Neuroblastoma (NB) is one of the most common cancer types that affects children and infants derived from the immature nerve cells.
Neuroblastoma is a solid extracranial tumor of the sympathetic nervous system. Usually it is found in the adrenal glands, although other body parts are known to be affected as well. Sometimes the tumor arises from the nerve cells near the spine.
The symptoms of neuroblastoma vary widely and depend on the size and location of the tumor. In some cases the tumor resolves spontaneously, although in the majority of cases the combination of surgery, chemo- and radiotherapy is necessary.
Neuroblastomas affect almost exclusively children younger than 5 years old (80% of cases). They occupy the third place after leukemias and central nervous system tumors as one of the most common tumors of infancy (neuroblastomas comprise about 6-10% of all the childhood cancers). In most cases the diagnosis is made when a child is 17-22 months of age.
Neuroblastoma consists of immature pluripotent nerve cells, which didn’t differentiate normally. These nerve cells derive from the sympathetic nervous system, paraspinal ganglia and adrenal medulla.
The development of neuroblastoma may be caused by the abnormal genes. Familial forms of neuroblastoma are associated with the mutations in an ALK oncogene (anaplastic lymphoma kinase).
In rare cases neuroblastoma may be associated with other disorders such as Beckwith-Wiedemann syndrome, central failure of ventilation, DiGeorge syndrome, Hirschsprung disease and neurofibromatosis type 1. A mutation in PHOX2B gene, which controls the development of the central nervous system is suspected to be the cause.
The amplification of MYCN oncogene is reported to be seen in neuroblastoma. Changes within LMO1 and NBPF10 genes, germline deletion at the 1p36 or 11q14-23 locus are also found.
Due to a possible genetic link a child with a family history of neuroblastoma is more likely to develop this tumor, although usually the disease is sporadic.
In 65% of cases the tumor is located in the abdomen, more specifically in the adrenal gland. Other sites of the tumor include chest, neck and pelvis along the sympathetic trunk and nerve plexus.
The tumor may result in various symptoms depending on the location of the tumor or may even remain asymptomatic. Usually the child fails to thrive, he may experience bladder and bowel control loss, constipation. Infants are nervous and irritable. Other symptoms include weight loss, anorexia, general malaise and hypertension.
Neuroblastomas located in the mediastinum usually are asymptomatic. The compression of the sympathetic trunk in the cervical region may result in Horner’s syndrome presented with the miosis (a constricted pupil), partial ptosis (dropping upper eyelid), apparent anhidrosis (decreased sweating) and enophthalmos (the posterior displacement of the eyeball). Cough, wheezing in the chest, fever, Cushing’s syndrome or weight loss may also develop.
Sometimes the spinal cord may be compressed by the growing tumor causing neurologic deficit (weakness, paralysis, bladder and bowel dysfunction). Paraneoplastic syndrome may include cerebellar ataxia or opsoclonus/myoclonus (involuntary fast eye movements).
Tumor in the abdomen causes abdominal distension, abdominal mass, loss of appetite, non-specific pain and general fatigue. Lymphadenopathy and hepatomegaly (liver enlargement, Pepper syndrome) develop due to metastases.When the metastases affect the bone or bone marrow, the person experiences limb, joint or back pain, lumps may be palpitated causing Hutchinson syndrome. Involvement of the bone marrow leads to anemia and pancytopenia. Bone metastases lead to pathologic bone fractures.
The skin involvement due to metastases is called “blueberry muffin baby”.
According to the International Neuroblastoma Staging System (INSS) the stage of the disease is identified based on the location and spread of the tumor:
- Stage 1: The tumor is localized in the area of origin. It can be removed completely during surgery.
- Stage 2A: The tumor locates in the area of origin, although it cannot be fully removed during surgery. Lymph nodes remain unaffected. However, the nodes nearby the tumor may contain the abnormal cells.
- Stage 2B: The tumor is found in the original area, it may be or may not be completely removed, on the side of the tumor the affected lymph node is identified. The lymph nodes on the other side of the body show no sigh of malignancy.
- Stage 3: One of three:
- The tumor grows across the midline (the spine) of the body with or without changes in regional lymph nodes; or
- The tumor located on the site of origin with lymph node involvement on the other side; or
- Midline tumor with involvement of the lymph nodes on both sides of the body.
- Stage 4: The tumor disseminates to distant lymph nodes, bone marrow, bone, liver, or other organs.
- Stage 4S (“special neuroblastoma”): The infant <1 year old who has localized tumor on one side of the body without lymph node involvement (although in some of the nearby nodes the neuroblastoma cells may be present) with dissemination to the liver, skin, or bone marrow.
The International Neuroblastoma Risk Group Staging System (INRGSS) distinguishes 4 stages of neuroblastoma:
- L1: Localized tumor without any signs of IDRFs*.
- L2: A tumor that spreads to a nearby structures and has at least one IDRF.
- M: Metastases are found in a distant part of the body.
- MS: Metastatic disease in infants <18 months of age with cancer spread only to skin, liver, and/or bone marrow.
* Image-defined risk factors (IDRFs)- the factors seen on imaging tests – tumor growth into a nearby vital organ or around main blood vessels.
To verify the diagnosis the following investigations should be performed:
- Abdominal ultrasound;
- CT/MRI of the abdomen, spine and the chest;
- Urine and serum catecholamines (specifically homovanillic (HVA) and vanillylmandelic acid (VMA) – The tumor may release various substances, including catecholamines,
vanillylmandelic acid, homovanillic acid, and 3-methoxy-4-hydroxy phenylglycol.;
- Serum neurone-specific enolase (NSE);
- Serum LDH;
- mIBG (meta-iodobenzylguanidine) scan – mIBG is trapped by the sympathetic neurons because of its similarity to noradrenaline;
- Bone marrow aspiration/biopsy;
- Core needle biopsy or postoperative biopsy of the tumor – on microscopy tumor cells appear as blue cells and Homer Wright rosettes;
See also: Myeloblastic leukemia
The treatment of neuroblastoma includes the combination of surgical measures, chemotherapy and radiation therapy. The treatment depends on the size of the tumor, its dissemination and risk categories. Occasionally the bone marrow is affected by the aggressive treatment and, therefore, bone marrow transplantation is needed.
- Low-risk tumor can be observed or removed surgically without any other treatment.
- Moderate-risk neuroblastoma requires chemotherapy along with surgery.
- High-risk disease must be treated with the combination of chemotherapy, surgery and radiation therapy. Bone marrow transplantation may be necessary.
Chemotherapy agents used in the treatment of neuroblastoma include:
- platinum compounds (cisplatin, carboplatin);
- alkylating agents (cyclophosphamide, ifosfamide, melphalan);
- topoisomerase II inhibitor (etoposide);
- anthracycline antibiotics (doxorubicin);
- vinca alkaloids (vincristine);
- topoisomerase I inhibitors (topotecan and irinotecan).
Dinutuximab, monoclonal antibody, may be used.
In children younger than 1 year the tumor is known to resolve spontaneously.
Survival rates depends on the risk categories. Five-year survival rates are:
- >95% for low-risk patients;
- 80-95% for moderate-risk neuroblastoma;
- About 50% for high-risk disease.