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]
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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.
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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.
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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]
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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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Pugh TJ, Morozova O, Attiyeh EF, et al.: The genetic landscape of high-risk neuroblastoma. Nat Genet 45 (3): 279-84, 2013. [PUBMED Abstract]
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]
Mossé YP, Deyell RJ, Berthold F, et al.: Neuroblastoma in older children, adolescents and young adults: a report from the International Neuroblastoma Risk Group project. Pediatr Blood Cancer 61 (4): 627-35, 2014. [PUBMED Abstract]
Kushner BH, Kramer K, LaQuaglia MP, et al.: Neuroblastoma in adolescents and adults: the Memorial Sloan-Kettering experience. Med Pediatr Oncol 41 (6): 508-15, 2003. [PUBMED Abstract]
Suzuki M, Kushner BH, Kramer K, et al.: Treatment and outcome of adult-onset neuroblastoma. Int J Cancer 143 (5): 1249-1258, 2018. [PUBMED Abstract]
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]
Vo KT, Matthay KK, Neuhaus J, et al.: Clinical, biologic, and prognostic differences on the basis of primary tumor site in neuroblastoma: a report from the international neuroblastoma risk group project. J Clin Oncol 32 (28): 3169-76, 2014. [PUBMED Abstract]
Oldridge DA, Truong B, Russ D, et al.: Differences in Genomic Profiles and Outcomes Between Thoracic and Adrenal Neuroblastoma. J Natl Cancer Inst 111 (11): 1192-1201, 2019. [PUBMED Abstract]
Hiyama E, Yokoyama T, Hiyama K, et al.: Multifocal neuroblastoma: biologic behavior and surgical aspects. Cancer 88 (8): 1955-63, 2000. [PUBMED Abstract]
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]
Seeger RC, Reynolds CP, Gallego R, et al.: Quantitative tumor cell content of bone marrow and blood as a predictor of outcome in stage IV neuroblastoma: a Children’s Cancer Group Study. J Clin Oncol 18 (24): 4067-76, 2000. [PUBMED Abstract]
Bochennek K, Esser R, Lehrnbecher T, et al.: Impact of minimal residual disease detection prior to autologous stem cell transplantation for post-transplant outcome in high risk neuroblastoma. Klin Padiatr 224 (3): 139-42, 2012. [PUBMED Abstract]
van Zogchel LMJ, Decarolis B, van Wezel EM, et al.: Sensitive liquid biopsy monitoring correlates with outcome in the prospective international GPOH-DCOG high-risk neuroblastoma RT-qPCR validation study. J Exp Clin Cancer Res 43 (1): 331, 2024. [PUBMED Abstract]
Yanik GA, Parisi MT, Shulkin BL, et al.: Semiquantitative mIBG scoring as a prognostic indicator in patients with stage 4 neuroblastoma: a report from the Children’s oncology group. J Nucl Med 54 (4): 541-8, 2013. [PUBMED Abstract]
Yanik GA, Parisi MT, Naranjo A, et al.: Validation of Postinduction Curie Scores in High-Risk Neuroblastoma: A Children’s Oncology Group and SIOPEN Group Report on SIOPEN/HR-NBL1. J Nucl Med 59 (3): 502-508, 2018. [PUBMED Abstract]
Streby KA, Parisi MT, Shulkin BL, et al.: Impact of diagnostic and end-of-induction Curie scores with tandem high-dose chemotherapy and autologous transplants for metastatic high-risk neuroblastoma: A report from the Children’s Oncology Group. Pediatr Blood Cancer 70 (8): e30418, 2023. [PUBMED Abstract]
Pinto N, Naranjo A, Hibbitts E, et al.: Predictors of differential response to induction therapy in high-risk neuroblastoma: A report from the Children’s Oncology Group (COG). Eur J Cancer 112: 66-79, 2019. [PUBMED Abstract]
George RE, Perez-Atayde AR, Yao X, et al.: Tumor histology during induction therapy in patients with high-risk neuroblastoma. Pediatr Blood Cancer 59 (3): 506-10, 2012. [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]
Moroz V, Machin D, Hero B, et al.: The prognostic strength of serum LDH and serum ferritin in children with neuroblastoma: A report from the International Neuroblastoma Risk Group (INRG) project. Pediatr Blood Cancer 67 (8): e28359, 2020. [PUBMED Abstract]
Horner MJ, Ries LA, Krapcho M, et al.: SEER Cancer Statistics Review, 1975-2006. National Cancer Institute, 2009. Also available online. Last accessed August 21, 2023.
Pinto NR, Applebaum MA, Volchenboum SL, et al.: Advances in Risk Classification and Treatment Strategies for Neuroblastoma. J Clin Oncol 33 (27): 3008-17, 2015. [PUBMED Abstract]
Bagatell R, DuBois SG, Naranjo A, et al.: Children’s Oncology Group’s 2023 blueprint for research: Neuroblastoma. Pediatr Blood Cancer 70 Suppl 6 (Suppl 6): e30572, 2023. [PUBMED Abstract]
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 2 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]
Simon T, Hero B, Benz-Bohm G, et al.: Review of image defined risk factors in localized neuroblastoma patients: Results of the GPOH NB97 trial. Pediatr Blood Cancer 50 (5): 965-9, 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]
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Gauguet JM, Pace-Emerson T, Grant FD, et al.: Evaluation of the utility of (99m) Tc-MDP bone scintigraphy versus MIBG scintigraphy and cross-sectional imaging for staging patients with neuroblastoma. Pediatr Blood Cancer 64 (11): , 2017. [PUBMED Abstract]
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Ladenstein R, Lambert B, Pötschger U, et al.: Validation of the mIBG skeletal SIOPEN scoring method in two independent high-risk neuroblastoma populations: the SIOPEN/HR-NBL1 and COG-A3973 trials. Eur J Nucl Med Mol Imaging 45 (2): 292-305, 2018. [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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Schleiermacher G, Michon J, Ribeiro A, et al.: Segmental chromosomal alterations lead to a higher risk of relapse in infants with MYCN-non-amplified localised unresectable/disseminated neuroblastoma (a SIOPEN collaborative study). Br J Cancer 105 (12): 1940-8, 2011. [PUBMED Abstract]
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Pinto N, Naranjo A, Hibbitts E, et al.: Predictors of differential response to induction therapy in high-risk neuroblastoma: A report from the Children’s Oncology Group (COG). Eur J Cancer 112: 66-79, 2019. [PUBMED Abstract]
Depuydt P, Boeva V, Hocking TD, et al.: Genomic Amplifications and Distal 6q Loss: Novel Markers for Poor Survival in High-risk Neuroblastoma Patients. J Natl Cancer Inst 110 (10): 1084-1093, 2018. [PUBMED Abstract]
Ognibene M, Morini M, Garaventa A, et al.: Identification of a minimal region of loss on chromosome 6q27 associated with poor survival of high-risk neuroblastoma patients. Cancer Biol Ther 21 (5): 391-399, 2020. [PUBMED Abstract]
Ambros PF, Ambros IM, Brodeur GM, et al.: International consensus for neuroblastoma molecular diagnostics: report from the International Neuroblastoma Risk Group (INRG) Biology Committee. Br J Cancer 100 (9): 1471-82, 2009. [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]
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]
Plantaz D, Vandesompele J, Van Roy N, et al.: Comparative genomic hybridization (CGH) analysis of stage 4 neuroblastoma reveals high frequency of 11q deletion in tumors lacking MYCN amplification. Int J Cancer 91 (5): 680-6, 2001. [PUBMED Abstract]
Maris JM, Hogarty MD, Bagatell R, et al.: Neuroblastoma. Lancet 369 (9579): 2106-20, 2007. [PUBMED Abstract]
Campbell K, Shyr D, Bagatell R, et al.: Comprehensive evaluation of context dependence of the prognostic impact of MYCN amplification in neuroblastoma: A report from the International Neuroblastoma Risk Group (INRG) project. Pediatr Blood Cancer 66 (8): e27819, 2019. [PUBMED Abstract]
Berbegall AP, Bogen D, Pötschger U, et al.: Heterogeneous MYCN amplification in neuroblastoma: a SIOP Europe Neuroblastoma Study. Br J Cancer 118 (11): 1502-1512, 2018. [PUBMED Abstract]
Ackermann S, Cartolano M, Hero B, et al.: A mechanistic classification of clinical phenotypes in neuroblastoma. Science 362 (6419): 1165-1170, 2018. [PUBMED Abstract]
Peifer M, Hertwig F, Roels F, et al.: Telomerase activation by genomic rearrangements in high-risk neuroblastoma. Nature 526 (7575): 700-4, 2015. [PUBMED Abstract]
Valentijn LJ, Koster J, Zwijnenburg DA, et al.: TERT rearrangements are frequent in neuroblastoma and identify aggressive tumors. Nat Genet 47 (12): 1411-4, 2015. [PUBMED Abstract]
Roderwieser A, Sand F, Walter E, et al.: Telomerase is a prognostic marker of poor outcome and a therapeutic target in neuroblastoma. JCO Precis Oncol 3: 1-20, 2019.
Mac SM, D’Cunha CA, Farnham PJ: Direct recruitment of N-myc to target gene promoters. Mol Carcinog 29 (2): 76-86, 2000. [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]
Hartlieb SA, Sieverling L, Nadler-Holly M, et al.: Alternative lengthening of telomeres in childhood neuroblastoma from genome to proteome. Nat Commun 12 (1): 1269, 2021. [PUBMED Abstract]
Koneru B, Lopez G, Farooqi A, et al.: Telomere Maintenance Mechanisms Define Clinical Outcome in High-Risk Neuroblastoma. Cancer Res 80 (12): 2663-2675, 2020. [PUBMED Abstract]
Meeser A, Bartenhagen C, Werr L, et al.: Reliable assessment of telomere maintenance mechanisms in neuroblastoma. Cell Biosci 12 (1): 160, 2022. [PUBMED Abstract]
Schmitt-Hoffner F, van Rijn S, Toprak UH, et al.: FOXR2 Stabilizes MYCN Protein and Identifies Non-MYCN-Amplified Neuroblastoma Patients With Unfavorable Outcome. J Clin Oncol 39 (29): 3217-3228, 2021. [PUBMED Abstract]
Sturm D, Orr BA, Toprak UH, et al.: New Brain Tumor Entities Emerge from Molecular Classification of CNS-PNETs. Cell 164 (5): 1060-72, 2016. [PUBMED Abstract]
Amoroso L, Ognibene M, Morini M, et al.: Genomic coamplification of CDK4/MDM2/FRS2 is associated with very poor prognosis and atypical clinical features in neuroblastoma patients. Genes Chromosomes Cancer 59 (5): 277-285, 2020. [PUBMED Abstract]
Martinez-Monleon A, Kryh Öberg H, Gaarder J, et al.: Amplification of CDK4 and MDM2: a detailed study of a high-risk neuroblastoma subgroup. Sci Rep 12 (1): 12420, 2022. [PUBMED Abstract]
Gundem G, Levine MF, Roberts SS, et al.: Clonal evolution during metastatic spread in high-risk neuroblastoma. Nat Genet 55 (6): 1022-1033, 2023. [PUBMED Abstract]
Pugh TJ, Morozova O, Attiyeh EF, et al.: The genetic landscape of high-risk neuroblastoma. Nat Genet 45 (3): 279-84, 2013. [PUBMED Abstract]
Molenaar JJ, Koster J, Zwijnenburg DA, et al.: Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes. Nature 483 (7391): 589-93, 2012. [PUBMED Abstract]
Sausen M, Leary RJ, Jones S, et al.: Integrated genomic analyses identify ARID1A and ARID1B alterations in the childhood cancer neuroblastoma. Nat Genet 45 (1): 12-7, 2013. [PUBMED Abstract]
Bresler SC, Weiser DA, Huwe PJ, et al.: ALK mutations confer differential oncogenic activation and sensitivity to ALK inhibition therapy in neuroblastoma. Cancer Cell 26 (5): 682-94, 2014. [PUBMED Abstract]
Janoueix-Lerosey I, Lequin D, Brugières L, et al.: Somatic and germline activating mutations of the ALK kinase receptor in neuroblastoma. Nature 455 (7215): 967-70, 2008. [PUBMED Abstract]
Bellini A, Pötschger U, Bernard V, et al.: Frequency and Prognostic Impact of ALK Amplifications and Mutations in the European Neuroblastoma Study Group (SIOPEN) High-Risk Neuroblastoma Trial (HR-NBL1). J Clin Oncol 39 (30): 3377-3390, 2021. [PUBMED Abstract]
Oldridge DA, Truong B, Russ D, et al.: Differences in Genomic Profiles and Outcomes Between Thoracic and Adrenal Neuroblastoma. J Natl Cancer Inst 111 (11): 1192-1201, 2019. [PUBMED Abstract]
Eleveld TF, Oldridge DA, Bernard V, et al.: Relapsed neuroblastomas show frequent RAS-MAPK pathway mutations. Nat Genet 47 (8): 864-71, 2015. [PUBMED Abstract]
Schramm A, Köster J, Assenov Y, et al.: Mutational dynamics between primary and relapse neuroblastomas. Nat Genet 47 (8): 872-7, 2015. [PUBMED Abstract]
Padovan-Merhar OM, Raman P, Ostrovnaya I, et al.: Enrichment of Targetable Mutations in the Relapsed Neuroblastoma Genome. PLoS Genet 12 (12): e1006501, 2016. [PUBMED Abstract]
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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]
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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
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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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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]
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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]
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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]
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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]
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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]
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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
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Current Clinical Trials
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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
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]
Cotterill SJ, Pearson AD, Pritchard J, et al.: Late relapse and prognosis for neuroblastoma patients surviving 5 years or more: a report from the European Neuroblastoma Study Group “Survey”. Med Pediatr Oncol 36 (1): 235-8, 2001. [PUBMED Abstract]
Mertens AC, Yasui Y, Neglia JP, et al.: Late mortality experience in five-year survivors of childhood and adolescent cancer: the Childhood Cancer Survivor Study. J Clin Oncol 19 (13): 3163-72, 2001. [PUBMED Abstract]
Morgenstern DA, London WB, Stephens D, et al.: Metastatic neuroblastoma confined to distant lymph nodes (stage 4N) predicts outcome in patients with stage 4 disease: A study from the International Neuroblastoma Risk Group Database. J Clin Oncol 32 (12): 1228-35, 2014. [PUBMED Abstract]
Kushner BH, LaQuaglia MP, Cardenas FI, et al.: Stage 4N neuroblastoma before and during the era of anti-GD2 immunotherapy. Int J Cancer 153 (12): 2019-2031, 2023. [PUBMED Abstract]
Kushner BH, LaQuaglia MP, Bonilla MA, et al.: Highly effective induction therapy for stage 4 neuroblastoma in children over 1 year of age. J Clin Oncol 12 (12): 2607-13, 1994. [PUBMED Abstract]
Park JR, Scott JR, Stewart CF, et al.: Pilot induction regimen incorporating pharmacokinetically guided topotecan for treatment of newly diagnosed high-risk neuroblastoma: a Children’s Oncology Group study. J Clin Oncol 29 (33): 4351-7, 2011. [PUBMED Abstract]
Decarolis B, Schneider C, Hero B, et al.: Iodine-123 metaiodobenzylguanidine scintigraphy scoring allows prediction of outcome in patients with stage 4 neuroblastoma: results of the Cologne interscore comparison study. J Clin Oncol 31 (7): 944-51, 2013. [PUBMED Abstract]
Yanik GA, Parisi MT, Shulkin BL, et al.: Semiquantitative mIBG scoring as a prognostic indicator in patients with stage 4 neuroblastoma: a report from the Children’s oncology group. J Nucl Med 54 (4): 541-8, 2013. [PUBMED Abstract]
Pinto N, Naranjo A, Hibbitts E, et al.: Predictors of differential response to induction therapy in high-risk neuroblastoma: A report from the Children’s Oncology Group (COG). Eur J Cancer 112: 66-79, 2019. [PUBMED Abstract]
Furman WL, McCarville B, Shulkin BL, et al.: Improved Outcome in Children With Newly Diagnosed High-Risk Neuroblastoma Treated With Chemoimmunotherapy: Updated Results of a Phase II Study Using hu14.18K322A. J Clin Oncol 40 (4): 335-344, 2022. [PUBMED Abstract]
Berthold F, Faldum A, Ernst A, et al.: Extended induction chemotherapy does not improve the outcome for high-risk neuroblastoma patients: results of the randomized open-label GPOH trial NB2004-HR. Ann Oncol 31 (3): 422-429, 2020. [PUBMED Abstract]
Garaventa A, Poetschger U, Valteau-Couanet D, et al.: Randomized Trial of Two Induction Therapy Regimens for High-Risk Neuroblastoma: HR-NBL1.5 International Society of Pediatric Oncology European Neuroblastoma Group Study. J Clin Oncol 39 (23): 2552-2563, 2021. [PUBMED Abstract]
De Ioris MA, Crocoli A, Contoli B, et al.: Local control in metastatic neuroblastoma in children over 1 year of age. BMC Cancer 15: 79, 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]
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]
DeCou JM, Bowman LC, Rao BN, et al.: Infants with metastatic neuroblastoma have improved survival with resection of the primary tumor. J Pediatr Surg 30 (7): 937-40; discussion 940-1, 1995. [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]
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]
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]
Seemann NM, Erker C, Irwin MS, et al.: Survival effect of complete surgical resection of the primary tumor in patients with metastatic, high-risk neuroblastoma in a large Canadian cohort. Pediatr Blood Cancer 70 (6): e30286, 2023. [PUBMED Abstract]
Holmes K, Pötschger U, Pearson ADJ, et al.: Influence of Surgical Excision on the Survival of Patients With Stage 4 High-Risk Neuroblastoma: A Report From the HR-NBL1/SIOPEN Study. J Clin Oncol 38 (25): 2902-2915, 2020. [PUBMED Abstract]
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]
Desai AV, Applebaum MA, Karrison TG, et al.: Efficacy of post-induction therapy for high-risk neuroblastoma patients with end-induction residual disease. Cancer 128 (15): 2967-2977, 2022. [PUBMED Abstract]
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]
Hattangadi JA, Rombi B, Yock TI, et al.: Proton radiotherapy for high-risk pediatric neuroblastoma: early outcomes and dose comparison. Int J Radiat Oncol Biol Phys 83 (3): 1015-22, 2012. [PUBMED Abstract]
Yu AL, Gilman AL, Ozkaynak MF, et al.: Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N Engl J Med 363 (14): 1324-34, 2010. [PUBMED Abstract]
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]
Kushner BH, Ostrovnaya I, Cheung IY, et al.: Lack of survival advantage with autologous stem-cell transplantation in high-risk neuroblastoma consolidated by anti-GD2 immunotherapy and isotretinoin. Oncotarget 7 (4): 4155-66, 2016. [PUBMED Abstract]
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]
Venstrom JM, Zheng J, Noor N, et al.: KIR and HLA genotypes are associated with disease progression and survival following autologous hematopoietic stem cell transplantation for high-risk neuroblastoma. Clin Cancer Res 15 (23): 7330-4, 2009. [PUBMED Abstract]
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.
Weiss BD, Yanik G, Naranjo A, et al.: A safety and feasibility trial of 131 I-MIBG in newly diagnosed high-risk neuroblastoma: A Children’s Oncology Group study. Pediatr Blood Cancer 68 (10): e29117, 2021. [PUBMED Abstract]
Sholler GLS, Ferguson W, Bergendahl G, et al.: Maintenance DFMO Increases Survival in High Risk Neuroblastoma. Sci Rep 8 (1): 14445, 2018. [PUBMED Abstract]
Cheung IY, Mauguen A, Modak S, et al.: Effect of Oral β-Glucan on Antibody Response to Ganglioside Vaccine in Patients With High-Risk Neuroblastoma: A Phase 2 Randomized Clinical Trial. JAMA Oncol 9 (2): 242-250, 2023. [PUBMED Abstract]
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.
References
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Schramm A, Köster J, Assenov Y, et al.: Mutational dynamics between primary and relapse neuroblastomas. Nat Genet 47 (8): 872-7, 2015. [PUBMED Abstract]
Parsons DW, Janeway KA, Patton DR, et al.: Actionable Tumor Alterations and Treatment Protocol Enrollment of Pediatric and Young Adult Patients With Refractory Cancers in the National Cancer Institute-Children’s Oncology Group Pediatric MATCH Trial. J Clin Oncol 40 (20): 2224-2234, 2022. [PUBMED Abstract]
London WB, Castel V, Monclair T, et al.: Clinical and biologic features predictive of survival after relapse of neuroblastoma: a report from the International Neuroblastoma Risk Group project. J Clin Oncol 29 (24): 3286-92, 2011. [PUBMED Abstract]
Pole JG, Casper J, Elfenbein G, et al.: High-dose chemoradiotherapy supported by marrow infusions for advanced neuroblastoma: a Pediatric Oncology Group study. J Clin Oncol 9 (1): 152-8, 1991. [PUBMED Abstract]
Castel V, Cañete A, Melero C, et al.: Results of the cooperative protocol (N-III-95) for metastatic relapses and refractory neuroblastoma. Med Pediatr Oncol 35 (6): 724-6, 2000. [PUBMED Abstract]
Lau L, Tai D, Weitzman S, et al.: Factors influencing survival in children with recurrent neuroblastoma. J Pediatr Hematol Oncol 26 (4): 227-32, 2004. [PUBMED Abstract]
Saylors RL, Stine KC, Sullivan J, et al.: Cyclophosphamide plus topotecan in children with recurrent or refractory solid tumors: a Pediatric Oncology Group phase II study. J Clin Oncol 19 (15): 3463-9, 2001. [PUBMED Abstract]
Kramer K, Kushner BH, Modak S, et al.: Compartmental intrathecal radioimmunotherapy: results for treatment for metastatic CNS neuroblastoma. J Neurooncol 97 (3): 409-18, 2010. [PUBMED Abstract]
Vo KT, DuBois SG, Neuhaus J, et al.: Pattern and predictors of sites of relapse in neuroblastoma: A report from the International Neuroblastoma Risk Group (INRG) project. Pediatr Blood Cancer 69 (9): e29616, 2022. [PUBMED Abstract]
Campbell K, Kao PC, Naranjo A, et al.: Clinical and biological features prognostic of survival after relapse or progression of INRGSS stage MS pattern neuroblastoma: A report from the International Neuroblastoma Risk Group (INRG) project. Pediatr Blood Cancer 70 (2): e30054, 2023. [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]
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]
Murphy JM, Lim II, Farber BA, et al.: Salvage rates after progression of high-risk neuroblastoma with a soft tissue mass. J Pediatr Surg 51 (2): 285-8, 2016. [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]
London WB, Bagatell R, Weigel BJ, et al.: Historical time to disease progression and progression-free survival in patients with recurrent/refractory neuroblastoma treated in the modern era on Children’s Oncology Group early-phase trials. Cancer 123 (24): 4914-4923, 2017. [PUBMED Abstract]
Mody R, Naranjo A, Van Ryn C, et al.: Irinotecan-temozolomide with temsirolimus or dinutuximab in children with refractory or relapsed neuroblastoma (COG ANBL1221): an open-label, randomised, phase 2 trial. Lancet Oncol 18 (7): 946-957, 2017. [PUBMED Abstract]
Foster JH, Voss SD, Hall DC, et al.: Activity of Crizotinib in Patients with ALK-Aberrant Relapsed/Refractory Neuroblastoma: A Children’s Oncology Group Study (ADVL0912). Clin Cancer Res 27 (13): 3543-3548, 2021. [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]
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]
Cole KA, Ijaz H, Surrey LF, et al.: Pediatric phase 2 trial of a WEE1 inhibitor, adavosertib (AZD1775), and irinotecan for relapsed neuroblastoma, medulloblastoma, and rhabdomyosarcoma. Cancer 129 (14): 2245-2255, 2023. [PUBMED Abstract]
Moreno L, Weston R, Owens C, et al.: Bevacizumab, Irinotecan, or Topotecan Added to Temozolomide for Children With Relapsed and Refractory Neuroblastoma: Results of the ITCC-SIOPEN BEACON-Neuroblastoma Trial. J Clin Oncol 42 (10): 1135-1145, 2024. [PUBMED Abstract]
Corbacioglu S, Lode H, Ellinger S, et al.: Irinotecan and temozolomide in combination with dasatinib and rapamycin versus irinotecan and temozolomide for patients with relapsed or refractory neuroblastoma (RIST-rNB-2011): a multicentre, open-label, randomised, controlled, phase 2 trial. Lancet Oncol 25 (7): 922-932, 2024. [PUBMED Abstract]
London WB, Frantz CN, Campbell LA, et al.: Phase II randomized comparison of topotecan plus cyclophosphamide versus topotecan alone in children with recurrent or refractory neuroblastoma: a Children’s Oncology Group study. J Clin Oncol 28 (24): 3808-15, 2010. [PUBMED Abstract]
Shusterman S, Naranjo A, Van Ryn C, et al.: Antitumor Activity and Tolerability of hu14.18-IL2 with GMCSF and Isotretinoin in Recurrent or Refractory Neuroblastoma: A Children’s Oncology Group Phase II Study. Clin Cancer Res 25 (20): 6044-6051, 2019. [PUBMED Abstract]
Mody R, Yu AL, Naranjo A, et al.: Irinotecan, Temozolomide, and Dinutuximab With GM-CSF in Children With Refractory or Relapsed Neuroblastoma: A Report From the Children’s Oncology Group. J Clin Oncol 38 (19): 2160-2169, 2020. [PUBMED Abstract]
Lerman BJ, Li Y, Carlowicz C, et al.: Progression-Free Survival and Patterns of Response in Patients With Relapsed High-Risk Neuroblastoma Treated With Irinotecan/Temozolomide/Dinutuximab/Granulocyte-Macrophage Colony-Stimulating Factor. J Clin Oncol 41 (3): 508-516, 2023. [PUBMED Abstract]
Raiser P, Schleiermacher G, Gambart M, et al.: Chemo-immunotherapy with dinutuximab beta in patients with relapsed/progressive high-risk neuroblastoma: does chemotherapy backbone matter? Eur J Cancer 202: 114001, 2024. [PUBMED Abstract]
DuBois SG, Groshen S, Park JR, et al.: Phase I Study of Vorinostat as a Radiation Sensitizer with 131I-Metaiodobenzylguanidine (131I-MIBG) for Patients with Relapsed or Refractory Neuroblastoma. Clin Cancer Res 21 (12): 2715-21, 2015. [PUBMED Abstract]
Polishchuk AL, Dubois SG, Haas-Kogan D, et al.: Response, survival, and toxicity after iodine-131-metaiodobenzylguanidine therapy for neuroblastoma in preadolescents, adolescents, and adults. Cancer 117 (18): 4286-93, 2011. [PUBMED Abstract]
Matthay KK, Yanik G, Messina J, et al.: Phase II study on the effect of disease sites, age, and prior therapy on response to iodine-131-metaiodobenzylguanidine therapy in refractory neuroblastoma. J Clin Oncol 25 (9): 1054-60, 2007. [PUBMED Abstract]
Matthay KK, Tan JC, Villablanca JG, et al.: Phase I dose escalation of iodine-131-metaiodobenzylguanidine with myeloablative chemotherapy and autologous stem-cell transplantation in refractory neuroblastoma: a new approaches to Neuroblastoma Therapy Consortium Study. J Clin Oncol 24 (3): 500-6, 2006. [PUBMED Abstract]
Matthay KK, Quach A, Huberty J, et al.: Iodine-131–metaiodobenzylguanidine double infusion with autologous stem-cell rescue for neuroblastoma: a new approaches to neuroblastoma therapy phase I study. J Clin Oncol 27 (7): 1020-5, 2009. [PUBMED Abstract]
DuBois SG, Chesler L, Groshen S, et al.: Phase I study of vincristine, irinotecan, and ¹³¹I-metaiodobenzylguanidine for patients with relapsed or refractory neuroblastoma: a new approaches to neuroblastoma therapy trial. Clin Cancer Res 18 (9): 2679-86, 2012. [PUBMED Abstract]
Johnson K, McGlynn B, Saggio J, et al.: Safety and efficacy of tandem 131I-metaiodobenzylguanidine infusions in relapsed/refractory neuroblastoma. Pediatr Blood Cancer 57 (7): 1124-9, 2011. [PUBMED Abstract]
French S, DuBois SG, Horn B, et al.: 131I-MIBG followed by consolidation with busulfan, melphalan and autologous stem cell transplantation for refractory neuroblastoma. Pediatr Blood Cancer 60 (5): 879-84, 2013. [PUBMED Abstract]
Zhou MJ, Doral MY, DuBois SG, et al.: Different outcomes for relapsed versus refractory neuroblastoma after therapy with (131)I-metaiodobenzylguanidine ((131)I-MIBG). Eur J Cancer 51 (16): 2465-72, 2015. [PUBMED Abstract]
Yanik GA, Villablanca JG, Maris JM, et al.: 131I-metaiodobenzylguanidine with intensive chemotherapy and autologous stem cell transplantation for high-risk neuroblastoma. A new approaches to neuroblastoma therapy (NANT) phase II study. Biol Blood Marrow Transplant 21 (4): 673-81, 2015. [PUBMED Abstract]
DuBois SG, Granger MM, Groshen S, et al.: Randomized Phase II Trial of MIBG Versus MIBG, Vincristine, and Irinotecan Versus MIBG and Vorinostat for Patients With Relapsed or Refractory Neuroblastoma: A Report From NANT Consortium. J Clin Oncol 39 (31): 3506-3514, 2021. [PUBMED Abstract]
Sevrin F, Kolesnikov-Gauthier H, Cougnenc O, et al.: Phase II study of 131 I-metaiodobenzylguanidine with 5 days of topotecan for refractory or relapsed neuroblastoma: Results of the French study MIITOP. Pediatr Blood Cancer 70 (11): e30615, 2023. [PUBMED Abstract]
Westerveld ASR, Tytgat GAM, van Santen HM, et al.: Long-Term Risk of Subsequent Neoplasms in 5-Year Survivors of Childhood Neuroblastoma: A Dutch Childhood Cancer Survivor Study-LATER 3 Study. J Clin Oncol 43 (2): 154-166, 2025. [PUBMED Abstract]
Bagatell R, London WB, Wagner LM, et al.: Phase II study of irinotecan and temozolomide in children with relapsed or refractory neuroblastoma: a Children’s Oncology Group study. J Clin Oncol 29 (2): 208-13, 2011. [PUBMED Abstract]
Kushner BH, Modak S, Kramer K, et al.: Ifosfamide, carboplatin, and etoposide for neuroblastoma: a high-dose salvage regimen and review of the literature. Cancer 119 (3): 665-71, 2013. [PUBMED Abstract]
Kushner BH, Kramer K, Modak S, et al.: Differential impact of high-dose cyclophosphamide, topotecan, and vincristine in clinical subsets of patients with chemoresistant neuroblastoma. Cancer 116 (12): 3054-60, 2010. [PUBMED Abstract]
Lode HN, Ehlert K, Huber S, et al.: Long-term, continuous infusion of single-agent dinutuximab beta for relapsed/refractory neuroblastoma: an open-label, single-arm, Phase 2 study. Br J Cancer 129 (11): 1780-1786, 2023. [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]
Prete A, Lanino E, Saglio F, et al.: Phase II Study of Allogeneic Hematopoietic Stem Cell Transplantation for Children with High-Risk Neuroblastoma Using a Reduced-Intensity Conditioning Regimen: Results from the AIEOP Trial. Transplant Cell Ther 30 (5): 530.e1-530.e8, 2024. [PUBMED Abstract]
Flaadt T, Ladenstein RL, Ebinger M, et al.: Anti-GD2 Antibody Dinutuximab Beta and Low-Dose Interleukin 2 After Haploidentical Stem-Cell Transplantation in Patients With Relapsed Neuroblastoma: A Multicenter, Phase I/II Trial. J Clin Oncol 41 (17): 3135-3148, 2023. [PUBMED Abstract]
Kushner BH, Cheung IY, Modak S, et al.: Phase I trial of a bivalent gangliosides vaccine in combination with β-glucan for high-risk neuroblastoma in second or later remission. Clin Cancer Res 20 (5): 1375-82, 2014. [PUBMED Abstract]
Kushner BH, Ostrovnaya I, Cheung IY, et al.: Prolonged progression-free survival after consolidating second or later remissions of neuroblastoma with Anti-GD2 immunotherapy and isotretinoin: a prospective Phase II study. Oncoimmunology 4 (7): e1016704, 2015. [PUBMED Abstract]
Del Bufalo F, De Angelis B, Caruana I, et al.: GD2-CART01 for Relapsed or Refractory High-Risk Neuroblastoma. N Engl J Med 388 (14): 1284-1295, 2023. [PUBMED Abstract]
Berlanga P, Pasqualini C, Pötschger U, et al.: Central nervous system relapse in high-risk stage 4 neuroblastoma: The HR-NBL1/SIOPEN trial experience. Eur J Cancer 144: 1-8, 2021. [PUBMED Abstract]
Kramer K, Kushner B, Heller G, et al.: Neuroblastoma metastatic to the central nervous system. The Memorial Sloan-kettering Cancer Center Experience and A Literature Review. Cancer 91 (8): 1510-9, 2001. [PUBMED Abstract]
Matthay KK, Brisse H, Couanet D, et al.: Central nervous system metastases in neuroblastoma: radiologic, clinical, and biologic features in 23 patients. Cancer 98 (1): 155-65, 2003. [PUBMED Abstract]
Luo LY, Kramer K, Cheung NV, et al.: Reduced-dose craniospinal irradiation for central nervous system relapsed neuroblastoma. Pediatr Blood Cancer 67 (9): e28364, 2020. [PUBMED Abstract]
Tringale KR, Wolden SL, Casey DL, et al.: Clinical outcomes of pediatric patients receiving multimodality treatment of second central nervous system relapse of neuroblastoma. Pediatr Blood Cancer 70 (2): e30075, 2023. [PUBMED Abstract]
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.
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About This PDQ Summary
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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.
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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)
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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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Neuroblastoma is a cancer of immature nerve cells that most often occurs in young children. It usually begins in the adrenal glands but can form in the neck, chest, abdomen, and spine. Explore the links on this page to learn more about neuroblastoma treatment, research, and clinical trials.
Langerhans cell histiocytosis is a rare disorder that can damage tissue or cause lesions to form in one or more places in the body.
It is not known whether LCH is a form of cancer or a cancer-like disease.
Family history of cancer or having a parent who was exposed to certain chemicals may increase the risk of LCH.
The signs and symptoms of LCH depend on where it is in the body.
Bone
Skin and nails
Mouth
Lymph nodes and thymus
Endocrine system
Eye
Central nervous system (CNS)
Liver and spleen
Lung
Bone marrow
Tests that examine the organs and body systems where LCH may occur are used to diagnose LCH.
Certain factors affect prognosis (chance of recovery) and treatment options.
Langerhans cell histiocytosis is a rare disorder that can damage tissue or cause lesions to form in one or more places in the body.
Langerhans cell histiocytosis (LCH) is a rare disease that begins in LCH cells. LCH cells are a type of dendritic cell that normally helps the body fight infection. Sometimes mutations (changes) develop in genes that control how dendritic cells function. These include mutations of the BRAF, MAP2K1, RAS, and ARAF genes. These mutations may cause too many LCH cells to grow and build up in certain parts of the body, where they can damage tissue or form lesions.
It is not known whether LCH is a form of cancer or a cancer-like disease.
Family history of cancer or having a parent who was exposed to certain chemicals may increase the risk of LCH.
Anything that increases a person’s risk of getting a disease is called a risk factor. Not every child with one or more of these risk factors will develop LCH, and it will develop in some children who don’t have any known risk factors. Talk with your doctor if you think you may be at risk.
Risk factors for LCH may include the following:
Having a parent who was exposed to certain solvents.
Having a parent who was exposed to metal, granite, or wood dust in the workplace.
The signs and symptoms of LCH depend on where it is in the body.
These and other signs and symptoms may be caused by LCH or by other conditions. Check with your doctor if you or your child have any of the following:
Bone
Signs or symptoms of LCH that affects the bone may include:
Swelling or a lump over a bone, such as the skull, jawbone, ribs, pelvis, spine, thigh bone, upper arm bone, elbow, eye socket, or bones around the ear.
Pain where there is swelling or a lump over a bone.
LCH in infants may affect the skin only. In some cases, skin-only LCH may get worse over weeks or months and become a form called high-risk multisystem LCH.
In infants, signs or symptoms of LCH that affects the skin may include:
Flaking of the scalp that may look like “cradle cap.”
Flaking in the creases of the body, such as the inner elbow or perineum.
Raised skin rash with brown or purple areas that occur anywhere on the body.
In children and adults, signs or symptoms of LCH that affects the skin and nails may include:
Flaking of the scalp that may look like dandruff.
Raised skin rash with red, brown, or crusted areas that may be itchy or painful. The rash can occur in the groin area or on the abdomen, back, or chest.
Signs or symptoms of LCH that affects the thyroid may include:
Swollen thyroid gland.
Hypothyroidism. This can cause tiredness, lack of energy, being sensitive to cold, constipation, dry skin, thinning hair, memory problems, trouble concentrating, and depression. In infants, this can also cause a loss of appetite and choking on food. In children and adolescents, this can cause behavior problems, weight gain, slow growth, and late puberty.
Trouble breathing.
Eye
Signs or symptoms of LCH that affects the eye may include:
Vision problems or blindness.
Central nervous system (CNS)
Signs or symptoms of LCH that affects the CNS (brain and spinal cord) may include:
Loss of balance, uncoordinated body movements, and trouble walking.
Tests that examine the organs and body systems where LCH may occur are used to diagnose LCH.
In addition to asking about your health history and doing a physical exam, your doctor may perform the following tests and procedures to diagnose LCH or conditions caused by LCH:
Blood chemistry studies: A procedure in which a blood sample is checked to measure the amounts of certain substances released into the body by organs and tissues in the body. An unusual (higher or lower than normal) amount of a substance can be a sign of disease.
Liver function test: A blood test to measure the blood levels of certain substances released by the liver. A high or low level of these substances can be a sign of disease in the liver.
BRAFgene testing: A laboratory test in which a sample of blood or tissue is tested for certain mutations in the BRAF gene.
Urinalysis: A test to check the color of urine and its contents, such as sugar, protein, red blood cells, and white blood cells.
Water deprivation test: A test to check how much urine is made and whether it becomes concentrated when little or no water is given. This test is used to diagnose diabetes insipidus, which may be caused by LCH.
Bone marrow aspiration and biopsy: The removal of bone marrow and a small piece of bone by inserting a hollow needle into the hipbone. A pathologist views the bone marrow and bone under a microscope to look for signs of LCH. EnlargeBone marrow aspiration and biopsy. After a small area of skin is numbed, a long, hollow needle is inserted through the patient’s skin and hip bone into the bone marrow. A sample of bone marrow and a small piece of bone are removed for examination under a microscope.
The following test may be done on the tissue that was removed:
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.
Bone scan: A procedure to check if there are rapidly dividing cells in the bone. A very small amount of radioactive material is injected into a vein and travels through the bloodstream. The radioactive material collects in the bones with LCH and is detected by a scanner. EnlargeBone scan. A small amount of radioactive material is injected into the child’s vein and travels through the blood. The radioactive material collects in the bones. As the child lies on a table that slides under the scanner, the radioactive material is detected and images are made on a computer screen.
X-ray: An x-ray of the organs and bones inside the body. 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. Sometimes a skeletal survey is done. This is a procedure to x-ray all the bones in the body.
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. EnlargeComputed tomography (CT) scan of the abdomen. The patient lies on a table that slides through the CT machine, which takes x-ray pictures of the inside of the body.
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. A substance called gadolinium may be injected into a vein. The gadolinium collects around the LCH cells so that 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 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. Tumor cells show up brighter in the picture because they are more active and take up more glucose than normal cells do. EnlargePositron emission tomography (PET) scan. The child lies on a table that slides through the PET scanner. The head rest and white strap help the child lie still. A small amount of radioactive glucose (sugar) is injected into the child’s vein, and a scanner makes a picture of where the glucose is being used in the body. Cancer cells show up brighter in the picture because they take up more glucose than normal cells do.
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. The picture can be printed to be looked at later. EnlargeAbdominal ultrasound. An ultrasound transducer connected to a computer is passed over the surface of the abdomen. The ultrasound transducer bounces sound waves off internal organs and tissues to make echoes that form a sonogram (computer picture).
Pulmonary function test (PFT): A test to see how well the lungs are working. It measures how much air the lungs can hold and how quickly air moves into and out of the lungs. It also measures how much oxygen is used and how much carbon dioxide is given off during breathing. This is also called lung function test.
Bronchoscopy: A procedure to look inside the trachea and large airways in the lung for abnormal areas. A bronchoscope is inserted through the nose or mouth into the trachea and lungs. A bronchoscope is a thin, tube-like instrument with a light and a lens for viewing. It may also have a tool to remove tissue samples, which are checked under a microscope for signs of LCH.
Endoscopy: A procedure to look at organs and tissues inside the body to check for abnormal areas in the gastrointestinal tract or lungs. An endoscope is inserted through an incision (cut) in the skin or opening in the body, such as the mouth. An endoscope is a thin, tube-like instrument with a light and a lens for viewing. It may also have a tool to remove tissue or lymph node samples, which are checked under a microscope for signs of disease.
Biopsy: The removal of cells or tissues so they can be viewed under a microscope by a pathologist to check for LCH cells. To diagnose LCH, a biopsy of bone, skin, lymph nodes, liver, or other sites of disease may be done.
Certain factors affect prognosis (chance of recovery) and treatment options.
LCH in organs such as the skin, bones, lymph nodes, or pituitary gland usually gets better with treatment and is called “low-risk.” LCH in the spleen, liver, or bone marrow is harder to treat and is called “high-risk.” Children with LCH in high-risk organs and the gastrointestinal tract have a greater risk of not responding to treatment than patients with high-risk LCH and no disease in the gastrointestinal tract. High-risk LCH is usually seen in children younger than 2 years.
The prognosis and treatment options depend on the following:
Which organs or body systems are affected by LCH.
How many organs or body systems the LCH affects.
Whether LCH is found in the liver, spleen, bone marrow, or certain bones in the skull.
How quickly LCH responds to initial treatment.
Whether there are certain mutations in the BRAF gene.
Whether LCH has just been diagnosed or has come back (recurred).
In infants up to 1 year of age, LCH may go away without treatment.
Stages of LCH
Key Points
There is no standard staging system for Langerhans cell histiocytosis (LCH).
Treatment of LCH is based on where LCH cells are found in the body and whether the LCH is low risk or high risk.
Sometimes LCH continues to grow or comes back after treatment.
There is no standard staging system for Langerhans cell histiocytosis (LCH).
The process used to find out if cancer has spread to other parts of the body is called staging. There is no standard staging system for LCH.
Treatment of LCH is based on where LCH cells are found in the body and whether the LCH is low risk or high risk.
LCH is described as single-system disease or multisystem disease, depending on how many body systems are affected:
Single-system LCH: LCH is found in one part of an organ or body system or in more than one part of that organ or body system. Bone is the most common single place for LCH to be found.
Multisystem LCH: LCH is found in two or more organs or body systems or may be found throughout the body. Multisystem LCH is less common than single-system LCH.
LCH may affect low-risk organs or high-risk organs:
Sometimes LCH continues to grow or comes back after treatment.
Progressive LCH describes LCH that continues to grow, spread, or get worse. Progressive disease may be a sign that the LCH has become refractory to treatment.
Refractory LCH describes LCH that does not respond to initial treatment.
Recurrent or reactivated LCH describes LCH that has come back after it has been treated.
Many patients with LCH get better with treatment. However, when treatment stops, new lesions may appear or old lesions may come back. This is called reactivation (recurrence) and may occur within 1 year after stopping treatment. Patients with multisystem disease are more likely to have a reactivation. Common sites of reactivation are bone, ears, or skin. Diabetes insipidus also may develop. Less common sites of reactivation include lymph nodes, bone marrow, spleen, liver, or lung. Some patients may have more than one reactivation.
Treatment Option Overview for LCH
Key Points
There are different types of treatment for patients with Langerhans cell histiocytosis (LCH).
Children with LCH should have their treatment planned by a team of health care providers who are experts in treating childhood cancer or LCH.
Nine types of standard treatment are used to treat LCH.
Chemotherapy
Surgery
Radiation therapy
Photodynamic therapy
Immunotherapy
Targeted therapy
Other drug therapy
Stem cell transplant
Observation
New types of treatment are being tested in clinical trials.
Treatment for Langerhans cell histiocytosis may cause side effects.
Patients may want to think about taking part in a clinical trial.
Patients can enter clinical trials before, during, or after starting their treatment.
Follow-up tests may be needed.
There are different types of treatment for patients with Langerhans cell histiocytosis (LCH).
Different types of treatments are available for patients with LCH. 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. Whenever possible, patients should take part in a clinical trial in order to receive new types of treatment for LCH. Some clinical trials are open only to patients who have not started treatment.
Clinical trials are taking place in many parts of the country. Information about ongoing clinical trials is available from the NCI website. Choosing the most appropriate treatment is a decision that ideally involves the patient, family, and health care team.
Children with LCH should have their treatment planned by a team of health care providers who are experts in treating childhood cancer or LCH.
Treatment will be overseen by a pediatric oncologist, a doctor who specializes in treating children with cancer. The pediatric oncologist works with other pediatrichealth care providers who are experts in treating children with LCH and who specialize in certain areas of medicine. These may include the following specialists:
Nine types of standard treatment are used to treat LCH.
Although it is unknown whether LCH is a type of cancer, some of the treatments used for cancer are effective at treating LCH.
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. Chemotherapy that is taken by mouth or injected into a vein or muscle enters the bloodstream and can reach cancer cells throughout the body (systemic chemotherapy). Chemotherapy may also be applied to the skin in a cream or lotion (topical chemotherapy).
Chemotherapy may be given by injection, by mouth, or applied to the skin to treat LCH.
Surgery
Surgery may be used to remove LCH lesions and a small amount of nearby healthy tissue. Curettage is a type of surgery that uses a curette (a sharp, spoon-shaped tool) to scrape LCH cells from bone.
When there is severe liver or lung damage, the entire organ may be removed and replaced with a healthy liver or lung from a donor.
Radiation therapy
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. External radiation therapy uses a machine outside the body to send radiation toward the area of the body with cancer. Ultraviolet B (UVB) radiation therapy may be given using a special lamp that directs radiation toward LCH skin lesions.
Photodynamic therapy
Photodynamic therapy is a cancer treatment that uses a drug and a certain type of laser light to kill cancer cells. A drug that is not active until it is exposed to light is injected into a vein. The drug collects more in cancer cells than in normal cells. For LCH, laser light is aimed at the skin and the drug becomes active and kills the cancer cells. Photodynamic therapy causes little damage to healthy tissue. Patients who have photodynamic therapy should not spend too much time in the sun.
Immunotherapy is a treatment that uses the patient’s immune system to fight cancer. Substances made by the body or made in a laboratory are used to boost, direct, or restore the body’s natural defenses against cancer. Thalidomide is a type of immunotherapy used to treat LCH.
Targeted therapy
Targeted therapy is a type of treatment that uses drugs or other substances to identify and attack specific cancer cells. There are different types of targeted therapy:
BRAF inhibitors block proteins needed for cell growth and may kill cancer cells. The BRAFgene is found in a mutated (changed) form in some LCH and blocking it may help keep LCH cells from growing.
MEK inhibitors block proteins called MEK1 and MEK2 that affect the growth and survival of cancer cells.
Trametinib is a MEK inhibitor that is being studied in the treatment of certain childhood tumors for use alone or combined with dabrafenib.
Monoclonal antibodies are immune systemproteins 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.
Rituximab is a monoclonal antibody used to treat LCH.
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.
Other drug therapy
Other drugs used to treat LCH include the following:
Anti-inflammatory drugs are drugs (such as pioglitazone and rofecoxib) that are commonly used to decrease fever, swelling, pain, and redness. Anti-inflammatory drugs and chemotherapy may be given together to treat adults with bone LCH.
Stem cell transplant
Chemotherapy is given to kill cancer cells. Healthy cells, including blood-forming cells, are destroyed by the LCH treatment. Stem cell transplant 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 or a donor and are frozen and stored. After the patient completes chemotherapy, the stored stem cells are thawed and given back to the patient through an infusion. These stem cells grow into (and restore) the body’s blood cells.
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 the following:
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. For more information, see Late Effects of Treatment for Childhood Cancer.
Many patients with multisystem LCH have late effects caused by treatment or by the disease itself. These patients often have long-term health problems that affect their quality of life.
Patients may want to think about taking part in a clinical trial.
For some patients, taking part in a clinical trial may be the best treatment choice. Clinical trials are part of the cancer research process. Clinical trials are done to find out if new cancer treatments are safe and effective or better than the standard treatment.
Many of today’s standard treatments for cancer are based on earlier clinical trials. Patients who take part in a clinical trial may receive the standard treatment or be among the first to receive a new treatment.
Patients who take part in clinical trials also help improve the way cancer will be treated in the future. Even when clinical trials do not lead to effective new treatments, they often answer important questions and help move research forward.
Patients can enter clinical trials before, during, or after starting their treatment.
Some clinical trials only include patients who have not yet received treatment. Other trials test treatments for patients whose cancer has not gotten better. There are also clinical trials that test new ways to stop cancer from recurring (coming back) or reduce the side effects of cancer treatment.
Clinical trials are taking place in many parts of the country. Information about clinical trials supported by NCI can be found on NCI’s clinical trials search webpage. Clinical trials supported by other organizations can be found on the ClinicalTrials.gov website.
Follow-up tests may be needed.
LCH patients should be monitored for many years because of the risk of reactivation (recurrence). Some of the tests that were done to diagnose LCH may be repeated. This is to see how well the treatment is working and if there are any new lesions. These tests may include:
Pulmonary function test (PFT): A test to see how well the lungs are working. It measures how much air the lungs can hold and how quickly air moves into and out of the lungs. It also measures how much oxygen is used and how much carbon dioxide is given off during breathing. This is also called a lung function test.
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.
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 or check-ups. Decisions about whether to continue, change, or stop treatment may be based on the results of these tests.
Treatment of newly diagnosed childhood LCH lesions in bones around the ears or eyes is done to lower the risk of diabetes insipidus and other long-term problems. Treatment may include:
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.
As in children, the signs and symptoms of LCH depend on where it is found in the body. See the General Information section for the signs and symptoms of LCH.
Tests that examine the organs and body systems where LCH may occur are used to detect (find) and diagnose LCH. See the General Information section for tests and procedures used to diagnose LCH.
In adults, there is not a lot of information about what treatment works best. Sometimes, information comes only from reports of the diagnosis, treatment, and follow-up of one adult or a small group of adults who were given the same type of treatment.
Adult patients with LCH have higher rates of other cancers than do adults of the same age without LCH. These cancers may be found before, at the same time, or after an LCH diagnosis, and occur more in patients who smoke.
Treatment for LCH of the lung in adults may include:
Quitting smoking. Lung damage will get worse over time in patients who do not quit smoking. In patients who quit smoking, lung damage may get better or it may get worse over time.
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.
To Learn More About Langerhans Cell Histiocytosis
For more from the National Cancer Institute about Langerhans cell histiocytosis treatment, see the following:
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 childhood and adult Langerhans cell histiocytosis. 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).
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PDQ® Pediatric Treatment Editorial Board. PDQ Langerhans Cell Histiocytosis Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/langerhans/patient/langerhans-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389196]
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Histiocytic diseases in children and adults are caused by an abnormal accumulation of cells of the mononuclear phagocytic system. This summary discusses only Langerhans cell histiocytosis (LCH), a myeloid-derived dendritic cell disorder.
Histiocytic diseases have been reclassified into five categories, with LCH in the L group (see Table 1).[1,2] LCH results from the clonal proliferation of immunophenotypically and functionally immature, morphologically rounded LCH cells found in relevant lesions, along with eosinophils, macrophages, lymphocytes, and, occasionally, multinucleated giant cells.[3,4] The pathological histiocytes and normal Langerhans cells of the epidermis (LCs) have identical immunophenotypic characteristics, including the presence of Birbeck granules identified by electron microscopy. There are clear morphological, phenotypic, and gene expression differences between the pathological variant of the LCH lesions (LCH cells) and the normal LCs, hence the term LCH cells.
bReprinted from Blood, Volume 135, Issue 16, Carlos Rodriguez-Galindo, Carl E. Allen, Langerhans cell histiocytosis, Pages 1319–1331, Copyright 2020, with permission from Elsevier.[1]
Primary HLH: Monogenic inherited conditions leading to HLH
Secondary HLH (non-Mendelian HLH)
HLH of unknown/uncertain origin
LCH cells, known for many years to be a clonal proliferation, have now been shown to likely derive from a myeloid precursor whose proliferation is uniformly associated with activation of the MAPK/ERK signaling pathway.[5,6]
Clinically, LCH is a heterogenous disease that may involve a single organ (single-system LCH), which may be a single site (unifocal) or involve multiple sites (multifocal). It may also involve multiple organs (multisystem LCH). Multisystem LCH may involve a limited number of organs or be disseminated. Involvement of specific organs such as the liver, spleen, and hematopoietic system separates multisystem LCH into high-risk (multisystem risk-organ positive) and low-risk (multisystem risk-organ negative) groups, where risk indicates the risk of death from the disease.
Emile JF, Abla O, Fraitag S, et al.: Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages. Blood 127 (22): 2672-81, 2016. [PUBMED Abstract]
Berres ML, Lim KP, Peters T, et al.: BRAF-V600E expression in precursor versus differentiated dendritic cells defines clinically distinct LCH risk groups. J Exp Med 211 (4): 669-83, 2014. [PUBMED Abstract]
Allen CE, Merad M, McClain KL: Langerhans-Cell Histiocytosis. N Engl J Med 379 (9): 856-868, 2018. [PUBMED Abstract]
Willman CL, Busque L, Griffith BB, et al.: Langerhans’-cell histiocytosis (histiocytosis X)–a clonal proliferative disease. N Engl J Med 331 (3): 154-60, 1994. [PUBMED Abstract]
Yu RC, Chu C, Buluwela L, et al.: Clonal proliferation of Langerhans cells in Langerhans cell histiocytosis. Lancet 343 (8900): 767-8, 1994. [PUBMED Abstract]
Histopathological, Immunologic, and Cytogenetic Characteristics of LCH
Cell of Origin and Biological Correlates
The pathological histiocyte or Langerhans cell histiocytosis (LCH) cell has a gene expression profile closely resembling that of a myeloid dendritic cell. Studies have also demonstrated that the BRAF V600E variant can be identified in mononuclear cells in peripheral blood and cell-free DNA, usually in patients with disseminated disease.[1–3] This suggests that multisystem LCH arises from a somatic variant within the marrow or a circulating precursor cell, while localized disease arises from a variant occurring in a precursor cell at the local site.[2]
Modern classification of the histiocytic diseases subdivides them into dendritic cell–related, monocyte/macrophage-related, or true malignancies. LCH is a dendritic cell disease.[4,5] Comprehensive data analysis on gene expression array of LCH cells is consistent with the concept that the skin Langerhans cell (LC) is not the cell of origin for LCH.[1] Rather, the origin is likely to be a hematopoietic progenitor cell before being a committed myeloid dendritic cell, which expresses the same antigens (CD1a and CD207) as the skin LC.[6,7] This concept was further supported by reports that the transcription profile of LCH cells was distinct from myeloid and plasmacytoid dendritic cells, as well as epidermal LCs.[1,6,8,9]
LCH is now considered a myeloid neoplasm. However, some controversy remains as to whether it is a true malignancy or a neoplasm with varying clinical behavior. The same BRAF V600E variant has been found in many cancers; however, V600E-altered BRAF is also present in benign nevi, possibly indicating that malignant transformation requires additional variants.[10] These findings have raised the possibility of treatment with targeted therapies. Several trials of BRAF and MEK inhibitors are open for adults and children with LCH.
The Langerhans histiocytosis cells in LCH lesions (LCH cells) are immature dendritic cells, making up fewer than 10% of the cells present in the lesion.[9,11] These cells are classically large oval cells with abundant pink cytoplasm and a bean-shaped nucleus on hematoxylin and eosin stain. LCH cells stain positively with antibodies to S100, CD1a, and/or anti-Langerin (CD207). Staining with CD1a or Langerin confirms the diagnosis of LCH, but care should be taken to correlate with clinical presentation in organs in which normal LC cells occur.[12]
Because LCH cells activate other immunologic cells, LCH lesions also contain other histiocytes, lymphocytes, macrophages, neutrophils, eosinophils, and fibroblasts, and they may contain multinucleated giant cells.
In the brain, the following three types of histopathological findings have been described in LCH:
Mass lesions in the meninges or choroid plexus with CD1a-positive LCH cells and predominantly CD8-positive lymphocytes.
Mass lesions in connective tissue spaces with CD1a-positive LCH cells and predominantly CD8-positive lymphocytes that cause an inflammatory response and neuronal loss.
Neurodegenerative lesions, consisting of cells staining for the altered BRAF protein with positive CD14, CD33, and CD163, identifying these as hematopoietic myeloid/monocytic cells. These are the pathological LCs that have migrated into the brain and do not stain with CD1a or CD207 and have become microglia-like.[13]
Immunologic Abnormalities
Normally, the LC is a primary presenter of antigen to naïve T lymphocytes. However, in LCH, the pathological dendritic cell does not efficiently stimulate primary T-lymphocyte responses.[14] Antibody staining for the dendritic cell markers, including CD80, CD86, and class II antigens, has shown that in LCH, the abnormal cells are immature dendritic cells. These cells present antigen poorly and are proliferating at a low rate.[11,14,15]
An expansion of regulatory T cells in patients with LCH has been reported.[15] The population of CD4-positive, CD25(high), FoxP3(high) cells was reported to comprise 20% of T cells and appeared to be in contact with LCH cells in the lesions. These T cells were present in peripheral blood in higher numbers in patients with LCH than in controls and returned to a normal level when patients were in remission.[15] Poorly functioning T cells expressing inhibitor receptors PD-1, TIM3, and LAG-3 have been found in LCH lesions but not in the peripheral blood of patients.[16] The dysfunctional T cells accumulate in LCH lesions, because PD-1 on the cell surface engages with the PD-L1 on the pathological dendritic cells.
Cytogenetic and Genomic Studies
Genomics of LCH
BRAF, NRAS, and ARAF variants
The genomic basis of LCH was advanced by a 2010 report of an activating variant of the BRAF oncogene (V600E) that was detected in 35 of 61 cases (57%).[17] Multiple subsequent reports have confirmed the presence of BRAF V600E variants in 50% or more of LCH cases in children.[2,18,19] Other BRAF variants that result in signal activation have been described.[18,20] ARAF variants are infrequent in LCH but, when present, can also lead to RAS-MAPK pathway activation.[21]
The presence of the BRAF V600E variant in blood and bone marrow was studied in a series of 100 patients, 65% of whom tested positive for the BRAF V600E variant by a sensitive quantitative polymerase chain reaction technique.[2] Circulating cells with the BRAF V600E variant could be detected in all high-risk patients and in a subset of low-risk multisystem patients. The BRAF V600E allele was detected in circulating cell-free DNA in 100% of patients with risk-organ–positive multisystem LCH, 42% of patients with risk-organ–negative LCH, and 14% of patients with single-system LCH.[22]
The myeloid dendritic cell origin of LCH was confirmed by finding CD34-positive stem cells with the variant in the bone marrow of high-risk patients. In those with low-risk disease, the variant was found in more mature myeloid dendritic cells, suggesting that the stage of cell development at which the somatic variant occurs is critical in defining the extent of disease in LCH.
Pulmonary LCH in adults was initially reported to be nonclonal in approximately 75% of cases,[23] while a later study of BRAF variants showed that 25% to 50% of adult patients with lung LCH had evidence of BRAF V600E variants.[23,24] Another study of 26 pulmonary LCH cases found that 50% had BRAF V600E variants and 40% had NRAS variants.[25] Approximately the same number of variants are polyclonal as are monoclonal. It has not been determined whether clonality and BRAF pathway variants are concordant in the same patients, which might suggest a reactive rather than a neoplastic condition in smoker’s lung LCH and a clonal neoplasm in other types of LCH.
In a study of 117 patients with LCH, 83 adult patients with pulmonary LCH underwent molecular analysis. Nearly 90% of these patients had variants in the MAPK pathway.[26][Level of evidence C3] Of the 69 patients who had their biopsy samples further analyzed using a next-generation sequencing panel of 74 genes, 36% had BRAF V600E variants, 29% had BRAF N486-P490 deletions, 15% had MAP2K1 variants or deletions, and 4% had NRAS variants. Only one patient had a KRAS variant. Additionally, 11 patients had their biopsy samples analyzed using whole-exome sequencing. An average of 14 variants were found per patient, which is markedly higher than the average of one variant found per pediatric patient.[27] There were no clinical correlates, including presence of a BRAF V600E variant and smoking status. Of the 117 patients with LCH, 60% experienced a relapse.
EnlargeFigure 1. Courtesy of Rikhia Chakraborty, Ph.D. Permission to reuse the figure in any form must be obtained directly from Dr. Chakraborty.
The RAS-MAPK signaling pathway (see Figure 1) transmits signals from a cell surface receptor (e.g., a growth factor) through the RAS pathway (via one of the RAF proteins [A, B, or C]) to phosphorylate MEK and then the extracellular signal-regulated kinase (ERK), which leads to nuclear signals affecting cell cycle and transcription regulation. The V600E variant of BRAF leads to continuous phosphorylation, and thus activation, of MEK and ERK without the need for an external signal. Activation of ERK occurs by phosphorylation, and phosphorylated ERK can be detected in virtually all LCH lesions.[17,28]
In a mouse model of LCH, the BRAF V600E variant was shown to inhibit a chemokine receptor (CCR7)–mediated migration of dendritic cells, forcing them to accumulate in the LCH lesion.[29] This variant also causes an increased expression of BCL2L1, which results in resistance to apoptosis. This process leads to the cells being less responsive to chemotherapy. The BRAF V600E variant also causes growth arrest of hematopoietic progenitor cells and a senescence-associated secretory phenotype that further promotes accumulation of the pathological cells.[30]
Another mouse model with the BRAF V600E variant under control of Scl or Map17 gene promoters added additional insights into the biology of neurodegenerative LCH.[31] These studies confirmed the hematopoietic origin of CD11a-positive macrophages with BRAF V600E variants. This process disrupts the blood-brain barrier and causes loss of Purkinje cells and progressive neurodegeneration by resistance to apoptosis and production of senescent associated secretory proteins, which include inflammatory cytokines IL-1, IL-6, and matrix metalloproteinases. Treatment with a MAP kinase inhibitor and a senolytic agent (navitoclax) decreased the pathogenic cell numbers and led to clinical improvement in the mice.
In summary, LCH is now considered a myeloid neoplasm primarily driven by activating variants of the MAPK pathway. Fifty percent to 60% of the activating variants are caused by BRAF V600E variants, which are enriched in patients with multisystem risk organ–positive LCH and in patients with neurodegenerative-disease LCH.[32] Ongoing studies are assessing whether low-level variant detection in peripheral blood can be used as a minimal residual disease marker to assist in therapeutic decisions.
Other RAS-MAPK pathway alterations
Because RAS-MAPK pathway activation (elevated phosphor-ERK) can be detected in all LCH cases, including those without BRAF variants, the presence of genomic alterations in other components of the pathway was suspected. The following genomic alterations were identified:
MAP2K1 variants. Whole-exome sequencing on biopsy samples of BRAF-altered versus BRAF–wild-type LCH tissue revealed that 7 of 21 BRAF–wild-type specimens had MAP2K1 variants, while no BRAF-altered specimens had MAP2K1 variants.[28] The variants in MAP2K1 (which codes for MEK1) were activating, as indicated by their induction of ERK phosphorylation.[28]
Another study showed MAP2K1 variants exclusively in 11 of 22 BRAF–wild-type cases.[33] One study showed that MAP2K1 and other variants associated with pediatric and adult LCH were mutually exclusive of BRAF variants.[34] The authors found a variety of variants in other pathways (e.g., JNK, RAS-ERK, and JAK-STAT) in pediatric and adult patients with BRAF V600E or MAP2K1 variants. Another study evaluated the kinase alterations and myeloid-associated variants in 73 adult patients with LCH.[35] They reported a median of two variants per adult patient, as opposed to children who usually have only one variant. BRAF V600E was found in 31%, BRAF indel in 29%, and MAP2K1 in 19% of patients with LCH. A variety of other protein kinase and related pathways were found in 89% of adult patients with LCH. MAP2K1 variants were exclusive of BRAF variants.
In-frame BRAF deletions and FAM73A::BRAF gene fusions. In-frame BRAF deletions and in-frame FAM73A::BRAF gene fusions have occurred in the group of BRAF V600E and MAP2K1 variant–negative cases.[27]
In summary, studies support the universal activation of ERK in LCH. ERK activation in most cases of LCH is explained by BRAF and MAP2K1 alterations.[17,27,28] Altogether, these variants in the MAP kinase pathway account for nearly 80% of the causes of the universal activation of ERK in LCH.[17,27,28] The remaining cases have a range of variants that include small deletions in BRAF, BRAF gene fusions (discussed above), as well as variants in ARAF, MAP3K1, NRAS, ERBB3, PI3CA, CSF1R, and other rare targets.[34,32][Level of evidence C1]
Clinical implications
Clinical implications of the described genomic findings include the following:
LCH is included in a group of other pediatric tumors with activating BRAF variants, such as select nonmalignant conditions (e.g., benign nevi) [36] and low-grade malignancies (e.g., pilocytic astrocytoma).[37,38] All of these conditions have a generally indolent course, with spontaneous resolution occurring in some cases. This distinctive clinical course may be a manifestation of oncogene-induced senescence.[36,39]
In some pediatric studies, BRAF V600E variants have been associated with more severe multisystem disease, treatment failure, increased reactivations, and an increased risk of neurodegeneration (see below).[40] These clinical correlates were recently investigated for non-BRAF V600E variants in an international study. Similar to the BRAF V600E cohort, all patients with multisystem risk organ–positive LCH had detectable variants in peripheral blood mononuclear cells. Of seven patients with multisystem risk organ–negative LCH, four had detectable variants. No patients with single-system disease had detectable variants in peripheral blood mononuclear cells. The authors concluded that other MAPK pathway variants are associated with risk status, similar to BRAF V600E variants.[32]
BRAF V600E variants can be targeted by BRAF inhibitors (e.g., vemurafenib and dabrafenib) or by the combination of BRAF inhibitors plus MEK inhibitors (e.g., dabrafenib/trametinib and vemurafenib/cobimetinib). These agents and combinations are approved for adults with melanoma. Treatment of melanoma in adults with combinations of a BRAF inhibitor and a MEK inhibitor showed significantly improved progression-free survival outcomes compared with treatment using a BRAF inhibitor alone.[41,42]
Circulating BRAF V600E–altered cells have been found in 59% of patients who developed neurodegenerative-disease LCH, compared with 15% of patients who did not develop neurodegenerative-disease LCH. Detectable altered circulating cells had a sensitivity of 0.59 and specificity of 0.86 for developing the neurodegenerative disease. Even after therapy, some patients with neurodegenerative-disease LCH had circulating BRAF V600E–altered cells.[13]
With additional research, the observation of the BRAF V600E variant (or potentially MAP2K1 variants) in circulating cells or cell-free DNA may become a useful diagnostic tool to define high-risk versus low-risk disease.[2] Additionally, for patients who have a somatic variant, persistence of circulating cells with the variant may be useful as a marker of residual disease.[2]
Cytokine Analysis
Immunohistochemical staining has shown upregulation of many different cytokines/chemokines, both in LCH lesions and in the serum/plasma of patients with LCH.[49,50] In an analysis of gene expression in LCH by gene array techniques, 2,000 differentially expressed genes were identified. Of 65 genes previously reported to be associated with LCH, only 11 were found to be upregulated in the array results. The most highly upregulated gene in both CD207-positive and CD3-positive cells was SPP1 (encoding the osteopontin protein); other genes that activate and recruit T cells to sites of inflammation are also upregulated.[1] The expression profile of the T cells was that of an activated regulatory T-cell phenotype with increased expression of FOXP3, CTLA4, and SPP1. These findings support a previous report on the expansion of regulatory T cells in LCH.[1] There was pronounced expression of genes associated with early myeloid progenitors such as CD33 and CD44, which is consistent with an earlier report of elevated myeloid dendritic cells in the blood of patients with LCH.[51] A model of Misguided Myeloid Dendritic Cell Precursors has been proposed, whereby myeloid dendritic cell precursors are recruited to sites of LCH by an unknown mechanism, and the dendritic cells, in turn, recruit lymphocytes by excretion of osteopontin, neuropilin-1, and vannin-1.[1]
One study evaluated possible biomarkers for central nervous system LCH. The study examined 121 unique proteins in the cerebrospinal fluid (CSF) of 40 pediatric patients with LCH and compared them with controls, which included 29 patients with acute lymphoblastic leukemia, 25 patients with brain tumors, 28 patients with neurodegenerative diseases, and 9 patients with hemophagocytic lymphohistiocytosis. Only osteopontin proved to be significantly increased in the CSF of LCH patients with either neurodegeneration or mass lesions (pituitary), compared with all of the control groups. Analysis of osteopontin expression in these tissues confirmed an upregulation of the SPP1 gene.[13]
Several investigators have published studies evaluating the level of various cytokines or growth factors in the blood of patients with LCH. These studies have included many of the genes found not to be upregulated by the gene expression results discussed above.[1] One explanation for elevated levels of these proteins is a systemic inflammatory response, with the cytokines/growth factors being produced by cells outside the LCH lesions. A second possible explanation is that macrophages in the LCH lesions produce the cytokines measured in the blood or are concentrated in lesions.
IL-1 beta and prostaglandin GE2 levels were measured in the saliva of patients with oral LCH lesions or multisystem high-risk patients with and without oral lesions. Levels of both were higher in patients with active disease and decreased after successful therapy.[52]
References
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Eckstein OS, Visser J, Rodriguez-Galindo C, et al.: Clinical responses and persistent BRAF V600E+ blood cells in children with LCH treated with MAPK pathway inhibition. Blood 133 (15): 1691-1694, 2019. [PUBMED Abstract]
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Childhood LCH
General Information About Childhood LCH
Incidence
The annual incidence of Langerhans cell histiocytosis (LCH) has been estimated to be between two and ten cases per 1 million children aged 15 years or younger.[1–3] The male-to-female ratio (M:F) is close to one, and the median age of presentation is 30 months.[4] A 4-year survey of 251 new LCH cases in France found an annual incidence of 4.6 cases per 1 million children younger than 15 years (M:F, 1.2).[5]
A population-based study identified 658 patients with LCH who were diagnosed in England from 2013 to 2019.[6] The prevalence of LCH was 9.95 cases per 1 million people at the end of 2019. Forty-nine percent of patients were younger than 15 years, with an incidence rate of 4.46 cases per 1 million children per year. The authors felt that this incidence is likely an underestimate, particularly for single-system LCH. This is the first study to accurately identify adult patients aged 30 years to 60 years and older. However, the study also included patients aged 15 to 29 years in the adult category, which resulted in a total adult incidence rate of 1.06 cases per 1 million adults per year. Patients living in lower socioeconomic circumstances and those older than 30 years had worse survival rates than those of higher socioeconomic status or children.
Surveillance, Epidemiology, and End Results (SEER) registry data from 2000 to 2009 were reviewed to identify high-risk LCH cases and assess demographic variables.[7] Of 145 cases, the age-standardized incidence for disseminated disease was 0.7 per 1 million children per year, with lower incidence in Black patients (0.41 per 1 million) and higher incidence in Hispanic patients (1.63 per 1 million) younger than 5 years. Crowded living conditions and lower socioeconomic circumstances were associated with a higher risk of LCH, possibly because of the correlation with maternal and neonatal infections.[8] In a population-based, case-control study, Hispanic mothers were more likely than non-Hispanic White mothers to have children who developed LCH; this risk increased when both parents were Hispanic. Non-Hispanic Black mothers were less likely than non-Hispanic White mothers to give birth to children who developed LCH.[9] In addition, a family-based genome-wide association study found that a polymorphism of the SMAD6 gene was highly associated with LCH, especially in Hispanic patients.[10] The study from England (described above) included 658 adults and children, 79% of whom were White. This study did not show an increased incidence in the Hispanic population, reflecting the differences in the U.K. population.[6]
Risk factors
Although the following risk factors have been proposed for LCH, strong and consistent associations have not been confirmed:
Efforts to define a viral cause have not been successful.[13,14]
Diagnostic evaluation
The complete evaluation of any patient presenting with LCH includes the following:[15]
History and physical examination: A complete history and physical examination with special attention to the skin, lymph nodes, ears, oral pharynx, gingiva, tongue, teeth, bones, lungs, thyroid, liver and spleen size, bone abnormalities, growth velocity, and history of excessive thirst and urination.
Other tests and procedures include the following:
Blood tests: Blood tests include complete blood count with leukocyte differential and platelet count, liver function tests (e.g., bilirubin, albumin, aspartate aminotransferase, alanine aminotransferase, gamma glutamyl transferase, and prothrombin time or international normalized ratio (INR)/partial thromboplastin time in patients with hepatomegaly, jaundice, elevations of liver enzymes, or low albumin), and serum electrolytes.
In patients with severe multisystem LCH, additional tests for secondary hemophagocytic lymphohistiocytosis such as ferritin, triglycerides, fibrinogen, d-dimers, lactate dehydrogenase, CXCL9, and sCD25, may be indicated.
Assessment of the RAS-RAF-MEK pathway: Although assessment of the RAS-RAF-MEK pathway is not a required part of the workup for patients with LCH, the BRAF variant can be detected by either immunohistochemistry or molecular diagnostic methods in fresh tissue, formalin-fixed tissue, and peripheral blood.
Urine tests: Urine tests include urinalysis and a water-deprivation test if diabetes insipidus is suspected. Water deprivation tests in very young children, especially infants, are performed under close medical monitoring.
Bone marrow aspirate and biopsy: A bone marrow aspirate and biopsy is indicated for patients with multisystem disease who have unexplained anemia or thrombocytopenia. The biopsy specimens should be stained with anti-CD1a and/or anti-CD207 (langerin) and anti-CD163 immunostains to facilitate the detection of LCH cells. Polymerase chain reaction (PCR) analysis for BRAF-altered cells is also important.
Radiological and imaging tests: Radiological tests for the first level of screening include skeletal survey, skull series, bone scans, and chest X-ray. Positron emission tomography (PET) scans are becoming more widely used because of superior diagnostic index and evaluation of response to therapy compared with bone scans.[16–18]
Computed tomography (CT) scan: CT scan of the head may be indicated if orbital, mastoid, or other maxillofacial involvement is suspected. Imaging tests may include magnetic resonance imaging (MRI) scan with gadolinium contrast of the brain for patients with diabetes insipidus or suspected brain or vertebral involvement.[19]
CT scan of the lungs may be indicated for patients with abnormal chest X-rays or pulmonary symptoms. High-resolution CT scans may show evidence of pulmonary LCH when the chest X-ray is normal. Thus, in infants and toddlers with normal chest X-rays, a CT scan may be considered when respiratory signs or symptoms are present. Patients with pulmonary LCH may also have normal chest X-rays and abnormal pulmonary function tests.[20]
LCH causes fatty changes in the liver or hypodense areas along the portal tract, which can be identified by CT scan, if indicated.[21]
Fluorine F 18-fludeoxyglucose (18F-FDG) PET scan: 18F-FDG PET scan abnormalities were reported in the brains of seven patients with LCH who exhibited neurological and radiographic signs of neurodegenerative disease.[18] There was good correlation with MRI findings in the cerebellar white matter, but less so in the caudate nuclei and frontal cortex. It was suggested that PET scans of patients at high risk of developing neurodegenerative LCH could show abnormalities earlier than MRI.[18] PET scans often demonstrate lesions not found by other modalities and show a decrease of activity of LCH after 6 weeks of therapy, providing a better assessment of response to therapy than bone scans or plain x-rays.[17,22] However, one study suggests that bone scans are more sensitive than PET scans for lesions in the hands and feet.[23]
MRI: MRI findings in patients with diabetes insipidus include thickening and nodularity of the pituitary stalk with loss of the posterior pituitary bright spot, reflecting absence of antidiuretic hormone.
All patients with vertebral body involvement need careful assessment of associated soft tissue, which may impinge on the spinal cord.
MRI findings of central nervous system (CNS) LCH include T2 FLAIR enhancement in the pons, basal ganglia, white matter of the cerebellum, and mass lesions or meningeal enhancement. In a report of 163 patients, meningeal lesions were found in 29% of patients and choroid plexus involvement was found in 6% of patients. Paranasal sinus or mastoid lesions were found in 55% of patients versus 20% of controls, and accentuated Virchow-Robin spaces were found in 70% of patients versus 27% of controls.[25]
Biopsy: Lytic bone lesions, skin, and lymph nodes are the sites most frequently biopsied for diagnosis of LCH. A liver biopsy is indicated when a child with LCH presents with hypoalbuminemia not caused by gastrointestinal LCH or another etiology. These patients usually have elevated levels of bilirubin or liver enzymes. An open lung biopsy may be necessary for obtaining tissue for diagnosis of pulmonary LCH when bronchoalveolar lavage is nondiagnostic. Diagnosing gastrointestinal involvement with LCH is difficult because of patchy involvement. Careful endoscopic examination that includes multiple biopsies is usually needed.
A pathological diagnosis is always required to make a definitive diagnosis. However, this may sometimes be difficult or contraindicated, such as in isolated pituitary stalk disease or vertebra plana without a soft tissue mass, when the risk outweighs the benefit of a firm diagnosis.
Prognostic factors
Survival is closely linked to the extent of disease at presentation when high-risk organs (liver, spleen, and/or bone marrow) are involved, as well as the response to initial treatment. Many studies have confirmed the high mortality rate (35%) in patients with high-risk multisystem disease, when they do not respond well to therapy in the first 6 weeks.[26] Because of treatment advances, including early implementation of additional therapy for poor responders, the outcome for children with LCH involving high-risk organs has improved.[27,28] Data from HISTSOC-LCH-III (NCT00276757) showed an overall survival (OS) rate of 84% for patients treated for 12 months with systemic chemotherapy.[29]
For many years, lungs were thought to be high-risk organs, but isolated lung involvement in pediatric LCH is no longer considered to pose a significant risk of death,[26] unless pneumothorax or bilateral pneumothoraces occur.
Patients with single-system disease and low-risk multisystem disease do not usually die of LCH, but recurrent disease may result in considerable morbidity and significant late effects.[30] Overall, recurrences have been found in 10% of patients with single-system unifocal disease, 25% of patients with single-system multifocal bone LCH, and 50% of patients with low-risk multisystem disease and those with high-risk multisystem disease who achieve nonactive disease status with chemotherapy. HISTSOC-LCH-III data showed a significant difference in reactivation rate for low–risk-organ patients randomly assigned to receive 6 months of treatment (54%) versus 12 months of treatment (37%).[29] Similarly, the nonrandomized high-risk group of patients who were all treated for 12 months had a reactivation rate of 30%, compared with more than 50% in previous studies in which patients were treated with the same therapy for 6 months.[29]
Most high-risk patients whose disease reactivated (30%) after achieving a no active disease (NAD) status will do so in low-risk organs such as bone. These patients will have the same risk of late effects as patients with low-risk multisystem disease.[29] The major current treatment challenge is to reduce this overall 20% to 30% incidence of reactivations and the significant risk of serious permanent consequences in this group of patients.
Apart from disease extent, prognostic factors for children with LCH include the following:
Age at diagnosis. Although age younger than 2 years was once thought to portend a worse prognosis, data from the HISTSOC-LCH-II study showed that patients aged 2 years or younger without high–risk-organ involvement had the same response to therapy as did older patients.[28] In contrast, the OS was poorer in neonates with risk-organ involvement compared with infants and children with the same extent of disease when patients were treated for only 6 months.[28]
Response to treatment. Response to therapy at 6 to 12 weeks has been shown to be a more important prognostic factor than age.[31] The overall response to therapy is influenced by the duration and intensity of treatment.[27,28]
Site of involvement.
BRAF or MAP2K1 variants.
A study of 173 patients with the BRAF V600E variant and 142 without the variant revealed that the variant occurred in 88% of patients with high-risk disease, 69% of patients with multisystem low-risk LCH, and 44% of patients with single-system low-risk LCH.[32] The variant was also found in 75% of patients with the neurodegenerative syndrome and 73% of patients with pituitary involvement. The BRAF V600E variant was also associated with an increased incidence of skin disease and a younger age of presentation. Resistance to initial treatment and relapse were higher in patients with the variant. MAP2K1 variants were associated with single-system bone disease.[32]
An earlier study of 100 patients did not find all these clinical correlations, except that relapses occurred more frequently in patients with low-risk and high-risk LCH and the BRAF V600E variant.[33]
An international collaborative study of 377 patients found 300 patients (79.6%) with MAPK pathway variants and compared them with patients without variants. This study confirmed the findings of a previous study. It also found an increased risk of CNS-risk bone LCH, gastrointestinal and skin involvement, and fewer cases of BRAF-positive single-system, multifocal bone LCH among patients with MAPK pathway variants.[34] A cohort of patients with the BRAF exon 12 variant had a higher incidence of lung LCH. MAP2K1 variants were more frequent in patients with single-system bone LCH, but not in patients with CNS-risk bone LCH. The prognostic impact of the BRAF variant was more strongly associated with having risk-organ and multisystem involvement, rather than the presence of the variant itself.
A significant proportion of patients who survive LCH experience disease relapses and/or develop permanent conditions. Central diabetes insipidus is the most common condition, and CNS neurodegenerative LCH is the most severe condition.[35]
Follow-up considerations in childhood LCH
Because of the risk of reactivation (which ranges from 10% in single-system unifocal bone lesions to close to 50% in low-risk and high-risk multisystem LCH) and the risk of permanent long-term effects, LCH patients need to be monitored for many years.
Patients with diabetes insipidus and/or skull lesions in the orbit, mastoid, or temporal bones appear to be at higher risk of LCH CNS involvement and LCH CNS neurodegenerative syndrome. These patients should have MRI scans with gadolinium contrast at the time of LCH diagnosis and every 1 to 2 years thereafter for 10 years to detect evidence of CNS disease.[36] The Histiocyte Society CNS LCH Committee does not recommend any treatment for radiological CNS LCH of the neurodegenerative type if there is no associated clinical neurodegeneration and the MRI findings remain stable. However, careful neurological examinations and appropriate imaging with MRI are suggested at regular intervals.[37]
Auditory brain-stem response tests should be done at regular intervals to define the onset of clinical CNS LCH as early as possible, as this may affect response to therapy.[38] When clinical signs are present, intervention is indicated in patients with radiological evidence of LCH-associated changes in the cerebellum. Available studies of different forms of therapy for CNS neurodegeneration suggest that the neurodegenerative changes may be stabilized or improved, but only if therapy is started early.[38] It is critical to monitor patients at risk with neurological examinations and serial brain MRI scans. For more information, see the Clinical neurodegenerative syndrome LCH (cND-LCH) section.
For children with LCH in the lung, pulmonary function testing and chest CT scans are sensitive methods for detecting disease progression.[39]
A 16-year follow-up study of patients from one institution suggested that children with LCH have an increased risk of developing adult smoker’s lung LCH compared with normal young adults who smoke. Ongoing re-education regarding this risk should be part of the routine follow-up of children with LCH at any site.[39]
In summary, many patients with multisystem disease will experience long-term sequelae caused by their underlying disease and/or treatment. Endocrine and CNS sequelae are the most common. These long-term sequelae significantly affect health-related quality of life in many of these patients.[40][Level of evidence C1] Specific long-term follow-up guidelines after treatment of childhood cancer or other conditions with chemotherapy have been published by the Children’s Oncology Group and are available on their website. For more information, see the Late Disease and Treatment Effects of Childhood LCH section.
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.[41] 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.[42] 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.
Low-Risk Disease: Single-System or Multisystem LCH
Clinical presentation of low-risk, single-system or multisystem LCH
LCH most commonly presents as a painful bone lesion, with skin being the second most commonly involved organ. Systemic symptoms of fever, weight loss, diarrhea, edema, dyspnea, polydipsia, and polyuria relate to specific organ involvement and single-system or multisystem disease presentation (see Table 2).[35]
aReprinted from Blood, Volume 135, Issue 16, Carlos Rodriguez-Galindo, Carl E. Allen, Langerhans cell histiocytosis, Pages 1319–1331, Copyright 2020, with permission from Elsevier.[35]
Multisystem
Two or more systems involved
With risk-organ involvement
Involvement of liver, spleen, or bone marrow
Without risk-organ involvement
Without involvement of liver, spleen, or bone marrow
Single-system
Only one system involved
Single site
Skin, bone, lymph node, other (thyroid, thymus)
Multiple sites
Multifocal bone disease
Special site
Skull-base lesion with intracranial extension or vertebral lesion with intraspinal soft tissue extension
Pulmonary LCH
Isolated lung disease
CNS LCH
Tumorous lesions
Neurodegenerative disease
LACI
LACS
Specific organs are considered high risk or low risk when involved at disease presentation. Risk refers to the risk of mortality in high-risk patients. Chronic recurrent involvement of low-risk organs, while usually not life-threatening, can result in potentially devastating long-term consequences.
High-risk organs include the liver, spleen, and hematopoietic system (defined by the presence of at least two lineage abnormalities in blood or by pathological CD1a-positive or CD207-positive cells in the bone marrow). Newer technologies (BRAF V600E detection PCR or immunostaining) are resulting in more-reliable detection of LCH cells in the bone marrow. High-risk patients are typically younger than 2 years. High-risk patients with intestinal involvement have a greater risk of not responding to therapy (49% do not respond to therapy) than patients without intestinal involvement (28% do not respond to therapy).[43] Nonetheless, intestinal disease is not an official criterion for high-risk disease.
Low-risk organs include the skin, bone, lung, lymph nodes, gastrointestinal tract, pituitary gland, thyroid, thymus, and CNS. Involvement of every organ except kidney and gonads has been described.
Patients may present with single-organ involvement (single-system LCH), which may involve a single site (unifocal) or multiple sites (multifocal). Bone is the most common single-organ site. Less commonly, LCH may involve multiple organs (multisystem LCH), which may involve a limited number of organs, or it may be disseminated. Patients can have LCH of the skin, bone, lymph nodes, and pituitary gland in any combination and still be considered at low risk of death, although there may be a relatively high risk of developing long-term consequences of the disease.
Treatment decisions for patients are based on whether high-risk or low-risk organs are involved and whether LCH presents as unifocal, multifocal, or multisystem disease.
Single-system low-risk disease presentation
In single-system low-risk LCH, the disease presents with involvement of a single site or organ, including the following:
Bone is the most commonly affected system, estimated to be involved in 80% of patients with LCH. LCH can occur in any bone of the body, although the hands and feet are often spared.[44]
Sites of LCH bone lesions in children include the following:
Lytic lesion of the skull: The most frequent site of LCH in children is a lytic lesion of the skull vault,[45] which may be asymptomatic or painful. It is often surrounded by a soft tissue mass that may extend internally to impinge on the dura. However, the presence of this mass does not affect prognosis.
Femur, ribs, humerus, pelvis, and vertebra: Other frequently involved skeletal sites are femur, ribs, humerus, pelvis, and vertebra. Spine lesions may involve any vertebra, although involvement of the cervical vertebrae is most common, and spine lesions are frequently associated with other bone lesions. Spine lesions may result in collapse of the vertebral body (vertebra plana). Vertebral lesions with soft tissue extension often present with pain and may present with significant neurological deficits.[46] This finding is an indication for evaluating spinal cord compression with MRI scan.
CNS-risk bones: Lesions of the facial bones or anterior or middle cranial fossae (e.g., temporal, orbit, sphenoid, ethmoid, zygomatic) with intracranial tumor extension comprise a CNS-risk group. These patients have a threefold increased risk of developing other CNS disease and diabetes insipidus. Systemic treatment is recommended for these patients because of the increased risk of diabetes insipidus. Proptosis from an LCH mass in the orbit mimics rhabdomyosarcoma, neuroblastoma, and benign fatty tumors of the eye.[47]
Skin and nails
Infants: Seborrheic involvement of the scalp may be mistaken for prolonged cradle cap in infants, unless the classic purpuric component is present. The second most common site involves the body creases, such as the antecubital fossa and perineum. Infants with LCH may also present with a generalized skin rash, which may mimic many other skin disorders and may or may not be pruritic. Vesicular LCH skin lesions need to be differentiated from congenital infections.
Skin LCH in infants may be limited to skin (skin-only disease) or may be part of multisystem LCH. In a report of 61 neonatal cases from 1,069 patients in the Histiocyte Society database, nearly 60% (36 of 61 patients) had multisystem disease, and 72% of the patients with multisystem disease had risk-organ involvement.[31] A retrospective analysis of 71 infants and children with apparent skin-only LCH found that those older than 18 months were more likely to have multisystem involvement and often relapsed after treatment with vinblastine and prednisone.[48] Eight of 11 patients in this category had circulating cells with the BRAF V600E variant, compared with only 1 of 13 patients in the skin-only group. Patients younger than 1 year with skin-only disease who were completely evaluated to exclude any other site of disease had a 3-year progression-free survival rate of 89% with initial therapy.
Skin-only LCH may be self-limited because the lesions may disappear without therapy during the first year of life. Therapy is used only for very extensive rashes, pain, ulceration, or bleeding. These patients must be monitored closely because skin-only LCH in neonates and very young infants may progress within weeks or months to high-risk multisystem disease, which may be life-threatening.[49–51]
In a review of patients presenting in the first 3 months of life with skin-only LCH, the clinical and histopathological findings of 21 children whose skin LCH regressed were compared with those of 10 children whose disease did not regress.[50] Patients with regressing disease had distal lesions that appeared in the first 3 months of life and were necrotic papules or hypopigmented macules. Patients with nonregressing disease who required systemic therapy more often had lesions in intertriginous areas. Immunohistochemical studies showed no difference in interleukin (IL)-10, Ki-67, E-cadherin expression, or T-reg number between the two clinical groups.
Hashimoto-Pritzker disease or congenital spontaneous regressing skin histiocytosis is a self-limited disease that has the same immunohistochemical staining as LCH but, on electron microscopy, shows dense bodies thought to be senescent mitochondria.[52] Careful review of the original cases revealed that some patients progressed to multisystem LCH; the distinction between skin-only LCH and Hashimoto-Pritzker disease is felt to be without clinical value because all of these infants should be carefully observed after diagnosis. It is not yet clear if the presence or absence of a BRAF V600E variant can be used to define whether systemic therapy is needed in skin-only LCH.
Children and adults: Children and adults may develop a red papular rash in the groin, abdomen, back, or chest that resembles a diffuse candidal rash. Seborrheic involvement of the scalp may be mistaken for a severe case of dandruff in older individuals. Ulcerative lesions behind the ears, involving the scalp, under the breasts, on the genitalia, or in the perianal region are often misdiagnosed as bacterial or fungal infections. Vesicular lesions may be seen and need to be differentiated from herpetic lesions.
Fingernail involvement is an unusual finding that may present as a single site or with other sites of LCH involvement. In this scenario, there are longitudinal, discolored grooves and loss of nail tissue. This condition often responds to the usual LCH therapies.[53]
Oral cavity
In the mouth, presenting symptoms include gingival hypertrophy and ulcers on the soft or hard palate, buccal mucosa, or tongue and lips. Hypermobile teeth (floating teeth) and tooth loss usually indicate involvement of underlying bone.[54,55] Lesions of the oral cavity may precede evidence of LCH elsewhere.
Lymph nodes and thymus
The cervical nodes are most frequently involved and may be soft-matted or hard-matted groups with accompanying lymphedema. An enlarged thymus or mediastinal node involvement can mimic an infectious process and may cause asthma-like symptoms. Accordingly, biopsy with culture is indicated for these presentations. Mediastinal involvement is rare (<5%) and usually presents with respiratory distress, superior vena cava syndrome, or cough and tachypnea. The 5-year survival rate for these patients is 87%, with deaths mostly attributable to hematologic involvement.[56]
Lung
In LCH, the lungs are less frequently involved in children than in adults because smoking in adults is a key etiologic factor.[57] Of 1,482 children in the French LCH registry, 7.4% of patients had pulmonary involvement and 1% of patients had severe disease requiring intensive care admission with multiple chest tube insertions for pneumothoraces and, sometimes, pleurodeses.[58] A review of 178 LCH cases from another center found that pulmonary involvement occurred in approximately 13 children (7.3%), 3 of whom had multisystem high-risk disease.[59] Multivariate analysis of pulmonary disease in multisystem LCH did not show pulmonary disease to be an independent prognostic factor. The 5-year OS rates were 94% for those with pulmonary involvement and 96% for those without pulmonary involvement.[26] Isolated pulmonary involvement is rarely seen in children.
The cystic/nodular pattern of disease reflects the cytokine-induced destruction of lung tissue. Classically, the disease is symmetrical and predominates in the upper and middle lung fields, sparing the costophrenic angle and giving a very characteristic picture on high-resolution CT scan.[60] Confluence of cysts may lead to bullous formation, and spontaneous pneumothorax can be the first sign of LCH in the lung, although patients may present with tachypnea or dyspnea. Ultimately, widespread fibrosis and destruction of lung tissue may lead to severe pulmonary insufficiency. Declining diffusion capacity may also indicate the onset of pulmonary hypertension.[39]
Widespread fibrosis and declining diffusion capacity are much less common in children. In young children with diffuse disease, therapy can halt the progress of the tissue destruction, and normal repair mechanisms may restore lung function, although scarring or even residual nonactive cysts may continue to be visible on radiological studies.
Pituitary gland
The posterior part of the pituitary gland and pituitary stalk can be affected in patients with LCH, causing central diabetes insipidus. Anterior pituitary involvement often results in growth failure and delayed or precocious puberty. Rarely, hypothalamic involvement may cause morbid obesity. For more information about diabetes insipidus, see the Endocrine system section.
Thyroid gland
Thyroid involvement has been reported in LCH. Symptoms include massive thyroid enlargement, hypothyroidism, and respiratory symptoms.[61]
Multisystem low-risk disease presentation
Bone and other organ systems
Patients with LCH may present with multiple bone lesions as the only organ involved (single-system multifocal bone) or with bone lesions and other organ systems involved (multisystem including bone). A Japanese LCH study (JLSG-02) included patients with single-system multifocal bone presentation and patients with multisystem-including-bone presentation. A review of the study found that patients in the multisystem-including-bone group were more likely to have lesions in the temporal bone, mastoid/petrous bone, orbit, and zygomatic bone (i.e., CNS-risk bones).[62] These patients also had a higher incidence of diabetes insipidus, correlating with the higher frequency of risk-bone lesions. A study from the Histiocyte Society found decreased mortality in patients with high-risk multisystem LCH who had bone involvement, suggesting that those with bone LCH may have more indolent disease.[63]
Abdominal organs and gastrointestinal system
In LCH, the liver and spleen are considered high-risk organs, and involvement of these organs affects prognosis. For more information, see the sections on Liver (sclerosing cholangitis) and Spleen.
Although rare, LCH infiltration of the pancreas and kidneys has been reported.[64]
Patients with diarrhea, hematochezia, perianal fistulas, or malabsorption have been reported.[65,66]
Endocrine system
Diabetes insipidus, caused by LCH-induced damage to the antidiuretic hormone-secreting cells of the posterior pituitary, is the most frequent endocrine manifestation in LCH.[67] MRI scans usually show nodularity and/or thickening of the pituitary stalk and loss of the pituitary bright spot on T2-weighted images. When the pituitary stalk is thickened or is very large, there is a 50% chance the patient will have a germinoma, LCH, or lymphoma.[68] Pituitary biopsies are rarely done. A biopsy of the pituitary gland may be indicated when the pituitary gland is the only site of disease and the stalk is thicker than 6.5 mm or there is a hypothalamic mass.[69] If the pituitary disease is associated with other sites of involvement, these other sites can be biopsied to establish the diagnosis.
Approximately 4% of patients with LCH present with an apparently idiopathic form of diabetes insipidus before other lesions of LCH are identified. A prospective follow-up study included pediatric patients who presented with idiopathic central diabetes insipidus and received only diabetes insipidus therapy. The study showed that 19% of patients eventually developed signs of LCH, while 18% were diagnosed with craniopharyngiomas and 10% with germinomas.[70] A prospective study of the etiology of central diabetes insipidus in children and young adults found that 15% of patients had LCH, 11% had germinomas, and 7% had craniopharyngiomas.[71] The other diagnoses were related to trauma, familial association, or midline defects, and 50% remained idiopathic. Decisions about whether or when to treat a patient with apparent isolated central diabetes insipidus as LCH without a biopsy remain controversial.
The approach is different for patients with known LCH and diabetes insipidus. These patients are 50% to 80% more likely to develop other lesions that are diagnostic of LCH (including bone, lung, and skin lesions) within 1 year of diabetes insipidus onset.[69,72] In general, patients with LCH present with diabetes insipidus later in the course of the disease, as noted in the following studies:
One study compared the incidence of diabetes insipidus in patients who received no systemic therapy with that in patients who received 6 months of vinblastine/prednisone therapy. Patients who received no systemic therapy had a 40% incidence of diabetes insipidus. Patients who were treated with chemotherapy had a 20% incidence of diabetes insipidus. This finding strongly supports treatment of CNS-risk bone lesions, even when the disease is isolated to a single bony site.[73]
In a study of 589 patients with LCH, the 10-year risk of pituitary involvement was 24%.[67] Diabetes insipidus was seen at a mean of 1 year after LCH diagnosis. Fifty-six percent of patients with LCH who developed diabetes insipidus developed anterior pituitary hormone deficiencies (growth, thyroid, or gonadal-stimulating hormones) within 10 years of the onset of diabetes insipidus. In this study, no decrease in the incidence of diabetes insipidus was seen in chemotherapy-treated patients, but this may reflect the length of the therapy and/or the number of drugs used.[67]
Giving therapy for a longer duration and with more chemotherapeutic agents, the German-Austrian-Dutch (Deutsche Arbeitsgemeinschaft für Leukämieforschung und Behandlung im Kindesalter [DAL]) group found a cumulative incidence of diabetes insipidus of 20% at 15 years after LCH diagnosis.[73] The incidence of diabetes insipidus was also lower in patients treated with more-intensive chemotherapy regimens on the HISTSOC-LCH-III (NCT00276757), JLSG-96, and JLSG-02 studies in Japan (8.9% for multisystem patients) compared with the HISTSOC-LCH-I and HISTSOC-LCH-II studies (14.2%).[27–29,74,75] Overall, diabetes insipidus occurred in 11% of patients treated with multiagent chemotherapy and in up to 50% of patients treated less aggressively.[76,77]
Patients with multisystem disease and craniofacial involvement (particularly of the orbit, mastoid, and temporal bones) at the time of diagnosis carried a significantly increased risk of developing diabetes insipidus during the disease course (relative risk, 4.6). Of LCH patients with diabetes insipidus, 75% had these CNS-risk bone lesions.[73] The risk of diabetes insipidus increased when LCH remained active for a longer period of time or reactivated.
Approximately 50% of patients who present with isolated diabetes insipidus (as the initial manifestation of LCH) either have anterior pituitary deficits at the time of diagnosis or develop them within 10 years of diabetes insipidus onset.[72,77] Anterior pituitary deficits include secondary amenorrhea, panhypopituitarism, growth hormone deficiency, hypoadrenalism, and abnormalities of gonadotropins. The incidence of anterior pituitary deficits appears to be higher in patients with LCH than in those with true idiopathic central diabetes insipidus.
Ocular
Ocular LCH, although rare, has been reported and can sometimes lead to blindness. Other organ systems may be involved, and ocular LCH may not respond well to conventional chemotherapy.[47]
CNS
CNS disease manifestations
Patients with LCH may develop mass lesions in the hypothalamic-pituitary region, the choroid plexus, the grey matter, or the white matter.[78] These lesions contain CD1a-positive LCH cells and CD8-positive lymphocytes and are, therefore, active LCH lesions.[79]
Patients with large pituitary tumors (>6.5 mm) have a higher risk of anterior pituitary dysfunction and neurodegenerative CNS LCH.[80] A retrospective study of 22 patients found that all had radiological signs of neurodegenerative CNS LCH detected at a median time of 3 years and 4 months after LCH diagnosis; it worsened in 19 patients. Five patients had neurological dysfunction, 18 of 22 patients had anterior pituitary dysfunction, and 20 had diabetes insipidus. Growth hormone deficiency occurred in 21 patients. Luteinizing hormone/follicle-stimulating hormone deficiency occurred in 10 patients. Thyroid hormone deficiency occurred in 10 patients.
Clinical neurodegenerative syndrome LCH (cND-LCH)
A chronic neurodegenerative syndrome, cND-LCH, occurs in 1% to 4% of patients with LCH. These patients may develop tremors, gait disturbances, ataxia, dysarthria, headaches, visual disturbances, cognitive and behavioral problems, and psychosis.
Among 1,897 patients with LCH, 36 patients were diagnosed with cND-LCH. The incidence of cND-LCH was 4.1% at 10 years of follow-up. cND-LCH was more frequent in patients with pituitary involvement (86.1% vs. 12.2% without pituitary lesions), skin involvement (75% vs. 34.2% without skin lesions), and base skull bone involvement (63.9% vs. 28.4% without skull lesions). Patients with the BRAF variant were more likely to have cND-LCH (93.7%) than those without the variant (54.1%). In the multivariable analysis, the odds ratio of developing cND-LCH was 2.13 for patients with base skull lesions, 9.8 for patients with the BRAF V600E variant, and 30.88 for patients with pituitary involvement. The risk of cND-LCH had not plateaued up to 20 years after LCH diagnosis.[81]
Brain MRI scans from these patients show hyperintensity of the dentate nucleus and white matter of the cerebellum on T2-weighted images or hyperintense lesions of the basal ganglia on T1-weighted images and/or atrophy of the cerebellum.[25] The radiological findings may precede the onset of symptoms by many years or be found coincidently. One study included 83 patients with LCH who had at least two MRI studies of the brain for evaluation of craniofacial lesions, diabetes insipidus, and/or other endocrine deficiencies of neuropsychological symptoms.[36] Forty-seven of 83 patients (57%) had radiological neurodegenerative changes at a median time of 34 months from diagnosis of LCH. Of the 47 patients, 12 (25%) developed clinical neurological deficits that presented 3 to 15 years after the LCH diagnosis. Fourteen of the 47 patients had subtle deficits in short-term auditory memory.
The first histological evaluation of neurodegenerative lesions reported prominent T-cell infiltration, usually in the absence of the CD1a-positive dendritic cells, along with microglial activation and gliosis.[79] However, in a report from 2018, analysis of brain tissue from patients with neurodegenerative-disease LCH showed perivascular infiltration of CD207-negative cells staining with the BRAF V600E altered protein in the pons, cerebellum, and basal ganglia. These are areas identified by the characteristic abnormal MRI findings on T2 fluid-attenuated inversion recovery (FLAIR) images. Quantitative PCR analysis of these areas showed increased numbers of BRAF-altered cells and elevated expression of osteopontin. Brain tissue in these areas showed active demyelination, correlating with the radiological findings and clinical deficits.[82]
A study evaluated CNS-related permanent consequences (neuropsychologic deficits) in 14 of 25 patients with LCH who were monitored for a median of 10 years.[83] Seven of these patients had diabetes insipidus, and five patients had radiographic evidence of LCH CNS neurodegenerative changes.[83] Patients with craniofacial lesions had lower performance and verbal IQ scores than those with other LCH lesions.
Treatment of low-risk disease: single-system or multisystem LCH
Over many years, national and international study groups have defined risk-based therapy groups for allocation of LCH patients on the basis of mortality risk and risk of late effects of the disease.
Depending on the site and extent of disease, treatment of LCH may include observation (after biopsy or curettage), surgery, radiation therapy, or oral, topical, and intravenous medication. The recommended duration of therapy is 12 months for patients who require chemotherapy for single-system bone, skin, or lymph node involvement.
For patients with high-risk and low-risk multisystem disease, the reactivation rate after 6 months of therapy was as high as 50% on the HISTSOC-LCH-I and HISTSOC-LCH-II trials.[28,84] The German-Austrian-Dutch (Deutsche Arbeitsgemeinschaft für Leukämieforschung und Behandlung im Kindesalter [DAL]) group trials treated patients for 1 year and had fewer relapses (29%).[76,85] On the basis of these findings, the HISTSOC-LCH-III trial was designed to administer 12 months of chemotherapy for all high-risk multisystem patients and to randomly assign low-risk multisystem patients to either 6 months or 12 months of therapy. In patients with low-risk or high-risk disease who received 12 months of therapy, the reactivation rate was significantly reduced to approximately 30%.[29]
The standard treatment for LCH is based on data from international trials with large numbers of patients. However, some patients may have LCH involving only the skin, mouth, pituitary gland, or other sites not studied in these international trials. In these cases, therapy recommendations are based on case series that lack the evidence-based strength of the trials.
Clinical trials organized by the Histiocyte Society have been accruing patients on childhood treatment studies since the 1980s. Information about centers enrolling patients on these trials can be found on the ClinicalTrials.gov website.
Treatment options for patients with low-risk, single-system or multisystem disease depend on the site of involvement, as follows:
Treatment options for patients with isolated skin involvement include the following:
Observation. Observation is recommended for all pediatric patients with asymptomatic skin-only LCH.[48]
Therapy. Therapy is suggested only for patients with symptomatic disease, which includes extensive rashes, pain, ulceration, or bleeding.
Patients with skin-only involvement need to have a complete staging evaluation because 41% of these patients referred to one center had multisystem disease requiring treatment.[48] Careful clinical (but not radiological) follow-up of young infants with skin-only LCH is suggested because progression to high-risk multisystem disease is possible. Young children with skin-only LCH should be monitored periodically for many years because 1 of 19 children and 1 of 25 children in two series developed late diabetes insipidus.[31,49]
For patients who require therapy, treatment options for symptomatic isolated skin lesions include the following:
Topical steroids. Medium- to high-potency steroids are effective, but recurrence after discontinuation is common.[50]
Oral methotrexate. Oral methotrexate (20 mg/m2) weekly for 6 to 12 months.[86]
Oral hydroxyurea. Oral hydroxyurea (20 mg/kg) daily for at least 12 months.[87]
Oral thalidomide/lenalidomide.[88,89] Oral thalidomide 50 mg to 200 mg nightly.[88] Oral thalidomide/lenalidomide may be effective for both pediatric and adult patients.
Topical nitrogen mustard. Topical application of nitrogen mustard can be effective for cutaneous LCH that is resistant to oral therapies, but not for disease involving large areas of skin.[90,91]
Psoralen and long-wave ultraviolet A radiation (PUVA) or UVB. Psoralen and PUVA or UVB can be effective in skin LCH, but its use is limited by the potential for late skin cancers, especially in patients with light skin tones.[92,93]
Chemotherapy. Systemic chemotherapy may be used in severe and symptomatic cases.
Radiation therapy. Although external-beam radiation therapy has been used, it has not proven to be reliably effective and may have severe side effects.[94,95]
Skeletal involvement
Single skull lesions of the frontal, parietal, or occipital regions, or single lesions of any other bone
Treatment options for patients with single skull lesions of the frontal, parietal, or occipital regions, or single lesions of any other bone, include the following:
Curettage. Curettage only is the recommended therapy, when possible, for isolated bone lesions. Curettage plus injection of methylprednisolone may also be used. LCH bone lesions do not need complete excision because this may increase healing time and the risk of long-term complications. Complete excision of skull lesions, which may require grafting, is not necessary.
Low-dose radiation therapy. Local radiation therapy could be considered for an isolated lesion.[94,96][Level of evidence C3] Low-dose radiation therapy (7–10 Gy) is effective,[95,97] but its use is limited in pediatric patients to lesions that threaten organ function or are painful and not amenable to other therapies.[98,99]; [100][Level of evidence C1] In a single-institution study of 39 patients with LCH (age range, 1.5–67 years; 15 patients aged <18 years) who received radiation therapy to 46 lesions, there were no local recurrences in the 31 bony sites (median radiation therapy dose, 10.8 Gy; range, 7.5–24 Gy), and the freedom from local failure rate was 63% at 3 years in the 15 nonbone lesions (95% confidence interval, 32%–83%; P = .0008). In this study, no subsequent cancers occurred,[94] although subsequent cancers have been previously reported.[101] Skeletal complications are uncommon after the low doses that are used, but they can occur.[96]
Skull lesions in the mastoid, temporal, or orbital bones
The CNS-risk bones include the mastoid, temporal, spheroidal, zygomatic, ethmoidal, maxillary, orbital bones, sinuses, and lesions of the anterior or middle cranial fossa. Risk refers to the increased risk of progression to diabetes insipidus followed by brain (CNS) involvement.
The purpose of treating patients with isolated CNS-risk lesions is to decrease the chance of developing diabetes insipidus and other long-term neurological problems.[27]
Treatment options for patients with skull lesions in the mastoid, temporal, or orbital bones include the following:
Weekly vinblastine (6 mg/m2) for 7 weeks for good response.
Daily prednisone (40 mg/m2) for 4 weeks, then tapered over 2 weeks.
Afterward, prednisone is given for 5 days at 40 mg/m2 every 3 weeks with the vinblastine injections (also every 3 weeks).
There is controversy about whether systemic therapy is required for the first presentation of unifocal bone LCH, even in the CNS-risk bones. One retrospective review reported a series of patients with orbital or mastoid lesions who underwent only surgical curettage. The treatment was completed by a single surgeon, specialized in orbital, ear, nose, or throat diseases.[102] None of these patients developed diabetes insipidus.
However, when comparing the incidence rates of diabetes insipidus in patients who received little or no chemotherapy (20%–50% incidence) with the incidence rates reported by the German-Austrian-Dutch group DAL-HX 83 trial (10% incidence in patients treated for LCH), it appears that the weight of evidence from the DAL-HX 83 trial supports chemotherapy treatment to prevent diabetes insipidus in patients with LCH in CNS-risk bones.[76,77] It should be noted, however, that the DAL-HX studies administered more drugs and treated patients for 12 months.
Vertebral or femoral bone lesions at risk of collapse
Treatment options for patients with vertebral or femoral bone lesions at risk of collapse include the following:
Observation. A single vertebral body lesion without soft tissue extension to the extradural space may be observed only.[103]
Low-dose radiation therapy. Low-dose radiation therapy may be used to promote resolution in an isolated vertebral body lesion or a large femoral neck lesion at risk of fracture, where chemotherapy is not usually indicated (single bone lesion). Despite the low dose required (7–10 Gy), radiation therapy should be used with caution because of concerns about secondary malignancies in adjacent tissues, skeletal deformities if the growth plates are irradiated in very young children,[96,101] or if the thyroid gland would be in the radiation field in cervical vertebral lesions.
Chemotherapy. Patients with soft tissue extension from vertebral lesions are often treated successfully with chemotherapy,[46][Level of evidence C2] but prolonged therapy does not appear to be needed beyond the period required to reduce the mass and any risk to the spinal cord. The risk of reactivation of a single bone lesion was only 9% in one large retrospective series.[104]
Bracing or spinal fusion. When instability of the cervical vertebrae and/or neurological symptoms are present, bracing—or rarely, spinal fusion—may be needed.[105]
Multiple bone lesions (single-system multifocal bone lesions)
Treatment options for patients with multiple bone lesions (single-system multifocal bone lesions) at risk of collapse include the following:
Chemotherapy. The most commonly used systemic chemotherapy regimen is the combination of vinblastine and prednisone. Based on the results of the HISTSOC-LCH-III (NCT00276757) trial, 12 months of treatment with weekly vinblastine (6 mg/m2) for 7 weeks, then every 3 weeks, is used for good responders.[29] Prednisone (40 mg/m2) is given daily for 4 weeks, then tapered over 2 weeks. Afterward, prednisone is given for 5 days at 40 mg/m2 every 3 weeks with the vinblastine injections.
A short treatment course (<6 months) with only a single agent (e.g., prednisone) is not sufficient, and the number of relapses is higher. A reactivation rate of 18% was reported with a multidrug treatment regimen that was used for 6 months versus a historical reactivation rate of 50% to 80% with surgery alone or with a single-drug treatment regimen.[106] A comparison of results from two trials in Japan revealed no improvement in progression-free survival rates (66% vs. 65%) when additional prednisone and a prolonged maintenance phase were added.[107]
Multiple bone lesions in combination with skin, lymph node, or diabetes insipidus (low-risk multisystem LCH)
Treatment options for patients with multiple bone lesions in combination with skin, lymph node, or diabetes insipidus (low-risk multisystem LCH) include the following:
Chemotherapy (vinblastine and prednisone in combination). Based on the results of the randomized HISTSOC-LCH-III (NCT00276757) trial, the same chemotherapy regimen of vinblastine and prednisone, as described above, is used for 12 months. Patients without risk-organ involvement who were randomly assigned to receive 12 months of treatment with vinblastine/prednisone had a lower 5-year reactivation rate (37%) than did patients who received only 6 months of treatment (54%; P = .03) and patients treated with historical 6-month schedules (52% [HISTSOC-LCH-I] and 48% [HISTSOC-LCH-II]; P < .001). Most disease reactivations were in bone, skin, or other non-risk locations.[29]
Patients with low-risk multisystem LCH have a survival rate of almost 100%, but reactivations were shown to be major risk factors for significant late effects on the DAL and Histiocyte Society trials.[29,76]
Chemotherapy (other regimens). Other chemotherapy regimens have also been effective, including the following:
Vincristine, cytarabine, and prednisone in combination.[108][Level of evidence C2] This combination has proven effectiveness as frontline or salvage therapy. However, prednisone is now given for a much shorter time than was originally published (52 weeks): 4 weeks at 40 mg/m2 then tapered to 20 mg/m2 by week 6 during the induction phase, and for 5 days every 3 weeks at 20 mg/m2 with a single dose of vincristine and 5 days of cytarabine during maintenance.
Cladribine. Cladribine given at 5 mg/m2 per day for 5 days every 3 weeks for two to six cycles can be an effective salvage therapy for recurrent bone or low-risk multisystem disease.[109][Level of evidence C2] More than six cycles is not recommended because of the risk of cumulative cytopenias.
Bisphosphonate therapy. Bisphosphonate therapy can also be effective for treating LCH bone lesions.[110,111][Level of evidence C2] A nationwide survey from Japan described 16 children treated with bisphosphonates for bone LCH. None had risk-organ disease. Most patients received six cycles of pamidronate at 1 mg/kg per course given at 4-week intervals. In 12 of 16 patients, all active lesions including skin (n = 3) and soft tissues (n = 3) resolved. Eight patients remained disease free at a median of 3.3 years.[112] Other bisphosphonates such as zoledronate have been used to successfully treat bone LCH.[113]
Although bisphosphonates are used for bone LCH, some publications report response in other organs, such as skin.[111,112]
CNS disease
CNS lesions
CNS LCH lesions include the following:
Mass lesions or tumors in the cerebrum, cerebellum, or choroid plexus.
Mass lesions of the hypothalamic-pituitary axis that are always associated with diabetes insipidus and are often associated with other endocrinopathies.
Drugs that cross the blood-brain barrier, such as cladribine, or other nucleoside analogs, such as cytarabine, are used for active CNS LCH lesions.
Treatment options for patients with CNS LCH lesions include the following:
Chemotherapy (cladribine). Treatment of mass lesions with cladribine has been effective in 13 reported cases.[114,115]; [116][Level of evidence C2] Mass lesions included enlargement of the hypothalamic-pituitary axis, parenchymal mass lesions, and leptomeningeal involvement. Doses of cladribine ranged from 5 mg/m2 to 13 mg/m2, given at varying frequencies.[116][Level of evidence C2]
Chemotherapy (other regimens). Patients with LCH and mass lesions in the hypothalamic-pituitary region, the choroid plexus, the grey matter, or the white matter may also respond to standard LCH chemotherapy.[117,118][Level of evidence C3] Treatment with vinblastine with or without corticosteroids for patients with CNS mass lesions (20 patients; mainly pituitary) demonstrated objective responses in 15 patients. Of 20 patients, 5 achieved complete responses and 10 achieved partial responses.
Clinical neurodegenerative syndrome LCH (cND-LCH)
There is no established optimal therapy for cND-LCH, and assessment of response can be difficult.[119]
In cND-LCH, T2 FLAIR hyperintense signals are present, most often in the cerebellar white matter, pons, basal ganglia, and, sometimes, in the cerebrum. It is not clear whether LCH changes in the cerebellum, pons, and basal ganglia diagnosed by MRI and without clinical neurological findings should be treated. Early studies suggested that not all LCH-related radiological changes progressed to clinical neurodegenerative disease. However, treatment in the early stages of clinical disease before permanent damage occurs appears to be important. The current recommendation is ongoing neurological evaluation both clinically and with MRI scanning. Therapy starts as soon as clinical neurodegenerative disease progression is noted. It is unclear whether progressive radiological changes should be an indication for treatment.[38]
Other drugs used in active LCH, such as dexamethasone, cladribine, and infliximab, have been used in small numbers of patients with mixed results. Many of these agents may result in the complete or partial resolution of radiographic findings, but definitive clinical response rates have not been rigorously defined.[38,120–123]; [116][Level of evidence C2]
Newer treatment options for patients with cND-LCH include the following:
Clinical experience suggests that BRAF V600E inhibitor therapy may be the most effective therapy for improving neurological symptoms in cND-LCH, but the therapy may need to be continued lifelong.[82][Level of evidence C3]; [124]
Chemotherapy. A study using cytarabine with or without vincristine for up to 24 months reported improved clinical and MRI findings in some patients and stable disease in the others.[38][Level of evidence C1] Seven of eight patients were monitored for more than 8 years after stopping therapy and had stable neurological and radiographic findings.
In the Japan LCH Study Group (JLSG)-96 Protocol, cytarabine failed to prevent the onset of neurodegenerative syndrome. Patients received cytarabine 100 mg/m2 daily on days 1 to 5 during induction and 150 mg/m2 on day 1 of each maintenance cycle (every 2 weeks for 6 months). Three of 91 patients developed neurodegenerative disease, which is similar to the rate reported for patients on the Histiocyte Society studies.[125][Level of evidence B4]
Rituximab. Eight patients with neurological symptoms for a median of 8 years and who developed new symptoms after being treated with cytarabine received rituximab (375 mg/m2 weekly for 4 weeks, repeated every 3 months and increased to 555 mg/m2 for no improvement or worsening of symptoms) for variable lengths of time. Clinical symptoms improved in seven of eight patients (five patients improved within 1 month of starting rituximab). Five patients remained free of progressive clinical symptoms for 3 years or longer.[126][Level of evidence C3]
Early recognition of clinical neurodegeneration and early institution of therapy appear to be vital for success of therapy. Studies combining MRI findings together with CSF markers of demyelination, to identify patients who require therapy even before onset of clinical symptoms, are under way in several countries. Studies of CSF and serum biomarkers in an attempt to predict and prevent neurodegenerative disease are also ongoing.[119]
High-Risk Disease: Multisystem LCH
Clinical presentation of high-risk multisystem LCH
Liver (sclerosing cholangitis)
The liver may be enlarged from direct infiltration of LCH cells or as a secondary phenomenon of excess cytokines, which cause macrophage activation or infiltration of lymphocytes around bile ducts. LCH cells have a portal (bile duct) tropism that may lead to biliary damage and ductal sclerosis. Peribiliary LCH cells and, rarely, nodular masses of LCH may also be present.[127]
Sonography, CT, or MRI of the liver will show hypoechoic or low-signal intensity along the portal veins or biliary tracts when the liver is involved with LCH.[127] While ultrasonography and/or MRI-cholangiogram can be helpful in the diagnosis of this complication, liver biopsy is the only definitive way to determine whether active LCH or residual hepatic fibrosis is present. Biopsy results often show lymphocytes and biliary obstructive effects without LCH cells.[128]
Patients with hepatic LCH present with hepatomegaly (>3 cm below the costal margin in the midclavicular line) or hepatosplenomegaly and dysfunction, as evidenced by hypoproteinemia (<55 g/L, hypoalbuminemia <25 g/L), or histological findings of active disease.[29] Patients may also have elevated alkaline phosphatase, liver transaminases, and gamma glutamyl transpeptidase levels, clotting dysfunction, or present with ascites.
One of the most serious complications of hepatic LCH is cholestasis and sclerosing cholangitis.[129] This usually occurs months after initial presentation, but occasionally may be present at diagnosis. The median age of children with this form of hepatic LCH is 23 months. The natural history of sclerosing cholangitis is variable. Some patients who are treated with chemotherapy improve, while other patients have stable disease or progress from sclerosis to biliary cirrhosis and portal hypertension, which may be seen even in the absence of active LCH cells. A report of 13 patients with LCH and liver disease found that all patients had BRAF V600E variants in skin, bone, or liver biopsy samples.[130] It is not known whether the early use of inhibitor therapy in this group of patients will reduce or prevent the progression of sclerosing cholangitis. This therapy remains to be investigated.
Spleen
Massive splenomegaly (usually >2 cm below costal margin in the midclavicular line),[29] resulting from either primary involvement by LCH or from portal hypertension secondary to biliary cirrhosis, may lead to cytopenias because of hypersplenism and may cause respiratory compromise. Splenectomy typically provides only transient relief of cytopenias, as increased liver size and reticuloendothelial activation result in peripheral blood cell sequestration and destruction. Splenectomy is performed only as a life-saving measure.
Bone marrow
Most patients with bone marrow involvement are young children who have diffuse disease in the liver, spleen, lymph nodes, and skin and who present with significant thrombocytopenia (<100,000 × 109/L) and anemia (hemoglobin <10 g/dL; infants, <9 g/dL) not secondary to other causes, with or without leucopenia (<4.0 × 109/L).[29,131] Other patients have only mild cytopenias and are found to have bone marrow involvement with LCH by sensitive immunohistochemistry, flow cytometry, or PCR for analysis of BRAF-altered cells in the bone marrow.[132,133] A large number of macrophages can obscure LCH cells in the bone marrow.[134] Patients with LCH who are considered at very high risk sometimes present with hemophagocytosis in the bone marrow.[135] The cytokine milieu driving LCH is probably responsible for the epiphenomenon of macrophage activation which, in the most severe cases, presents with typical manifestations of hemophagocytic lymphohistiocytosis such as cytopenias and hyperferritinemia.
Treatment of high-risk multisystem LCH
Over many years, national and international study groups have defined risk-based therapy groups for allocation of LCH patients on the basis of mortality risk and risk of late effects of the disease.
Depending on the site and extent of disease, treatment of LCH may include observation (after biopsy or curettage), surgery, radiation therapy, or oral, topical, and intravenous medication. The recommended duration of therapy is 12 months for patients who require chemotherapy for single-system bone, skin, or lymph node involvement.
For patients with high-risk and low-risk multisystem disease, the reactivation rate after 6 months of therapy was as high as 50% on the HISTSOC-LCH-I and HISTSOC-LCH-II trials.[28,85] The German-Austrian-Dutch (DAL) group trials treated patients for 1 year and had fewer relapses (29%).[76,85] On the basis of these findings, the HISTSOC-LCH-III trial was designed to administer 12 months of chemotherapy for all high-risk multisystem patients and to randomly assign low-risk multisystem patients to either 6 months or 12 months of therapy. In patients with low-risk or high-risk disease who received 12 months of therapy, the reactivation rate was significantly reduced to approximately 30%.[29]
The standard treatment for LCH is based on data from international trials with large numbers of patients. However, some patients may have LCH involving only the skin, mouth, pituitary gland, or other sites not studied in these international trials. In these cases, therapy recommendations are based on case series that lack the evidence-based strength of the trials.
Clinical trials organized by the Histiocyte Society have been accruing patients on childhood treatment studies since the 1980s. Information about centers enrolling patients on these trials can be found on the ClinicalTrials.gov website.
Treatment options for patients with high-risk multisystem disease (spleen, liver, and bone marrow involving one or more sites) include the following:
In the HISTSOC-LCH-II and HISTSOC-LCH-III (NCT00276757) studies, the standard treatment arm consisted of vinblastine and prednisone, as described above, but mercaptopurine was added to the continuation phase of the protocol.[27,76][Level of evidence A1]
The standard therapy length recommended for LCH involving the spleen, liver, or bone marrow (high-risk organs) is now 12 months, based on the DAL-HX 83 and HISTSOC-LCH-III studies.
In the HISTSOC-LCH-II study, patients were randomly assigned to treatment with either vinblastine, prednisone, and mercaptopurine or vinblastine, prednisone, mercaptopurine, and etoposide.[28][Level of evidence A1]
There was no statistically significant difference in outcomes (response at 6 weeks, 5-year probability of survival, relapses, and permanent consequences) between the two treatment groups. Hence, etoposide has not been used in subsequent Histiocyte Society trials.
Late review of the results, however, reported reduced mortality for patients with risk-organ involvement in the etoposide arm.
Although controversial, a comparison of patients in the HISTSOC-LCH-I trial with patients in the HISTSOC-LCH-II trial suggested the following results:[26]
Increased treatment intensity promoted additional early responses and reduced mortality.
It is important to note that those studies included lungs as risk organs. However, subsequent analyses have shown that lung involvement lacks prognostic significance.
In the HISTSOC-LCH-III (NCT00276757) study, risk-organ–affected patients were randomly assigned to receive either vinblastine/prednisone/mercaptopurine or vinblastine/prednisone/mercaptopurine plus methotrexate (intravenous during the induction phase and oral in the continuation phase).[29]
The response rates at 6 and 12 weeks and OS were no different between arms; however, there were significantly increased grade 3 and grade 4 toxicities in patients who received methotrexate.
An important finding of the HISTSOC-LCH-III study was that the survival of patients with high-risk LCH on both arms of the study was significantly improved compared with that of patients on the earlier HISTSOC-LCH-II study, even though the standard arm used the same drugs. Possible explanations for better survival include the following:
A second 6-week induction phase of weekly vinblastine with oral prednisone was administered for 3 days per week. This reinduction phase was given to all patients who did not achieve an NAD status by the end of the 6-week induction phase, before going onto the every-3-weeks maintenance courses. The rate of NAD increased after the second induction phase; this course may have played a significant role in the improved survival rate.
Better supportive care.
Earlier change to an effective salvage strategy for nonresponsive lesions.
It should be noted that although survival was improved in the HISTSOC-LCH-III study, only 60% of patients achieved an NAD status in risk organs after a year of therapy, and 25% to 29% of patients relapsed.
In the JLSG-96 trial, treatment included a 6-week induction regimen of cytarabine, vincristine, and prednisolone followed by 6 months of maintenance therapy with cytarabine, vincristine, prednisolone, and low-dose intravenous methotrexate. If patients had a poor response to the initial regimen, they were switched to a salvage regimen of intensive combination doxorubicin, cyclophosphamide, methotrexate, vincristine, and prednisolone.[125][Level of evidence B1]
The 5-year response rate was 78%, and the OS rate was 95% for patients with multisystem disease.
Diabetes insipidus occurred in 8.9% of patients with multisystem disease.
Similar to the HISTSOC-LCH-III (NCT00276757) study, the important finding of this study was the increased survival compared with previous JLSG studies and the HISTSOC-LCH-II study. This was attributed to the early change to a more effective salvage therapy for patients with nonresponsive disease, as well as better supportive care.
The study had a high reactivation rate, which prompted several changes, including an increase in the duration of the trial to 12 months and the addition of vinblastine, prednisone, mercaptopurine, and methotrexate.[62]
The JLSG-02 protocol was similar to the JLSG-96 study, except that cyclosporine was added to the reinduction of poor responders and the length of treatment was increased to 54 weeks for good responders and 60 weeks for poor responders.[136][Level of evidence B1]
Despite a markedly increased intensity of treatment, the event-free survival (EFS) rates were only 46% for high-risk patients and 70% for low-risk patients. In the HISTSOC-LCH-III study, the EFS rates were 33% for high-risk patients and 50% for low-risk patients.[137]
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 are examples of national and/or institutional clinical trials that are currently being conducted:
HISTSOC-LCH-IV (NCT02205762) (LCH-IV, International Collaborative Treatment Protocol for Children and Adolescents With LCH): On the basis of features at presentation and response to treatment, the LCH-IV study tailors treatment to one of the following seven strata:
Stratum I: First-line treatment for multisystem LCH patients (group 1) and patients with single-system LCH with multifocal bone or CNS-risk lesions (group 2).
Stratum II: Second-line treatment for non–risk-organ patients (patients without risk-organ involvement who fail first-line therapy or have a reactivation after completion of first-line therapy).
Stratum III: Salvage treatment for risk-organ LCH (patients with dysfunction of risk organs who fail first-line therapy).
Stratum IV: Hematopoietic stem cell transplant for risk-organ LCH (patients with dysfunction of risk organs who fail first-line therapy).
Stratum V: Monitoring and treatment of isolated tumorous and neurodegenerative CNS LCH.
Stratum VI: Natural history and management of other single-system LCH (patients who do not need systemic therapy at the time of diagnosis).
Stratum VII (long-term follow up): All patients, regardless of previous therapy, will be monitored for reactivation or permanent consequences once complete disease resolution has been achieved and the respective protocol treatment has been completed.
NCT02670707 (Cytarabine or Vinblastine Sulfate and Prednisone in Treating Patients With LCH): The purpose of this trial is to compare previously used vinblastine/prednisone to single therapy with cytarabine for LCH.
It is preferable that patients with LCH be enrolled in a clinical trial whenever possible so that advances in therapy can be achieved more quickly, using evidence-based recommendations, and to ensure optimal care. Information about clinical trials for LCH in children is available from the NCI website, Histiocyte Society website, and the North American Consortium for Histiocytosis (NACHO) 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.
Recurrent, Refractory, or Progressive Childhood LCH
Reactivation of single-system and multisystem LCH
Reactivation of LCH after complete response is common.[138] In a large study, the percentage of patients with reactivations was 9% to 17.4% for single-site disease; 37% for single-system, multifocal disease; 46% for multisystem (non–risk-organ) disease; and 54% for risk-organ involvement. Forty-three percent of reactivations were in bone, 11% in ears, 9% in skin, and 7% developed diabetes insipidus; a lower percentage of patients had lymph node, bone marrow, or risk-organ relapses.[138] The median time to reactivation was 12 to 15 months in non-risk patients and 9 months in high-risk patients. One-third of patients had more than one reactivation, varying from 9 to 14 months after the initial reactivation. Patients with reactivations were more likely to have long-term sequelae in the bones, diabetes insipidus, or other endocrine, ear, or lung problems.[138]
A comprehensive review of the German-Austrian-Dutch (DAL) and Histiocyte Society clinical trials revealed a reactivation rate of 46% at 5 years for patients with multisystem LCH, with most reactivations occurring within 2 years of first remission. A second reactivation occurred in 44% of patients, again within 2 years of the second remission. Involvement of the risk organs in these reactivations occurred only in those who were initially in the high-risk group (meaning they had liver, spleen, or bone marrow involvement at the time of original diagnosis).[84][Level of evidence C2] Most reactivations, even in patients with high-risk disease who initially responded to therapy, were in bone, skin, or other low-risk locations.
Consistent with these findings, the percentage of reactivations in multisystem disease was 45% in one trial from Japan [125][Level of evidence A1] and 46% in the HISTSOC-LCH-II trial.[28] There was no statistically significant difference in reactivations between the high-risk and low-risk groups. The DAL-HX studies and the studies from Japan concluded that intensified treatment increased the rapidity of response, particularly in young children and infants younger than 2 years, and together with rapid switch to salvage therapy for nonresponders, mortality was reduced for patients with high-risk multisystem LCH. Based on the HISTSOC-LCH-III (NCT00276757) randomized trial, prolongation of therapy also significantly reduced the rate of reactivation. The optimal duration of therapy (12 vs. 24 months) is being addressed in the HISTSOC-LCH-IV (NCT02205762) trial.
Treatment of recurrent, refractory, or progressive low-risk disease: single-system or multisystem LCH
The optimal therapy for patients with recurrent, refractory, or progressive LCH has not been determined.
Treatment options for patients with recurrent, refractory, or progressive low-risk, single-system or multisystem LCH include the following:
The following chemotherapy regimens have been used to treat patients with recurrent, refractory, or progressive low-risk disease:
Vinblastine and prednisone. Patients with recurrent bone disease that recurs months after vinblastine and prednisone are stopped can benefit from treatment with a reinduction of vinblastine weekly and daily prednisone for 6 weeks. If there is NAD or very little evidence of active disease, treatment can be changed to every 3 weeks, with the addition of oral mercaptopurine nightly.[106]
Vincristine, prednisone, and cytarabine. An alternative treatment regimen for patients with any combination of low-risk disease sites employs vincristine, prednisone, and cytarabine.[108][Level of evidence C3]
Single-agent cytarabine. Single-agent cytarabine at doses of 100 to 170 mg/m2 per day for five days has also proven to be effective.[139]
Cladribine. Cladribine at 5 mg/m2 per day for 5 days per course has demonstrated effectiveness for recurrent low-risk LCH (multifocal bone and low-risk multisystem LCH), with very little toxicity.[109][Level of evidence C3] Cladribine therapy should, if possible, be limited to a maximum of six cycles to avoid cumulative and potentially long-lasting cytopenias.
In a study of 44 pediatric patients with low-risk LCH who were treated with cladribine, 5 patients achieved complete remissions after a median follow-up of over 5 years.[140] Grade 3 or higher neutropenia occurred in 32% of patients, and grade 3 or higher lymphopenia occurred in 72% of patients. Patients with stable disease or partial responses after 6 months of treatment may ultimately attain a complete response.
Clofarabine. Clofarabine is a proven effective therapy for patients with multiple relapses of low-risk or high-risk LCH.[141][Level of evidence C3]
Hydroxyurea, alone or in combination with oral methotrexate. In one single-center trial, treatment with hydroxyurea, alone or in combination with oral methotrexate, reported the following results:[87][Level of evidence C3]
Twelve of fifteen patients with low-risk recurrent LCH had responses to treatment.
Thalidomide. A phase II trial of thalidomide in patients with LCH (ten low-risk patients; six high-risk patients) who failed primary treatment and at least one secondary regimen demonstrated the following:[88][Level of evidence C3]
Of the ten low-risk patients, four had complete responses and three had partial responses. Complete response was defined as healing of bone lesions on plain radiographs (n = 3) or complete resolution of skin rash (n = 4, including 3 with bone lesions that had complete resolution). Partial response was defined as healing of a bone lesion, but then worsening of a skin rash that was partially resolved.
Dose-limiting toxicities, such as neuropathy and neutropenia, may limit the overall usefulness of thalidomide.
Thalidomide is not a significant agent in treating pediatric patients.
Bisphosphonate therapy
Bisphosphonate therapy is also effective for treating patients with recurrent LCH bone lesions.[142]
Evidence (bisphosphonate therapy):
In a survey from Japan, 16 patients with bone lesions were treated with bisphosphonate therapy. None of the patients had risk-organ disease. Most patients received six cycles of pamidronate at 1 mg/kg per course, given at 4-week intervals.[110][Level of evidence C3]
Of the 16 patients, 12 were successfully treated.
Skin and soft tissue LCH lesions also resolved in the responding patients.
Eight of the 12 patients remained disease free at a median of 3.3 years.
Other bisphosphonates, such as zoledronate and oral alendronate, have also been successful in treating bone LCH.[111–113][Level of evidence C3]
Treatment of recurrent, refractory, or progressive high-risk disease: multisystem LCH
Data from the DAL group studies showed that patients with high-risk multisystem LCH who had progressive disease by week 6 of standard induction treatment or who did not achieve at least a partial response by week 12 had only a 10% chance of survival.[27] These results were consistent with those of the less-intensive HISTSOC-LCH-II trial in which patients treated with vinblastine/prednisone who did not respond well by week 6 had a 27% chance of survival, compared with 52% for good responders.[28][Level of evidence A1] To improve on these results, patients with poorly responsive disease need to move to salvage strategies by week 6 for progressive disease and no later than week 12 for those without at least a good response.
Treatment options for patients with recurrent, refractory, or progressive high-risk multisystem LCH include the following:
Ten patients with refractory high–risk-organ involvement (liver, spleen, or bone marrow) and resistant multisystem low–risk-organ involvement were treated with an intensive acute myeloid leukemia–like protocol consisting of cladribine and cytarabine.[143][Level of evidence C3] The follow-up HISTSOC-LCH-S-2005 trial accrued 27 patients and demonstrated the following results:[144]
The progression-free survival rate was 63%, and the 5-year OS rate was 85% in this refractory, high-risk patient population.
All patients developed grade 4 hematologic toxicity, and five of these patients had severe sepsis.
For centers that cannot provide the intensive supportive care needed for this protocol, an alternative protocol using lower doses of cladribine (5 mg/m2/day × 5 days) and cytarabine (100 mg/m2/day × 4 days) was published.[145][Level of evidence C2]
Six of nine patients achieved NAD status, and one patient had improved status after six courses.
Some patients received maintenance therapy.
Seven of nine patients remained in complete remission, with a median follow-up of 6.5 years.
Clofarabine
Patients who did not respond to treatment with cladribine were reported to respond to treatment with clofarabine.[146]; [147][Level of evidence C2]
Evidence (clofarabine):
Eleven patients with recurrent multisystem high-risk and low-risk disease were treated with clofarabine.[141]
The OS rate was 90%.
If confirmed in prospective trials, the reduced toxicity of this regimen compared with the cladribine/cytarabine combination could be advantageous, despite the cost of the drug.
Targeted therapy
MAPK inhibitors
The discovery that most patients with LCH have BRAF V600E or other variants that result in activation of the RAS pathway suggests that new therapies that target molecules within this pathway (MAP2K/ERK inhibitors) will become an important part of LCH therapy.
Evidence (vemurafenib):
Forty-four LCH patients with risk-organ involvement and ten LCH patients without risk-organ involvement were treated with vemurafenib. Of the 44 risk-organ–involved patients, 31 received vemurafenib as their original therapy and 13 received vemurafenib as treatment after disease progression. The ten risk-organ–negative patients also received vemurafenib after disease progression.[148][Level of evidence C3]
After 8 weeks of treatment, there were 38 complete responses and 16 partial responses. Most patients were treated for 6 months.
Thirty patients stopped taking vemurafenib; 24 of these patients subsequently relapsed: 72% of patients at 6 months and 84% of patients at 12 months off therapy.
The relapse rate was 95% for patients with risk-organ involvement and 57% for patients without risk-organ involvement.
Relapse was associated with the persistence of circulating BRAF-positive cells.
The most frequent adverse effects of the drug were dermatologic. In a review of 57 patients with LCH who received vemurafenib for refractory disease, 72% of patients had cutaneous adverse events, 86% of which were grade 1 or grade 2.[149] Most patients had photosensitivity, keratosis pilaris, macular or follicular rashes, or xerosis. No skin tumors were observed.
A systematic review and meta-analysis evaluated the efficacy and safety of vemurafenib for the treatment of patients with LCH. The analysis found 416 studies, 22 of which fit the inclusion criteria. There were 104 patients with relapsed or refractory disease and 3 patients with newly diagnosed disease.[150]
With vemurafenib treatment, the median time to first response was 1 week and the median time to best response was 5.25 months.
Sixty-two patients (58%) achieved NAD status, and 36% had decreased active disease.
The overall response rate was 94.4%.
Major toxicity included rash and photosensitivity.
The authors concluded that vemurafenib was highly efficacious and safe to treat patients with refractory LCH, but the duration of therapy has yet to be established.
A multicenter, retrospective analysis of experiences that used various MAPK inhibitors to treat 21 pediatric patients with LCH who had failed at least one previous therapy (median, three previous therapies) demonstrated the following:[124][Level of evidence C3]
An overall response rate of 86% (complete response, 19%; partial response, 67%).
Stable disease in 10% of patients.
The most frequent toxicities were skin rashes and arthralgias. Other toxicities included neutropenia, fatigue, and uveitis.
Evidence (dabrafenib with or without trametinib):
One study compared dabrafenib alone (13 patients) with dabrafenib and trametinib (12 patients) for the treatment of patients with relapsed or progressive LCH.[151]
With a 2-year follow-up, the responses were similar in both arms (46.2% complete response, 30.8% regressive disease, and 23.1% stable disease for dabrafenib alone vs. 33.3% complete response, 25.0% regressive disease, and 25.0% stable disease for combination therapy).
Adverse events were also similar and included pyrexia and vomiting, cough, and increased serum creatinine.
This study would suggest that combination therapy is not more effective in patients with LCH. However, more data are needed.
Although malignancies such as squamous cell carcinoma have been reported in adults treated with MAPK inhibitors, such malignancies have not been reported in pediatric patients.[149] Like adults, children develop acneform rashes, photosensitivity, diarrhea, and, sometimes, myalgias.[124]
Tyrosine kinase inhibitors
Evidence (tyrosine kinase inhibitors):
Imatinib has been shown to decrease differentiation of CD34-positive stem cells to dendritic cells. Small case reports of its efficacy in patients with LCH have been published.[152,153]
Hematopoietic stem cell transplant (HSCT)
HSCT has been used in patients with multisystem high–risk-organ involvement that is refractory to chemotherapy.[142,154–157] Early results showing very high treatment-related mortality in these ill young infants led to the development of reduced-intensity conditioning.
Evidence (reduced-intensity conditioning vs. myeloablative conditioning for HSCT):
A review from the United Kingdom suggested that in transplant centers that have LCH HSCT experience, there was no advantage to reduced-intensity conditioning in their setting.[158][Level of evidence C2]
Reduced-intensity conditioning provided no OS advantage over myeloablative conditioning for LCH patients; the relapse rate after reduced-intensity conditioning was significantly higher (28%) than the relapse rate after myeloablative conditioning (8%).
Many of the patients who received reduced-intensity conditioning and relapsed were successfully re-treated with chemotherapy alone.
Treatment options for sclerosing cholangitis and macrophage activation
Seventy-five percent of children with sclerosing cholangitis will not respond to chemotherapy because the LCH is no longer active, but the fibrosis and sclerosis remain. Despite the limitations, liver biopsy may be the only way to distinguish active LCH from end-stage fibrosis. Liver transplant is the only alternate treatment when hepatic function worsens. A review of 60 patients with LCH (55 children) who underwent hepatic transplant for LCH-associated liver failure reported a 5-year survival rate of 82%. Posttransplant rejection occurred in 55% of patients, 22% of whom received a second transplant. The 5-year overall graft survival rate was 62% for patients who underwent deceased-donor liver transplant and 81% for patients who underwent living-donor liver transplant (not statistically significant). Nine patients died (15%). There was one case of posttransplant lymphoproliferative disease (PTLD), and no data on LCH recurrences. The authors conducted a literature review to identify an additional 50 patients with LCH who underwent a liver transplant. Of these patients, 47% experienced rejection, 11% had PTLD, and 8% had recurrent LCH. Seven patients (14%) with graft loss were treated with retransplant.[159][Level of evidence C2]
Case reports and case series have documented the efficacy of MAPK inhibitors for the treatment of progressive hepatic LCH.[148,160]
Some patients develop a macrophage activation of their marrow. This could be confusing to clinicians, who may think the patient has hemophagocytic lymphohistiocytosis (HLH) and LCH. The best therapy for this life-threatening manifestation is not clear because it tends not to respond well to standard HLH therapy. Clofarabine, anti-CD52 antibody alemtuzumab, or reduced-intensity allogeneic stem cell transplant could be considered.[161][Level of evidence C3] It is unknown whether newer HLH therapies, such as the antibody to interferon-gamma or the JAK-STAT inhibitor ruxolitinib, will be more effective in the LCH-macrophage activation than the above options.
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:
NCT04079179 (Cobimetinib for the Treatment of Refractory LCH): This study is open to children or adults with relapsed or refractory LCH or other newly diagnosed, relapsed, or refractory histiocytic disorders.
Assessment of Response to Treatment
Response assessment remains one of the most difficult areas in LCH therapy. It is easier when there is a specific area that can be monitored clinically or with ultrasonography, CT, PET, or MRI scans, such as the skin, hepato/splenomegaly, and other mass or lytic bone lesions. Clinical judgment, including evaluation of pain and other symptoms, remains important.
Bone lesions may take many months to heal and are difficult to evaluate on plain radiographs, although sclerosis around the periphery of a bone lesion suggests healing. CT or MRI scans are useful in assessing response of a soft tissue mass associated with a bone lesion, but are not particularly helpful in assessing the response of lytic bone lesions. Technetium Tc 99m bone scans remain positive in healing bone. PET scans may be helpful in monitoring the response to therapy because the intensity of the PET image diminishes with the response of lesions and healing of bone.[17]
For children or adults with lung LCH, pulmonary function testing and high-resolution CT scans are sensitive methods for detecting disease progression.[20] Residual interstitial changes reflecting residual fibrosis or residual inactive cysts must be distinguished from active disease; somatostatin analog scintigraphy may be useful in this regard.[162]
Treatment Options No Longer Considered Effective for Childhood LCH
Treatments that have been used in the past but are no longer recommended for pediatric patients with LCH include cyclosporine [163] and interferon-alpha.[164]
Extensive surgery is also not indicated. For lesions of the mandible, extensive surgery may destroy any possibility of secondary tooth development. Surgical resection of groin or genital lesions is contraindicated because these lesions can be healed by chemotherapy.
Radiation therapy use in LCH has been significantly reduced in pediatric patients, and even low-dose radiation therapy should be limited to single-bone, vertebral body lesions or other single-bone lesions compressing the spinal cord or optic nerve that do not respond to chemotherapy or are painful and not amenable to other therapy.[94,101,165]
Late Disease and Treatment Effects of Childhood LCH
The reported frequency of long-term consequences of LCH has ranged from 20% to 70%. Children with low–risk-organ involvement (skin, bones, lymph nodes, or pituitary gland) have an approximately 20% chance of developing long-term sequelae.[30,166]; [167][Level of evidence B4] Patients with multisystem involvement have a reported rate of long-term complications of approximately 70% when treatment was only 6 months.[30,101,168,169] However, the extent of long-term sequelae in patients who are treated for a year has not been reported.
This wide variation in frequency results from case definition, sample size, therapy used, method of data collection, and follow-up duration. Quality-of-life studies have reported the following:
In one study of long-term survivors of skeletal LCH, the quality-of-life scores were not significantly different from those of healthy control children and adults.[104] In addition, the quality-of-life scores were very similar between those with and without permanent sequelae.
In another study of 40 patients who were carefully screened for late effects, adverse quality-of-life scores were found in more than 50% of patients.[40] Seventy-five percent of patients had detectable long-term sequelae. Hypothalamic/pituitary dysfunction (50%), cognitive dysfunction (20%), and cerebellar involvement (17.5%) were the most common side effects.
The late effects of LCH may occur in the following body systems:
Endocrine. Patients with diabetes insipidus are at risk of panhypopituitarism and should be monitored carefully for adequacy of growth and development. In a retrospective review of 141 patients with LCH and diabetes insipidus, 43% developed growth hormone (GH) deficiency.[101,168,169] The 5-year risk of GH deficiency among children with LCH and diabetes insipidus was 35%, and the 10-year risk was 54%. There was no increased reactivation of LCH in patients who received GH compared with those who did not.[168] Growth and development problems are more frequent because of the young age at presentation and the more toxic effects of long-term prednisone therapy in the very young child.
Special senses (hearing loss). Hearing loss has been found in 38% of children who were treated for LCH.[101] Seventy percent of patients with LCH in this study had ear involvement, which included aural discharge, mastoid swelling, and hearing loss. Of those with CT or MRI abnormalities in the mastoid, 59% had hearing loss.[170][Level of evidence C1]
Neurological. Neurological symptoms secondary to vertebral compression of cervical lesions have been reported in 3 of 26 patients with LCH and spinal lesions.[101] CNS LCH occurs most often in children with LCH of the pituitary or CNS-risk skull bones (mastoid, orbit, or temporal bone). Significant cognitive defects and MRI abnormalities may develop in some long-term survivors with CNS-risk skull lesions.[171] Some patients have markedly abnormal cerebellar function and behavior abnormalities, while others have subtle deficits in short-term memory and brain stem–evoked potentials.[83]
Skeletal. Orthopedic problems from lesions of the spine, femur, tibia, or humerus may be seen in 20% of patients. These problems include vertebral collapse or instability of the spine that may lead to scoliosis and facial or limb asymmetry.
Respiratory. Diffuse pulmonary disease may result in poor lung function with higher risk of infections and decreased exercise tolerance. These patients should be monitored with pulmonary function testing, including the diffusing capacity of carbon monoxide and ratio of residual volume to total lung capacity.[39]
Digestive. Liver disease may lead to sclerosing cholangitis, which rarely responds to any treatment other than liver transplant.[129] Dental problems characterized by loss of teeth have been significant for some patients, usually related to overly aggressive dental surgery.[172]
Subsequent neoplasms. Bone marrow failure secondary to LCH or from therapy is rare and is associated with a higher risk of malignancy. Patients with LCH have a higher-than-normal risk of developing secondary cancers.[173,174]
Leukemia (usually acute myeloid leukemia) occurs after treatment, as does lymphoblastic lymphoma. Concurrent LCH and malignancy has been reported in a few patients, and some patients had their malignancy first, followed by development of LCH. Three patients with T-cell acute lymphoblastic leukemia (ALL) and aggressive LCH were reported and, as with all histiocytic disorders associated with or following lymphoblastic malignancies, the same genetic changes were found in both diseases, suggesting a shared clonal origin.[175–177] One study reported two cases in which clonality with the same T-cell receptor gamma genotype was found.[176] The authors of this study emphasized the plasticity of lymphocytes developing into Langerhans cells. The second study described one patient with LCH after T-cell ALL who had the same T-cell receptor gene rearrangements and activating variants of the NOTCH1 gene.[177]
A publication based on surveying Histiocyte Society members and a literature review reported 116 cases of childhood LCH-malignancy pairs. Leukemias and myeloproliferative disorders (n = 58; 50.0%) prevailed over solid tumors (n = 43; 37.1%) and lymphomas (n = 15; 12.9%). In most children, malignancy followed LCH (n = 69; 59.5%). However, ALL, including T-cell ALL, was sometimes seen preceding the onset of LCH or histiocytic neoplasms. The histiocytic disorder commonly carried the same underlying genetic findings as the preceding leukemia.[178]
Another study reported a population-based analysis of subsequent malignancies in pediatric patients in the Surveillance, Epidemiology, and End Results (SEER) Program database from 2000 to 2016.[179] Of the 936 pediatric cases, there were 2 cases of non-Hodgkin lymphoma, 2 cases of Hodgkin lymphoma, and 1 case of T-cell ALL. However, the median follow-up was 38 months, which may not be sufficient to capture secondary solid tumors.
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Favara BE, Jaffe R, Egeler RM: Macrophage activation and hemophagocytic syndrome in langerhans cell histiocytosis: report of 30 cases. Pediatr Dev Pathol 5 (2): 130-40, 2002 Mar-Apr. [PUBMED Abstract]
Morimoto A, Shioda Y, Imamura T, et al.: Intensified and prolonged therapy comprising cytarabine, vincristine and prednisolone improves outcome in patients with multisystem Langerhans cell histiocytosis: results of the Japan Langerhans Cell Histiocytosis Study Group-02 Protocol Study. Int J Hematol 104 (1): 99-109, 2016. [PUBMED Abstract]
Allen CE, Merad M, McClain KL: Langerhans-Cell Histiocytosis. N Engl J Med 379 (9): 856-868, 2018. [PUBMED Abstract]
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Simko SJ, McClain KL, Allen CE: Up-front therapy for LCH: is it time to test an alternative to vinblastine/prednisone? Br J Haematol 169 (2): 299-301, 2015. [PUBMED Abstract]
Barkaoui MA, Queheille E, Aladjidi N, et al.: Long-term follow-up of children with risk organ-negative Langerhans cell histiocytosis after 2-chlorodeoxyadenosine treatment. Br J Haematol 191 (5): 825-834, 2020. [PUBMED Abstract]
Simko SJ, Tran HD, Jones J, et al.: Clofarabine salvage therapy in refractory multifocal histiocytic disorders, including Langerhans cell histiocytosis, juvenile xanthogranuloma and Rosai-Dorfman disease. Pediatr Blood Cancer 61 (3): 479-87, 2014. [PUBMED Abstract]
Kudo K, Ohga S, Morimoto A, et al.: Improved outcome of refractory Langerhans cell histiocytosis in children with hematopoietic stem cell transplantation in Japan. Bone Marrow Transplant 45 (5): 901-6, 2010. [PUBMED Abstract]
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Donadieu J, Bernard F, van Noesel M, et al.: Cladribine and cytarabine in refractory multisystem Langerhans cell histiocytosis: results of an international phase 2 study. Blood 126 (12): 1415-23, 2015. [PUBMED Abstract]
Rosso DA, Amaral D, Latella A, et al.: Reduced doses of cladribine and cytarabine regimen was effective and well tolerated in patients with refractory-risk multisystem Langerhans cell histiocytosis. Br J Haematol 172 (2): 287-90, 2016. [PUBMED Abstract]
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Donadieu J, Larabi IA, Tardieu M, et al.: Vemurafenib for Refractory Multisystem Langerhans Cell Histiocytosis in Children: An International Observational Study. J Clin Oncol 37 (31): 2857-2865, 2019. [PUBMED Abstract]
Tardieu M, Néron A, Duvert-Lehembre S, et al.: Cutaneous adverse events in children treated with vemurafenib for refractory BRAFV600E mutated Langerhans cell histiocytosis. Pediatr Blood Cancer 68 (9): e29140, 2021. [PUBMED Abstract]
Mohapatra D, Gupta AK, Haldar P, et al.: Efficacy and safety of vemurafenib in Langerhans cell histiocytosis (LCH): A systematic review and meta-analysis. Pediatr Hematol Oncol 40 (1): 86-97, 2023. [PUBMED Abstract]
Whitlock JA, Geoerger B, Dunkel IJ, et al.: Dabrafenib, alone or in combination with trametinib, in BRAF V600-mutated pediatric Langerhans cell histiocytosis. Blood Adv 7 (15): 3806-3815, 2023. [PUBMED Abstract]
Janku F, Amin HM, Yang D, et al.: Response of histiocytoses to imatinib mesylate: fire to ashes. J Clin Oncol 28 (31): e633-6, 2010. [PUBMED Abstract]
Akkari V, Donadieu J, Piguet C, et al.: Hematopoietic stem cell transplantation in patients with severe Langerhans cell histiocytosis and hematological dysfunction: experience of the French Langerhans Cell Study Group. Bone Marrow Transplant 31 (12): 1097-103, 2003. [PUBMED Abstract]
Nagarajan R, Neglia J, Ramsay N, et al.: Successful treatment of refractory Langerhans cell histiocytosis with unrelated cord blood transplantation. J Pediatr Hematol Oncol 23 (9): 629-32, 2001. [PUBMED Abstract]
Caselli D, Aricò M; EBMT Paediatric Working Party: The role of BMT in childhood histiocytoses. Bone Marrow Transplant 41 (Suppl 2): S8-S13, 2008. [PUBMED Abstract]
Kudo K, Maeda M, Suzuki N, et al.: Nationwide retrospective review of hematopoietic stem cell transplantation in children with refractory Langerhans cell histiocytosis. Int J Hematol 111 (1): 137-148, 2020. [PUBMED Abstract]
Veys PA, Nanduri V, Baker KS, et al.: Haematopoietic stem cell transplantation for refractory Langerhans cell histiocytosis: outcome by intensity of conditioning. Br J Haematol 169 (5): 711-8, 2015. [PUBMED Abstract]
Ziogas IA, Kakos CD, Wu WK, et al.: Liver Transplantation for Langerhans Cell Histiocytosis: A US Population-Based Analysis and Systematic Review of the Literature. Liver Transpl 27 (8): 1181-1190, 2021. [PUBMED Abstract]
Lee LH, Krupski C, Clark J, et al.: High-risk LCH in infants is serially transplantable in a xenograft model but responds durably to targeted therapy. Blood Adv 4 (4): 717-727, 2020. [PUBMED Abstract]
Jordan MB, McClain KL, Yan X, et al.: Anti-CD52 antibody, alemtuzumab, binds to Langerhans cells in Langerhans cell histiocytosis. Pediatr Blood Cancer 44 (3): 251-4, 2005. [PUBMED Abstract]
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Egeler RM, Neglia JP, Aricò M, et al.: The relation of Langerhans cell histiocytosis to acute leukemia, lymphomas, and other solid tumors. The LCH-Malignancy Study Group of the Histiocyte Society. Hematol Oncol Clin North Am 12 (2): 369-78, 1998. [PUBMED Abstract]
Castro EC, Blazquez C, Boyd J, et al.: Clinicopathologic features of histiocytic lesions following ALL, with a review of the literature. Pediatr Dev Pathol 13 (3): 225-37, 2010 May-Jun. [PUBMED Abstract]
Feldman AL, Berthold F, Arceci RJ, et al.: Clonal relationship between precursor T-lymphoblastic leukaemia/lymphoma and Langerhans-cell histiocytosis. Lancet Oncol 6 (6): 435-7, 2005. [PUBMED Abstract]
Rodig SJ, Payne EG, Degar BA, et al.: Aggressive Langerhans cell histiocytosis following T-ALL: clonally related neoplasms with persistent expression of constitutively active NOTCH1. Am J Hematol 83 (2): 116-21, 2008. [PUBMED Abstract]
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Adult LCH
The natural history of disease in adults with Langerhans cell histiocytosis (LCH) is poorly understood. Pulmonary LCH is the exception to this finding. Delays of many months or years commonly occur before adults are diagnosed, and they have long-term issues with chronic pain and fatigue. There are other differences from childhood LCH, including frequency of various bone sites of disease. It also appears that multisystem high-risk LCH in adults may be less aggressive than high-risk disease in children. A consensus group reported on the evaluation and treatment of adult patients with LCH.[1] However, treatment discussions continue, particularly regarding optimal first-line therapy.
A multicenter retrospective review of 219 adult patients (aged >18 years) with LCH was conducted to assess long-term outcomes. The median follow-up was 74 months. The 5-year disease-free survival rate was 58%, and the overall survival (OS) rate was 88%. About one-third of deaths were LCH-related and occurred within 5 years of diagnosis. Second cancers occurred in 16.4% of cases (both hematologic and solid tumors). Deaths that occurred 5 or more years after diagnosis were predominantly non-LCH related (i.e., second cancers, chronic obstructive pulmonary disease, and cardiovascular disease). Compared with the general U.S. population, patients with LCH had a higher standard mortality ratio (SMR) if diagnosed before age 55 years (SMR, 5.94) or had multisystem disease (SMR, 4.12).[2]
Incidence
A population-based study in England found that the incidence of LCH in patients older than 15 years was 1.05 cases per 1 million people.[3] Of these individuals, 44% were younger than 45 years. A higher incidence of LCH in economically disadvantaged areas was associated with a higher incidence of smoking in those areas.
More than 90% of adult pulmonary LCH cases occur in young adults who smoke, often more than 20 cigarettes per day.[4,5]
Clinical Presentation
Adult patients may have signs and symptoms of LCH for many months before receiving a definitive diagnosis and treatment. LCH in adults is often similar to that in children and appears to involve the same organs, although the incidence in each organ may be different. There is a predominance of lung disease in adults, usually occurring as single-system disease and closely associated with smoking and some unique biological characteristics. Most isolated lung LCH cases in adults are polyclonal and possibly reactive, while fewer lung LCH cases are monoclonal.[6,7]
A German registry with 121 registrants showed that 62% had single-organ involvement and 38% had multisystem involvement. Pulmonary LCH occurred in 34% of the total study population. Lungs are the most common site, followed by bone and skin involvement. The median age at diagnosis was 44 years (±12.8 years). All organ systems found in childhood LCH were seen in these adults, including endocrine and central nervous system (CNS), liver, spleen, bone marrow, and gastrointestinal tract. The major difference is the much higher incidence of isolated pulmonary LCH in adults, particularly in young adults who smoke. Other differences appear to be the more frequent involvement of genital and oral mucosa.[8]
Presenting signs and symptoms from published studies include the following:
Dyspnea or tachypnea.
Polydipsia and polyuria.
Bone pain.
Soft tissue swelling near bone lesions.
Skin rash or scalp nodules.
Lymphadenopathy.
Weight loss.
Fever.
Gingival hypertrophy.
Ataxia.
Memory problems.
Hepatosplenomegaly.
Patients who present with isolated diabetes insipidus should be carefully observed for the onset of other signs or symptoms characteristic of LCH. At least 80% of patients with diabetes insipidus had involvement of other organ systems, including bone (68%), skin (57%), lung (39%), and lymph nodes (18%).[9] However, isolated diabetes insipidus in adults is similar to that in pediatric patients, with progression from posterior to anterior pituitary/hypothalamus and to cerebellar involvement. For more information, see the Endocrine system section.
Skin and oral cavity
Thirty-seven percent of adults with multifocal LCH have skin involvement. Skin-only LCH occurs but it is less common in adults than in children. The prognosis for adults with skin-only LCH is excellent, with a 5-year survival probability of 100%. The cutaneous involvement is clinically similar to that seen in children and may take many forms.[10] Infra-mammary and vulvar involvement are frequent sites of presentation in adult women.
Many patients have a papular rash with brown, red, or crusted areas ranging from the size of a pinhead to a dime. In the scalp, the rash is similar to that of seborrhea. Skin in the inguinal region, genitalia, or around the anus may have open ulcers that do not heal after antibacterial or antifungal therapy. The lesions are usually asymptomatic but may be pruritic or painful. In the mouth, swollen gums or ulcers along the cheeks, soft or hard palate, gingiva, or tongue may be signs of LCH.
Diagnosis of LCH is usually made by skin biopsy performed for persistent skin lesions.[10]
Bone
The relative frequency of bone involvement in adults differs from that in children. The frequency of mandible involvement is 30% in adults and 7% in children, and the frequency of skull involvement is 21% in adults and 40% in children.[8,9,11,12] The frequencies of lesions in the vertebrae (13%), pelvis (13%), extremities (17%), and ribs (6%) in adults are similar to those found in children.[8]
Lung
Pulmonary LCH in adults (40%–50% of patients) is usually single-system disease. However, in some patients, other organs may be involved, including bone, skin, and hypothalamus/pituitary.[13]
Pulmonary LCH is more prevalent in smokers than in nonsmokers, and the male-to-female ratio is nearly 1:1, depending on the incidence of smoking in the population studied.[13,14] However, a study of pulmonary LCH from China reported that 73% of the patients were male.[15] Patients with pulmonary LCH usually present with a dry cough, dyspnea, or chest pain, although nearly 20% of adults with lung involvement have no symptoms.[16,17] Chest pain may indicate a spontaneous pneumothorax (10%–28% of adult pulmonary LCH cases).[15]
Pulmonary LCH can be diagnosed by bronchoscopy in about 50% of adult patients, as defined by immunostaining of at least 5% of CD1a-positive cells in the sample.[18] High-resolution lung computed tomography (CT) shows characteristic changes with cysts and nodules, more prevalent at the mid and upper zones. These findings have been characterized as pathognomonic for lung LCH.[16]
The LCH cells in adult lung lesions were shown to be mature dendritic cells expressing high levels of the accessory molecules CD80 and CD86, unlike Langerhans cells (LCs) found in other lung disorders.[17] MAPK pathway variants have been demonstrated in more than two-thirds of pulmonary LCH lesions in adults, suggesting a clonal process in a significant proportion of patients.[7,19]
In a review of 206 patients with pulmonary LCH from France (median follow-up, 5 years), the 10-year survival rate was 93%.[20] Patients who had chronic respiratory failure or pulmonary hypertension, both less than 5% of the study group, had much worse outcomes. Of these patients, 58% died. Patients with pulmonary LCH had a 17-fold higher incidence of lung carcinomas than an age- and sex-matched French population cohort.
Favorable prognostic factors for adult LCH of the lung include the following:
Minimal symptoms. Adults with pulmonary LCH who have minimal symptoms have a good prognosis, although some have steady deterioration over many years.[5]
Smoking cessation or treatment. Fifty-nine percent of patients do well with either spontaneous remission after cessation of smoking, or with some form of therapy.[5] However, one study reported that smoking cessation did not increase the longevity of adults with pulmonary LCH, apparently because the tempo of disease is so variable.[21] The authors of the review of 206 patients from France (see above) [20] noted that the two studies cited here had fewer patients, were retrospective, and did not perform high-resolution CT scans as frequently.[5,21] These older studies likely included patients with more severe disease than the French study.[20]
Lung transplant. In one multicenter study, patients who received lung transplants for the treatment of pulmonary LCH had a 1-year survival rate of 77% and a 10-year survival rate of 54%, with a 20% chance of LCH recurrence.[22]
Unfavorable prognostic factors for adult LCH of the lung include the following:
Altered pulmonary function. Lower forced expiratory volume/forced vital capacity (FEV1/FVC) ratio and higher residual volume/total lung capacity (RV/TLC) ratio are adverse prognostic variables.[21] Some patients have normal ventilatory function but abnormal carbon monoxide diffusion capacity.[15][Level of evidence C2] About 10% to 20% of patients have early severe progression to respiratory failure, severe pulmonary hypertension, and cor pulmonale. Adults who have progression with diffuse bullae formation, multiple pneumothoraces, and fibrosis have a poor prognosis.[23,24]; [15][Level of evidence C2]
Age. Age older than 26 years is an adverse prognostic variable.[21]
Smoking.
Most patients have a variable course, with stable disease in some patients and relapses and progression of respiratory dysfunction in others, often after many years.[25] A natural history study of 58 patients with pulmonary LCH found that 38% had deterioration of lung function after 2 years.[26] The most significant adverse prognostic variables were positive smoking statuses and low PaO2 levels at the time of inclusion.
The following results may be noted on diagnostic tests:
Pulmonary function testing. The most frequent pulmonary function abnormality finding in patients with pulmonary LCH is a reduced carbon monoxide diffusing capacity, which is found in 70% to 90% of cases.[21,27]
CT scan. A high-resolution CT scan, which reveals a reticulonodular pattern with cysts and nodules, usually in the upper lobes and sparing the costophrenic angle, is characteristic of LCH.[28] The presence of cystic abnormalities on high-resolution CT scans appears to be a poor predictor of which patients will have progressive disease.[29]
Biopsy. Despite the typical CT findings, most pulmonologists agree that a lung biopsy is needed to confirm the diagnosis. A study that correlated lung CT findings and lung biopsy results in 27 patients with pulmonary LCH observed that thin-walled and bizarre cysts had active LCs and eosinophils.[30]
Liver
In one study, liver involvement was reported in 27% of adult patients with multiorgan disease.[31] Hepatomegaly (48%) and liver enzyme abnormalities (61%) were usually present. CT, magnetic resonance imaging (MRI), or ultrasonography imaging often find abnormalities along the biliary tract.
The early histopathological stage of liver LCH includes infiltration of CD1a-positive cells and periductal fibrosis with inflammatory infiltrates with or without steatosis. The late stage is biliary tree sclerosis. Treatment with ursodeoxycholic acid may be helpful.[31]
Endocrine system
Diabetes insipidus occurs in 25% of patients and may precede the diagnosis of LCH.[9] Anterior pituitary abnormalities are seen in approximately 20% of these patients.[32] Sometimes imaging studies of the pituitary are normal.[33]
Central nervous system (CNS)
The most frequent abnormalities in the CNS are enlargement of the pituitary, its stalk, and/or the hypothalamus. Brain involvement is typically in the cerebellum, pons, and basal ganglia, with abnormalities seen on the T2 and fluid-attenuated inversion recovery (FLAIR) images. Some patients have only imaging changes, but others have ataxia, dysmetria, dysarthria, and behavioral and psychological difficulties.[34]
Bone marrow and lymph nodes
Bone marrow involvement with LCH is uncommon and is usually heralded by abnormal blood counts, which could also be a sign of an underlying malignancy.[35] Lymph node infiltration in LCH is uncommon as an isolated finding, but can occur in up to 30% of patients with multisystem LCH.[34]
Gastrointestinal and cardiovascular systems
Gastrointestinal involvement is rare and usually presents with diarrhea and pain.[36] Abnormalities in the heart or around the great vessels often suggest a hybrid disease of Erdheim-Chester (ECD) and LCH.[37]
Multisystem disease
In a large series of patients from the Mayo Clinic, 31% had multisystem LCH, compared with 69% registered on the Histiocyte Society adult registry. This finding likely reflects referral bias.[10,38] In the adult patients with multisystem disease, the sites of disease included the following:
Skin (50%).
Mucocutaneous (40%).
Pituitary/CNS (diabetes insipidus, 29.6%).
Liver/spleen (hepatosplenomegaly, 16%).
Thyroid (hypothyroidism, 6.6%).
Lymph nodes (lymphadenopathy, 6%).
LCH and associated malignancies
Adult patients with LCH have higher rates of malignancies than do age-matched patients without LCH, by ratios of 2 to 4, depending on patient age.[39] A review of 132 patients with LCH from a single institution found 31 patients with other malignancies before their LCH diagnosis, 11 patients with concurrent malignancies, and 11 patients with other malignancies after their LCH diagnosis. Solid tumors comprised 74% of the malignancies, lymphomas comprised 17% of the cases, and hematologic malignancies comprised 9% of the cases. Seventy-one percent of the patients were smokers.[39] These results are in contrast to an earlier study that was based on a literature review and institutional surveys that reported a higher incidence of lymphomas concurrent with the LCH diagnosis.[40]
The association between LCH and malignancy occurs more frequently than would be expected by chance, based on questionnaires sent to investigators in the Histiocyte Society and a literature review. In one publication, LCH-malignancy cases were collected between 1991 and 2015. A total of 285 LCH-malignancies were seen in 270 patients. In 154 adults with LCH, solid tumors were reported in 61 patients (39.6%), lymphomas in 56 patients (36.4%), and leukemias and myeloproliferative disorders in 37 patients (24.0%). Thyroid malignancy was also seen with some frequency. In adults, LCH and malignancy occurred concurrently in 69 patients (44.8%).[41]
A review of Surveillance, Epidemiology, and End Results (SEER) Program data for subsequent malignancies in 456 adults with LCH found 16 cases.[42] There were two cases of non-Hodgkin lymphoma, two cases of myelodysplastic neoplasms, three cases of breast cancer, three cases of lung cancer, and one case each of colorectal cancer, thyroid cancer, vulvar cancer, meningioma, and adenocarcinoma, not otherwise specified.
A study of 156 adults with LCH reported on the relationship of LCH with the BRAF V600E variant and secondary primary malignancies.[43] Patients with LCH and the variant had a 17.3% incidence of second primary malignancies, compared with 4.1% for patients without the variant. The standardized incidence ratio (SIR) was 5.72 for second malignancies in patients with LCH, compared with 1.7 in age-matched adults. Unlike children with LCH, there was no correlation with the extent of the disease or progression-free survival in adults with BRAF V600E variants.
Diagnostic Evaluation
Positron emission tomography (PET) scans are the most sensitive modality for finding affected sites and are done to diagnose people with LCH.[1,44] MRI of the brain is indicated for patients with pituitary-associated symptoms and those with evidence of neurodegeneration. Spine MRIs are indicated for people with vertebral pain or lower motor neuropathy.
Treatment of Adult LCH
Treatment options for adult LCH
The lack of clinical trials limits the ability to make evidence-based recommendations for adult patients with LCH.
Many investigators have previously recommended treatment according to the guidelines for childhood LCH. It is unclear, however, whether adult LCH responds as well as the childhood form of the disease. In addition, the drugs used in the treatment of children are not as well tolerated when used in adults. Excessive neurological toxicity from vinblastine, for example, prompted closure of the LCH-A1 trial. BRAF and MEK inhibitors are increasingly used as initial treatment for many adults.[1] For more information, see the Targeted therapies for the treatment of single-system and multisystem disease section.
An international expert consensus panel has proposed a treatment algorithm for adult patients and is summarized below.[1]
Bone-only LCH: Treatment includes curettage, bisphosphonates, oral methotrexate, or hydroxyurea. Radiation therapy may be used for patients with progressive disease and fewer than three lesions. Patients with more than three lesions may receive chemotherapy (cladribine, cytarabine, or others) or MAPK inhibitors.
Skin-only LCH: Treatment includes hydroxyurea, oral methotrexate, thalidomide or lenalidomide, or topical therapy.
Single-system pulmonary LCH: Treatment is smoking cessation. Patients with progressive disease receive chemotherapy with similar drugs used for bone LCH.
Multisystem LCH: Treatment includes chemotherapy with similar drugs used for bone LCH.
Critical organ involvement (bone marrow, spleen, liver, brain): Patients with LCH and BRAF V600E variants receive a BRAF inhibitor. For patients without BRAF V600E variants, a MEK inhibitor may be used if tests are positive for MAPK variants. If no variants are found, patients receive chemotherapy based on the regimen used for bone LCH.
Treatment of pulmonary LCH
It is difficult to judge the effectiveness of various treatments for pulmonary LCH because patients can recover spontaneously or have stable disease without treatment.
Treatment options for adult patients with pulmonary LCH include the following:
Smoking cessation. Smoking cessation is mandatory because of the apparent causal effect of smoking in pulmonary LCH.[45] Most adult patients with LCH have gradual disease progression with continued smoking. The disease may regress or progress with the cessation of smoking.[46] A study of 27 patients with pulmonary LCH observed that 52% of patients improved after a mean follow-up of 14 months. Most patients improved with smoking cessation, and some patients improved with steroid treatment. Four patients (15%) had stable disease at a mean follow-up of 26 months, and nine patients (33%) demonstrated disease progression during the mean follow-up of 22 months.[30][Level of evidence C3]
Steroid therapy. It is not known whether steroid therapy is efficacious in the treatment of adult pulmonary LCH because reported case series did not control for smoking cessation.[45]
Chemotherapy. Some patients have been reported to respond to treatment with cladribine or cytarabine.[45,47]; [15][Level of evidence C2]
Lung transplant. Lung transplant may be necessary for adults with extensive pulmonary destruction from LCH.[22] One multicenter study reported a survival rate of 54% at 10 years posttransplant, with 20% of patients having recurrent LCH that did not impact survival. Longer follow-up of these patients is needed.[22] Another study confirmed a survival rate of approximately 50% at 10 years and improved hemodynamic changes associated with pulmonary arterial hypertension therapies, without oxygen worsening or pulmonary edema.[48]
The best strategy for follow-up of pulmonary LCH includes physical examination, chest radiographs, lung function tests, and high-resolution CT scans.[49]
Treatment of bone LCH
Treatment options for adult patients with bone LCH include the following:
Curettage followed by observation, with or without intralesional corticosteroids. As in children, adults with single-bone lesions should undergo curettage of the lesion followed by observation, with or without intralesional corticosteroids.[50] Extensive or radical surgery leading to loss of function and disfigurement is contraindicated at any site, including the teeth or jaw bones.
Low-dose radiation therapy. For patients who do not respond to chemotherapy, low-dose radiation therapy may be indicated and should be attempted before any radical surgery. Radiation therapy is also indicated for impending neurological deficits from vertebral body lesions or visual problems from orbital lesions. Two series and a study have reported the following:
A German cooperative radiation therapy group reported on a series of 98 adult patients with LCH. Most of the patients (60 of 98) had only bone lesions and 24 had multisystem disease including bone, who were treated with radiation therapy.[53][Level of evidence C3] Of 89 evaluable patients, 77% achieved a complete remission, 9% developed an infield recurrence, and 15.7% (14 of 89) experienced a progression outside the radiation field(s).
A retrospective analysis of 80 patients treated with radiation therapy alone reported a complete remission rate of 77% and a partial remission rate of 12.5%. The long-term control rate was 80% in adults. No adverse late effects were reported.[54][Level of evidence C3]
A single-institution study included 39 patients with LCH (age range, 1.5–67 years; 24 patients aged >18 years) who received radiation therapy to 46 lesions. The study reported no local recurrences in the 31 bony sites. In comparison, the 3-year freedom from local failure rate was 63% in the 15 nonbone lesions (95% confidence interval, 32%–83%; P = .0008).[55]
Bisphosphonate therapy. Case reports and case series have described the successful use of bisphosphonates, both intravenous pamidronate and oral zoledronate, in controlling severe bone pain in patients with multiple osteolytic LCH bone lesions.[56–58] A multi-institutional review of bisphosphonate therapy in children and adults with LCH found that most adult patients were given oral zoledronic acid, and most pediatric patients were given pamidronate.[59][Level of evidence C3] Because of the increased toxicity of chemotherapy in adults, bisphosphonate therapy could be used before chemotherapy in multifocal bone disease. Response of other organs, such as skin and soft tissue, to bisphosphonate therapy has been reported.[60]
Anti-inflammatory agents with trofosfamide. Another approach using anti-inflammatory agents (pioglitazone and rofecoxib) coupled with trofosfamide in a specific timed sequence was successful in two patients who had disease resistant to standard chemotherapy treatment.[61][Level of evidence C3]
Treatment of single-system skin disease
Treatment options for adult patients with single-system skin disease include the following:
Surgical excision. Localized lesions are rarely treated by surgical excision. Mutilating surgery, including hemivulvectomy, should be avoided unless the disease is refractory to all available therapy.
Topical therapy. Topical therapies are described in greater detail in the childhood isolated skin involvement section and include the following:
Psoralen and long-wave ultraviolet A radiation (PUVA) and UVB. Therapies such as PUVA/UVB may be more useful in adults because long-term toxicity may be reduced.[62,65][Level of evidence C3]
Systemic therapy. Systemic therapy for severe skin LCH includes oral methotrexate, hydroxyurea, oral thalidomide, oral interferon-alpha, or combinations of interferon and thalidomide.[66–68][Level of evidence C3] Interferon and thalidomide are also used to treat chronic skin LCH in adults.[69][Level of evidence C3] Recurrences are possible after treatment is stopped but lesions usually respond to re-treatment.
Oral isotretinoin has induced remissions in some adult patients with refractory skin LCH.[70][Level of evidence C3]
Chemotherapy and radiation therapy for the treatment of other single-system disease and multisystem disease
Evidence (chemotherapy for the treatment of other single-system disease [not mentioned above] and multisystem disease):
A single-center, retrospective review of 58 adult patients with LCH reported on the efficacy and toxicities of treatment with vinblastine/prednisone, cladribine, and cytarabine.[51][Level of evidence C3]
Patients treated with vinblastine/prednisone had the worst outcome, with 84% of patients not responding within 6 weeks or relapsing within a year.
The no-response/relapse rate was 59% for patients treated with cladribine and 21% for patients treated with cytarabine.
Grade 3 or 4 neurological toxic effects occurred in 75% of patients treated with vinblastine.
Grade 3 or 4 neutropenia occurred in 37% of patients treated with cladribine and in 20% of patients who received cytarabine.
One report evaluated adult patients who were treated with either vindesine and prednisone or cyclophosphamide, etoposide, vindesine, and prednisone.[71][Level of evidence C2]
More than 70% of patients relapsed with either regimen.
Etoposide has been used with some success in adult patients with single-system and multisystem LCH.
Minimal toxicity was reported with the use of prolonged oral etoposide in adults with skin LCH, while 3-day courses of intravenous etoposide (100 mg/m2/day) induced complete remission in a small number of patients with resistant single-system and multisystem disease.[72][Level of evidence C3]
Another study at the same center found that azathioprine was the most successful drug for localized disease in adults, with the addition of etoposide for refractory and multisystem disease.[73][Level of evidence C3]
Cladribine is effective for adults with skin, bone, lymph node, and probably pulmonary and CNS disease.[74,75][Level of evidence C3]; [52]
In a retrospective multicenter study, 23 patients who had at least one previous therapy were treated with cladribine, using various dosing and treatment schedules.[76][Level of evidence C2] The overall response rate was 91%, and the complete response rate was 50%. A literature review identified an additional 48 patients who were treated with cladribine. The pooled analysis confirmed these results.
A study reported on 38 patients with newly diagnosed or relapsed/refractory LCH treated with one to nine cycles of cladribine.[1][Level of evidence C2] The overall response rate was 79%. The complete response rate was 26%, and the partial response rate was 53%.[52]
An adult lymphoma treatment regimen of methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (MACOP-B) was used in 11 patients.[77]
The overall response rate was 100%, and the progression-free survival rate was 64%.
Methotrexate and cytarabine were given to 83 patients with newly diagnosed lung (68%), liver (28%), spleen (13%), or nonpituitary (4%) LCH.[78]
The objective response rate was 88%, and one-third of the patients progressed after 3 years.
There was a high rate of grades 3 to 4 neutropenia, with nearly one-half of patients developing fevers.
One-third of patients had grades 3 to 4 thrombocytopenia.
In a study of 61 adult patients with LCH who were treated with subcutaneous cytarabine, the following results were reported:[79]
The estimated 3-year event-free survival (EFS) rate was 58.5%.
Poor prognostic factors for EFS included three or more involved organs and baseline lung involvement.
Grades 3 to 4 neutropenia occurred in 27.9% of patients.
Of the 61 patients, 47 completed 12 months of treatment, and 14 left the study (6 had a poor response to therapy and 8 decided to withdraw).
Radiation therapy. A report of stereotactic radiosurgery for the treatment of adult patients with pituitary LCH showed efficacy in reducing the masses.[80]
Targeted therapies for the treatment of single-system and multisystem disease
Early reports on the use of targeted therapies for adult patients with low-risk or high-risk LCH sites include the following:
MAP2K/ERK pathway inhibitors. The finding that most patients with LCH have BRAF or other RAS pathway variants led to several reports of good responses to vemurafenib, a BRAF V600E inhibitor, in adult patients with LCH and severe cutaneous LCH.[81–85][Level of evidence C3]
Of four patients with LCH who were treated with vemurafenib on the VE-BASKET (NCT01524978) trial, one patient had a complete response and three patients had partial responses.[84][Level of evidence C3] One patient with LCH who was treated with vemurafenib had improvement in ataxia.[84][Level of evidence C3]
One series reported on six patients who were treated with BRAF inhibitors as initial therapy.[86] Five patients had multisystem disease, and one patient had bone-only LCH. There were two complete responses, three partial responses, and one stable disease after 4 to 27 months of treatment.
A proof-of-concept clinical trial of cobimetinib, an oral inhibitor of MEK1 and MEK2, was carried out in 18 adult patients with various histiocytoses, including histiocytic sarcomas. Patients were treated regardless of genomic findings. Responses were seen in patients with ARAF, BRAF, NRAS, KRAS, MAP2K1, and MAP2K2 variants. The overall response rate was 89%, with responses being durable. At 1 year, 94% of patients remained progression free.[83][Level of evidence C2]
Early results of targeted inhibitor therapy are encouraging, but many questions remain, particularly the optimal duration of therapy and the reactivation rate after therapy is discontinued. A BRAF inhibitor in combination with a MEK inhibitor have been shown to be effective in patients with melanoma who have BRAF variants (with reduced toxicity). This combination may also be effective in patients with LCH, but it is generally not used for patients with histiocytic diseases.[81][Level of evidence C3] A number of clinical trials of BRAF and other RAS pathway inhibitors in adults and children with LCH are ongoing.
Other targeted therapies. A case report suggests some benefit to treating neurodegenerative CNS LCH disease with infliximab, a tumor necrosis factor (TNF)-alpha inhibitor.[87][Level of evidence C3] However, the TNF inhibitors infliximab and etanercept have limited ability to cross the blood-brain barrier. Thalidomide, which also has anti-TNF activity, has been effective in adults with skin and bone LCH.[66,88][Level of evidence C3]; [88,89]
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:
NCT04079179 (Cobimetinib for the Treatment of Refractory LCH): This study is open to children or adults with relapsed or refractory LCH or other newly diagnosed, relapsed, or refractory histiocytic disorders.
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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Charles J, Beani JC, Fiandrino G, et al.: Major response to vemurafenib in patient with severe cutaneous Langerhans cell histiocytosis harboring BRAF V600E mutation. J Am Acad Dermatol 71 (3): e97-9, 2014. [PUBMED Abstract]
Diamond EL, Durham BH, Ulaner GA, et al.: Efficacy of MEK inhibition in patients with histiocytic neoplasms. Nature 567 (7749): 521-524, 2019. [PUBMED Abstract]
Diamond EL, Subbiah V, Lockhart AC, et al.: Vemurafenib for BRAF V600-Mutant Erdheim-Chester Disease and Langerhans Cell Histiocytosis: Analysis of Data From the Histology-Independent, Phase 2, Open-label VE-BASKET Study. JAMA Oncol 4 (3): 384-388, 2018. [PUBMED Abstract]
Hyman DM, Puzanov I, Subbiah V, et al.: Vemurafenib in Multiple Nonmelanoma Cancers with BRAF V600 Mutations. N Engl J Med 373 (8): 726-36, 2015. [PUBMED Abstract]
Hazim AZ, Ruan GJ, Ravindran A, et al.: Efficacy of BRAF-Inhibitor Therapy in BRAFV600E -Mutated Adult Langerhans Cell Histiocytosis. Oncologist 25 (12): 1001-1004, 2020. [PUBMED Abstract]
Chohan G, Barnett Y, Gibson J, et al.: Langerhans cell histiocytosis with refractory central nervous system involvement responsive to infliximab. J Neurol Neurosurg Psychiatry 83 (5): 573-5, 2012. [PUBMED Abstract]
Sander CS, Kaatz M, Elsner P: Successful treatment of cutaneous langerhans cell histiocytosis with thalidomide. Dermatology 208 (2): 149-52, 2004. [PUBMED Abstract]
Crickx E, Bouaziz JD, Lorillon G, et al.: Clinical Spectrum, Quality of Life, BRAF Mutation Status and Treatment of Skin Involvement in Adult Langerhans Cell Histiocytosis. Acta Derm Venereol 97 (7): 838-842, 2017. [PUBMED Abstract]
Latest Updates to This Summary (01/06/2025)
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.
Editorial changes were made to this summary.
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 childhood and adult Langerhans cell histiocytosis. 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).
Board members review recently published articles each month to determine whether an article should:
be discussed at a meeting,
be cited with text, or
replace or update an existing article that is already cited.
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 reviewers for Langerhans Cell Histiocytosis Treatment are:
Louis S. Constine, MD (James P. Wilmot Cancer Center at University of Rochester Medical Center)
Thomas G. Gross, MD, PhD (National Cancer Institute)
Michael Jeng, MD (Stanford Medicine Children’s Health)
Kenneth L. McClain, MD, PhD (Texas Children’s Cancer Center and Hematology Service at Texas Children’s Hospital)
Carlos Rodriguez-Galindo, MD (St. Jude Children’s Research Hospital)
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.
Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
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PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”
The preferred citation for this PDQ summary is:
PDQ® Pediatric Treatment Editorial Board. PDQ Langerhans Cell Histiocytosis Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/langerhans/hp/langerhans-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389240]
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Sometimes there is a problem with the fertilized egg and trophoblast cells. Instead of a healthy fetus developing, a tumor forms. Until there are signs or symptoms of the tumor, the pregnancy will seem like a normal pregnancy.
Most GTD is benign (not cancer) and does not spread, but some types become malignant (cancer) and spread to nearby tissues or distant parts of the body.
Gestational trophoblastic disease (GTD) is a general term that includes different types of disease:
Placental-site trophoblastic tumors (PSTT; very rare).
Epithelioid trophoblastic tumors (ETT; even more rare).
Hydatidiform mole (HM) is the most common type of GTD.
HMs are slow-growing tumors that look like sacs of fluid. An HM is also called a molar pregnancy. The cause of hydatidiform moles is not known.
HMs may be complete or partial:
A complete HM forms when sperm fertilizes an egg that does not contain the mother’s DNA. The egg has DNA from the father and the cells that were meant to become the placenta are abnormal.
A partial HM forms when sperm fertilizes a normal egg and there are two sets of DNA from the father in the fertilized egg. Only part of the fetus forms and the cells that were meant to become the placenta are abnormal.
Most hydatidiform moles are benign, but they sometimes become cancer. Having one or more of the following risk factors increases the risk that a hydatidiform mole will become cancer:
Gestational trophoblastic neoplasia (GTN) is a type of gestational trophoblastic disease (GTD) that is almost always malignant.
Gestational trophoblastic neoplasia (GTN) includes the following:
Invasive moles
Invasive moles are made up of trophoblast cells that grow into the muscle layer of the uterus. Invasive moles are more likely to grow and spread than a hydatidiform mole. Rarely, a complete or partial HM may become an invasive mole. Sometimes an invasive mole will disappear without treatment.
Choriocarcinomas
A choriocarcinoma is a malignant tumor that forms from trophoblast cells and spreads to the muscle layer of the uterus and nearby blood vessels. It may also spread to other parts of the body, such as the brain, lungs, liver, kidney, spleen, intestines, pelvis, or vagina. A choriocarcinoma is more likely to form in women who have had any of the following:
Molar pregnancy, especially with a complete hydatidiform mole.
Normal pregnancy.
Tubal pregnancy (the fertilized egg implants in the fallopian tube rather than the uterus).
Miscarriage.
Placental-site trophoblastic tumors
A placental-site trophoblastic tumor (PSTT) is a rare type of gestational trophoblastic neoplasia that forms where the placenta attaches to the uterus. The tumor forms from trophoblast cells and spreads into the muscle of the uterus and into blood vessels. It may also spread to the lungs, pelvis, or lymph nodes. A PSTT grows very slowly and signs or symptoms may appear months or years after a normal pregnancy.
Epithelioid trophoblastic tumors
An epithelioid trophoblastic tumor (ETT) is a very rare type of gestational trophoblastic neoplasia that may be benign or malignant. When the tumor is malignant, it may spread to the lungs.
Age and a previous molar pregnancy affect the risk of GTD.
Anything that increases your risk of getting a disease is called a risk factor. Having a risk factor does not 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. Risk factors for GTD include the following:
Being pregnant when you are younger than 20 or older than 35 years of age.
Signs of GTD include abnormal vaginal bleeding and a uterus that is larger than normal.
These and other signs and symptoms may be caused by gestational trophoblastic disease or by other conditions. Check with your doctor if you have any of the following:
Tests that examine the uterus are used to detect (find) and diagnose gestational trophoblastic disease.
The following tests and procedures may be used:
Physical exam and history: An exam of the body to check general signs of health, including checking for signs of disease, such as lumps or anything else that seems unusual. A history of the patient’s health habits and past illnesses and treatments will also be taken.
Pelvic exam: An exam of the vagina, cervix, uterus, fallopian tubes, ovaries, and rectum. A speculum is inserted into the vagina and the doctor or nurse looks at the vagina and cervix for signs of disease. A Pap test of the cervix is usually done. The doctor or nurse also inserts one or two lubricated, gloved fingers of one hand into the vagina and places the other hand over the lower abdomen to feel the size, shape, and position of the uterus and ovaries. The doctor or nurse also inserts a lubricated, gloved finger into the rectum to feel for lumps or abnormal areas. EnlargePelvic exam. A doctor or nurse inserts one or two lubricated, gloved fingers of one hand into the vagina and presses on the lower abdomen with the other hand. This is done to feel the size, shape, and position of the uterus and ovaries. The vagina, cervix, fallopian tubes, and rectum are also checked.
Ultrasound exam of the pelvis: A procedure in which high-energy sound waves (ultrasound) are bounced off internal tissues or organs in the pelvis and make echoes. The echoes form a picture of body tissues called a sonogram. Sometimes a transvaginal ultrasound (TVUS) will be done. For TVUS, an ultrasound transducer (probe) is inserted into the vagina to make the sonogram.
Blood chemistry studies: A procedure 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. An unusual (higher or lower than normal) amount of a substance can be a sign of disease. Blood is also tested to check the liver, kidney, and bone marrow.
Serum tumor marker test: A procedure in which a sample of blood is checked to measure the amounts of certain substances made by organs, tissues, or tumor cells in the body. Certain substances are linked to specific types of cancer when found in increased levels in the body. These are called tumor markers. For GTD, the blood is checked for the level of beta human chorionic gonadotropin (beta-hCG), a hormone that is made by the body during pregnancy. Beta-hCG in the blood of a woman who is not pregnant may be a sign of GTD.
Urinalysis: A test to check the color of urine and its contents, such as sugar, protein, blood, bacteria, and the level of beta-hCG.
Certain factors affect prognosis (chance of recovery) and treatment options.
Gestational trophoblastic disease usually can be cured. Treatment and prognosis depend on the following:
The type of GTD.
Whether the tumor has spread to the uterus, lymph nodes, or distant parts of the body.
The number of tumors and where they are in the body.
The size of the largest tumor.
The level of beta-hCG in the blood.
How soon the tumor was diagnosed after the pregnancy began.
Whether GTD occurred after a molar pregnancy, miscarriage, or normal pregnancy.
Previous treatment for gestational trophoblastic neoplasia.
Treatment options also depend on whether the woman wishes to become pregnant in the future.
Stages of Gestational Trophoblastic Tumors and Neoplasia
Key Points
After gestational trophoblastic neoplasia has been diagnosed, tests are done to find out if cancer has spread from where it started 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.
There is no staging system for hydatidiform moles.
The following stages are used for gestational trophoblastic neoplasia:
Stage I
Stage II
Stage III
Stage IV
The treatment of gestational trophoblastic neoplasia is based on the type of disease, stage, or risk group.
After gestational trophoblastic neoplasia 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 disease. For gestational trophoblastic neoplasia (GTN), stage is one of the factors used to plan treatment.
The following tests and procedures may be done to help find out the stage of the disease:
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 onto film, making pictures of areas inside the body.
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.
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, such as brain and spinal cord. 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).
Lumbar puncture: A procedure used to collect cerebrospinal fluid (CSF) from the spinal column. This is done by placing a needle between two bones in the spine and into the CSF around the spinal cord and removing a sample of the fluid. The sample of CSF is checked under a microscope for signs that the cancer has spread to the brain and spinal cord. This procedure is also called an LP or spinal tap.
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 choriocarcinoma spreads to the lung, the cancer cells in the lung are actually choriocarcinoma cells. The disease is metastatic choriocarcinoma, not lung 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.
There is no staging system for hydatidiform moles.
Hydatidiform moles (HM) are found in the uterus only and do not spread to other parts of the body.
The following stages are used for gestational trophoblastic neoplasia:
In stage IV, the tumor has spread to distant parts of the body other than the lungs.
The treatment of gestational trophoblastic neoplasia is based on the type of disease, stage, or risk group.
Invasive moles and choriocarcinomas are treated based on risk groups. The stage of the invasive mole or choriocarcinoma is one factor used to determine risk group. Other factors include the following:
The age of the patient when the diagnosis is made.
There are two risk groups for invasive moles and choriocarcinomas: low risk and high risk. Patients with low-risk disease usually receive less aggressive treatment than patients with high-risk disease.
Placental-site trophoblastic tumor (PSTT) and epithelioid trophoblastic tumor (ETT) treatments depend on the stage of disease.
Recurrent and Resistant Gestational Trophoblastic Neoplasia
Recurrent gestational trophoblastic neoplasia (GTN) is cancer that has recurred (come back) after it has been treated. The cancer may come back in the uterus or in other parts of the body.
Gestational trophoblastic neoplasia that does not respond to treatment is called resistant GTN.
Treatment Option Overview
Key Points
There are different types of treatment for patients with gestational trophoblastic disease.
Three types of standard treatment are used:
Surgery
Chemotherapy
Radiation therapy
New types of treatment are being tested in clinical trials.
Treatment for gestational trophoblastic disease may cause side effects.
Patients may want to think about taking part in a clinical trial.
Patients can enter clinical trials before, during, or after starting their cancer treatment.
Follow-up tests may be needed.
There are different types of treatment for patients with gestational trophoblastic disease.
Different types of treatment are available for patients with gestational trophoblastic disease. Some treatments are standard (the currently used treatment), and some are being tested in clinical trials. Before starting treatment, patients may want to think about taking part in a clinical trial. 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.
Clinical trials are taking place in many parts of the country. Information about ongoing clinical trials is available from the NCI website. Choosing the most appropriate cancer treatment is a decision that ideally involves the patient, family, and health care team.
Three types of standard treatment are used:
Surgery
The doctor may remove the cancer using one of the following operations:
Dilatation and curettage (D&C) with suction evacuation: A surgical procedure to remove abnormaltissue and parts of the inner lining of the uterus. The cervix is dilated and the material inside the uterus is removed with a small vacuum-like device. The walls of the uterus are then gently scraped with a curette (spoon-shaped instrument) to remove any material that may remain in the uterus. This procedure may be used for molar pregnancies. EnlargeDilatation and curettage (D and C). A speculum is inserted into the vagina to widen it in order to look at the cervix (first panel). A dilator is used to widen the cervix (middle panel). A curette is put through the cervix into the uterus to scrape out abnormal tissue (last panel).
Hysterectomy: Surgery to remove the uterus, and sometimes the cervix. If the uterus and cervix are taken out through the vagina, the operation is called a vaginal hysterectomy. If the uterus and cervix are taken out through a large incision (cut) in the abdomen, the operation is called a total abdominal hysterectomy. If the uterus and cervix are taken out through a small incision (cut) in the abdomen using a laparoscope, the operation is called a total laparoscopic hysterectomy. EnlargeHysterectomy. The uterus is surgically removed with or without other organs or tissues. In a total hysterectomy, the uterus and cervix are removed. In a total hysterectomy with salpingo-oophorectomy, (a) the uterus plus one (unilateral) ovary and fallopian tube are removed; or (b) the uterus plus both (bilateral) ovaries and fallopian tubes are removed. In a radical hysterectomy, the uterus, cervix, both ovaries, both fallopian tubes, and nearby tissue are removed. These procedures are done using a low transverse incision or a vertical incision.
After the doctor removes all the cancer that can be seen at the time of the surgery, some patients may be given chemotherapy after surgery to kill any cancer cells that are left. Treatment given after the surgery, to lower the risk that the cancer will come back, is called adjuvant therapy.
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). When chemotherapy is placed directly into the cerebrospinal fluid, an organ, or a body cavity such as the abdomen, the drugs mainly affect cancer cells in those areas (regional chemotherapy). The way the chemotherapy is given depends on the type and stage of the cancer being treated, or whether the tumor is low-risk or high-risk.
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 two types of radiation therapy:
The way the radiation therapy is given depends on the type of gestational trophoblastic disease being treated. External radiation therapy is used to treat gestational trophoblastic disease.
New types of treatment are being tested in clinical trials.
Information about ongoing clinical trials is available from the NCI website.
Treatment for gestational trophoblastic disease may cause side effects.
Patients may want to think about taking part in a clinical trial.
For some patients, taking part in a clinical trial may be the best treatment choice. Clinical trials are part of the cancer research process. Clinical trials are done to find out if new cancer treatments are safe and effective or better than the standard treatment.
Many of today’s standard treatments for cancer are based on earlier clinical trials. Patients who take part in a clinical trial may receive the standard treatment or be among the first to receive a new treatment.
Patients who take part in clinical trials also help improve the way cancer will be treated in the future. Even when clinical trials do not lead to effective new treatments, they often answer important questions and help move research forward.
Patients can enter clinical trials before, during, or after starting their cancer treatment.
Some clinical trials only include patients who have not yet received treatment. Other trials test treatments for patients whose cancer has not gotten better. There are also clinical trials that test new ways to stop cancer from recurring (coming back) or reduce the side effects of cancer treatment.
Clinical trials are taking place in many parts of the country. Information about clinical trials supported by NCI can be found on NCI’s clinical trials search webpage. Clinical trials supported by other organizations can be found on the ClinicalTrials.gov website.
Follow-up tests may be needed.
As you go through treatment, you 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 condition has changed or if the cancer has recurred (come back).
Blood levels of beta human chorionic gonadotropin (beta-hCG) will be checked for up to 6 months after treatment has ended. This is because a beta-hCG level that is higher than normal may mean that the tumor has not responded to treatment or it has become cancer.
Treatment Options for Gestational Trophoblastic Disease
After surgery, beta human chorionic gonadotropin (beta-hCG) blood tests are done every week until the beta-hCG level returns to normal. Patients also have follow-up doctor visits monthly for up to 6 months. If the level of beta-hCG does not return to normal or increases, it may mean the hydatidiform mole was not completely removed and it has become cancer. Pregnancy causes beta-hCG levels to increase, so your doctor will ask you not to become pregnant until follow-up is finished.
For disease that remains after surgery, treatment is usually 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.
If the level of beta-hCG in the blood does not return to normal or the tumor spreads to distant parts of the body, chemotherapy regimens used for high-risk metastatic GTN are given.
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.
High-dose chemotherapy or intrathecal chemotherapy and/or radiation therapy to the brain (for cancer that has spread to the brain).
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.
Placental-Site Gestational Trophoblastic Tumors and Epithelioid Trophoblastic Tumors
Treatment of stage I placental-site gestational trophoblastic tumors and epithelioid trophoblastic tumors may include the following:
Treatment of stage III and IV placental-site gestational trophoblastic tumors and epithelioid trophoblastic tumors may include following:
Combination chemotherapy.
Surgery to remove cancer that has spread to other places, such as the lung or abdomen.
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.
Recurrent or Resistant Gestational Trophoblastic Neoplasia
Surgery for tumors that do not respond to 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.
To Learn More About Gestational Trophoblastic Disease
For more information from the National Cancer Institute about gestational trophoblastic tumors and neoplasia, see the following:
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 gestational trophoblastic disease. 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 Adult 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® Adult Treatment Editorial Board. PDQ Gestational Trophoblastic Disease Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/gestational-trophoblastic/patient/gtd-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389509]
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.
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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.
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