What is Neuroblastoma
Neuroblastoma is a type of cancer that mainly affects children under 5 years old, including newborns and infants. It is the third most common neoplasm in childhood and adolescence, behind only leukemia and central nervous system tumors.
In Brazil, neuroblastoma accounts for 8% to 10% of cases of childhood and adolescent tumors and has an annual prevalence of approximately 7.3 cases per million children, which is why it is also known as childhood Neuroblastoma. Worldwide, the frequency of diagnoses of the disease varies from 7 to 12 cases per million children. More than 80% of cases occur in children under five years of age. In infants (breastfeeding babies), it is the most common cancer, considered the most frequent malignancy in the first year of life.
It is a neoplasm originating from the sympathetic nervous system, and its clinical behavior is quite heterogeneous, ranging from low-risk cases, in which spontaneous remission is possible, to extreme cases, called high risk, in which rapid progression occurs and can be fatal if not properly managed.
The disease can originate in any part of the sympathetic nervous system, with about 80% developing in the abdomen. It generally arises in the adrenal glands, located on top of the kidneys, and can reach sizes that cause enlargement of the abdomen. However, it can also occur in other locations, such as the cervical, thoracic, and/or pelvic regions, following the path of the entire sympathetic nervous system.
Symptoms and signs of neuroblastoma
The symptoms of neuroblastoma vary depending on the location of the tumor.
Patients with localized disease may be relatively asymptomatic in the initial phase, while those with metastatic disease may experience fever, weight loss, pain, and irritability, as well as pallor.
The spread can occur via lymphatic or hematogenous routes to lymph nodes, bone marrow, bones, liver, skin, orbits, dura mater, and rarely to the lungs and central nervous system. In this group, periorbital ecchymoses (known as raccoon eyes) may appear, due to tumor infiltration of the tissue around the eye and bones, as well as fever, anemia, or bleeding, due to bone marrow infiltration by the tumor. Other symptoms include bone pain, limping, paralysis, hepatomegaly/enlargement of the liver (Pepper syndrome), and exophthalmos/abnormal protrusion of the eyeball (Hutchinson syndrome).
In infants, there is a different pattern of metastasis, characterized by subcutaneous nodules and/or diffuse hepatic infiltration with associated hepatomegaly and bone marrow infiltration of less than 10%. These cases are labeled as “S” for special.
The most frequent site of neuroblastoma occurrence is the abdomen, causing abdominal distension associated with pain and palpable mass, which draws the attention of the pediatrician. In these cases, it is necessary to immediately assess the size of this mass, its exact location, and involvement of other structures using ultrasound. Enlargement of the liver can lead to respiratory failure, especially in infants.
Thoracic neuroblastoma presents with mediastinal masses in the posterior region of the chest.
In cases of paravertebral tumors, there may be weakness in the limbs. It is also important to watch for signs of spinal cord compression, such as acute and subacute paraplegia, intestinal or urinary dysfunction, or radicular pain. This condition is considered a medical emergency and requires immediate hospitalization and treatment.
Diagnosis of neuroblastoma
Diagnosis of neuroblastoma is based on the histological evaluation of tumor tissue using light microscopy, with immunohistochemistry, or the presence of tumor cells in aspirated bone marrow material/bone marrow biopsy associated with increased urinary or serum catecholamines (or their metabolites).
Imaging tests of the initial tumor, such as ultrasound and computed tomography or magnetic resonance imaging, should also be performed. MIBG scintigraphy and bone marrow analysis to identify metastases are essential.
There are situations in which neuroblastoma can grow in the fetus, before the child is born. In these cases, the tumor can be identified in prenatal exams, through ultrasound. If this diagnosis occurs, appropriate clinical follow-up can be provided after the baby is born.
Once diagnosed, the patient with neuroblastoma is individually examined to determine the staging of the disease, i.e., whether the disease is localized or already disseminated. It is also important to assess whether the tumor affects the functions of other organs.
International Neuroblastoma Staging System (INSS)
The INSS – International Neuroblastoma Staging System – is the system used to determine the stage at which the disease is. They are:
- Stage 1 – the tumor is confined to the area where it originated and can be completely removed by surgery. The lymph nodes within the tumor may contain neuroblastoma cells, but lymph nodes outside the tumor do not;
- Stage 2A – the tumor is still in the area where it originated but may only be partially removed by surgery. Like stage 1, the lymph nodes within the tumor may contain neuroblastoma cells, but lymph nodes outside the tumor do not;
- Stage 2B – the tumor is only in one region of the body and may or may not be completely removed by surgery. Lymph nodes outside the vicinity of the tumor contain neuroblastoma cells, but the disease has not spread to other lymph nodes; and
- Stage 3 – the tumor has not spread to other organs, but one of the following is true:
– The tumor cannot be completely removed by surgery and has crossed the midline (defined as the spine), to the other side of the body. It may or may not have spread to nearby lymph nodes;
– The tumor is still in the area where it originated, and on only one side of the body. It has spread to the lymph nodes on the contralateral side of the body; and
– The tumor is in the middle of the body, invades both sides, and cannot be completely removed by surgery.
Stage 4 – The tumor has spread to other parts of the body (such as distant lymph nodes, bones, liver, skin, bone marrow, or other organs), but the patient does not meet the criteria for stage 4S; and
Stage 4S (or special neuroblastoma) – The child is younger than 1 year old. The tumor is only on one side of the body and may have spread to the lymph nodes on that same side, but not to the lymph nodes on the other side. The neuroblastoma has spread to the liver, skin, or bone marrow – but no more than 10% of the cells in the bone marrow may be neoplastic. Imaging studies, including MIBG scintigraphy, do not show that the tumor has spread to the bones and/or bone marrow.
Treatment for neuroblastoma cancer
The treatment of a patient with neuroblastoma is individualized and defined according to the stage and clinical and biological characteristics of the disease, as well as histopathological data. The risk group classification in which the child is classified is also taken into account to determine the treatment approach.
The risk group classification for neuroblastoma cancer was created by the Children’s Oncology Group and is divided as follows:
- Low risk – all children in stage 1; any child in stage 2A or 2B under 1 year of age; any child in stage 2A or 2B over 1 year of age whose tumor does not have extra copies of the MYCN oncogene; any child in stage 4S under 1 year of age whose tumor has favorable histology, is hyperdiploid, and does not have extra copies of the MYCN gene;
- Intermediate risk – any child in stage 3 under 1 year of age whose tumor does not have extra copies of the MYCN oncogene; any child in stage 3 over 1 year of age whose tumor does not have extra copies of the MYCN oncogene and has favorable histology; any child in stage 4 under 1 year of age whose tumor does not have extra copies of the MYCN oncogene; any child in stage 4S under 1 year of age whose tumor does not have extra copies of the MYCN oncogene and has normal DNA ploidy and/or unfavorable histology; and
- High risk – any child in stage 2A or 2B over 1 year of age whose tumor has extra copies of the MYCN oncogene; any child in stage 3 under 1 year of age whose tumor has extra copies of the MYCN oncogene; any child in stage 3 over 1 year of age whose tumor has extra copies of the MYCN oncogene; any child in stage 3 over 18 months of age whose tumor has unfavorable histology; any child in stage 4 whose tumor has extra copies of the MYCN oncogene, regardless of age; any child in stage 4 over 18 months of age; any child in stage 4, between 12 and 18 months of age, whose tumor has extra copies of the MYCN oncogene, unfavorable histology, and/or normal DNA ploidy; any child in stage 4S under 1 year of age whose tumor has extra copies of the MYCN oncogene.
Patients identified as low risk are referred for local treatment with surgery. Occasionally, these patients also receive chemotherapy with low doses for a short period.
Those in the intermediate risk group are recommended systemic chemotherapy combined with surgery.
And those in the high-risk group receive intensive treatment with chemotherapy, followed by surgery, autologous bone marrow transplant, radiotherapy, and the use of retinoic acid and immunotherapy.
The patient should continue with outpatient follow-up over the years, with clinical and radiological exams in the early years to detect and control possible disease relapses.
After five years of control, the follow-up is annual with the aim of detecting treatment-related sequelae. These late effects may include hearing loss, orthopedic problems (mainly scoliosis), hormonal changes (such as hypothyroidism), growth retardation, infertility, neurological, psychological, and emotional problems. Less frequently, the development of a second cancer.
Prevention
There is no way to prevent or avoid neuroblastoma, as its causes are unknown and there are no environmental factors or maternal exposures that can influence the occurrence of the disease, especially in cases of childhood neuroblastoma.
