Neuroblastoma in children: causes, diagnosis, treatment

In pediatric oncology, one of the most common extracranial neoplasms is neuroblastoma in children, which refers to malignant embryonic tumors from neural crest neuroblasts, that is, germinal (immature) nerve cells of the sympathetic nervous system. 

Epidemiology

According to statistics from the International Neuroblastoma Risk Group (INRG), neuroblastoma accounts for about 8% of all oncological diseases in children worldwide and ranks third in prevalence after leukemia and brain tumors.

According to others, neuroblastoma accounts for about 28% of all cancers in infants. In more than a third of cases, neuroblastoma is diagnosed in children under one year of age; the median age at diagnosis is 19-22 months. More than 90% of diagnosed cases occur in children aged two to five years (with a predominance of boys); the peak incidence occurs at the age of two to three years, and cases in children older than five years are less than 10%. 

Causes of the neuroblastoma

Studying the causes of neuroblastoma, the researchers concluded that this tumor in children occurs due to sporadic genetic mutations during embryogenesis or early postnatal development. But what causes these gene changes is unknown, since no influence of teratogenic environmental factors has been identified. 

Such tumors can occur anywhere, including the mediastinum, neck, abdomen, adrenal glands, kidneys, spine, pelvis.

In rare cases, neuroblastoma in infants may be due to an inherited mutation. In particular, a mutation in the CD246 membrane protein gene on chromosome 2, the ALK tyrosine kinase enzyme, which provides intercellular communications and plays an important role in the functioning of the nervous system; in the PHOX2B protein gene (on chromosome 4), which is involved in the maturation of nerve cells. 

Neuroblastoma may also be associated with  neurofibromatosis type  1 in children,  Beckwith-Wiedemann syndrome,  and hyperinsulinemic hypoglycemia (pancreatic nesidioblastosis). 

Risk factors

To date, heredity is recognized as risk factors for the development of neuroblastoma in children - the presence of this tumor in a family history, as well as congenital anomalies associated with gene mutations during fetal development. This is especially true in cases of the development of several neoplasms in different organs.

None of the exogenous factors that increase the risk of this tumor have been identified by researchers.

Pathogenesis

The mechanism of development of neuroblastomas is due to impaired differentiation and maturation of neural crest cells - bilateral cell lines that form along the edges of the neural tube from the ectodermal germ layer of the human embryo. These cells migrate (move) and differentiate into many cell types: sensory and autonomic neurons, neuroendocrine and adrenal medulla cells, craniofacial cartilage and bone cells, and pigment cells. 

In neuroblastoma, the migrated neuroblasts do not mature, but continue to grow and divide, forming a tumor. And the pathogenesis of its formation is associated with the following gene mutations:

• with duplication of part of the chromosome sequence or duplication of segments of the LMO1 gene on chromosome 11, encoding the RBTN1 protein in the cells of the neural crest of the embryo;
• with a copy number change in the NBPF10 gene on chromosome 1q21.1, encoding the DUF1220 protein, which controls the proliferation of human neural stem cells. These disorders lead either to the duplication of this chromosome, or to its deletion - the absence of part of the DNA;
• with changes in the tumor suppressor gene ATRX (on chromosome Xq21.1);
• with the presence of additional copies (amplification) of the N-Myc transcription factor gene on chromosome 2, which encodes one of the transcription factors (DNA-binding protein), which regulates the activity of other genes and controls the proliferation of progenitor cells in the formation of proteins for the formation of tissues and organs of the fetus. Amplification of this gene turns it into an oncogene, which provokes a violation of the cell cycle, increased cell proliferation and tumor formation.

Symptoms of the neuroblastoma

The first signs of neuroblastoma are nonspecific and can be manifested by loss of appetite (and weight loss), fatigue during feeding, fever, and joint pain.

Clinical symptoms depend on the location of the primary tumor and the presence of metastases (which occur in 60-73% of cases).

Very often, primary neuroblastoma is localized in the adrenal medulla, which has a similar origin with nerve cells. At the age of one year, neuroblastoma of the adrenal gland in children is diagnosed in 35-40% of cases. Its symptoms are abdominal pain, fever, weight loss, bone pain, anemia, or concomitant Pepper's syndrome: diffuse liver damage with severe hepatomegaly and respiratory distress syndrome.

Retroperitoneal neuroblastoma or retroperitoneal neuroblastoma in children, as it grows, begins to put pressure on the bladder or intestines, which can cause problems with urination or defecation, swelling of the legs (scrotum swells in boys).

Mediastinal neuroblastoma in children (mediastinal neuroblastoma) often presses on the superior vena cava, and this can cause swelling of the face, neck, arms, and upper chest (skin becomes bluish-red, with subcutaneous nodules). There is a cough and wheezing, problems with breathing (in the form of shortness of breath) or swallowing (dysphagia); there is an increase in lymph nodes in the neck, above the collarbone, in the armpits.

The spread  of tumor cells  to the bone marrow leads to anemia, thrombocytopenia and leukopenia with a tendency to bleed.

And with metastases in the periorbital region, dark circles or bruises appear around the eyes. Such a tumor can also cause headaches and dizziness, exophthalmia (protrusion of the eyeballs), and due to compression of nerve endings, drooping of the eyelids (ptosis) and a decrease in the size of the pupils (miosis).

Abdominal neuroblastoma or neuroblastoma of the abdominal cavity in children leads to the formation of palpable seals in the abdomen, bloating, lack of appetite, constipation, and increased blood pressure. A tumor pressing on the spinal cord or nerve root can lead to numbness and weakness in the limbs, inability to stand, crawl, or walk. If the bones are affected, bone pain may occur.

With a tumor of stage 3-4 in the abdominal cavity with damage to the lymph nodes, tumor cells can enter the kidney parenchyma, and then an extensive neuroblastoma of the kidney develops in children, leading to a violation of its functions. 

Stages

• Stage 1 neuroblastoma is a primary tumor localized and isolated in one area of the body; lymph nodes on both sides are not affected.
• Neuroblastoma stage 2. In stage 2A, the primary tumor is limited to one area but is large; bilateral lymph nodes were not affected. In stage 2B, the lymph nodes on the side of the body where the tumor is located are positive for metastases.
• Neuroblastoma stage 3: the primary tumor crosses the area of the spinal cord or the midline of the body, unilateral or bilateral metastases in the lymph nodes are found.
• Stage 4 neuroblastoma: The tumor has spread to distant lymph nodes, bone marrow, bones, liver, or other organs. And stage 4S will be determined in children under one year old with a localized primary tumor, with dissemination to the skin, liver or bone marrow.

International Neuroblastoma Risk Staging System (INRGSS) 

INRGSS uses imaging-defined risk factors (IDRFs), which are factors seen on imaging tests that may mean that a tumor will be more difficult to remove. 

INRGSS divides neuroblastomas into 4 stages:

• L1: The tumor has not spread from where it started and has not grown into vital structures. It is limited to one part of the body, such as the neck, chest, or abdomen.
• L2: The tumor has not spread (metastasized) far from where it started (for example, it may have grown from the left side of the abdomen to the left side of the chest), but it has at least one IDRF.
• M: The tumor has metastasized to a distant part of the body (except tumors in the MS stage).
• MS: Metastatic disease in children under 18 months of age in which the cancer has spread only to the skin, liver, and/or bone marrow. 

Complications and consequences

Neuroblastoma is characterized by such complications and consequences as:

• spread (metastasis) to lymph nodes, bone marrow, liver, skin and bones;
• spinal cord compression (which can cause pain and lead to paralysis);
• the development of paraneoplastic syndrome  (due to the action of certain chemicals secreted by the tumor, as well as the GD2 disialoganglioside antigen expressed by its cells), which are manifested by rapid involuntary eye movements, coordination disorder, muscle cramps, diarrhea;
• relapses after completion of primary therapy (as clinical practice shows, high-risk neuroblastomas relapse in 50% of cases).

Diagnostics of the neuroblastoma

Diagnosis of suspected neuroblastoma in a child requires physical examination, laboratory testing, and imaging.

Blood and urine tests are taken for catecholamines (norepinephrine and dopamine) and homovanic or vanillylmandelic acids (formed during the metabolism of these hormones); a blood test for neurospecific enolase, an enzyme-linked immunosorbent assay (ELISA) of blood serum, and a bone marrow test (which is sampled by aspiration puncture). A DNA test is performed to determine mutations, and a biopsy is performed for a cytomorphological study of tumor tissue.

After the biopsy samples have been taken, they are sent to a laboratory where they are examined under a microscope by a pathologist (a doctor who is specially trained to detect cancer cells). Special lab tests are also often done on the samples to show if the tumor is a neuroblastoma.

If it is a neuroblastoma, lab tests can also help determine how quickly the tumor may be growing or spreading, as well as what treatments may work best. 

Instrumental diagnostics visualizes a neoplasm using ultrasound, X-ray, MRI or CT, PET with the introduction of 18F-fluorodeoxyglucose or MIBG scan - scintigraphy with metaiodobenzylguanidine.  [1]

Differential diagnosis

Differential diagnosis includes benign ganglioneuroma, ganglioneuroblastoma. Rhabdomyosarcoma, nephroblastoma.

Treatment of the neuroblastoma

In neuroblastoma, treatment depends on the patient's risk group (stage of the tumor process), the location of the neoplasm, the genomic characteristics of the tumor cells, and the age of the child. And it can include monitoring, surgery, chemotherapy, radiation therapy, immunotherapy,  hematopoietic stem cell transplantation .

Neoadjuvant or adjuvant (pre- or postoperative) chemotherapy for neuroblastoma in children, like any  chemotherapy for cancer , is carried out in courses: the drug is administered for several days in a row, followed by a break to restore the body. Cycles usually repeat every three to four weeks.

The following drugs are used (and their combination): Cyclophosphamide, Cisplatin or Carboplatin, Doxorubicin (Adriamycin), Vincristine, Etoposide.

Common side effects  of chemotherapy drugs  include hair loss, loss of appetite, increased fatigue, nausea and vomiting, mouth ulcers, diarrhea, or constipation. Chemotherapy can negatively affect the bone marrow and provoke a decrease in the number of blood cells. 

In targeted immunotherapy (aimed at the GD2 tumor antigen), drugs from the group of monoclonal antibodies (anti-GD2 MAb) Dinutuximab (Unituxin) and Naxitamab are used. They are administered intravenously by continuous infusion, in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF cytokine) and interleukin-2.

Side effects of these drugs are manifested in the form of pain (often very severe), lowering blood pressure, palpitations, shortness of breath (with possible swelling of the airways), fever, nausea, vomiting and diarrhea, changes in the cellular and mineral composition of the blood.

To reduce the risk of cancer recurrence after high-dose chemotherapy and stem cell transplantation, children with high-risk neuroblastoma are treated with systemic retinodes, 13-cis-retinoic acid (Isotretinoin). [2]

Surgical treatment of neuroblastoma - removal of the tumor, for example, open adrenalectomy or laparoscopic resection of adrenal neuroblastoma; lymphedectomy  (removal of affected lymph nodes), etc. [3]

For high-risk neuroblastoma, radiation therapy may be given  . [4]

Prevention

Given the causes of neuroblastoma in children, the only way to prevent it may be genetic counseling when planning a pregnancy. But it should be borne in mind that this tumor is associated with inherited mutations only in 1-2% of cases.

Forecast

Neuroblastoma of infancy has the ability to spontaneously regress.

Prognostic markers 

• High-risk tumors, as well as neuroblastoma in children of all age groups and all stages (except stage 4S) - with increased expression of the N-MYC gene and amplification of the N-Myc oncogene - have an unfavorable prognosis that affects life expectancy.
• The presence of tumor cells that lack certain parts of chromosomes 1 or 11 (known as 1p or 11q deletions) gives a less favorable prognosis. Having an extra portion of chromosome 17 (an increase in 17q) is also associated with worse prognosis.
• Neuroblastoma cells with more DNA have a better prognosis, especially in children younger than 2 years of age.
• Neuroblastomas that have more neurotrophin receptors, especially the nerve growth factor receptor TrkA, have a more favorable prognosis. 

Survival by childhood cancer group (COG) at risk 

• Low-risk group: Children in the low-risk group have a 5-year survival rate above 95%.
• Intermediate risk group: Children in the intermediate risk group have a 5-year survival rate of 90% to 95%.
• High-risk group: High-risk children have a 5-year survival rate of about 50%.

About 15% of cancer deaths in children are associated with neuroblastoma. With this high-risk malignancy, the chances of long-term survival do not exceed 40%. The overall five-year survival rate is 67-74%, in the age group from one to four years - 43%, and for neuroblastoma diagnosed during the first year of life - more than 80%.