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Neuroblastoma and Neuroblastoma Treatment

Neuroblastoma is a type of cancer that occurs in infants and young children. It is rarely seen in children older than 10 years. The cells of neuroblastoma usually resemble very primitive developing nerve cells found in an embryo or fetus. (The term “neuro” means nerves, while “blastoma” means a cancer that affects immature or developing cells). Neuroblastoma is a somewhat rare cancer of the sympathetic nervous system, which is a network of nerves carrying messages from the brain throughout the body.

The nervous system has two main divisions, somatic & autonomic. The somatic nervous system regulates activities under conscious control, such as body movements and reactions to external stimuli.  The autonomic nervous system regulates activities that are involuntary, things we rarely think of, but which are essential, such as heart rate, blood pressure, breathing (respiration), and digestion. The critical component of the nervous system is neurons (nerve cells), which are the primary piece of the brain, spinal cord and the nerves that connect them to the body. These cells are necessary for all nervous functions; thinking, breathing, feeling, movement, etc. The sympathetic nervous system is a part of the autonomic nervous system which includes:

  • Nerve fibers that run alongside the spinal cord
  • Ganglia (plural of ganglion)  = clusters of nerve cells located along the path of the nerve fibers
  • Nerve-like cells found in the center (medulla) of the adrenal glands (adrenals) which are triangular-shaped glands located above the kidneys and which produce the hormone adrenalin (epinephrine).

Each year approximately 500+ children in the United States will develop neuroblastoma, which accounts for half of all malignancies in infants. Neuroblastomas are solid tumors that take the form of a lump or mass commonly beginning in one of the adrenal glands, though they can also develop in nerve tissues in the abdomen, neck, chest, or pelvis.  Two thirds (66%) of neuroblastoma tumors tend to start somewhere in the abdomen with one-third (33%) of neuroblastoma tumors starting in the adrenals and another one-third (33%) of neuroblastoma tumors beginning in the abdominal ganglia of the sympathetic nervous system. The remaining one-third of neuroblastomas usually arise from sympathetic ganglia located in the chest, neck or pelvis. In rare cases, neuroblastomas may begin in the spinal cord or have spread extensively making doctors unable to determine where the neuroblastoma originally began.

The first symptoms of neuroblastoma are often vague and may include fatigue and loss of appetite. Later, the signs and symptoms of neuroblastoma depend on the location of the original tumor and the extent of spread to nearby or distant parts of the body.  The most common sign of a neuroblastoma is an unusual lump or mass that is usually not tender or sore to the touch. These lumps/masses are usually found in the child's abdomen, causing it to swell. The child may complain of abdominal fullness, discomfort, pain, and/or constipation  - all of which is the direct result of a neuroblastoma being present. Neuroblastoma often spreads to bones, and if it has done so, a child who can talk may complain of pain in the bones. The pain may become so bad that the child limps, refuses to walk, or is unable to walk. If the neuroblastoma spreads to the spinal cord, the tumor may compress the spinal cord and cause weakness, numbness, or paralysis. Neuroblastoma can also spread to the back of the eye causing it to stick out somewhat (protrude).

Since neuroblastoma symptoms can be similar to symptoms of other more common diseases and health complaints, there is often a delay in making the diagnosis, and because symptoms are indistinct, half of all neuroblastomas have already spread to other parts of the body by the time a diagnosis is made.

Neuroblastoma is a unique cancer in many ways. It is one of the few cancers in children that release hormones that can cause changes in the body. Changes caused by neuroblastoma hormone production may be constant diarrhea, high blood pressure (which may be seen as irritability), rapid heartbeat, reddening of the skin, sweating,  and fever in about 25% of children.  There may also be changes in the some brain functions, such as rotary movements of the eyes (opsoclonus) and spastic jerks of muscles (myoclonus), and opsoclonus-myoclonus-ataxia syndrome or “dancing eyes, dancing feet.” In this situation, the child has an unsteady, trembling gait, myoclonus & opsoclonus, and they may also have difficulty speaking. For unknown reasons, neuroblastoma tumors that produce this syndrome are less life-threatening than other forms of the disease.  These hormonal induced changes are called paraneoplastic syndromes.

Sometimes, swelling may affect parts of the body that do not contain any cancer cells, especially the legs and, in males, the scrotum, when neuroblastoma tumors in the abdomen or chest press against or invade blood and lymph vessels, clogging them and preventing fluids from circulating back to the heart.  Pressure from the growing neuroblastoma may cause problems with the child's bladder or bowel movements. Pressure from neuroblastomas on, or invasion into, the superior vena cava (the large vein in the chest that returns blood from the head and neck to the heart) may cause swelling in the face or throat, which may make it hard for the child to breathe or swallow.

Blue or purple patches, resembling small bruises, may indicate spread to the skin. Sometimes there is bruising around the eyes. Neuroblastoma tumors involving the  bone marrow may cause affected children to not have enough red blood cells, white blood cells, or platelets, and shortages of blood cells can result in weakness, increased infections, and excessive bleeding from small cuts or scrapes.  Rarely, bleeding caused by loss of platelets in the blood due to clotting and excessive breakdown of tissue inside a large neuroblastoma may lead to a life threatening condition known as consumption coagulopathy.
 
Finally, there is a special form of disseminated neuroblastoma that only occurs during the first few months of life. In this special form, also called 4S, the neuroblastoma has spread to the liver, skin and bone marrow. The liver can enlarge significantly, and skin lesions have been compared to blueberries (called “blueberry syndrome”). Despite this aggressive presentation, stage 4S neuroblastoma is very treatable, and almost all children can be cured, most of the times with minimal treatment.
 
Neuroblastoma itself can also behave strangely when tumor cells sometimes die without any cause and the tumor disappears; part of a normal process known as programmed cell death (apoptosis). Neuroblastoma tumor disappearance is more common in very young infants than in older children. Another unusual behavior for childhood tumors is that the cells sometimes mature spontaneously into normal ganglion cells and stop dividing & growing.  This causes the tumor to become a ganglioneuroma, which is benign (non-cancerous).

Another nervous tissue tumor is the ganglioneuroblastoma, which is a tumor that has both malignant and benign parts. It contains neuroblasts (immature nerve cells) that can grow and spread abnormally in a malignant manner, and also has areas of benign tissue that are similar to ganglioneuroma. Ganglioneuromas are usually removed by surgery and carefully examined under a microscope to be certain they do not have areas of ganglioneuroblastoma. If the final diagnosis is ganglioneuroma, no additional treatment is needed. In contrast, ganglioneuroblastomas & neuroblastomas are treated the same and will be discussed later.

Diagnosis of neuroblastoma is made by an oncologist or pathologist based upon either a biopsy of the tumor or the results of urine and bone marrow tests. Screening tests are available for neuroblastoma, but these tests will not discover a neuroblastoma before it has spread throughout the body, and thus the screening of newborns or young children for neuroblastoma is generally not recommended. Prognostic factors after diagnosis with neuroblastoma depend on many things including age, location, spread of disease, and stage of the disease.

The stages of neuroblastoma are:

  • Stage 1: Neuroblastoma confined to the area of origin, complete gross resection, with or without microscopic residual disease and lymph nodes near the localized tumor (both sides of body) negative for neuroblastoma.
  • Stage 2A: Neuroblastoma confined to one adrenal or one side of the body (unilateral) with incomplete gross resection and lymph nodes near the localized tumor (both sides of body) negative for neuroblastoma.
  • Stage 2B: Neuroblastoma confined to one adrenal or one side of the body with complete or incomplete gross resection, lymph node on same side of body (ipsilateral) positive for neuroblastoma, and lymph node on opposite side of body (contralateral) negative for neuroblastoma.
  • Stage 3: Neuroblastoma infiltrating across midline with or without regional lymph node involvement, or unilateral neuroblastoma with contralateral lymph node involvement, or midline tumor with bilateral (both sides of the body) lymph node involvement.
  • Stage 4: Spread of neuroblastoma to distant lymph nodes, bone marrow, bone, liver, or other organs except as those defined by Stage 4S.
  • Stage 4S: Localized primary neuroblastoma as defined in Stage 1 or 2, with dissemination limited to liver, skin, or bone marrow.

Every child with neuroblastoma can be treated. The treatment each child receives depends on the age at diagnosis, neuroblastoma location, stage of disease, and tumor biology. Treatments usually include surgery, chemotherapy, and/or radiation therapy or combinations of these. Due to the highly diverse behavior of neuroblastomas some will go away without any treatment, and others may be cured by surgery alone, but half of neuroblastomas spread quickly to the bone and bone marrow and will require one or more of chemotherapy, radiation therapy, stem cell transplantation, and immunotherapy. The right treatment for each child depends mainly on the child's age, the tumor's location, and where the tumor has spread to.

TREATMENT
Children's Oncology Group is currently enrolling patients (age 3-21 years) in a Phase I study for NTX-010 in the treatment of pediatric neuroblastoma. Treatment is administered as a single 100mL intravenous infusion over 1 hour. NTX-010 is a naturally occurring virus that has shown to be very effective in treating neuroblastoma tumors in pre-clinical studies. Patients previously treated with NTX-010 have only had minimal flu-like symptoms lasting 2-3 days and no typical chemotherapy side effects.

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