiganglioside antibodies that can replicate the antineoplastic activities of intravenously administered monoclonal antibodies are ongoing. Patients also receive a beta-glucan treatment, which has a broad range of immunostimulatory effects and synergizes with anti-GD2/GD3 monoclonal antibodies. In a phase I study of 15 children with high-risk neuroblastoma, the therapy was tolerated without any dose-limiting toxicity.[53] Long-term PFS has been reported in patients who achieve a second or later complete or very good partial remission followed by consolidation with anti-GD2 immunotherapy and isotretinoin with or without maintenance therapy. This includes patients who had previously received anti-GD2 immunotherapy and isotretinoin.[54]
In a phase I/II trial, the use of autologous chimeric antigen receptor (CAR)–expressing T cells directed against GD2 was feasible and safe in treating children with relapsed or refractory, high-risk neuroblastoma. This treatment resulted in a response rate of 63%.[55] These findings contrast with earlier reports that showed only modest activity of other GD2-directed CAR T-cell approaches in this same population.
Recurrent Neuroblastoma in the Central Nervous System
Central nervous system (CNS) involvement, although rare at initial presentation, may occur in 3% to 10% of patients with recurrent neuroblastoma. CNS relapses represented 6% of all metastatic relapses in a series of 1,161 first relapses in 1,977 patients with stage 4 disease treated in a trial of patients with high-risk neuroblastoma.[56] Because up-front treatment for newly diagnosed patients does not adequately treat the CNS, the CNS has emerged as a sanctuary site leading to relapse.[56–58]
Significant risk factors for CNS relapse identified in the International Society of Paediatric Oncology Europe Neuroblastoma (SIOPEN) trial were patient and disease features at diagnosis. These features included female sex (HR, 2.0; P = .016), MYCN amplification (HR, 2.4; P = .0008), hepatic disease (HR, 2.5; P = .01), or more than one metastatic system/compartment involvement (HR, 7.1; P = .047). Neither high-dose chemotherapy nor immunotherapy was associated with higher risk of recurrence. Investigators noted stable incidence of CNS relapse reported over time.[56]
CNS relapses are almost always fatal, with a median time to death of 6 months. The 1-year and 3-year postrelapse OS rates were 25% and 7%, respectively, in the SIOPEN trial.[56] Patients with isolated CNS relapses may be able to achieve long-term survival.[56]
Treatment options for recurrent neuroblastoma in the CNS include the following:
Surgery and radiation therapy.
Chemotherapy (including temozolomide-containing regimens) in combination with surgery and radiation therapy.
Novel therapeutic approaches.
Current treatment approaches generally include eradicating bulky and microscopic residual disease in the CNS and minimal residual systemic disease that may herald further relapses. Neurosurgical interventions serve to decrease edema, control hemorrhage, and remove bulky tumor before starting therapy.
A single institution had some success while testing intraventricular compartmental radioimmunotherapy using intrathecal radioiodinated anti-B7H3 monoclonal antibodies, combined with 18 Gy or 21 Gy of craniospinal irradiation with boosts to gross CNS disease, in patients with recurrent metastatic CNS neuroblastoma.[13] The posttreatment 5-year CNS DFS rate was about 69%, and the 5-year OS rate was about 45%.[59][Level of evidence C2]
For patients who experience prolonged survival after an initial CNS relapse, some may develop a second relapse after cranial spinal irradiation (CSI). Published data for patients who experience a second CNS relapse are limited. A second CNS relapse indicates a poor prognosis.[57]
In a single-institution study that included 128 patients treated with CSI for first CNS relapse, 40 developed a second CNS relapse at a median of 6.3 months from the initial CSI treatment. Patient outcomes after second CNS relapse are poor, although treatment with radiation therapy at the time of second CNS relapse may be associated with longer OS.[60][Level of evidence C1]
The 1-year survival rate was 32.5%.
Patients in this group with initial leptomeningeal involvement were more likely to relapse than those who had exclusively parenchymal lesions (HR, 2.5; 95% CI, 1.3–4.9; P = .006). The median time to second CNS relapse was 6.8 months, 51% of which occurred outside the CSI boost field.
Most patients (24 of 40) received radiation as part of the multimodality approach for the second CNS relapse. Receipt of radiation therapy at time of second CNS relapse was associated with improved OS (median, 30 vs. 5.1 months; HR, 0.5; log-rank P < .001).
Eight of the 40 patients received compartmental intrathecal radioimmunotherapy (cRIT) with radioiodinated anti-GD2 and/or anti-B7H3 monoclonal antibodies as part of their treatment. The prolonged median OS from the time of second relapse was 22 months for patients who received cRIT. In comparison, the median OS was 5 months for patients who did not receive cRIT. Five of these patients had previously received cRIT at the time of initial CNS relapse.
Treatment Options Under Clinical Evaluation for Recurrent or Refractory Neuroblastoma
Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website.
The following is an example of a national and/or institutional clinical trial that is currently being conducted:
ADVL1621 (NCT02332668) (A Phase I/II Study of Pembrolizumab [MK-3475] in Children With Advanced Melanoma or a PD-L1–Positive Advanced, Relapsed or Refractory Solid Tumor or Lymphoma): Part 1 of this study will find the maximum tolerated dose, confirm the dose, and find the recommended phase II dose for pembrolizumab therapy. Part 2 of the study will further evaluate the safety and efficacy at the pediatric phase II recommended dose.
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
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Latest Updates to This Summary (04/28/2025)
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
This summary was comprehensively reviewed and extensively revised.
This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.
About This PDQ Summary
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of neuroblastoma. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
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The lead reviewers for Neuroblastoma Treatment are:
Steven DuBois, MD, MS (Dana Farber Cancer Institute)
Andrea A. Hayes-Dixon, MD, FACS, FAAP (Howard University)
Karen J. Marcus, MD, FACR (Dana-Farber of Boston Children’s Cancer Center and Blood Disorders Harvard Medical School)
Nita Louise Seibel, MD (National Cancer Institute)
Malcolm A. Smith, MD, PhD (National Cancer Institute)
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PDQ® Pediatric Treatment Editorial Board. PDQ Neuroblastoma Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/neuroblastoma/hp/neuroblastoma-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389190]
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