All About Neuroblastoma

Neha Vapiwala, MD,John P. Plastaras, MD, PhD, and Christine Hill-Kayser, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 8, 2016

What is neuroblastoma?

Neuroblastoma is a tumor of early childhood. It usually involves nerve tissue, and under the microscope neuroblastoma cells look like small, round, blue cells. Neuroblastoma most commonly arises in the abdomen (from the adrenal glands, which sit on top of the kidneys), but can also start in the neck, chest, or pelvis. Neuroblastoma does have potential to spread, usually to the lymph nodes, liver, lungs, bones, or bone marrow.

Who gets neuroblastoma?

Neuroblastoma is the most common non-brain solid pediatric tumor. It is mainly a tumor of infancy and early childhood. In fact, the majority of neuroblastoma cases are diagnosed in children younger than 5 years of age. It is rarely found in children older than 10 years. Sometimes, the tumor is often present at birth but not detected until later, when it has grown to a noticeable size and/or starts to cause symptoms.

What are the symptoms?

The typical symptoms of neuroblastoma are related to the location of the tumor. They occur when the tumor grows and exerts pressure on surrounding organs or within bone. An abdominal tumor may cause abdominal pain, nausea, vomiting, and/or constipation. Involvement of the bones and bone marrow can cause diffuse bony pain or pain in a specific bone or joint. Parents of young children who cannot yet speak may note that a child with neuroblastoma has started refusing to walk; this may be due to pain with walking. A trademark sign of orbit involvement by tumor cells is a young child with bulging eyes and dark circles under the eyes ("raccoon eyes"). General findings may include fever, weight loss, and anemia. Occasionally, neuroblastoma tumors may release hormones and neurotransmitters that can cause high blood pressure, severe watery diarrhea, jerky muscle spasms, and/or uncontrollable eye movement (a syndrome called "opsoclonus/myoclonus" or "dancing eyes/dancing feet."

How is it diagnosed?

There are a few reports of neuroblastoma cases that are incidentally detected before birth by fetal ultrasound. Such cases are exceedingly rare; much more commonly, neuroblastoma is diagnosed after symptoms such as the above are noted. In such a situation, the child should be examined by the pediatrician, who will perform a careful physical examination and typically order some laboratory tests and imaging studies. The urine can be tested for catecholamines, which are special hormones normally produced only by the adrenal gland but are also produced by 90% of neuroblastomas. A computed tomographic (CT) scan or magnetic resonance imaging (MRI) scan may also be ordered.

Ultimately, a definitive diagnosis of neuroblastoma requires a tissue sample, and thus a tissue biopsy from the tumor and/or bone marrow is obtained. A biopsy is a small sample of the suspected tumor tissue that is surgically removed and examined under a microscope. It can sometimes be done by making a small hole and using a needle to extract a sample of the tissue.

Once the diagnosis of neuroblastoma is made, a bone marrow biopsy and other scans will be performed to see if the tumor has spread. The I-123 MIBG scan is a nuclear medicine study that is used specifically to stage and evaluate neuroblastoma. It is uses a radioactive tracer (metaiodobenzylguanidine, or MIBG) that is specifically taken up by neuroblastoma cells and may detect hidden deposits of tumor using a special type of camera that can detect the MIBG.

How Is Neuroblastoma Staged?

For the purposes of understanding the full spectrum of neuroblastoma and extent of disease, think of neuroblastoma as falling into one of the following categories:

Localized and resectable

  • Cancer is confined to the site of origin with NO evidence of spread
  • Cancer can be surgically removed

Localized and unresectable

  • Cancer is confined to the site of origin
  • BUT the cancer cannot be completely removed surgically

Regional

  • Cancer has extended beyond the site of origin to regional lymph nodes and/or surrounding organs or tissues, but has not spread to distant parts

Disseminated

  • Cancer has spread from the site of origin to distant lymph nodes, bone, liver, skin, bone marrow, and/or other organs (except as defined for stage 4S)

A special circumstance: Stage MS (may also be called 4S)

  • Stage MS neuroblastoma is also called "special" neuroblastoma because it is treated differently. The cancer is localized, with spread limited to liver, skin, and/or, to a very limited extent, bone marrow, and occurs only in children 18 months of age or less.

Recurrent

  • Recurrent neuroblastoma means that the cancer has come back (recurred) or continued to spread (progressed) after it was treated. It may come back in the original site or in another part of the body.

The actual medical staging system used by healthcare professionals is the International Neuroblastoma Risk Group Staging System (INRGSS), introduced in 2008.

  • Stage L1: Locoregional tumor without certain risk factors determined on imaging
  • Stage L2: Locoregional tumor with one or more risk factors
  • Stage M: Distant metastatic disease (except MS)
  • Stage MS: INRG Stage L1 or L2 tumor with metastatic disease confined to skin and/or liver and/or bone marrow

What is the prognosis of a child with neuroblastoma?

The prognosis for a child with neuroblastoma ranges from excellent to guarded, depending on many factors. Generally speaking, the chance of recovery for any given patient with neuroblastoma depends on the child's age at diagnosis, the location of the tumor, the appearance of the tumor cells under a microscope, and the stage of disease. These factors help determine a "risk group" for each patient. Patients with low-risk disease have a better prognosis and require less aggressive treatment than do those with high-risk disease. The Children’s Oncology Group (COG) has defined risk groups based on disease extent, age, and the presence or absence of extra copies of the MYCN gene. These risk groups continue to evolve over time.

Specifically, the following features of cancer tend to predict the child's likelihood of cure better than the prediction using only disease stage:

  • Tumor grade - Tumor grade is based on appearance of neuroblastoma cells under the microscope, which include estimates of proliferative activity (proportion of actively dividing cells) and ratios of very immature cells to more mature, normal nerve tissue-resembling cells.
  • DNA ploidy - Ploidy refers to the amount of DNA in each cell, aka ploidy, measured by special lab techniques like flow cytometry or imaging cytometry. Normal cells are diploid. Neuroblastoma cells with increased amounts of DNA are termed hyperdiploid, and in infants, hyperdiploid cells are associated with earlier stages of disease, better response to therapy, and thus a generally better outcome than diploid cells.
  • Cytogenetics -The cytogenetic make up of a cell refers to the number of chromosomes the cell as counted under a microscope, with notation of any abnormalities. Normal cells have 46 chromosomes (2 sets of 23), which are made of DNA and protein. Neuroblastomas with normal chromosome numbers tend to be more aggressive than those with extra chromosomes. Tumors that are missing certain parts of chromosomes 1 or 11 (known as "1p deletions" or "11q deletions") have a worse prognosis. Neuroblastomas with too many copies of the N-MYC oncogene (amplification) tend to grow more quickly and are associated with a worse prognosis than children without the amplification.
  • Oncogene amplifications - Oncogenes are regions of DNA that are vital in controlling cell growth. Changes within those genes can make cells grow and divide too quickly, which is what cancer cells do.
  • Serum markers - neuroblastoma cells may release chemicals into the blood:
    • High levels of ferritin, a chemical that is important for normal iron metabolism, may be associated with a worse prognosis
    • Increased levels of neuron-specific enolase (NSE) and lactate dehydrogenase (LDH) may also predict a worse outlook

What are the recommended treatment options?

Because neuroblastoma is relatively rare, it is best treated at a facility by clinicians who have experience. If possible, children should be treated on a cooperative group clinical protocol.

Low Risk

Children with low risk disease usually only require surgery, as this should remove all visible and microscopic tumor from the body in this group of patients. However, for those few children that might be symptomatic, chemotherapy or radiotherapy may be required to control the symptoms.

Intermediate Risk

Children with intermediate risk disease should receive 4 to 8 cycles (1 or 2 courses) of chemotherapy before or after surgery to control the disease, usually given as a combination of agents. The typical drugs used in neuroblastoma include: cyclophosphamide, doxorubicin, cisplatin, carboplatin, and etoposide. "Second look" surgery (repeat surgery after chemotherapy and/or radiation therapy to check the results of therapy and to remove any remaining cancerous tissue if possible) or radiation therapy may or may not be needed.

High Risk

Children with high-risk disease require very intensive chemotherapy. This is usually followed by resection of the primary tumor, followed by more chemotherapy. Often, this second period of chemotherapy, called consolidation, is intensive enough to require peripheral stem cell rescue (meaning that the patient receives his or her own stem cells in order to rescue the immune system following chemotherapy administration). After recovery from consolidation chemotherapy, patients usually require external beam irradiation followed by biologic agents such as 13-cis retinoic acid and antibody treatments. MIBG, which is often used as part of the diagnosis and staging for neuroblastoma (see above) can also sometimes be used therapeutically.

MS

Children with MS disease can often be observed without active treatment, as MS disease can resolve without any therapy. If a patient with MS disease has extra copies of the MYCN gene in his or her tumor, this will usually be treated with high-risk therapy. Even without the MYCN gene amplification, some patients with MS disease require chemotherapy and/or radiation for persistent disease, or disease that is causing symptoms.

Recurrence

Unfortunately, some children will have disease recurrence after initial therapy. Treatment options at this point will depend on many factors, including the initial risk group and where in the body the cancer came back. Chemotherapy, surgery, radiation therapy, or even simple observation may be appropriate, depending on the circumstances.

Has Proton Radiotherapy Been Used for Neuroblastoma?

Some children with neuroblastoma may be good candidates for proton therapy. Proton therapy has been used for neuroblastoma at some specialized centers, including the Children's Hospital of Philadelphia and the Massachusetts General Hospital. The decision of whether proton therapy is the best treatment for a certain patient must be made by the team of physicians caring for the child, as well as a team from a proton referral center.

Follow-up Care and Survivorship

After treatment for childhood cancer, the patient will be followed closely to monitor for the cancer coming back, to help them heal from ongoing side effects, and to help them to transition to survivorship. Initially they will be seen often and have ongoing tests to monitor their health. As time goes on, these visits and testing will become less frequent. The oncology team will discuss each patient’s individual follow up plan with them.

Survivors often wonder what steps they can take to live healthier after cancer. There is no supplement or specific food you can eat to assure good health, but there are things you can do to live healthier, prevent other diseases, detect any subsequent cancers early and work with the social and emotional issues, including insurance, employment, relationships, sexual functioning, and fertility, that a prior cancer diagnosis sometimes brings with it. Your oncology team is there to support you and can help you find support resources.

It is important to have a plan for who will provide your cancer-focused follow up care (an oncologist, survivorship doctor or primary care doctor). Talk with your oncology team about developing a survivorship care plan. If you would like to find a survivorship doctor to review your history and provide recommendations, you can contact cancer centers in your area to see if they have a survivor's clinic or search for a clinic on OncoLink's survivorship clinic list.

References for Further Reading

Neuroblastoma – from the American Cancer Society

Neuroblastoma in Children – from CureSearch

Neuroblastoma – from the National Cancer Institute

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