Neuroblastoma

Neuroblastoma is a form of cancer that occurs in infants and young children. It is rarely found in children older than 10 years. The cells of this cancer usually resemble very primitive developing nerve cells found in an embryo or fetus. (The term neuro indicates "nerves," while blastoma refers to a cancer that affects immature or developing cells). Tumors can be found in the neck, thorax, pelvis, adrenal gland, and retroperitoneum.

Description

This CT scan of the upper abdomen shows neuroblastoma (shown by arrow). The tumor is behind the liver and is pushing the organ forward. Source: Wikimedia Commons.

Neuroblastoma is a cancer of the neuroblasts, which are stem cells that migrate to tissues of the nervous system during development of an embryo. These neuroblasts can become malignant, or cancerous, which causes neuroblastoma.

Cells of the neural crest form the adrenal medulla (the central portion of the adrenal gland) and the sympathetic nerve chain. Tumors can then occur anywhere along this chain in the following areas:

• Neck
• Chest
• Pelvis
• Adrenal gland
• Retroperitoneum (in the back portion of the abdomen)

Most cases of neuroblastoma occur in the retroperitoneum. The second most common site is the adrenal gland and the third is the sympathetic chain.

The sympathetic nervous system is the branch of the nervous system that responds to situations of “fight or flight.” Often neuroblastoma begins in the adrenal glands, which are retroperitoneal organs. There are two adrenal glands, one atop each kidney. They function to release hormones that control heart rate, blood pressure, and blood sugar. They are also important in the regulation of the body's reaction to stress.

Signs and Symptoms

The most common symptoms of neuroblastoma are caused by the growing tumor as it presses against nearby tissues, or after the cancer spreads to bone. Some common symptoms of neuroblastoma include the following:

• Abdominal pain
• Lumps in the chest, abdomen, or neck
• Bone pain
• Bulging eyes
• Dark circles around the eyes
• Weakness or paralysis
• Swollen stomach and trouble breathing in infants
• Painless, bluish lumps under the skin in infants
• Vomiting

Below are some less common symptoms of neuroblastoma:

• Fever
• Shortness of breath
• Feeling tired
• High blood pressure
• Easy bruising or bleeding, especially flat, pinpoint spots under the skin caused by the bleeding
• Jerky muscle movements
• Severe watery diarrhea
• Uncontrolled eye movement
• Swelling of the legs, ankles, feet

Causes

In general, cancer begins with a genetic mutation that allows normal, healthy cells to continue growing without responding to the signals to stop, which normal cells do. Cancer cells grow and multiply out of control. The accumulating abnormal cells form a mass (tumor). Cancer cells may invade nearby tissues and can break off from an initial tumor to spread elsewhere in the body (metastasize).

Neuroblastoma begins in neuroblasts — immature nerve cells that a fetus makes as part of its development process in the womb. As the fetus matures, neuroblasts eventually turn into nerve cells and fibers and the cells that make up the adrenal glands. The majority of neuroblasts mature by birth, though studies have found a small number of immature neuroblasts in newborns. In most cases, these neuroblasts will mature or disappear. Others, however, form a tumor — a neuroblastoma.

It isn't clear what causes the initial genetic mutation that leads to neuroblastoma. However, because neuroblastoma usually affects very young children, researchers believe the mutation occurs during pregnancy, or possibly even before conception.

Diagnosis

Exams and tests

Several different tests are used to diagnose neuroblastoma.

Laboratory tests

A microscopic image of a neuroblastoma rosette formation magnified 40X. Source: National Cancer Institute

Neuroblastoma can also be detected by performing a biopsy, which is an examination of the tissue suspected of being cancerous. Tissue can be sampled from the tumor mass or bone marrow. A pathologist will look at the cells under the microscope and can identify whether there are characteristics of cancer. In neuroblastoma, the cells typically form patterns called rosettes. At the level of DNA, some neuroblastoma cells have many copies of an oncogene called MYCN. An oncogene is a gene that has the potential to turn a cell cancerous. Other markers such as dyes or antibodies are used to tag cells in order to identify the particular type of cancer because many different types of cancer show changes to cell structure.

Diagnostic imaging

The majority of neuroblastoma cells take up a chemical called meta-iodobenzylguanidine (MIBG). When attached to a radioisotope and injected into the body, a machine can be used to scan the body for the chemical. This scan, called a MIBG scan, detects MIBG in cancerous cells. The scan is also be used to monitor the progress of treatment. X-rays, ultrasound, and CT scan are also used to detect abnormal structures of organs and tissues that may be due to neuroblastoma.

MRI of abdominal neuroblastoma stage IV with arrows showing tumor localization. Source: Wikimedia Commons

Neuroblastoma can form before birth, but it is usually not detected until the tumor begins to grow and cause symptoms. A fetal ultrasound can detect neuroblastoma before birth in rare cases.

Neurological tests

Neurological tests are also performed to check the function of the brain, spinal cord, and nerves in the periphery such as the arms and legs. This evaluation includes tests of mental status, coordination, and the ability to walk normally, as well as tests of the muscles, senses, and reflexes.

Determining the cancer stage

The stage of the cancer is determined by the results of the diagnostic tests. Staging determines whether the cancer has spread throughout the body. Staging helps guide appropriate treatment and also is used to evaluate the prognosis. The International Neuroblastoma Staging System places neuroblastoma into one of several stages:

• Stage 1—The tumor is confined to one local area and is completely removed with surgery.

• Stage 2A—The tumor is confined to one local area, and the tumor is incompletely removed during surgery.

• Stage 2B—The tumor is confined to one area and tumor which can be seen may be completely removed during surgery; cancer is also found in nearby lymph nodes.

• Stage 3—This stage is characterized by one of the following:
  • The tumor cannot be completely removed during surgery and has spread from one side of the body to the other side and may also have spread to nearby lymph nodes.
  • The tumor is in only one area, on one side of the body, but has spread to lymph nodes on the other side of the body.
  • The tumor is in the middle of the body and has spread to tissues or lymph nodes on both sides of the body, and the tumor cannot be removed by surgery.

• Stage 4—The tumor has spread to distant lymph nodes, bone marrow, bone, liver, skin, or other parts of the body.

• Stage 4S—A child is younger than one year of age, the cancer has spread to the skin, liver, and/or bone marrow, all the tumor is in only one area, and all of the tumor that can be seen may be completely removed during surgery, or cancer cells may be found in the lymph nodes near the tumor.

Progressive neuroblastoma

Progressive neuroblastoma is cancer that has progressed (continued to grow) despite treatment.

Recurrent neuroblastoma

Recurrent neuroblastoma is cancer that has recurred (come back) after it has been treated. Neuroblastoma may come back in the same place or in other parts of the body

Treatment

Patients with neuroblastoma are placed into one of three risk groups to guide treatment. The age of the patient, tumor histology (appearance of the cells), extent of disease spread, tumor biology, and other factors help classify the patients into these risk groups. The three risk treatment groups are low-risk, intermediate-risk, and high-risk. Low-risk treatment patients may not need treatment, but rather close monitoring. Intermediate- and low-risk treatment groups are most likely to be treated successfully, whereas high-risk treatment patients are unlikely to respond to treatment.

Several approaches to treatment are used in neuroblastoma: surgery, radiation, drugs, and stem cells. Surgery is used to remove as many cancer cells as possible, and radiation is used to help kill tumors that cannot be removed by surgery. Chemotherapy is done with drugs that target rapidly growing and dividing cells, and often chemotherapeutic drugs are used in combination to increase the likelihood of success and to limit the dose of another drug. These drugs are used to kill cancerous cells and to prevent them from dividing or multiplying. Some types of drugs used to treat neuroblastoma are listed below:

• Platinum-based compounds (e.g., cisplatin, carboplatin)
• Topoisomerase inhibitors (e.g., irinotecam, etoposide)
• Alkylating agents (e.g., cyclophosphamide)
• Anthracyclines (e.g., doxorubicin)
• Vinka alkaloids (e.g., vincrisine)

Stem cells are used to repopulate the body with healthy cells. Stem cells have the potential to develop into one of several different types of cells. Stem cells can be taken either from the patient's own body or from a donor. A drug called 13-cis retinoic acid may be used with chemotherapy or with stem cells. This drug slows the ability of the cancer cells to replicate or divide into more cancer cells.

Standard treatment

In the low-risk group, surgery or close monitoring of the patient is the first approach. Chemotherapy is often added if surgery does not completely remove the tumor, or if symptoms are not relieved by surgery. Radiation is used on tumors that do not respond to chemotherapy. In some cases, low-dose chemotherapy is used alone.

In the intermediate-risk group, chemotherapy is often used, or chemotherapy followed by radiation or surgery. Radiation is used to treat tumors that are not responding quickly enough to chemotherapy, or in tumors that are causing serious problems.

In the high-risk group, treatment consists of high-dose chemotherapy followed by surgery to remove as much of the tumor as possible. Radiation is applied to the tumor sites as well as any other sites that the tumor has invaded. Stem cells may need to be replenished by transplant and some patients receive chemotherapy followed by 13-cis retinoic acid.

Treatments under investigation in high-risk patients

Treatments for patients at high-risk are being investigated in clinical trials. Some of these treatments include chemotherapy followed by monoclonal antibody therapy; radiation therapy with radioactive iodine, alone or before stem cell transplant; or stem cell transplant. Monoclonal antibodies are proteins that attach to cancer cells causing them to die or stop dividing. These antibodies also bind to healthy cells, which is why their use is associated with many side effects. Treatment with radioactive iodine is a way to treat cells with radiation from within the body, rather than externally with a machine, because iodine is taken up into cancer cells.

Treatment of recurrent neuroblastoma

In patients who are low-risk, treatment for recurrent neuroblastoma found locally in one place in the body may include surgery, surgery followed by radiation, chemotherapy, high-dose chemotherapy, stem cell transplant, or 13-cis retinoic acid. Treatment for recurrent neuroblastoma that has spread to other parts of the body includes monitoring the patient, surgery followed by chemotherapy, chemotherapy alone, high-dose chemotherapy, stem cell transplant, or 13-cis retinoic acid.

In intermediate-risk patients with recurrent neuroblastoma that is found in one place in the body, treatment is usually surgery, with or without chemotherapy. For recurrent neuroblastoma that has spread to other parts of the body, treatment is usually high-dose chemotherapy, stem cell transplant, and 13-cis retinoic acid.

Many drugs are under investigation for the treatment of neuroblastoma in the high-risk group. These treatments are similar to those used in initial treatment, such as antibodies, radioactive iodine, or stem cell transplants. Because the drugs are still being studied, patients need to be enrolled in a clinical trial to have access.

Side effects of treatment

Side effects of treatment can occur years after therapy has stopped. Most often these late-onset effects can be treated and controlled. Patients who received intermediate- and high-risk treatment are more likely to have long lasting effects of treatment. Some of these side effects include the following:

• Physical problems (e.g., growth restriction)
• Changes in mood, feelings, thinking, learning, or memory
• Second cancers (new types of cancer)
• Hearing loss
• Thyroid disease
• Learning problems

Cures

Cure rates for patients with low-risk, intermediate-risk, and high-risk treatment are approximately 90%, 70%-90%, and 25%-30%, respectively.^[1]

Chances of Developing Neuroblastoma

In children, neuroblastoma is the most common solid tumor located outside the head. Approximately 650 new cases of neuroblastoma are reported in the United States each year.^[2] According to St. Jude's Children's Research Hospital ^[3],

• Each year, 1 in 100,000 children in the United States develops neuroblastoma.
• Neuroblastoma accounts for 7% to 10% of childhood cancers.
• Neuroblastoma accounts for 50 percent of all malignancies encountered in infants.
• Boys are slightly more likely to develop neuroblastoma than girls.

Clinical Trials

For a list of American government-sponsored clinical trials researching neuroblastoma, click here.

For industry-sponsored trials, click here.

Research

Researchers are continuing to work on ways to improve the treatment of neuroblastoma, especially in patients with recurrent cancer. More monoclonal antibodies are being developed, and the usefulness of radioisotopes, such as iodine, continue to be investigated. Drugs that prevent the formation of blood vessels in tumors (a process called anti-angiogenesis) are being investigated as well. Other drugs under development are protein kinase inhibitors. Protein kinases are enzymes that add a small molecule, a phosphate, to proteins in cells. These enzymes are thought to be involved in the survival and replication of cancer cells, so inhibiting them might help stop the cancer.

Expected Outcome

Frequently neuroblastoma begins during early childhood, usually in children younger than four years of age. It is the most common cancer in infants, and 95% of cases are diagnosed before 10 years of age. Unfortunately, more than half of these children will have cancer that has spread when diagnosis is made. The cancer has usually spread (metastasized) to organs such as the bone (including bone marrow), lymph nodes, liver, and skin.

Many factors affect prognosis (chance of recovery) and follow-up treatment options:

• Age of the child when diagnosed (Children less than one year of age have a better prognosis with treatment.^[4])
• Stage of the cancer
• Where the tumor is in the body
• Tumor histology (the shape, function, and structure of the tumor cells)
• Tumor biology (for example, the patterns of the tumor cells, how different the tumor cells are from normal cells, MUYCN expression, and how fast the tumor cells are growing)

Survival rates

Cure rates for patients with low-risk, intermediate-risk, and high-risk treatment are approximately 90%, 70%-90%, and 25%-30%, respectively.^[1] A study of the Children’s Cancer group found that survival in patients aged 13 to 18 years was 4% after 10 years.^[4] In patients aged 1 to 13 years, the survival after 10 years was 23%. A study covering 30 years of neuroblastoma treatment found that, in patients of all ages and risk groups, the survival at 1, 2, 5, and 20 years was 81%, 70%, 61%, and 59%, respectively.^[5]

References

1. ↑ ^{1.0 1.1} Kushner BH. Neuroblastoma: a disease requiring a multitude of imaging studies. J Nucl Med 2004;45:1172-88. Full Text
2. ↑ Lacayo NJ. eMedicine. Neuroblastoma.
3. ↑ St. Jude's Children's Research Hospital web site. Disease Information - Solid Tumor: Neuroblastoma
4. ↑ ^{4.0 4.1} Franks LM, Bollen A, Seeger RC, Stram DO, Matthay KK. Neuroblastoma in adults and teenagers has an indolent course with poor survival. Cancer 1997;79:2028-35. Abstract | PDF
5. ↑ Gutierrez JC, Fischer AC, Sola JE, et al. Markedly improving survival of neuroblastoma: a 30-year analysis of 1,646 patients. Pediatr Surg Int 2007;23:637-46. Abstract

External Links

American Cancer Society: All About Neuroblastoma

Ohio State University: Neuroblastoma: Biological Insights into a Clinical Enigma

National Cancer Institute: Neuroblastoma

American Pediatric Surgical Association: Neuroblastoma

St. Jude Children's Research Hospital