The disease appears mainly in babies and infants under the age of five years (more common with boys) and is considered rare compared to other types of pediatric cancer. Despite the fact that neuroblastoma appears in as low as 8% of tumors in children, it is responsible for 12% of death causes for children with cancer. Reasons for the formation of neuroblastoma or risk factors to develop it are unknown in most cases.
The prognosis for neuroblastoma varies widely, from tumors that spontaneously regress and require no intervention to those that present widely metastatic and resistant to therapy with resulting high mortality. This disparate prognosis is largely dependent on tumor biology, and extensive research has been completed identifying tumor characteristics that associate with aggressive tumor behavior and poor prognosis. Therefore, the road for improvement is long and challenging.
Neuroblastoma is the most common extracranial solid tumor of childhood. Neuroblastoma represents a neoplastic expansion of neural crest cells in the developing sympathetic nervous system. It originates during embryogenesis when neuroblasts (immature sympathetic system cells) fail to evolve into functional nerve cells. Instead, they grow and split uncontrollably, forming cancerous cells.
Most primary tumors (around 65%) originate in the adrenal gland, located above the kidney. However, the tumor could originate anywhere along the sympathetic chain of nervous system, including the neck, chest, abdomen, and pelvis. For less than half of the patients the tumor might appear as a localized disease at the time of diagnosis, but others may find it has spread from its original location to the lymph nodes, bone marrow, bones, liver, skin or, more rarely, to the lungs or brain (metastatic disease).
The common presenting symptoms in metastatic disease include:
Loss of appetite
Joint or bone pain
Urinary retention or difficulty in urinating
Symptoms depend on primary tumor locations and metastases if present:
In the abdomen, a tumor may cause abdominal distension, vomiting, constipation.
A tumor in the chest may cause breathing problems.
A tumor invading the spinal canal and pressing on the spinal cord may cause leg weakness, thus an inability to stand, crawl, or walk, Urinary retention or difficulty in urinating.
Bone lesions may cause pain and limping. In advanced cases where bones and bone marrow are involved- bulging facial bones and bleeding around the eyeball (raccoon eyes).
Infiltration of the bone marrow may cause pallor from anemia or bleeding from thrombocytopenia.
Infiltration of the bone marrow may cause pallor from anemia
Infiltration of the cervical ganglia may cause Ptosis (dropping of the eyelid), Pupil miosis (constriction of the pupil) and anhidrosis (inability to sweat properly because of pressure on nerves in the neck)
Neuroblastoma often spreads to different parts of the body before these symptoms are discovered, so that in ~50% of cases identified metastases are already present.
High blood pressure
Long lasting liquid diarrhea (secretion of Vasoactive Intestinal Peptides)
Less common symptoms, caused by hormones secreted by neuroblastoma cells, may include:
The specific clinical presentation of each patient depends on the location of the primary tumor, and the metastatic spread.
Diagnostic imaging scans: to determine the location, size of the tumor, and the stage of the disease, several imaging scans are needed
Intravenous Contrast Injection CT scan
During the examination contrast is injected into the vein followed by a series of X-rays. The contrast allows better differentiation of soft tissues and helps the doctor observe tissues and tumors.
Uses magnets and radio wave to create an imaging of soft tissues and use of Gadolinium as a contrast media.
A nuclear imaging scan uses a radioactive chemical called MIBG together with an iodine 123 isotope which attach themselves to the cancerous cells. This chemical is injected into the vein of the patient and the next day, a special scanner will scan the body of the child. This allows for a general image and understanding of how far the cancerous cells have spread. This scan is used for an initial diagnosis, to estimate the extent of the disease, and as an examination of the efficiency of the response to treatment. A high dose of MIBG attached to radioactive isotope can be used for treatment of patients with neuroblastoma.
In about 10% of the patients, the MIBG is not properly absorbed by the cancerous cells. In these cases, a different type of nuclear scan called PET DOPA, PET FDG or Gallium DOTATET are recommended to continue to monitor the disease.
Ultrasound examinations use sound waves in high frequency for an imaging of soft tissues. It is usually used for tumors in the cervical or abdominal areas.
An imaging of the chest of stomach can assist the doctors in assessing the location of the tumor and its effect on other tissues in the body.
The diagnosis is based on a biopsy of the primary tumor and rarely from the bone marrow. Bilateral bone marrow biopsies are needed to determine the invasion of neuroblastoma cells into the bone marrow. Tissues extracted from these procedures are sent to pathology as well as a special laboratory which examines certain chromosomal and genetic changes in the tumor cells, which assists in of risk assessment and the treatment plan for the child.
According to pathology evaluation, Neuroblastoma tumor cells show varying degrees of differentiation that help predict patient prognosis. While neuroblastoma primarily contains immature cells, some have a component of fully mature ganglion cells that are typically found in a ganglioneuroma. A tumor with both elements of mature and immature cells is called a ganglioneuroblastoma. In addition to tumor histology, several genetic and chromosomal markers are strongly associated with tumor biology. The MYCN gene is the most important genetic marker of neuroblastoma aggressiveness. MYCN is an oncogene whose amplification is strongly associated with unfavorable clinical outcomes. Segmental chromosomal anomalies with prognostic significance have also been identified for neuroblastoma. Recent studies on familial neuroblastoma, which is rare, have also identified ALK and PHOX2B gene mutations. ALK aberrations in particular are now being factored into the new study protocols for treating high risk neuroblastoma
Blood and urine tests
Most patients will undertake a series of different blood tests including a full blood count, a chemical test to assess the functioning of the kidneys, the liver function tests, LDH and blood test for NSE (neuron specific enolase).
In 90% of neuroblastoma cases, the tumor cells produce high levels of neurotransmitors/hormones. The body breaks down these materials into catecholamines metabolites (mainly Vanillylmandelic acid (VMA) and homovanillic acid (HVA)), which can be measured in the urine. The catecholamines metabolites is being used for primary diagnosis and treatment response monitoring.
Stages of the disease
The most updated division of the disease into stages is based on the levels of the outspread of the disease and different risk factors which allow or prevent the removal of the tumor. The new INRG risk assignment is based on a new International Neuroblastoma Risk Group Staging System (INRGSS). The main groups:
A tumor which can be removed; a localized disease with no risk factors determined in imaging.
A tumor which cannot be removed; a localized disease with no risk factors determined in imaging.
A disease which has spread to other organs (metastasized).
A metastasized disease, the patient’s age is under 18 months, with a localized tumor which answers the definitions of stage L1 or L2, and has spread to the liver, skin, or bone marrow.
Furthermore, there is a further division into sub-groups based on age (18 months line), biological, and histological measurements. Treatment is determined based on these subgroups.
Following the diagnosis and completion of the comprehensive tests to determine the extent of the disease, a treatment plan can be determined according to the risk grouping and based on age, disease stage, and biological characteristics.
Neuroblastoma treatment is multi-modal and may include chemotherapy, surgery, stem cell transplant, radiation, retinoic acid (a derivative of vitamin A), and immunotherapy based on specific antibodies against neuroblastoma cells (Anti-GD2). Treatment for high-risk disease have improved 5-year overall survival to 50%. Currently, new approaches targeting genetic pathways and the tumor microenvironment hold promise for further improvements in survival and long-term quality of life.
Factors which determine survival rates include patient’s age, the outspread of the disease, and different biological/genetic findings (amplification of oncogenes etc., where current treatment efforts are focusing on among others).
When the tumor is localized, the disease is usually curable. However, for high-risk patients the prognosis is dismal, despite the multi-modal treatment.
Chances of relapse
Neuroblastoma is a heterogeneous disease and the chances of recovery largely depend on the characteristics of the tumor.
On the one hand, it is one of the only malignant tumors which can undergo spontaneous regress to a fully benign shape. On the other hand, experience shows that on average 50-60% of children with high-risk neuroblastoma eventually suffer from relapse. Within children with low or medium risk neuroblastoma, relapse only occurs in 5-15% of cases. The longer the time that passes from treatment completed, the lower the chance of relapse.
Generally speaking, only ~50% of high-risk neuroblastoma patients will be cured, but survivors have life-long co-morbidities such as deafness, endocrinopathies and an up to 20% risk for a treatment-related second malignancy. For the 50% of kids with high-risk disease who suffer a relapse, there is no known curative therapy.
The road for improvement is long and challenging.
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