What Is Neuroblastoma?

Overview

Neuroblastoma is a rare type of paediatric cancer originating in premature nerve cells during embryonic development. It amounts to 8% of the total malignancies observed in children and contributes to 15% of childhood deaths caused by cancer. It is caused by the overexpression of proteins during embryonic development that can lead to an accelerated rate of cell division in neural cells, leading to tumour formation. Since the disease is rare and is prevalent in children, it has been difficult to mark the exact source that causes the disease. However, there are multiple factors implicated in the pathogenesis of neuroblastoma, which will be discussed in the article.^1,2

Stages of Neuroblastoma

Staging the tumour is crucial to determine the most efficient treatment plan. Based on what stage the tumour is in, how fast it is accelerating and whether it has metastasised (in other words, whether cancerous cells have spread to other parts of the body beyond the brain or not), doctors will determine the course of treatment that is most effective for each individual case.

It is important to identify metastasis in order to provide a prognosis. Tumour cells target lymph nodes, such as the bone marrow and the thymus, in order to initiate metastasis. It has been shown that this is done in order to initiate immunogenic tolerance, which is when immune cells do not attack cancer cells because they do not view them as foreign. Therefore, once the cancerous cells begin infecting the lymph nodes, migration of the tumour mass and metastasis can be expected to follow soon after.³ 

Before imaging techniques were used to detect neuroblastoma, the stage was determined by the amount of tumour mass which was excised from the brain after surgery. These stages were described by the International Neuroblastoma Staging System (INSS). Neuroimaging techniques, such as the MIBG scan that uses safe radioactivity to trace the spread of a tumour within the brain, have helped in detecting and staging the cancer prior to any surgical intervention. Therefore, the International Neuroblastoma Risk Group Staging System (INRGSS) has redefined the staging process and devised the stages based on the spread of the tumour determined by imaging studies, like MIBG, MRI and CT scans. The stages defined by INRGSS are as follows:⁴

• Stage L1: L1 tumours bear the lowest risk and are limited to one structure in the body. There is no spread of the cancer to other parts of the body
• Stage L2: The L2 stage is defined by the tumour being confined to one body structure but the cells having the ability to spread to other regions, such as within the lymph nodes. The L2 stage is defined by tumour cells being found surrounding vital structures, such as blood vessels
• Stage M: Stage M bears the highest risk as the tumour mass breaks up and spreads to other structures within the body. The tumour has metastasised and can now affect other parts of the body. Controlling the spread becomes crucial and time-sensitive. This stage is referred to as Distant Metastatic Disease
• Stage MS: This stage is noted in children younger than 18 months of age. It is generally considered a low-risk condition, characterised by metastasis to the skin or bone marrow only. The prognosis for children with MS stage of neuroblastoma is generally considered very positive

The stages defined by the INSS are categorised based on how excisable the tumour mass is. The stages are described in the following way:

• Stage 1: These are localised tumours which can be excised completely as their margins are clear 
• Stage 2: Stage 2 is split into stages 2a and 2b. Stage 2a tumours are localised with incomplete gross excision whereas 2b is defined by localised tumours which could or could not be excised grossly
• Stage 3: Tumours found in Stage 3 generally cannot be excised. They are largely limited to tumours that develop around the vertebral column. Regional lymph nodes may or may not be involved
• Stage 4: Tumours at stage 4 can migrate to distant sites, such as the lymph nodes, skin, liver, and bone marrow
• Stage 4S: Tumours in this stage are localised but can further migrate to other sites within the body. Stage 4S is typically found in infants younger than 12 months

Causes of neuroblastoma

During embryonic development, tissue on the spinal cord, called the ectoderm, gives rise to neural crest cells. These cells eventually become neuroblasts. Neuroblasts are a group of cells which further divide to form integral structures within the nervous system. The uncontrollable division within neuroblasts has been attributed to genetic mutations. Several genes which are responsible for the differentiation of crest cells, such as MYCN, ALK and PHOX2B, have been implicated in the origins of neuroblastomas. Certain conditions have been shown to make individuals more vulnerable to neuroblastomas, such as Turner Syndrome and Hirschsprung disease. In most cases, the site at which the tumour originates is the adrenal gland in the abdomen. Tumours can also be found around the vertebral column. In rare cases, the primary site cannot be located and the tumour metastasises through the blood and lymph.^5,6

Beyond this, in 1% of all the diagnosed cases, patients have a familial history of neuroblastoma. Therefore, there could be a hereditary component to the disease that causes inheritance of genetic mutations associated with this cancer.^6,7

Signs and symptoms

The symptoms can be categorised as mild or severe, based on how much the disease has spread within the body. In most cases, metastasis is marked by signs and symptoms appearing. Some of these include:¹

• Stiff lumps in the abdominal region (in the belly) or along the vertebral column (the neck, pelvis or chest)
• Bulging eyes due to increased intracranial pressure
• Gastrointestinal symptoms, such as constipation, loss of appetite or diarrhoea
• Anaemia
• Loss of energy and weakness
• Cough and fever
• Bloating
• Issues with breathing
• Symptoms like high blood pressure and Horner’s syndrome can appear as the disease advances

Diagnosis of neuroblastoma

Neuroblastoma is often diagnosed before the age of 5. In certain cases, it is also possible to identify the tumour during a prenatal ultrasound. The diagnosis involves checking nerve functions, reflexes and coordination of the body. In case of doubts, there are a number of tests that can be conducted to determine an accurate diagnosis:¹

• Blood test and urine tests: A set of biochemistry tests are carried out to check the function of the immune system
• Biopsy: This is a process where doctors extract a small tissue from the tumour and analyse it under a microscope. Additionally, bone marrow biopsies help determine metastasis and the severity of the cancer
• MIBG scans: These radioactive tracer-guided scans can determine the spread and severity of cancer. However, in around 10% of the cases, the tumour cells do not absorb the MIBG compound. In these cases, we use other nuclear options, such as PET scans
• Imaging techniques, such as X-ray, ultrasound, MRI and CT scans, also help recognise tumour cells

Management and treatment for neuroblastoma

There are several modes of treatment for neuroblastomas, depending on the size and spread of the tumour masses. Beyond surgery and excision, clinicians use chemotherapy, radiation therapy, immunotherapy, and medications.^1,5

Low-Risk

The treatment plans for neuroblastomas are devised according to risk assessment and the severity of the tumour. Low-risk neuroblastomas in children under 6 months old do not necessarily need any treatment as the cancer often resolves by itself. Other low-risk tumours can be treated with surgery and chemotherapy.

Intermediate-risk

Treatment for intermediate-risk neuroblastomas is primarily surgery. Any tumour covering the lymph nodes is also excised. The removal of the mass is followed by chemotherapy to ensure any residual cancerous cells are removed. In cases where the tumour is large in size and encroaches surrounding areas, making it hard to reach during surgery, chemotherapy is used to shrink the size of the tumour.

High-risk

High-risk neuroblastomas are treated with a combination of high-dose chemotherapy, radiation and stem cell rescue. Medication is prescribed for several months after treatment to maintain a tumour-free condition.

Since oncogenes, such as MYCN, render a higher predisposition to tumour formation, children with these genes are put on the high-risk treatment no matter what the progression of the disease.

Other treatments include Iodine 131-MIBG therapy, which uses radioactive iodine tracers to target and kill tumour cells with radiation. It is often used with stubborn masses, where other modes have failed, or in case of a relapse.

FAQs

How can I prevent neuroblastoma?

Currently, no preventative measures have been identified. However, due to the genetic implication, it is important for any children with a family history of the disease to undergo genetic testing for relevant oncogenes.¹ 

How common is neuroblastoma?

Neuroblastoma accounts for 15% of the total childhood malignancies and contributes to 8% of the total deaths caused by cancer in children. It is rare but easy to detect. If you have a family history of the disease, you should consult your healthcare provider about genetic counselling when planning a family.¹ 

When should I see a doctor? 

Tumours in infants who are 6 months old and younger are considered low risk if there is no family history and often go unnoticed. For older infants, it is important to pay attention to signs and symptoms. If the baby appears to show physical symptoms, such as bulging eyes, or appears to be abnormally irritated for long periods of time, it is important to seek medical help as soon as possible.¹

Summary 

Neuroblastoma is a rare disease that often causes significant distress in families. It is important to look out for signs and symptoms and seek genetic counselling in case of any family history. Staging and analysing the risk level is another crucial step in understanding the situation as this will help take the necessary steps needed to tackle the disease. The signs and symptoms of the disease are physically evident. Diagnostic tools, such as scans and radioactive tracers, can help spot the growing tumour. Neuroblastoma can be treated with a combination of surgery, chemotherapy and medication.