Neuroblastoma, a nerve cancer, primarily affects young children. The tumor originates from the immature nerve cells. It is one of the most common extracranial solid tumors seen in pediatric patients. Oncologists should determine the type of neuroblastoma for treatment optimization and prognosis prediction.
Neuroblastoma cancer occurs in immature nerve cells that are commonly found in a fetus or embryo. These immature nerve cells are known as neuroblasts and are involved in nervous system development. Neuroblastoma cancer occurs most often in young children and infants (≤5 years of age). This cancer most frequently affects the adrenal glands (glands above the kidneys). The other sites for neuroblastoma development include the abdomen, neck, chest, and spinal cord. The symptoms range from a benign, palpable mass to serious complications due to the spread of the tumor.
Neuroblastoma cancer constitutes about 8 - 12% of all childhood cancer cases. The rate of neuroblastoma incidence is about 11 to 13 per million in children <15 years of age. The incidence rate varies according to age. It is 1 per million in children between 10 and 14 years of age and 65 per million in children below the age of 1 year.
Some of the common types of neuroblastoma cancer are:
Localized neuroblastoma refers to the type of neuroblastoma that is confined to the origin site and has not spread to other body parts. Localized neuroblastoma is further divided into various risk groups based on several factors, such as tumor location, potential to spread, and age of the patient. These risk groups include low-risk, intermediate-risk, and high-risk. The low-risk neuroblastoma has a small tumor, and the prognosis is favorable, while tumors of intermediate risk have a high risk of recurrence. High-risk neuroblastoma is the most aggressive and has the highest potential to metastasize. Localized neuroblastoma may be completely resectable or unresectable.
Regional neuroblastoma is the stage of neuroblastoma in which the tumor has spread to the nearby lymph nodes and/or surrounding tissues or organs. Still, it has not spread to distant organs. Regional neuroblastoma is generally categorized as stage 3 of the disease. The treatment generally involves a combination of surgery, radiation therapy, and chemotherapy. The customized treatment plan depends upon the tumor's location, the age and overall health of the child, and the characteristics of the tumor.
Metastatic neuroblastoma is the neuroblastoma stage characterized by the spread of the tumor to various parts of the body, including distant lymph nodes, skin, bones, bone marrow, and liver. Patients with metastatic neuroblastoma require a very aggressive treatment approach and usually have a relatively unfavorable prognosis.
Histopathological classification for neuroblastoma is important to determine the disease's characteristics and optimize treatment choices. The oncologists histopathologically classify neuroblastoma through several methods. The two most common methods include the Shimada system and the International Neuroblastoma Pathology Classification (INPC). The classification under the Shimada system includes differentiated neuroblastoma and undifferentiated or poorly differentiated neuroblastoma. The INPC provides a more detailed classification and has three major categories. These are neuroblastoma (Schwannian stroma-poor), ganglioneuroblastoma (intermixed), and ganglioneuroma (Schwannian stroma-rich).
Neuroblastoma is also classified based on the genetic characteristics of tumor cells. The genetic characteristics also affect the prognosis of the disease. Segmental chromosomal aberrations, such as chromosomal alterations or deletions, also categorize neuroblastoma into various groups. Two of the most clinically relevant chromosomal aberrations include the loss of chromosome 1p and the gain of chromosome 17q. Both are associated with high-risk, aggressive neuroblastoma with a poor prognosis.
Following are the different neuroblastoma stages:
At neuroblastoma cancer stage 1, the tumor is localized and is not spread to other body parts or surrounding lymph nodes. The cancer is completely removed through surgery.
At neuroblastoma stage 2A, the neuroblastoma cells are confined to the area of origin and have not invaded the lymph nodes or distant organs. Though surgery removes all the visible tumors, they are not completely resectable.
At this stage, the tumors are not completely removed by the surgery. Although the tumor has not spread to distant organs, it has spread to the surrounding lymph nodes on the same side.
At stage 3 neuroblastoma, the cancer is not completely resectable and has spread to the lymph nodes on the other side of the body. However, cancer does not spread to distant lymph nodes or distant organs.
At this stage, the tumor spreads to the lymph nodes and organs, including the liver, bone, bone marrow, and skin. However, the patient does not meet the criteria for stage 4s.
There are several criteria for neuroblastoma cancer type 4s. These are the age of the child <1 year, cancer is on the single side, may affect the lymph nodes of the same side, may spread to the skin, liver, or bone marrow, has not affected >10% of bone marrow cells, and is not shown on the MIBG scan of the bone marrow.
In recurrent neuroblastoma cancer, the cancer recurs after it has been completely treated. The cancer may recur at the same or different sites.
Neuroblastoma is more commonly seen in children. Childhood neuroblastoma symptoms include persistent fatigue, weakness, diarrhea, abdominal pain, and bloating. The neuroblastoma symptoms in adults are almost similar to those in children. Although the disease's exact cause is unknown, it is believed to occur due to mutations, congenital anomalies, and chromosomal aberrations.
Although neuroblastoma may occur in any individual, some are at a relatively higher risk of developing this condition. Neuroblastoma most commonly affects children and individuals with a genetic predisposition to neuroblastoma, chromosomal aberrations, and MYCN amplification, people of specific races and ethnicities, and individuals who are exposed to environmental factors.
Some of the neuroblastoma cancer symptoms are:
Patients with neuroblastoma in the abdomen experience several symptoms, such as abdominal swelling and pain, palpable mass, weight loss, and altered bowel habits. In advanced stages, the tumor compresses the tissues of other organs, leading to specific symptoms.
Commonly observed chest neuroblastoma cancer symptoms include chest pain, persistent coughing, and difficulty breathing. Some patients may have a palpable mass in the chest.
Pain in the back, bones, and legs may be signs of neuroblastoma due to the presence of neuroblastoma cancer at these sites. Further, compression of nerves by neuroblastoma tumors may also cause pain in the legs and back.
Fatigue is also a sign of neuroblastoma and is due to the excessive consumption of nutrients and energy by the cancer cells. The fatigue may also be due to various effects of cancer treatment, such as anemia.
High fever as a neuroblastoma cancer symptom may be caused by the cancer itself, the treatment, and the complications. The activation of the immune system by the cancer cells may raise the body's temperature.
Loss of appetite is a common neuroblastoma cancer symptom. The presence of tumors in the abdominal regions may result in reduced appetite. The cancer treatment and psychological factors related to the disease may also reduce hunger.
Bulging eyes may be a rare sign of neuroblastoma. Several mechanisms related to bulging eyes include the spread of the tumor to the bone of the eye orbit, compression of the optic nerve, and the initiation of cancer in the retrobulbar space.
Pale skin may be one of the neuroblastoma cancer symptoms, mainly when the tumor affects the bone marrow. The tumor in the bone marrow affects the production of blood cells, leading to a pale appearance of the skin.
Some of the signs of neuroblastoma of the urinary system include urinary incontinence, urinary obstruction, and urinary retention. In advanced cases, the patients may also experience hydronephrosis.
Changes in bowel habits and an altered appearance of the bowel are also neuroblastoma cancer symptoms. These symptoms may be due to bowel obstruction, the effect on the sympathetic nervous system (which regulates the gastrointestinal system), and the invasion of the neuroblastoma cancer cells into the abdominal organs.
Breathing problems may be a sign of neuroblastoma experienced by patients with neuroblastoma of the chest. The tumor compresses the chest and the lungs, causing breathing problems.
Some of the neurological neuroblastoma cancer symptoms include pain due to nerve compression, paralysis, Horner's syndrome (lack of sweating, contracted pupils, and drooping of the upper eyelid on one side of the face), headaches, seizures, and balance problems.
Bleeding may be a sign of neuroblastoma and may be due to invasion of the tumor cells, especially in the abdomen (leading to abdominal bleeding). It may also be due to reduced production of blood cells, especially platelets, in patients with bone marrow involvement.
Severe and persistent diarrhea is a neuroblastoma cancer symptom, especially in patients with invasion or origin of neuroblastoma cells into the abdomen and gastrointestinal organs.
Weakness, movement problems, and paralysis are the signs of neuroblastoma and occur when the tumor compresses the nerves regulating the movement of muscles.
High blood pressure may be one of the neuroblastoma symptoms. It may be due to sympathetic nervous system involvement, excessive production of catecholamines, and chemotherapy treatment.
Uncontrollable eye movement, also known as opsoclonus myoclonus syndrome, is a sign of neuroblastoma. Almost 50% of the patients with this syndrome are diagnosed with neuroblastoma.
A bloated belly may be a neuroblastoma symptom, especially in patients with abdominal organ involvement. It may be due to GI tract obstruction or constipation.
Bluish skin nodules are the initial childhood neuroblastoma symptoms. When rubbed, these nodules may be blanched and surrounded by the halo of erythema.
When it comes to understanding what causes neuroblastoma, there is no concrete information on the exact cause. However, some factors do increase the risk of neuroblastoma, and they are referred to as risk factors or possible causes. The following are the possible causes of neuroblastoma:
Chromosomal abnormalities are one of the most common causes of neuroblastoma. The type of chromosomal abnormalities indicates the potential to manifest low-risk, intermediate-risk, or high-risk neuroblastoma symptoms (malignant neuroblastoma). It may also predict the neuroblastoma survival rate.
Like most other cancers, genetic mutations are also the cause of neuroblastoma. The information in the DNA is mutated for various reasons, resulting in uncontrolled cellular growth, division, and proliferation.
It is a possible cause of neuroblastoma. It is clinically significant and diagnosed through polymerase chain reaction and fluorescence in situ hybridization.
Several predisposing factors may also be the cause of neuroblastoma. These include the age of the patient and hereditary and congenital abnormalities.
Some environmental factors may also be attributed to the cause of neuroblastoma. Pregnant women exposed to certain chemicals, such as polycyclic aromatic hydrocarbons, carbon tetrachloride, and hexavalent chromium, may have neuroblastoma in the offspring.
Individuals below the age of 5 have an increased risk of developing neuroblastoma, with peak incidence during the initial two years of life.
The patients should consult with the oncologists if they experience symptoms of concern, such as persistent fever, abdominal pain, sudden change in bowel habits, unexplained weight loss, constant fatigue, severe and persistent diarrhea, weakness, leg pain, back pain, and breathing problems.
The diagnosis of neuroblastoma is based on the combination of several methods, including clinical evaluation, laboratory tests, imaging studies, and biopsy. Neuroblastoma treatment in adults is almost similar to that in children. Neuroblastoma treatment cost depends upon several factors, including the stage of the disease, the location of the tumor, and the treatment options recommended.
Following are some of the methods for neuroblastoma diagnosis:
Oncologists perform comprehensive physical examinations of patients suspected to have neuroblastoma or other underlying disorders that are causing the symptoms. The patients may be asked about the severity and progression of the symptoms. If the patient is a child, the parents are asked about symptoms, the onset of symptoms, and the family history of neuroblastoma. The doctor may check for any palpable mass or swelling in the abdomen. The blood pressure may also be determined, as patients with neuroblastoma have high blood pressure. The strength and movement of the legs are also evaluated, as neuroblastoma growing near the spine may cause muscle weakness in the legs.
Although neuroblastoma may result in enlarged lymph nodes and a high fever, doctors initially recommend checking for infection. Clinicians recommend blood tests, imaging tests, and biopsy in patients strongly suspected of having neuroblastoma or other cancers.
Blood tests are not the confirmatory tests for neuroblastoma. However, they provide detailed information about the overall health of the patients. Further, blood tests also measure the level of certain substances for diagnosing neuroblastoma. However, the levels of these chemicals may also be elevated in conditions other than neuroblastoma.
An enzyme, Neuron-Specific Enolase (NSE), is elevated in various cases of neuroblastoma. This marker may be used to determine the progression of the disease and treatment response in patients with neuroblastoma. Further, the level of ferritin increases in patients with neuroblastoma.
The serum concentration of the lactate dehydrogenase enzyme is increased if there is any cellular injury or cell death. Patients with neuroblastoma may have elevated levels of the lactate dehydrogenase enzyme.
Chromogranin A is the protein synthesized and released by the neuroendocrine cells. The concentration of this substance may increase in patients with neuroblastoma.
In patients with neuroblastoma, malignant neuroblasts release certain substances detected in urine. Although elevated levels of these substances in urine are not exclusive to neuroblastoma, oncologists may recommend checking them to detect disease progression and treatment response.
Neuroblastoma cells release several catecholamines, such as adrenaline and noradrenaline, resulting in their elevated levels in urine.
The metabolism of neurotransmitters results in several metabolites, such as homovanillic acid and vanillylmandelic acid. Measuring the urine concentration of these substances may be crucial for patients suspected of having neuroblastoma.
Imaging modalities play a role in diagnosing and monitoring neuroblastoma and evaluating treatment responses. The choice of imaging tests depends upon several factors, including the patient's age, the tumor's location and spread, and the requirement for specific information about treatment planning.
Ultrasound is a non-invasive technique that uses non-ionizing radiation. It is a useful imaging modality for neuroblastoma diagnosis, especially in children and infants, where it is well tolerated. It is a preliminary method to evaluate the palpable mass in the abdomen and is especially useful in diagnosing the neuroblastoma of adrenal glands.
CT scans assist oncologists in visualizing tumors, evaluating their characteristics, determining the spread of tumors, and planning the treatment. Determining tumor characteristics, such as shape, size, density, and extent of the disease spread, helps in staging the disease. However, it is important to consider that CT scans use ionizing radiation and, thus, should be used in children with appropriate precautions.
Oncologists may recommend magnetic resonance imaging for neuroblastoma diagnosis, especially neural involvement and assessing soft tissues. It determines the shape and size of the tumor, along with its association with the surrounding structures. It accurately assesses the extent of the tumor by differentiating it from the surrounding healthy tissues. MRI does not use ionizing radiation. Thus, it is a preferred imaging modality for pediatric patients, especially when repeated imaging is required.
An MIBG scan is an imaging modality used for neuroblastoma diagnosis and management. It is usually recommended with other imaging modalities, such as CT scans, MRIs, and ultrasounds. MIBG is similar to norepinephrine and is taken up by neuroblastoma cells. As MIBG is associated with radioactive iodine, a special camera is used to detect the radiation emitted by iodine.
An X-ray scan is less effective than other imaging modalities, such as CT or MRI, in providing detailed images of soft tissues, such as solid tumors or nerves. An X-ray may help detect the tumor in the chest through a chest X-ray. It also assists oncologists in detecting the presence of cancer in the bone through bone scans.
Nuclear scans include MIBG scans and PET scans. A PET scan helps diagnose neuroblastoma by determining the areas with high metabolic activity. PET scans use a radioactive glucose analog, which is rapidly taken up by the malignant cells. It assists in staging the disease and allows the oncologists to deliver optimal treatment. The PET scan also determines the response to neuroblastoma treatment.
During a biopsy, the doctor obtains a sample of suspected or abnormal tissues and sends it to the laboratory for further investigation. A biopsy helps oncologists confirm the presence of neuroblastoma. Further, the biopsy also provides histopathological characteristics of the sample. It helps in developing an appropriate treatment strategy. The neuroblastoma diagnosis tests through biopsy include needle biopsy and surgical biopsy. In some cases, the biopsy may be guided by various imaging techniques, such as CT scans (CT-guided biopsy) and MRI (MRI-guided biopsy).
The following are the commonly recommended approaches for neuroblastoma cancer treatment:
Surgery is the primary neuroblastoma cancer treatment, especially in patients with early-stage disease. The neuroblastoma surgery aims to remove the neuroblastoma tumor as much as possible. The extent of cancer removal depends upon several factors, such as the size of the tumor and its association with surrounding structures. The tumor may be completely or partially resectable.
Chemotherapy is used in cases where a complete resection of the tumor is not possible. It is an important component of neuroblastoma cancer treatment in the majority of cases. Chemotherapy involves the administration of anticancer drugs to destroy cancer cells. It may be administered before or after the surgery. Some high-risk neuroblastoma treatments involve the administration of high-dose chemotherapy. Chemotherapy may also be combined with radiotherapy.
Radiation therapy is also an effective modality for neuroblastoma cancer treatment. Radiation therapy is used along with surgery or chemotherapy in patients with high-risk neuroblastoma or recurrent neuroblastoma. External beam radiation therapy is usually used for neuroblastoma cancer treatment.
Immunotherapy is an emerging modality for neuroblastoma cancer treatment, particularly in cases of high-risk neuroblastoma. Immunotherapy drugs enhance the efficacy of the immune system to detect and destroy neuroblastoma cancer cells. Studies have reported an improvement in survival with some of the immunotherapy drugs.
Stem cell transplantation is also an effective modality for neuroblastoma cancer treatment, especially in cases of high-risk neuroblastoma with or without bone marrow involvement. High-dose chemotherapy is administered after collecting stem cells. Then, these stem cells are injected back into the patients.
Several targeted therapy drugs are used for neuroblastoma cancer treatment. These drugs interfere with the essential pathways required for the growth and survival of cancer cells. The oncologists may also provide personalized, targeted therapy after obtaining the histopathological characteristics of the tumor. Targeted therapy is usually used for neuroblastoma stage 4 treatment.
Retinoid plays a crucial role in neuroblastoma cancer treatment, especially during maintenance therapy after surgery, chemotherapy, or radiation therapy. This therapy aims to target minimal disease residue and prevent neuroblastoma recurrence.
Certain medications, other than chemotherapy, are also used for neuroblastoma cancer treatment. These drugs may stop the flow of blood to the cancer cells, depriving them of essential nutrients and leading to their death.
This is a relatively newer neuroblastoma cancer treatment. It involves the use of a radioactive form of MIBG. The cancerous cells take up this radioactive chemical, which then releases radiation, killing cancer cells. It may sometimes be used with a bone marrow transplant or chemotherapy.
Neuroblastoma is a childhood cancer and may be fatal if left undiagnosed or untreated. HCG has all the facilities required for the appropriate diagnosis and management of neuroblastoma. Apart from pediatric oncologists, the care team also comprises pediatricians and pediatric surgeons in order to ensure that patients diagnosed with neuroblastoma receive the highest quality care possible. The hospital has advanced facilities for caring after surgery. HCG also offers various services to families, such as counseling services.
Several factors increase the risk of neuroblastoma cancer. However, neuroblastoma occurs spontaneously without any underlying risk factors in many cases. Individuals with genetic abnormalities that increase their risk of neuroblastoma should consult with a genetic counselor to determine the severity of the risk. Currently, effective neuroblastoma prevention measures are not available.
Some of the common neuroblastoma risk factors are:
Age is one of the most predominant neuroblastoma risk factors. Neuroblastoma commonly occurs in children, and studies suggest a strong association between age and the incidence of neuroblastoma. The highest incidence of neuroblastoma is reported in infants, especially during the initial two years of their lives. The majority of these cases are diagnosed during the first year. The doctors may classify some of them as congenital neuroblastoma in cases where the disease is diagnosed in infants at birth or during the early few weeks of their lives. The condition becomes rarer as individuals age and is much less common in individuals above 10.
Heredity may also be a neuroblastoma risk factor. However, the majority of the neuroblastoma cases are sporadic and occur spontaneously without any family history of the disease. Families with multiple members with neuroblastoma are considered to have familial neuroblastoma. Hereditary neuroblastoma may be linked to specific genetic mutations, such as PHOX2B and ALK (anaplastic lymphoma kinase). Studies have also reported that a combination of genetic and environmental conditions may be a neuroblastoma risk factor.
Genetic predisposition is another neuroblastoma risk factor. Several types of genetic predispositions increase the risk of neuroblastoma. These genetic predispositions include a family history of the disease, genetic mutations, chromosomal aberrations, and MYCN amplification.
Family history is also a neuroblastoma risk factor. Additionally, siblings of children affected by neuroblastoma are at higher risk compared with the normal population.
Chromosomal abnormalities are one of the most predominant neuroblastoma risk factors. Patients with neuroblastoma may have several types of chromosomal abnormalities. These include MYCN amplification, chromosome 17q gain, chromosome 11q deletion, chromosome 1p deletion, and chromosome 3p deletion. The type of chromosomal abnormality also affects the severity, aggressiveness, and prognosis of the disease. Identifying specific chromosomal abnormalities in patients diagnosed with neuroblastoma assists oncologists in optimizing their treatment.
MYCN amplification is a crucial neuroblastoma risk factor. The MYCN gene is situated on chromosome 2. Amplification involves an abnormal increase in the number of copies of the MYCN gene in cancer cells. It is an established marker of neuroblastoma. The presence of MYCN amplification indicates the aggressiveness of cancer, poor prognosis, and high-risk neuroblastoma cancer. It is more prevalent in older children with advanced-stage diseases. The presence of MYCN amplification may alter treatment strategies.
Studies have reported that congenital abnormalities are associated with the occurrence of neuroblastoma, especially in children aged <1 year. However, no strong association was reported between congenital anomalies and neuroblastoma in children >1 year of age. The location of congenital malformations may include the heart, urinary system, gastrointestinal system, genital organs, and skeleton.
Like other childhood cancers, there are currently no established neuroblastoma prevention measures for preventing the occurrence of this condition. However, a healthy lifestyle and consumption of healthy food reduce the risk of neuroblastoma by enhancing the activity of the immune system. It has also been reported that women consuming folic acid or multivitamins during pregnancy have offspring that have a reduced neuroblastoma risk. Further studies are required to establish this neuroblastoma prevention measure. Individuals with a family history of neuroblastoma or having familial neuroblastoma in their families should consult with a genetic counselor to determine the exact risk of developing this condition.
Neuroblastoma is a cancer that originates from immature nerve cells. It is one of the most common childhood cancers and occurs often in children less than five years old. There are several methods to determine types of neuroblastoma cancer. One classification is based on the spread of the disease. These include localized, regional, and metastatic neuroblastomas. The other classification is based on histopathological characteristics and sequential chromosome aberrations. The stages of neuroblastoma range from stage 1 to stage 4.
