Childhood Neuroblastoma Neuroblastoma is a cancer of the sympathetic nervous system. The average age at diagnosis is two years, with the majority of cases presenting before the age of five years. While neuroblastoma can arise at any place along the sympathetic nervous system from the neck to the pelvis, more than half originate at the adrenal gland in the abdomen. Symptoms of this disease vary depending on the location of the primary tumor. The sympathetic nervous system Chemical messengers, called neurotransmitters, relay information throughout the body using the two networks which comprise the nervous system. The central nervous system (CNS) includes the brain and spinal cord. The brain acts as the central control room, while the spinal cord operates as a link to other important elements of the nervous system. The peripheral nervous system (PNS) connects the CNS to other organs and systems. The network of nerves that make up the sympathetic nervous system is part of the PNS. The sympathetic nervous system performs automatically in response to the environment and emotions. For example, if a person is surprised or angered, the sympathetic nervous system leaps into action by accelerating the heartbeat, increasing blood sugar, and cooling the body through perspiration. The adrenal glands are relatively small glands that sit on top of each kidney and are responsible for producing many different hormones. The adrenal gland has two parts. The outer portion, called the cortex, secretes hormones such as cortisone and aldosterone that are used by the body for fluid and electrolyte balance. The central portion, called the medulla, produces the hormones adrenaline and noradrenaline, which help the body respond to stress. Who gets neuroblastoma? Neuroblastoma accounts for approximately 8 to 10 percent of all childhood cancers. Each year more than 600 new cases are diagnosed in the United States and an additional 65 are diagnosed in Canada. Males are diagnosed more often than females, and there is a slightly higher incidence among white than black children. About half of all neuroblastomas are diagnosed by two years of age, and about 75 percent are diagnosed before five years of age. Neuroblastoma is also diagnosed in newborns. Genetic factors There is no known genetic cause of neuroblastoma. Children with some disorders, however, have a higher risk of developing neuroblastoma. Two examples of these associated disorders are Hirschsprung disease (a developmental abnormality which involves the colon) and von Recklinghausen neurofibromatosis. Environmental factors Although certain types of cancer have been linked to environmental factors, this is not true for neuroblastoma. Many research studies have been conducted to evaluate possible environmental causes, but no conclusive answers have yet been found. Signs and symptoms Children with neuroblastoma may exhibit a number of different symptoms. The signs and symptoms of disease depend largely on the location of the primary tumor and whether the disease has spread (metastasized) to other distant locations in the body. Without distinct symptoms in their children over a worrisome period of time, these parents had little reason to suspect cancer: Mikey (four years old) was always a sickly child and he was constantly on antibiotics for one ailment or another. The night before we took him to the emergency room, he had fallen into his toy box and hurt his abdomen. He wasn't in any pain, but overnight a huge mass began to appear. He was asleep on my bed lying on his side and we could see a mass protruding from his upper left abdomen area. We never imagined it could be a tumor. •  •  •  •  •   My son was fourteen years old when he was diagnosed. Greggory could run a mile in 5 minutes and 4 seconds. Who would have thought that he had a 5 x 6 inch tumor attached to his kidney? He complained off and on about back pain, but it was usually after shoveling snow or sledding or whatever else boys his age do. There was always a reason. In many cases, parents find a lump or mass in the abdomen while dressing or bathing their child. The abdomen may appear enlarged. The child may stop eating, lose weight, and experience diarrhea and vomiting. If disease has spread to the skeleton, the child may begin to limp, refuse to stand, or complain of pain in the bones. Children with neuroblastoma may have fever, and they may be unusually tired and irritable. In addition, children whose disease has spread to the bones around the eye socket may have dark circles around the eyes. This is often referred to as "raccoon eyes." If the tumor involves the spinal cord, the child may complain of back pain and have difficulty passing urine or stool. Tumors located in this area sometimes cause spinal cord compression, which can result in paralysis. Children whose disease has spread to the bone marrow may have pale skin and sometimes tiny red dots under the skin (petechiae). Tumors growing in the chest may cause a chronic cough or difficulty breathing. Horner syndrome is a rare disorder that is sometimes associated with a mediastinal (in the chest) or cervical (in the neck) neuroblastoma. This syndrome occurs when the sympathetic nerve to the eye is damaged or disrupted. The eyelid droops, the pupil looks small, and the child may not sweat on the side of the face of the affected eye. This parent describes the condition: Scott has a minor complication from surgery called Horner syndrome. His left eyelid droops, and the pupil is smaller than that of the right eye. It doesn't impact his vision, but it is clearly noticeable when you look at him. Opsoclonus-myoclonus is another rare and unusual sign that can accompany neuroblastoma. It is sometimes referred to as "dancing eyes-dancing feet syndrome" because of its symptoms--rapid, uncontrollable movement of the eyes, and sudden, jerky movements of the feet and legs. A parent recounts daughter Justina's symptoms: At the age of nineteen months, Justina lost all her motor skills. At first she was clumsy and staggering, but it progressed very rapidly (over a period of four days) to a point where she was not able to pull herself up or even sit. Her eyes would bounce, roll back, and circle. She was scared, since she had no concept of where her body was in space. She always felt as if she was falling. Justina was misdiagnosed for four months until we finally learned what was wrong. She had neuroblastoma along with opsoclonus-myoclonus. Diagnosis Many tests are necessary to confirm a diagnosis of neuroblastoma because symptoms of this disease can mimic other illnesses, including other cancers. The oncologist will perform a thorough physical examination and order a complete blood count (CBC). Computed tomography (CT) or magnetic resonance imaging (MRI) scans are obtained. Chest x-rays and ultrasonography of the abdomen help determine if a mass is present. A bone scan is usually ordered to check the presence or extent of skeletal involvement. An MIBG scan, performed in the nuclear medicine department, is frequently ordered since it is very specific in detecting the presence of neuroblastoma. However, the radiopharmaceutical used for this scan can be difficult to get, so it is not available at all pediatric facilities. Hormone tests, biopsies, and evaluation of a host of biologic factors also help the oncologist diagnose neuroblastoma. Approximately 95 percent of all neuroblastomas secrete hormones called catecholamines, which are usually produced by the adrenal medulla. Catecholamines, and their metabolic end products vanillylmandelic acid (VMA) and homovanillic acid (HVA), are found in the urine. A 24-hour or "spot" urine sample (urine collected one time, rather than all urine collected for a 24-hour period) is collected and tested for catecholamine levels. This test is valuable for making the initial diagnosis and for following the child's response to treatment, although there are exceptions, as this parent indicates: Rachel was three years old when she first developed symptoms. One of her eyes started turning in, and she lost most of her vision in that eye (she regained it after treatment). The doctor did some scans and a biopsy and diagnosed her neuroblastoma. She had a primary tumor on her right adrenal gland, but there was a much larger tumor in her sinus cavity, behind her right eye. Her urine catecholamine levels were never elevated. In order to make a diagnosis, the oncologist needs actual tumor tissue obtained from a biopsy or operation. Every child with suspected neuroblastoma will also have a bone marrow aspiration. The tumor sample and bone marrow aspirate are studied under a microscope by a pathologist. These samples are then tested for a variety of biologic factors. Staging Once a diagnosis of neuroblastoma has been made, the oncologist will order further tests and scans to determine the extent (stage) of the disease. There are three systems currently in use to stage neuroblastoma: the Children's Cancer Group (CCG) system, the Pediatric Oncology Group (POG) system, and the International Neuroblastoma Staging System (INSS). The INSS was developed to provide researchers with a system to compare data and facilitate the international exchange of information. Using the INSS, neuroblastoma is categorized into five distinct stages: Stage 1. The tumor is limited to the site of origin and can be completely removed (resected), with or without microscopic residual disease (extremely small amounts that are visible only with the aid of a microscope); lymph nodes on both sides of the abdomen are negative (no cancer found when viewed under a microscope). Stage 2A. The tumor affects only one side of the body and is limited to the site of origin; the cancer cannot be completely resected (microscopic disease remains); lymph nodes on both sides of the body are negative microscopically. Stage 2B. The tumor affects only one side of the body and is limited to the site of origin; complete resection may or may not be possible; lymph nodes on the same side of the body near the tumor are positive (contain neuroblastoma cells); lymph nodes on the opposite side of the body are negative microscopically. Stage 3. The tumor has moved across the midline and is unresectable; regional lymph nodes may or may not be positive; or the tumor affects only one side of the body with related lymph node involvement of the opposite side of the body; or the tumor begins in the midline with lymph node involvement on both sides of the body. Stage 4. The tumor has spread from the site of origin to distant lymph nodes beyond the cavity, bone, bone marrow, liver, and/or other organs in which the tumor began (except as defined for stage 4S). Stage 4S. This stage includes only infants under one year of age. The tumor is confined to the site of origin as described in stage 1 or 2, with spread limited to liver, skin, and/or, to a limited extent, bone marrow. Prognosis Treatment for childhood neuroblastoma has steadily improved in the last two decades. In the 1960s, virtually all children with neuroblastoma died. Now, the success rate of treatment varies with the stage at diagnosis. The majority of children with stage 1, 2, 4S, or 4 (if the child is less than one year old at diagnosis) are cured. Doctors determine the appropriate treatment for each child by considering the child's age, the stage of the tumor, and a variety of biologic factors. Children with neuroblastoma are grouped into low-, intermediate-, and high-risk subgroups in order to give the child the best possible treatment for her disease. To determine these risk levels, several prognostic factors are used, including the following: N-myc amplification. N-myc (also known as MYCN) is a gene that under certain conditions helps to change a normal cell into a cancerous cell. Amplification means that the cell makes multiple copies of the gene. Tumor pathology. The Shimada index is a method to grade the tumor based on how it looks under a microscope (histopathologic classification). This index, developed by Dr. H. Shimada, is widely used to evaluate neuroblastoma tumors. Abnormalities of chromosome 1. DNA index. This is a measurement of the amount of DNA material in neuroblastoma cells. An increase in the number of chromosomes is called hyperdiploid DNA. Treatment At diagnosis, many parents are confused about how to find the best doctors and treatments for their child. State-of-the-art care is available from physicians who participate in the Children's Cancer Group (CCG) and/or the Pediatric Oncology Group (POG). These study groups, composed of pediatric surgeons and oncologists, urologists, radiation oncologists, researchers, and nurses, establish the standard of care for patients worldwide, conduct new studies to discover better therapies, and establish follow-up for survivors. They are in the process of merging into one entity called the Children's Oncology Group (COG). If the treatment center you are referred to is a member of one of these groups, you can rest assured that your child will have access to the best thinking on the treatment of pediatric cancers. The oncologist chooses the best treatment or clinical trial based on these risk categories: Low risk. Children with early stage disease and infants with stage 4S do not require aggressive treatment. They usually have surgery and in some cases, mild chemotherapy. Intermediate risk. Children with intermediate risk disease generally require chemotherapy and surgery. Occasionally radiation is necessary. High risk. Children at high risk of relapse need aggressive treatment, including chemotherapy, surgery, radiation, and sometimes bone marrow or peripheral stem cell transplantation. The goal is to achieve a complete remission by obliterating all cancer cells as quickly as possible. Complete remission occurs when all signs and symptoms of neuroblastoma disappear, and abnormal cells are no longer found by any standard evaluation (CT, bone scan, routine bone marrow aspirate, and biopsy). Surgery Surgery is used to treat virtually all neuroblastomas and has many important roles. It is used to establish the diagnosis, to obtain tumor tissue for examination, to stage the disease, and for second-look procedures. If the tumor is localized and appears resectable, surgery is performed soon after diagnosis before further therapy is begun. Most often, however, this is not possible, and chemotherapy is used to shrink the tumor prior to surgery. Even after chemotherapy, surgical removal is often incomplete, and radiation is required to ensure that all tumor cells are destroyed, notably for stage 3 and 4 disease. A father remembers the relief that followed his son's operation: The surgery to remove the tumor took about four hours, and there were no major complications. Scott spent three hours in the recovery room before being ready to go to the ward. His first words after waking were, "I love you, Mom," which obviously touched Karen. While in the recovery room, we realized that Scott's stuffed Yoshi toy, who also went to the operating room, returned with a neck bandage identical to Scott's. Someone had a sense of humor! Complications can occur in 5 to 10 percent of aggressive surgical procedures. The goals of initial surgeries should be developed on an individual basis because each child is unique. Factors considered include tumor location, resectability, relationship to major blood vessels, and the child's prognosis. Lymph nodes near the tumor are usually sampled to determine if the disease has spread. Sometimes a liver biopsy is taken during the initial surgery, although the value of this practice is unclear if the liver appears normal on the scans and during surgery. Spinal cord compression, often called "dumbbell" extension, occurs when a tumor invades the spinal canal. In this situation, a surgical procedure called laminectomy is sometimes performed. A laminectomy removes part of the bone covering the spinal canal, relieving symptoms caused by compression of the cord and nerve roots. Most often, spinal cord compression from neuroblastoma is treated with chemotherapy, avoiding the need for laminectomy. Chemotherapy Chemotherapy is used to treat almost all children with neuroblastoma. Response rates have improved considerably through the use of multidrug regimens (treatments using more than one chemotherapeutic agent). The most commonly used chemotherapy agents include cyclophosphamide, cisplatin, doxorubicin, vincristine, teniposide, and etoposide. Some studies use only one drug at the beginning of therapy in a "window" study. This kind of study attempts to find out if the drug being studied has an effect on neuroblastoma on its own. These drugs include carboplatin and ifosfamide. Other chemotherapy drugs that are used to treat neuroblastoma include topotecan, irinotecan, and melphalan. Not all children have serious side effects from chemotherapy, as this child's experience demonstrates: Luke (two years old) had side effects from his chemo protocol that were relatively minor compared to what other children experience. He did have nausea, but it usually consisted of one to three vomiting episodes over one or two days and were over quickly. Over the entire eight-course cycle, he did have numerous neutropenic bouts, with several visits to the emergency room for night-onset fevers resulting in short-term hospitalizations to get IV antibiotics. He did get two or three infections in his broviac, which also required hospitalizations for antibiotics. However, he only needed one blood and one platelet transfusion during the entire protocol. He ate incredibly well all during his protocol and even gained steadily in weight and height. Generally, therapy will be mapped out in a protocol, which is an outline of the drugs to be used, the maximum dose to be given, and the preferred schedule and routes of administration. Radiation Neuroblastoma is very sensitive to radiation. The primary role of radiation is to locally control tumors that cannot be resected even after several courses of chemotherapy. It is also a component of some bone marrow transplant programs (total body radiation). Finally, it can be used for symptomatic relief of painful bony lesions at any time. Children with INSS stages 2B and 3 often are given radiation therapy in combination with chemotherapy. Radiation in doses of 1500 cGy (centigrays--measured units of radiation) to 2500 cGy are given in 150 cGy fractions over ten to twenty days. These parents describe their sons' experiences with radiation therapy: Matthew received palliative doses of radiation to bony areas that were causing him great pain. It worked very well, and generally he had considerable relief within 24 hours. •  •  •  •  •   My son experienced very few side effects from the local radiation he received to his abdomen and chest. He was premedicated each time with Zofran and only had a few bouts of vomiting over a two-week course. Other than diarrhea, he tolerated it great and wasn't even very fatigued. In infants with stage 4S disease, 300 cGy to 600 cGy given to the liver is sometimes used in single or multiple fractions if there is respiratory distress because of a markedly enlarged liver. Bone marrow transplantation In the last decade, autologous bone marrow transplants and peripheral blood stem cell transplants have been used with increasing frequency to treat children with high-risk or relapsed neuroblastoma. Various regimens are used to prepare the child for transplant. These include chemotherapy drugs such as melphalan, cisplatin, teniposide, and doxorubicin with or without total body irradiation (TBI). This parent describes the period that led up to a successful outcome from a bone marrow transplant: Rachel was three years old when she received an autologous bone marrow transplant as part of her protocol for high-risk neuroblastoma. It was a difficult experience for her, and she was incredibly sick. During transplant, her personality changed and for weeks she just didn't seem like Rachel. She had awful sores on her mouth and bottom. She developed a severe case of mucositis and was placed in an oxygen tent to maintain her oxygen levels. Morphine was given to control pain, and we were in the hospital for a month. She's seven years old now, and has done well since she finished treatment in 1996. Biologic modifiers and more Many brilliant researchers have devoted their lives to unlocking the neuroblastoma mystery, resulting in vastly improved prognoses for many children. Some exciting new treatments are currently under investigation: Promising results have been achieved using a derivative of vitamin A, called 13-cis-retinoic acid, following autologous bone marrow transplants. 13-cis-retinoic acid has minimal toxicity and can cause neuroblastoma cells to stop growing. Confirmation of its efficacy is underway. GD2 is a substance found in large amounts in some neuroblastoma cells. Some institutions are researching using antibodies that attack the GD2 in neuroblastoma cells while limiting damage to healthy cells. Cytokine gene therapy (also called vaccine therapy) uses agents such as IL-2 to help the child's immune system destroy cancerous cells. Neuroblastoma cells are removed from the child, modified in a lab, then injected back into the child. Some institutions are getting good results with a new radiotherapy technique using 131I-MIBG and 125I-MIBG. Newest treatment options To learn of the newest treatments available, call (800) 4-CANCER and ask for the PDQ (Physicians Data Query) for neuroblastoma. These free statements, also available on the Internet at http://cancernet.nci.nih.gov/, explain the disease, state-of-the-art treatments, and ongoing clinical trials. There are two versions available: one for patients, which uses simple language and contains no statistics, and one for professionals, which is technical, thorough, and includes citations to scientific literature. This fact sheet was adapted from Childhood Cancer Survivors: A Practical Guide to the Future, by Nancy Keene, Wendy Hobbie, and Kathy Ruccione, © 2001 Patient-Centered Guides). For more information, call (800) 998-9938 or check www.patientcenters.com for publication announcement.