Neuroblastoma
Neuroblastoma
last updated 8/08
Ped-Onc Research Center

Neuroblastoma is a cancer of the sympathetic nervous system, a nerve network throughout the body that carries messages from the brain. (See a picture and description of the sympathetic nervous system on the Dr. Eric Chudler's Neuroscience for Kids pages.) Neuroblastoma is a solid, malignant tumor that manifests as a lump or mass in the abdomen or around the spinal cord in the chest, neck, or pelvis. Neuroblastoma is often present at birth, but is most often diagnosed much later when the child begins to show symptoms of the disease. A condition known as "opsoclonus-myoclonus syndrome" can sometimes be a symptom of neuroblastoma. It is bursts of rapid and involuntary, chaotic eye movement in all directions. It's important to note that not all children with this syndrome have neuroblastoma. In the majority of cases (73%), neuroblastoma has already spread to areas outside of the original site at the time of diagnosis.

Diagnosis
Diagnosis of neuroblastoma can be complicated. It has been called the "great masquerader" because its symptoms mimic so many other diseases. Even a pathological study (biopsy) might reveal cells that can resemble other small round blue tumor cells, like lymphomas and rhabdomyosarcomas. Only a pathologist familiar with neuroblastoma can distinguish the difference (and neuroblastoma is rare). Other characteristics of the suspected neuroblastoma cells can be studied by immunohistochemistry and electron microscopy. In about 90% of cases of neuroblastoma, elevated levels of catecholamines or its metabolites are found in the urine or blood. Catecholamines and its metabolites include dopamine, homovanillic acid (HVA), and/or vanillylmandelic acid (VMA).

Another way to detect neuroblastoma is the mIBG scan (meta-iodobenzylguanidine), but it doesn't diagnose the disease in 100% of the cases. It works like this: mIBG is taken up by sympathetic neurons, and is a functioning analog of the neurotransmitter norepinephrine. When it is radio-ionated with I-131 (a radioactive iodine), it is a very good radiopharmaceutical for diagnosis of this disease.

To make a definite diagnosis of neuroblastoma and enter a clinical trial, certain criteria have to be met. A pathologic diagnosis from actual tumour tissue OR bone marrow contains tumour cells AND urine contains increased urinary catecholamine metabolites. (HVA and VMA).

Screening for Neuroblastoma
Of all the diagnostic tests listed above, the test for urinary catecholamine metabolites is non-invasive, inexpensive, and easy. So, why not use it to screen all children for neuroblastoma?

Screening studies have been conducted in Japan, England, and parts of North America. The studies check the urine of infants for abnormal levels of catecholamines, in the hope of earlier detection to improve prognosis. However, whether or not this is effective depends on whom you ask. Many oncologists disagree on the benefits of such a test. There have been instances of false positives, and this is where many of them take issue. A study in Kyoto, Japan, demonstrated that mass screening can improve the survival rate for diagnosed neuroblastomas. However, a study done in England did not yield the same results. Out of 20,829 children tested, 2 showed positive for the disease, 8 were false positives, and 3 were missed all together on screening, but later presented with the disease. The study concluded that this type of screening is possible, but requires more study."

Children picked up as having neuroblastoma through screening tend to have excellent prognostic indicators. These children have a higher incidence of spontaneous regression, and treatment may not be necessary. Many researchers believe that if the disease had not been detected through screening, they may have never been diagnosed. The disease would simply disappear (spontaneously regress) on its own. Therein lies the dilemma. Once a diagnosis is made, physicians generally have an ethical obligation to treat. This may be unnecessarily exposing a child to the potentially harmful side effects of anti-cancer therapy, some of which are long-term.

Further reading on screening for neuroblastoma:

MedNews from NCI
Histology and Cytogenetics
Your child's cancer cells exhibit a defined "histology", or profile of molecular and biological characteristics. These features are often indicators of treatment success and some of them direct treatment decisions to more or less intensive protocols. The characteristics below are known to be important in neuroblastoma:

N-myc amplification. N-myc is an oncogene, or a gene (DNA sequence) that turns on cell growth. Amplification means that more than one copy is found in the cell.

Hyperploidy. A normal cell has 46 chromosomes. Cancer cells often have extra chromosomes, and this is termed "hyperploidy".

VMA/HVA ratio. This is the ratio of catecholamine metabolites found in the urine.

NSE. Neuron-specific enolase, a serum marker. This is an enzyme specific to the sympathetic nervous cells from which the neuroblastoma derives.

Serum ferritin. An accurate estimate of the body's iron stores; a serum marker.

LDH. Lactate dehydrogenase (LDH) is a group of enzymes that have a similar biological activity; a serum marker.

Gd2. Presence of this serum marker (a sialic acid-containing glycosphingolipid) may play a role in faster tumour progression.

CD44 antigen. The presence of this antigen indicates a particular developmental stage of the neuroblastoma cells.

TRK-A protooncogene. Again, oncogenes turn on cell growth.

1p deletion. Deletion on chromosome 1.

Treatment
Clinical trial search form:

NCI trials on the Cancer.gov site
Treatment will be determined by many factors, including the stage of the disease at diagnosis and your child's age, site of the primary tumor and metastases, and tumor histology. In general, neuroblastoma has a more favorable prognosis if it is localized or the child is under one year old at diagnosis.

Staging
If a child is diagnosed with neuroblastoma, more tests are performed to determine if the cancer has spread from where it started to other parts of the body, or "staged". Treatment protocols depend on the stage of the neuroblastoma. In simple terms, the stages are called "localized, regional, disseminated, special". CCG and POG use more specific terms of the stages, and each organization uses different nomenclatures. A good explanation of the stages and of their designations is linked to from the Cancer.gov Neuroblastoma pages.

Treatment may include:
Surgery. This is common in neuroblastoma treatment and serves to take out as much of the cancer as possible. If necessary, surgery is delayed until chemotherapy and/or radiation has decreased tumor size.

Radiation therapy. Both high dose X-rays (external beam) and radioisotopes through thin plastic tubes, (internal radiation) therapies may be used.

Chemotherapy. Common chemotherapy agents are: daunorubicin, cyclophosphamide, carboplatin, and epotoside.

Bone marrow transplantation. Autologous BMT may be used following aggressive chemotherapy.

How to Find New Treatments
With the sometimes overwhelming amount of information there is on the Internet about various forms of therapy, it can be difficult to determine where to begin your search. Here are some tips that you might find helpful in researching treatment options for your child.

First of all, it would be very beneficial for you to have a good understanding of the type of cancer with which your child has been diagnosed. Knowing your enemy as intimately as possible always provides you with access to more ammunition in the fight. If you are seeking out medical opinions from physicians and researchers that specialize in neuroblastoma, it is a good idea to have a copy of your child's medical reports and any relevant information you might need. Keep a record of details, beginning at diagnosis, and include information such as the following:

Date of diagnosis and age of your child
Disease stage
Location of primary tumour and metastases
Histology (ask your child's oncologist if you are unsure; can include N-myc amplification, hyperploidy, VMA/HVA ratio, NSE, serum ferritin, lactate, dehydrogenase, GD2, CD44 antigen, TRK-A protooncogene, 1p deletion)
Treatments used to date
Description of how your child tolerated therapy
Any short or long term side effects experienced
How soon after completion of therapy did relapse occur
Options presented by your child's oncologist
Once you have gathered together your information, you will be in a much better position to research possible treatment options.

At the clinical trials sites listed above under "Treatment", you will find lists of active clinical trials for neuroblastoma. Clinical trials are available in three phases (see the ped-onc treatment page for a description of clinical trial phases). Keep in mind that your child will have to meet certain criteria to be accepted into these studies. This is done for the protection of your child. Phase III studies show the most promise. However, Phase I and II studies are also worth considering, as they have demonstrated themselves to be potentially beneficial. If your child has recently relapsed, consider enrolling him/her into a Phase III study. If this does not provide a remission or at least stable disease, you may wish to consider a Phase II or Phase I study. The decision, at this point, is largely a personal one. Only you, together with the expert opinion of your child's oncologist, can make that determination.

Another avenue available is to contact an oncologist that specializes in neuroblastoma treatment and research. Again, it would be to your advantage to have as much medical information on your child as possible handy when making contact with one of these physicians. Provide them with a synopsis of your child's medical history, and ask them if they have any current treatments and/or suggestions as to what your next step should be. It might be a good idea to give them contact information for your child's present oncologist. Ask them if they would call your child's doctor to discuss his/her case.

Finally, it would be to your advantage if you are able to connect with other parents fighting the same battle. Experience has shown me that most parents are very knowledgeable about their child's cancer, and are very willing to help others in the same situation. Other parents can prove to be one of your greatest resources.

If a disease is not responding to therapy or recurs, what next? How can you find new treatments? Honna wrote an Essay on emotional aspects of this situation.

Newer Treatments for Neuroblastoma
(This section last updated 2003)

Chemotherapy, surgery, radiation, and autologous bone marrow transplantation has been the mainstay of treatment for neuroblastoma. Promising new approaches used in various clinical trials across the continent include:

Immunotherapy using monoclonal antibodies.
Therapeutic dosing of I-131 mIBG, sometimes in combination with chemotherapy.
Vaccines that attempt to initiate the immune system against the disease, including a natural substance called IL-2.
New combinations of anti-cancer drugs, such as BSO/melphalan.
A derivative of vitamin A, called fenretinide.
Tandem (or "back-to-back") transplantation.
One of the major breakthroughs in neuroblastoma research came from a 5 year, CCG randomized study (CCG-3891). The study determined that the use of a vitamin A derivative, called 13-cis-retinoic acid (also called 13-cis-RA, or accutane), improved the event free survival for children with neuroblastoma, especially those that had been given autologous bone marrow transplantation. Subsequently, most centers treating children for this disease now include 13-cis-RA as part of the treatment protocol.

Statistics
5%-7% of all childhood malignancies
about 1 in 6000 children will be diagnosed with neuroblastoma by the age of five
1 in 100,000 per year in US
The average age at diagnosis is two
About 25% of newly diagnosed neuroblastomas are found in children under the age of one
Children under the age of one have a cure rate as high as 90%
Neuroblastoma Frequently Asked Questions (FAQs)
In the late 1990s, one mom wrote a FAQs section for this ped-onc site. Many of these are still pertinent: follow the link below.

neuroblastoma FAQs
Ped-Onc Resources for Neuroblastoma
The following ped-onc resource lists have appropriate sections for parents of children with neuroblastoma:

childhood cancer e-mail lists - the ACOR neuroblastoma list (N-blastoma) and the general childhood cancer list, ped-onc, are both appropriate
support organizations
books and printed materials - especially the book Childhood Cancer, A Parents's Guide to Solid Tumor Cancers, by Honna Janes-Hodder and Nancy Keene.
young people with neuroblastoma - personal home pages
Links to More Information
The following web sites provide good, general information on neuroblastoma.

Excellent resource, added in 7/08: Children's Neuroblastoma Cancer Foundation. Covers all aspects of neuroblastoma. Facts are both reviewed by nbl specialists and referenced. Of particular interest is the Neuroblastoma Handbook:
Neuroblastoma Handbook
Treating High-Risk Neuroblastoma at the Turn of the Century by C. Patrick Reynolds, MD PhD and Beth Hasenauer, RN MS. Spring 2001 Candlelighters Newsletter.
The Children's Cancer Web neuroblastoma section info plus listings
The Neuroblastoma Children's Society
St. Jude's - section on neuroblastoma
University Hospital Gent Belgium
Some basic information and X-ray pictures at an X-ray museum.
Band of Parents Foundation. Sells cookies and other items to raise funds for neuroblastoma research at MSKCC.
Soupy for Loopy. A nonprofit organization that is committed to raising awareness and funds to find a cure for neuroblastoma. Links to information on neuroblastoma.

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