OVERVIEW: What every practitioner needs to know

Are you sure your patient has Neuroblastoma? What are the typical findings for this disease?

Neuroblastoma is a tumor of the sympathetic nervous system and can occur anywhere along the sympathetic chain, most commonly in the abdomen. The presenting signs and symptoms vary widely and depend on the location of the primary tumor and the degree of disease spread.

The most common primary tumor location is the abdomen (65%). Signs/symptoms include: asymptomatic palpable mass, abdominal distension and/or pain and hypertension secondary to renal vessel compression. Occasionally bowel obstruction or lower extremity edema can be seen. Very rarely neuroblastoma presents with sudden dramatic abdominal enlargement and anemia due to tumor hemorrhage.

Primary tumors in the cervical or upper thoracic region can present as a supraclavicular mass or with Horner’s syndrome and/or anisocoria. Lower thoracic tumors are usually asymptomatic and picked up incidentally on chest radiographs (x-rays) done for other complaints. Rarely thoracic masses can present with superior vena cava syndrome or respiratory distress.

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Paraspinal masses anywhere along the sympathetic chain can present with symptoms of cord compression including paraplegia and bladder and/or bowel dysfunction. This is an oncologic emergency, needing urgent biopsy and initiation of therapy.

Neuroblastoma most commonly metastasizes to the bone, bone marrow and liver. Signs/symptoms include: bone pain, limp, periorbital ecchymosis (caused by tumor infiltration of the periorbital bones), cytopenias and hepatomegally. Nonspecific signs/symptoms are also commonly seen including fever, irritability and weight loss. Infants with metastatic neuroblastoma can have a unique presentation (known as stage 4S disease) characterized by massive hepatomegally and bluish subcutaneous nodules.

Paraneoplastic syndromes associated with neuroblastoma

Rarely neuroblastoma can present with signs/symptoms of the following paraneoplastic syndromes:

– Opsoclonus-myoclonus syndrome (OMS) occurs in 2 to 3% of children with NB. This syndrome is characterized by rapid eye movements, ataxia, myoclonus of the limbs and trunk and behavioral disturbances. OMS is also known as dancing eyes, dancing feet syndrome. OMS is thought to be immune-mediated and caused by the presence of an anti-neural antibody that cross-reacts with a common antigen on neuroblastoma and normal nervous system tissue. It is generally associated with favorable tumor features (see below) but neurologic symptoms can be difficult to treat and the majority of patients suffer from long-term neurologic sequelae. OMS is usually treated with immuno-modulating agents, most commonly steroids and intravenous gammaglobulin. Low dose chemotherapy and Rituximab are also used.

– Vasoactive intestinal peptide (VIP) syndrome is caused by tumor secretion of VIP causing chronic watery diarrhea and failure to thrive. This syndrome is also associated with favorable tumor features. The symptoms resolve when the tumor is removed.

– Catecholamine excess syndrome: Symptoms include flushing, sweating, tachycardia, headache and hypertension.

What other disease/condition shares some of these symptoms?

Neuroblastoma has a broad oncologic differential diagnosis. The differential diagnosis of an abdominal mass includes Wilms tumor, Burkitts lymphoma, germ cell tumors and hepatoblastoma. The differential diagnosis of a thoracic mass includes lymphoma, T-cell leukemia and germ cell tumors. Pathologically neuroblastoma appears as a “small round blue cell” tumor and needs to be distinguished from lymphomas, Ewing sarcoma and rhabdomyosarcoma.

Abdominal masses in infant are less likely to be malignant. Non-oncologic differential diagnosis in infant includes: multicycstic kidney, hydronephorsis, duplication cyst, pulmonary sequestration.

What caused this disease to develop at this time?

  • The cause of neuroblastoma is largely unknown.

  • Due to the young age of presentation, pre- and peri-natal exposures have been explored, but none have shown a strong association.

  • Hereditary neuroblastoma (<1%) represents a small subgroup of cases where a pattern of autosomal dominal inheritance is seen. Activating mutations in the tyrosine kinase domain of the ALK oncogene are seen in the majority of these cases.

  • Neuroblastoma seen in conjunction with Hirschprung’s disease or congenital central hypoventillation is associated with PHOX2B mutations.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

  • CBC – can see cytopenias if marrow disease or anemia if intratumoral bleeding

  • Electrolytes, BUN, Creatinine – to assess for adequate renal function, unusual occurrence of tumor lysis syndrome

  • Liver function tests – although usually normal even with liver infiltration

  • Urine catecholamines – measure spot homovanillic acid (HVA) and vanillylmandelic acid (VMA) by HPLC, increased in 90-95% of neuroblastoma

  • Ferritin – non-specific, increased especially in high-risk tumors

  • Lactate Dehydrogenase – non-specific, increased level can be a marker of rapid cell turnover and large tumor burden

Would imaging studies be helpful? If so, which ones?

The purpose of imaging studies in the initial evaluation of patients with suspected neuroblastomas is to characterize the primary tumor and presence and degree of metastatic disease.

  • Computed tomograhy (CT) and magnetic resonance imaging (MRI) are used to evaluate the extent and origin of the primary tumor and solid organ metastases. MRI is better for assessing paraspinal lesions particularly those with possible intraspinal extension and spinal cord impingement.

  • Bone scan are used to detect occult bony metastases, although not highly specific.

  • MIBG scan is a more sensitive and specific method for detecting bony metastases and can also be used to assess the primary tumor and other soft tissue disease. Metaiodobenzylguanidine (MIBG) is a norephinephrine analog that is taken up by the majority of neuroblastomas (90-95%) and can be combined with 123I or 131I for imaging.
    123I-MIBG is preferred due to higher resolution images.

  • PET scan can be used to assess for occult metastases for patients with MIBG non-avid tumors.

  • Would only do brain imaging if clinically indicated by symptoms or physical exam.

Confirming the diagnosis

The diagnosis of neuroblastoma is established by histologic evaluation of primary tumor tissue. Microscopically appears as small round blue cells. Histology can vary on a spectrum based on the degree of tumor cell differentiation from neuroblastoma to more mature phenotypes ganglioneuroblastoma and ganglioneuroma.

Primary tumor tissue is also needed to evaluate tumor biology.

If primary tumor tissue can not be obtained, the diagnosis can also be established by the presence of small round blue cells in the marrow in conjunction with elevated urinary catecholamines.

If you are able to confirm that the patient has Neuroblastoma, what treatment should be initiated?

Newly diagnosed patients with neuroblastoma should be given supportive care based on their symptoms including fluid and electrolyte replacement, respiratory support and blood pressure management (hypertension can be caused by renal vessel compression).

Patients who present with spinal cord compression should be treated emergently after biopsy is done. Preferred emergency treatment is chemotherapy. Avoid laminectomy and radiation therapy if possible due to significant late effects.

Surgery, chemotherapy and radiation therapy are used in the treatment of neuroblastoma.

Specific therapy of neuroblastoma is based on risk group stratification (low, intermediate and high). Assignment of risk group depends on prognostic factors of age, stage and tumor biology as follows:

Low-risk: Surgery alone. Observation only is appropriate for some patients (i.e. small adrenal masses detected in perinatal period and infants with Stage 4S disease with favorable biology).

Intermediate-risk: Moderate dose chemotherapy with surgical resection after tumor reduction.

High-risk: Intensive multimodal therapy including: High dose chemotherapy, surgical resection of primary tumor, myeloablative chemotherapy with autologous stem cell rescue and maintenance biologic therapy with anti-GD2 antibody and isotretinoin.

International Neuroblastoma Staging System

Prognostic factors used for risk-group assignment:

Age: less than 12 months is favorable.

Stage: Lower stage is favorable. Staging is done using the International Neuroblastoma Staging System.

MYCN status: Amplification of MYCN oncogene is unfavorable.

Ploidy: DNA index > 1 is favorable. (Ploidy is only prognostic in children up to 18 months of age.)

International Neuroblastoma Staging System:

Stage 1: Localized tumor with gross total resection

Stage 2: Localized tumor with incomplete gross total resection and/or positive nonadherent ipsilateral lymph nodes

Stage 3: Unresectable tumor that crosses the midline, +/- regional lymph node involvement

Stage 4: Metastatic disease present

Stage 4S: Localized primary tumor with dissemination limited to skin, liver and/or bone marrow (only applies to infants < 1 year)

What are the adverse effects associated with each treatment option?

The acute toxicities of chemotherapy in general most commonly include alopecia, nausea and vomiting, mucositis and pancytopenia. Due to pancytopenia patients often require transfusions and may require hospitalization for IV antibiotics due to fever and neutropenia.

What are the possible outcomes of Neuroblastoma?

Prognosis is directly correlated to risk group. The overall survival for patients with low risk disease is approximately 98%. The overall survival for patients with intermediate risk neuroblastoma is > 95% with a slightly lower survival (approximately 90%) for patients with unfavorable biologic features. Patients who relapse following treatment for low or intermediate risk disease are usually salvageable with either further surgery or chemotherapy.

The overall survival for patients with high-risk neuroblastoma is 40 -50%. Treatment related long term morbidity can be significant.

What causes this disease and how frequent is it?

  • Incidence 1:7000 children less than 5 years.

  • 650 new cases diagnosed per year in the United States.

  • Median age of diagnosis is 22 months, rarely diagnosed after the age of 10 years.

  • Most common cancer diagnosed in infancy.

  • The cause of neuroblastoma is largely unknown.

  • Due to the young age of presentation, pre- and peri-natal exposures have been explored, but none have shown a strong association.

  • Hereditary neuroblastoma (<1%) represents a small subgroup of cases where a pattern of autosomal dominal inheritance is seen. Activating mutations in the tyrosine kinase domain of the ALK oncogene are seen in the majority of these cases.

  • Neuroblastoma seen in conjunction with Hirschprung’s disease or congenital central hypoventilation is associated with
    PHOX2B mutations.

How do these pathogens/genes/exposures cause the disease?


Other clinical manifestations that might help with diagnosis and management


What complications might you expect from the disease or treatment of the disease?

Chemotherapy and radiation therapy can both be associated with late sequelae in disease survivors. The chemotherapy-related late effects are usually dose-related and include most commonly: hearing loss due to platinum chemotherapy (cisplatin and carboplatin) and sterility due to alkylator therapy. Patients treated for neuroblastoma are also at a small risk for late cardiac toxicity (due to anthracycline therapy) and secondary leukemias (due to alkylating agents and topoisomerase inhibitors). Patients who receive local external beam radiation are at risk for secondary cancers. Those who receive total body irradiation (currently rarely used) are also at risk for growth delay, thyroid insufficiency and cataracts.

Are additional laboratory studies available; even some that are not widely available?


How can Neuroblastoma be prevented?


What is the evidence?

Baker, DL. “Outcome after reduced chemotherapy for intermediate risk neuroblastoma”. N Eng J Med. 2010. pp. 1313-23. (Study on which current treatment of intermediate risk neuroblastoma is based.)

Matthay, KK. “Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation and cis-retinoic acid. Children's Cancer Group”. N Engl J Med. 1999. pp. 1165-73. (Randomized study showing efficacy of autologous transplant in high-risk neuroblastoma.)

u, AL. “Anti-GD2 antibody with GM-CSF, Interleukin-2 and isotretinoin for neuroblastoma”. N Engl J Med. vol. 363. 2010 Sep 30. pp. 1324-34. (Randomized study which shows efficacy of anti-GD2 antibody in high-risk neuroblastoma following treatment.)

Ongoing controversies regarding etiology, diagnosis, treatment