What is neuroblastoma
Neuroblastoma is a type of cancer that mainly affects children under 5 years of age, including newborns and breastfeeding babies. It is the third most common neoplasm in childhood and adolescence, after leukemia and central nervous system tumors.
In Brazil, neuroblastoma corresponds to 8% to 10% of cases of childhood tumors and has an annual prevalence of approximately 7.3 cases/million children. Worldwide, the frequency of diagnosis of the disease varies from 7 to 12 cases/million children. More than 80% of cases are 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 even spontaneous remission is possible, to extreme cases, called high risk, in which a rapid progression occurs and can be fatal if not properly assisted.
The disease can originate anywhere in the sympathetic nervous system, with about 80% developing in the abdomen. In general, it arises in the adrenal glands, located in the upper part of the kidney, and can reach sufficient dimensions to determine an increase in the size of the abdomen. But it can arise in other locations, such as the cervical, thoracic and/or pelvic regions, following the path of the entire sympathetic nervous system chair.
Symptoms and signs of neuroblastoma
The symptoms of neuroblastoma vary depending on the location of the tumor.
Patients with disease located in the area where the cancer originated may be relatively asymptomatic in the initial phase, while those with metastatic disease may manifest fever, weight loss, pain and irritability, in addition to pallor.
Spread may occur via lymphatic or hematogenous route to lymph nodes, bone marrow, bones, liver, skin, orbits, dura mater and, rarely, to the lungs and central nervous system. In this group, periorbital ecchymosis (known as Raccoon’s sign) may arise due to tumor infiltration of the tissue around the eye and bones, in addition to fever, anemia or bleeding, due to bone marrow infiltration by the tumor. Other symptoms include bone pain, limp, paralysis, hepatomegaly/enlargement of the liver (Pepper syndrome) and exophthalmos/abnormal bulging of the eyeball (Hutchinson syndrome).
In infants, there is a different pattern of metastasis, characterized by subcutaneous nodules and/or diffuse hepatic infiltration with hepatomegaly associated with bone marrow infiltration of less than 10%2. In these cases, the designation “S” is used, for special.
The most frequent place for neuroblastoma to occur is the abdomen, causing abdominal distension associated with pain and a palpable mass, which draws the pediatrician’s attention. In these cases, it is necessary to immediately evaluate, with ultrasound, the size of this mass, its exact location and the involvement of other structures. Liver enlargement can lead to respiratory failure, especially in infants.
Thoracic neuroblastoma has mediastinal masses in the posterior region of the chest as symptoms.
In cases of paravertebral tumors, there may be weakness in the limbs. It is also important to pay attention to 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.
The diagnosis of neuroblastoma is based on histological assessment of tumor tissue by optical microscopy, with immunohistochemistry, or the presence of tumor cells in bone marrow aspirated/bone marrow biopsy material associated with increased urinary or serum catecholamines (or its metabolites).
Imaging tests of the initial tumor should also be performed, through ultrasound and tomography or magnetic resonance imaging. MIBG scintigraphy and spinal cord analysis to identify metastases are indispensable.
There are situations in which neuroblastoma can still grow in the fetus, before the child is born. In these cases, the tumor can be identified in prenatal exams, through ultrasound. Once this diagnosis occurs, adequate clinical follow-up can be provided after the baby is born.
Once diagnosed, the patient with neuroblastoma is examined individually to determine its staging, that is, if the disease is only localized or if it has already spread. It is also important to assess whether the tumor affects the functions of other organs.
The INSS – an acronym for International Staging System for Neuroblastoma – is the system used to determine the stage of the disease. They are:
- Stage 1 – the tumor is restricted to the area where it originated and can be removed completely by surgery. Lymph nodes inside the tumor may have neuroblastoma cells, but lymph nodes outside the tumor may not;
- Stage 2A – the tumor is still in the area where it originated, but can only be partially removed by surgery. As with stage 1, lymph nodes inside the tumor may have neuroblastoma cells, but lymph nodes outside the tumor may not;
- Stage 2B – the tumor is in only 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 these possibilities 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 spread to nearby lymph nodes;
– The tumor is still in the area where it started, and only on one side of the body. It has already spread to 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 criteria for stage 4S; and
- Stage 4S (or special neuroblastoma) – the child is less than 1 year old. The tumor is only on one side of the body and may have spread to lymph nodes on that side, but not to lymph nodes on the other side. Neuroblastoma has spread to the liver, skin or bone marrow – but no more than 10% of marrow cells can be neoplastic. Imaging tests, including MIBG scintigraphy, do not show that the tumor has spread to the bones and/or bone marrow.
The treatment of the patient with neuroblastoma is individualized and defined according to the stage and the clinical and biological characteristics of the disease, in addition to the histopathological data. It also takes into account the risk group classification in which the child is to determine the line to be followed.
The neuroblastoma risk group classification was created by the Children’s Oncology Group and is broken down as follows:
- Low risk – all children in stage 1; any stage 2A or 2B child under 1 year of age; any stage 2A or 2B child over 1 year of age whose tumor does not have extra copies of the MYCN oncogene; any stage 4S child 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 stage 3 child under 1 year of age whose tumor does not have extra copies of the MYCN oncogene; any stage 3 child over 1 year of age whose tumor lacks extra copies of the MYCN oncogene and has favorable histology; any stage 4 child under 1 year of age whose tumor does not have extra copies of the MYCN oncogene; any stage 4S child under 1 year of age whose tumor lacks extra copies of the MYCN oncogene and has normal DNA ploidy and/or unfavorable histology; and
- High risk – any stage 2A or 2B child over 1 year of age whose tumor has extra copies of the MYCN oncogene; any stage 3 child under 1 year of age whose tumor has extra copies of the MYCN oncogene; any stage 3 child over 1 year of age whose tumor has extra copies of the MYCN oncogene; any stage 3 child over 18 months of age whose tumor has unfavorable histology; any stage 4 child whose tumor has extra copies of the MYCN oncogene, regardless of age; any stage 4 child over 18 months of age; any stage 4 child between 12 and 18 months of age whose tumor has extra copies of the MYCN oncogene, unfavorable histology, and/or normal DNA ploidy; any stage 4S child under 1 year of age whose tumor has extra copies of the MYCN oncogene.
Patients identified as a low-risk group are referred for local treatment with surgery. Eventually, these patients also receive low-dose, short-term chemotherapy.
Those at intermediate risk are indicated for systemic chemotherapy associated with surgery.
And those at high risk receive intensive treatment with chemotherapy, followed by surgery, autologous bone marrow transplantation, radiotherapy and use of retinoic acid and immunotherapy.
The patient should continue with outpatient follow-up over the years, with clinical and radiological examinations in the first few years, to detect and control possible relapses of the disease.
After five years of control, the return is annual and aiming to detect post-treatment sequelae. These late effects can include hearing loss, orthopedic problems (especially scoliosis), hormonal changes (such as hypothyroidism), growth retardation, infertility, neurological, psychological and emotional problems. Less often, the development of the second cancer.
There is no way to prevent or avoid neuroblastoma, since its causes are unknown and there are no environmental factors or maternal exposures that could influence the occurrence of the disease.