Childhood Neuroblastoma
Childhood Neuroblastoma
Ananya Rao & Dr. Lopamudra Das Roy
Published 2021
@BreastCancerHub, All Rights reserved
What are Neuroblastomas?
Neuroblastomas are a type of cancer, especially prevalent in children. First, let’s go over what cancer actually is. Cancer is a genetic mutation in which normal, healthy cells continue to split and overgrow without recognizing the signals to stop the growth, which is present in non-cancerous cells. Neuroblastomas, specifically, are a type of cancer developed from immature nerve cells, also known as neuroblasts, found in several areas of the body¹. According to the data collected in 2020-2021, this deadly disease affects approximately 8 per 1,000,000 children, with approximately 600-700 cases diagnosed annually in the United States. Despite representing just 5% of overall pediatric cancer diagnoses, neuroblastoma causes up to 12% of childhood cancer mortality; overall survival across all risk groups is approximately 80% but falls below 50% for children with high-risk disease². Neuroblastomas are slightly more common in boys than girls and are usually diagnosed in children before the age of 5. Neuroblastoma accounts for 50 percent of all cancers in infants, making it the most common tumor in infants younger than 1 year³. It is extremely important to educate ourselves on this disease as it is getting more and more common and is affecting countless children’s lives every day.
Causes and Risk Factors
We already know that neuroblastomas are developed from immature nerve cells known as neuroblasts. A more precise explanation is that nerve cells and cells in the medulla (center) of the adrenal gland start out as neuroblasts in a growing fetus. Most often, neuroblasts grow and develop into mature cells. Neuroblastomas can occur when normal fetal neuroblasts do not become mature cells, but instead continue to grow and divide⁴. A genetic mutation (a change in the neuroblast’s genes) causes the cells to grow and divide uncontrollably. Healthcare providers aren’t sure what causes the genetic mutation. Neuroblastoma can also develop in nerve tissue in the spinal cord, abdomen, chest or neck. It can spread to other parts of the body⁵. There are not many risk factors to take into consideration when it comes to neuroblastomas as they are usually formed in fetuses. Environmental and lifestyle factors, which hold a prevalent role in other types of cancers, do not play a role at all in neuroblastomas. This is also the reason why there have not been many prevention methods identified for this type of cancer.
Symptoms
Neuroblastoma symptoms range from mild to severe. They vary depending on the tumor’s location and the stage of the disease. Most often, cancer has spread to other parts of the body by the time signs appear. Symptoms include:
Bump or lump in the neck, chest, pelvis or abdomen (belly), or several lumps just under the skin that may appear blue or purple (in infants).
Bulging eyes or dark circles under eyes (it may look like the child has a black eye).
Diarrhea, constipation, upset stomach or loss of appetite.
Fatigue, cough and fever.
Pale skin, which is a sign of anemia (low red blood cells).
Painful, bloated belly.
Trouble breathing (usually in young babies).
Weakness, movement problems or paralysis in the legs and feet.
As the tumor progresses, symptoms may worsen and you may see things such as:
High blood pressure and a fast heartbeat.
Horner’s syndrome, which causes droopy eyelids, small pupils and sweating on only one side of the face.
Pain in the bones, back or legs.
Problems with balance, coordination and movement.
Shortness of breath.
Uncontrollable eye movements or eyes that dart around quickly⁵.
It is highly recommended that the child is immediately taken to the doctor if they are experiencing any of these signs or symptoms. It is crucial to take note of any change or discrepancies in the child’s behavior and note that to the doctor in order to maximize the efficiency of the diagnosis and treatment process¹.
Sporadic vs. Hereditary Neuroblastomas
Neuroblastomas usually occur in children with no family history of the disease, and that is known as sporadic neuroblastomas. About 1-2% of children inherit the neuroblastomas from their parents and that is known as hereditary neuroblastoma. Children with hereditary neuroblastoma are more likely to have a higher number of tumors and to be diagnosed at a younger age than people with sporadic neuroblastoma. Hereditary neuroblastoma often varies in how severe it is, even among people in the same family. Some people may have many tumors, while others do not even develop one tumor. Even within the same person with the condition, some tumors might shrink and go away on their own, while other tumors are more aggressive and continue to grow.
Genetic Factors
Hereditary neuroblastoma is caused by changes in one of two genes: ALK or PHOX2B. Genes carry information telling cells within the body how to function. The ALK and PHOX2B genes control how and when nerve cells grow, divide and die. Researchers believe that ALK and PHOX2B mutations lead to neuroblastoma by influencing the growth and development of neural cells, which makes them more likely to become cancerous. People without hereditary neuroblastomas inherit one of each of those genes from their mother and father. Cells from people with hereditary neuroblastoma carry one working copy of the ALK or PHOX2B gene and one copy that is changed. This change causes the cell not to work properly, also known as a mutation. Most children with hereditary neuroblastoma caused by a mutation in the ALK gene have inherited the mutation from a parent. However, some children with ALK gene mutations are the first people in their families to carry the mutation. Most children with hereditary neuroblastoma caused by a mutation in the PHOX2B gene did not inherit the mutation from a parent. These children have no history of the condition in their families. In these cases, the change either happened in an egg or sperm cell when the child was formed or in one of the child’s cells during pregnancy. These children are the first in their families to have hereditary neuroblastoma related to PHOX2B⁶. If it is known that neuroblastomas run in the family, it is best to get a genetic screening done during the pregnancy and consult with your doctor for possible prevention methods or to prepare yourself for what is about to come.
Stages of Neuroblastoma
Neuroblastoma treatments depend on which stage of the cancer that the patient is in when diagnosed. The system used to identify the stage of the neuroblastoma is International Neuroblastoma Risk Group Staging System (INRGSS). The stage of neuroblastoma is determined by how much tumor spread is seen on initial imaging studies (such as CT scan or MRI, as discussed below), called “image-defined risk factors.” The INRG stages of neuroblastoma are⁵:
Stage L1: This is the stage with the lowest risk. L1 tumors are confined to one body compartment and have not spread. Also, the tumor does not involve vital structures of the body (no image-defined risk factors are present).
Stage L2: In this stage, the tumor is confined to one body compartment, but cancer cells can spread to regional lymph nodes, for instance. Also, there is involvement of vital structures of the body, such as tumor wrapping around large blood vessels (i.e., at least one image-defined risk factor is present).
Stage M: In this stage, the cancer cells have spread to more than one body compartment – called “distant metastatic disease.” This stage carries the highest risk.
Stage MS: This is a “special” category of neuroblastoma, affecting children younger than 18 months of age. In this stage, the cancer cells have spread (or metastasized) to either the skin, liver or bone marrow only.
Treatment Options
Children with neuroblastoma and their families have special needs that can best be met by children's cancer centers. These centers have teams of specialists who understand the differences between cancers in adults and those in children, as well as the unique needs of younger people with cancer. Some treatment options include:
Chemotherapy
Surgery
Radiation
Immunotherapy
Iodine 131-MIBG therapy
Stem Cell Transplant
Targeted Therapy
Treatment pathways also depend on if the patient is at high risk, intermediate risk, or at low risk.
Low Risk: If a child is low risk and the tumor can easily be removed, surgery might be the only treatment needed. Even if some neuroblastoma is left behind after surgery, the child can usually be watched carefully without further treatment because the remaining tumor will often mature or go away on its own⁴.
Intermediate Risk: Surgery is an important part of treatment for children at intermediate risk, but it is rarely enough on its own. Children are typically given 4 to 8 cycles (about 12 to 24 weeks) of chemotherapy before or after surgery. The chemo drugs used usually include carboplatin, cyclophosphamide, doxorubicin, etoposide, etc. If chemo is used first, surgery may then be done to remove any remaining tumor. Radiation therapy is usually followed by the chemo treatments⁴.
High Risk: Healthcare providers often treat high-risk neuroblastoma with a combination of chemotherapy, surgery, high-dose chemotherapy with stem cell rescue (also known as autologous stem cell transplantation), radiation and immunotherapy. Children with high-risk neuroblastoma may need to take medications (such as 13-cis-retinoic acid) for several months after treatment. Children with extra copies of a gene called MYCN will receive treatment for high-risk neuroblastoma no matter what stage of the disease they have. Providers use the most aggressive treatment when a child has more of this gene. The MYCN gene drives abnormal cell growth. It can cause tumors to grow faster and spread throughout the body⁵.
Neuroblastomas in Developed vs. Developing Countries
There are reports indicating a low incidence of neuroblastoma in some developing countries but no conclusive data are available from population-based studies at a national level. This is the reason there was a study done in La Plata, Argentina in which researchers analyzed data from 39 patients observed over 16 years in La Plata, Argentina to address a gap in the literature about survival of high-risk pediatric neuroblastoma patients treated with stem cell transplantation in developing countries. The results suggest markedly worse survival in this setting compared with high-risk pediatric neuroblastoma patients in North America, Europe, and Asia. Specifically, 5-year overall survival in Argentina was 24%, whereas the highest reported 5-year overall survival in North America was 76% in a highly select group of high-risk pediatric neuroblastoma patients. Some factors that contribute to the low survival rates in developing countries are that they do not have the resources to diagnose and catch the disease when it is at low risk, people are not educated enough to recognize the symptoms, and treatment delays, as well as host prognostic factors, may contribute to variation in survival between settings. In conclusion, survival among high-risk neuroblastoma patients is generally poor regardless of geographic location, but these results illustrate dramatically worse survival for high-risk neuroblastoma patients in a developing country. These resource limitations may be addressed with a focus on capacity building through collaborative efforts. For example, twinning programs, which are based on partnering and interaction between hospitals in developing countries and cancer centers in developed countries, have improved survival and outcomes for pediatric cancer patients in developing countries. Even though these twinning programs have been successful with other types of cancers, there is not enough research to prove that they would work with high-risk neuroblastomas. Future studies are needed to assess the effectiveness of twinning programs and other approaches for improving survival among high-risk neuroblastoma patients in developing countries⁷. Many other sources and researchers refer back to this specific study when talking about this topic. More research and time needs to be put in in order to learn and collect more data about this topic as there are not many studies done whatsoever about it.
Global Scenario of Neuroblastomas
During the years of 2001-2009, there was a study done where 3,500 patients of different ethnicities with neuroblastomas were examined to determine if ethnicity made any difference on the overall survival rate. This is the largest neuroblastoma cohort ever analyzed for outcome disparities, and the first to show that black, Asian, and Native American children have a significantly worse outcome than white children. The exact reason for these rates is not known yet. It could be due to limited resources, genetic reasons, or other unknown causes. This is the first time that it is proven that blacks and Native American neuroblastoma patients are statistically significantly more likely to present with high-risk disease than whites, and that, overall, this likely accounts for the inferior EFS observed in these populations. However, a higher prevalence of late-occurring events among blacks is reported compared to white patients after controlling for clinical and biologic features of disease, suggesting that blacks may be more resistant to chemotherapy. Even though there is a bit of research collected about this topic, more research and a better understanding of the genetic basis of the outcome disparities observed in children with neuroblastoma will further refine risk classification, and may also direct us to more effective, individualized treatment strategies⁸. Similar to the data about the developing/developed countries, there has not been much research done recently about the global scenario of neuroblastomas, but it is an extremely important issue that needs to be covered as soon as possible.
Conclusion
A cancer diagnosis can be extremely challenging and life changing for families, especially when the patient is a child. But, there is hope. Healthcare workers are working extremely hard everyday to find new cures, medications, and procedures to better the lives of millions. In the meantime, it is important that the general public and the families dealing with such tough times educate themselves upon the topic and try to get the best help possible. It is very important to keep an eye out for any symptoms and visit your primary care physician yearly for check ups. Keeping a healthy lifestyle is the best way you can help yourself and the people you love.
Bibliography
https://www.mayoclinic.org/diseases-conditions/neuroblastoma/symptoms-causes/syc-20351017
Ritenour, Laura E et al. “Genetic susceptibility to neuroblastoma: current knowledge and future directions.” Cell and tissue research vol. 372,2 (2018): 287-307. doi:10.1007/s00441-018-2820-3
https://www.cancer.org/cancer/neuroblastoma/causes-risks-prevention/what-causes.html
https://my.clevelandclinic.org/health/diseases/14390-neuroblastoma
https://www.stjude.org/disease/hereditary-neuroblastoma.html
Easton, Joseph C et al. “Survival of high-risk pediatric neuroblastoma patients in a developing country.” Pediatric transplantation vol. 20,6 (2016): 825-30. doi:10.1111/petr.12731
Henderson, Tara O et al. “Racial and ethnic disparities in risk and survival in children with neuroblastoma: a Children's Oncology Group study.” Journal of clinical oncology : official journal of the American Society of Clinical Oncology vol. 29,1 (2011): 76-82. doi:10.1200/JCO.2010.29.6103