Neuroblastoma is a cancer that develops from immature nerve cells (neuroblasts) found in several areas of the body and most commonly arises in and around the adrenal glands, which have similar origins to nerve cells and sit atop the kidneys. However, neuroblastoma can also develop in other areas of the abdomen and in the chest, neck and near the spine, where groups of nerve cells exist.
Some forms of neuroblastoma go away on their own, while others may require multiple treatments.
Signs and symptoms of neuroblastoma vary depending on what part of the body is affected.
Neuroblastoma in the abdomen — the most common form — may cause signs and symptoms such as:
- Abdominal pain
- A mass under the skin that isn't tender when touched
- Changes in bowel habits, such as diarrhea or constipation
Neuroblastoma in the chest may cause signs and symptoms such as:
- Chest pain
- Changes to the eyes, including drooping eyelids and unequal pupil size
Other signs and symptoms that may indicate neuroblastoma include:
- Lumps of tissue under the skin
- Eyeballs that seem to protrude from the sockets (proptosis)
- Dark circles, similar to bruises, around the eyes
- Back pain
- Unexplained weight loss
- Bone pain
Neuroblastoma begins in neuroblasts — immature nerve cells that a fetus makes as part of its development process. As the fetus matures, neuroblasts eventually turn into nerve cells and fibers and the cells that make up the adrenal glands. Most neuroblasts mature by birth, though a small number of immature neuroblasts can be found in newborns. In most cases, these neuroblasts mature or disappear. Others, however, form a tumor — a neuroblastoma. It isn't clear what causes the initial genetic mutation that leads to neuroblastoma
Neuroblastoma cannot be prevented and children with a family history of neuroblastoma may be more likely to develop the disease. Yet, familial neuroblastoma is thought to comprise a very small number of neuroblastoma cases. In most cases of neuroblastoma, a cause is never identified.
The diagnosis is usually confirmed by a surgical pathologist, taking into account the clinical presentation, microscopic findings, and other laboratory tests.
In about 90% of cases of neuroblastoma, elevated levels of catecholamines or their metabolites are found in the urine or blood. Catecholamines and their metabolites include dopamine, homovanillic acid (HVA), and/or vanillylmandelic acid (VMA).
Another way to detect neuroblastoma is the mIBG scan (meta-iodobenzylguanidine), which is taken up by 90 to 95% of all neuroblastomas, often termed "mIBG-avid." The mechanism is that mIBG is taken up by sympathetic neurons, and is a functioning analog of the neurotransmitter norepinephrine. When it is radio-ionated with I-131 or I-123 (radioactive iodine isotopes), it is a very good radiopharmaceutical for diagnosis and monitoring of response to treatment for this disease. With a half-life of 13 hours, I-123 is the preferred isotope for imaging sensitivity and quality. I-131 has a half-life of 8 days and at higher doses is an effective therapy as targeted radiation against relapsed and refractory neuroblastoma.
On microscopy, the tumor cells are typically described as small, round and blue, and rosette patterns (Homer-Wright rosettes) may be seen. Homer-Wright rosettes are tumor cells around neuropil, not to be confused with pseudorosettes which are tumor cells around a blood vessel. They are also distinct from the pseudorosettes of an ependymoma which consist of tumor cells with glial fibrillary acidic protein (GFAP)–positive processes tapering off toward a blood vessel (thus a combination of the two). A variety of immunohistochemical stains are used by pathologists to distinguish neuroblastomas from histological mimics, such as rhabdomyosarcoma, Ewing's sarcoma, lymphoma and Wilms' tumor.
Neuroblastoma is one of the peripheral neuroblastic tumors (pNTs) that have similar origins and show a wide pattern of differentiation ranging from benign ganglioneuroma to stroma-rich ganglioneuroblastoma with neuroblastic cells intermixed or in nodules, to highly malignant neuroblastoma. This distinction in the pre-treatment tumor pathology is an important prognostic factor, along with age and mitosis-karyorrhexis index (MKI). This pathology classification system describes "favorable" and "unfavorable" tumors by the International Neuroblastoma Pathology Committee (INPC, also called Shimada system) which was established in 1999 and revised in 2003.
The "International Neuroblastoma Staging System" (INSS) established in 1986 and revised in 1988 stratifies neuroblastoma according to its anatomical presence at diagnosis:
Stage 1: Localized tumor confined to the area of origin.
Stage 2A: Unilateral tumor with incomplete gross resection; identifiable ipsilateral and contralateral lymph node negative for tumor.
Stage 2B: Unilateral tumor with complete or incomplete gross resection; with ipsilateral lymph node positive for tumor; identifiable contralateral lymph node negative for tumor.
Stage 3: Tumor infiltrating across midline with or without regional lymph node involvement; or unilateral tumor with contralateral lymph node involvement; or midline tumor with bilateral lymph node involvement.
Stage 4: Dissemination of tumor to distant lymph nodes, bone marrow, bone, liver, or other organs except as defined by Stage 4S.
Stage 4S: Age <1 year old with localized primary tumor as defined in Stage 1 or 2, with dissemination limited to liver, skin, or bone marrow (less than 10 percent of nucleated bone marrow cells are tumors).
Although international agreement on staging (INSS) has been used, the need for an international consensus on risk assignment has also been recognized in order to compare similar cohorts in results of studies. Beginning in 2005, representatives of the major pediatric oncology cooperative groups have met to review data for 8,800 neuroblastoma patients treated in Europe, Japan, USA, Canada, and Australia between 1990 and 2002. This task force has proposed the International Neuroblastoma Risk Group (INRG) classification system. Retrospective studies revealed the high survival rate of 12-18 month old age group, previously categorized as high-risk, and prompted the decision to reclassify 12-18 month old children without N-myc (also commonly referred to as MYCN) amplification to intermediate risk category.
The new INRG risk assignment will classify neuroblastoma at diagnosis based on a new International Neuroblastoma Risk Group Staging System (INRGSS):
Stage L1: Localized disease without image-defined risk factors.
Stage L2: Localized disease with image-defined risk factors.
Stage M: Metastatic disease.
Stage MS: Metastatic disease "special" where MS is equivalent to stage 4S.
The new risk stratification will be based on the new INRGSS staging system, age (dichotomized at 18 months), tumor grade, N-myc amplification, unbalanced 11q aberration, and ploidy into four pre-treatment risk groups: very low, low, intermediate, and high risk.
Between 20% and 50% of high-risk cases do not respond adequately to induction high-dose chemotherapy and are progressive or refractory. Relapse after completion of frontline therapy is also common. Further treatment is available in phase I and phase II clinical trials that test new agents and combinations of agents against neuroblastoma, but the outcome remains very poor for relapsed high-risk disease.
Most long-term survivors alive today had low or intermediate risk disease and milder courses of treatment compared to high-risk disease. The majority of survivors have long-term effects from the treatment. Survivors of intermediate and high-risk treatment often experience hearing loss. Growth reduction, thyroid function disorders, learning difficulties, and greater risk of secondary cancers affect survivors of high-risk disease. An estimated two of three survivors of childhood cancer will ultimately develop at least one chronic and sometimes life-threatening health problem within 20 to 30 years after the cancer diagnosis.
Based on a series of 493 neuroblastoma samples, it has been reported that overall genomic pattern, as tested by array-based karyotyping, is a predictor of outcome in neuroblastoma:
- Tumors presenting exclusively with whole chromosome copy number changes were associated with excellent survival.
- Tumors presenting with any kind of segmental chromosome copy number changes were associated with a high risk of relapse.
- Within tumors showing segmental alterations, additional independent predictors of decreased overall survival were N-myc amplification, 1p and 11q deletions, and 1q gain.
Earlier publications categorized neuroblastomas into three major subtypes based on cytogenetic profiles:
- Subtype 1: favorable neuroblastoma with near triploidy and a predominance of numerical gains and losses, mostly representing non-metastatic NB stages 1, 2 and 4S.
- Subtypes 2A and 2B: found in unfavorable widespread neuroblastoma, stages 3 and 4, with 11q loss and 17q gain without N-myc amplification (subtype 2A) or with N-myc amplification often together with 1p deletions and 17q gain (subtype 2B).
Virtual karyotyping can be performed on fresh or paraffin-embedded tumors to assess copy number at these loci. SNP array virtual karyotyping is preferred for tumor samples, including neuroblastomas, because they can detect copy neutral loss of heterozygosity (acquired uniparental disomy). Copy neutral LOH can be biologically equivalent to a deletion and has been detected at key loci in neuroblastoma. ArrayCGH, FISH, or conventional cytogenetics cannot detect copy neutral LOH.
Your child's doctor selects a treatment plan based on several factors that affect your child's prognosis. Factors include your child's age, the stage of the cancer, the type of cells involved in the cancer, and whether there are any abnormalities in the chromosomes and genes
Your child's doctor uses this information to categorize the cancer as low risk, intermediate risk or high risk. The treatment or combination for neuroblastoma depends on the risk category.
Surgeons use scalpels and other surgical tools to remove cancer cells. In children with low-risk neuroblastoma, surgery to remove the tumor may be the only treatment needed.
Whether the tumor can be completely removed depends on its location and its size. Tumors that are attached to nearby vital organs — such as the lungs or the spinal cord — may be too risky to remove.
In intermediate-risk and high-risk neuroblastoma, surgeons may try to remove as much of the tumor as possible. Other treatments, such as chemotherapy and radiation, may then be used to kill remaining cancer cells.
Chemotherapy uses chemicals to destroy cancer cells. Chemotherapy targets rapidly growing cells in the body, including cancer cells. Unfortunately, chemotherapy also damages healthy cells that grow quickly, such as cells in the hair follicles and in the gastrointestinal system, which can cause side effects.
Children with intermediate-risk neuroblastoma often receive a combination of chemotherapy drugs before surgery to improve the chances that the entire tumor can be removed.
Children with high-risk neuroblastoma usually receive high doses of chemotherapy drugs to shrink the tumor and to kill any cancer cells that have spread elsewhere in the body. Chemotherapy is usually used before surgery and before bone marrow stem cell transplant.
Radiation therapy uses high-energy beams, such as X-rays, to destroy cancer cells.
Children with low-risk or intermediate-risk neuroblastoma may receive radiation therapy if surgery and chemotherapy haven't been helpful. Children with high-risk neuroblastoma may receive radiation therapy after chemotherapy and surgery, to prevent cancer from recurring.
Radiation therapy primarily affects the area where it's aimed, but some healthy cells may be damaged by the radiation. What side effects your child experiences depends on where the radiation is directed and how much radiation is administered.
Stem cell transplant
Children with high-risk neuroblastoma may receive a transplant using their own blood stem cells (autologous stem cell transplant).
Before the stem cell transplant, your child undergoes a procedure that filters and collects stem cells from his or her blood. The stems cells are stored for later use. Then high doses of chemotherapy are used to kill any remaining cancer cells in your child's body. Your child's stem cells are then injected into your child's body, where they can form new, healthy blood cells.
Immunotherapy uses drugs that work by signaling your body's immune system to help fight cancer cells. Children with high-risk neuroblastoma may receive immunotherapy drugs that stimulate the immune system to kill the neuroblastoma cells.
Doctors are studying a newer form of radiation therapy that may help control high-risk neuroblastoma. The treatment uses a radioactive form of the chemical metaiodobenzylguanidine (MIBG). When injected in to the bloodstream, the MIBG travels to the neuroblastoma cells and releases the radiation.
MIBG therapy is sometimes combined with chemotherapy or stem cell transplant. After receiving an injection of the radioactive MIBG, your child will need to stay in a special hospital room until the radiation leaves his or her body in the urine. MIBG therapy usually takes a few days.
- dinutuximab (Unituxin) - FDA-approved indication: For use in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2) and 13-cis-retinoic acid (RA), for the treatment of pediatric patients with high-risk neuroblastoma who achieve at least a partial response to prior first-line multiagent, multimodality therapy