Neuroblastoma

Background

  • Neuroblastoma is a malignant tumor made of neural crest cells that can occur at any point along the sympathetic ganglia or the adrenal medulla
  • Neuroblastoma can have an incredibly variable clinical presentation and behavior. It can undergo spontaneous regression, metastatic progression, or differentiation into a benign sub-type.
  • It is primarily a cancer of infants and children. Median age at diagnosis is 2 years, with 35% of cases in children under 1 year.
  • The incidence of neuroblastoma is around 1 in 10,000, with about 530 new cases diagnosed per year in the United States. There is a slight male predominance.
  • It is the most common solid tumor of childhood outside the CNS, and it accounts for 7% of all childhood cancers
  • About one fourth of cases present with a solitary mass that may be cured by surgical excision, but up to 60% of cases present as disseminated disease.
  • Age often plays an important role in clinical outcome with the majority of infants having disseminated disease showing good response to therapy whereas children > 1 year of age with disseminated disease generally having poor outcomes.

Clinical Features

The clinical features of neuroblastoma are incredibly variable due to the wide distribution of neural crest tissue. In approximately 1% of cases primary tumor cannot be identified. Common primary sites include:

Adrenal gland (40%) or other abdominal sites (25%) such as the retroperitoneal sympathetic ganglia. Features at presentation of abdominal tumors include:

  • Abdominal mass (detected by PCP during routine WCC in 11% of cases)
  • Abdominal discomfort or pain
  • Intestinal obstruction and compression of bowel or bladder (esp. when arising from organ of Zuckerkandl)
  • Systemic hypertension if renal vasculature is compressed; can also occur due to tumor production of catecholamine metabolites (VMA, HMA)

Thoracic tumors (15%) located in the posterior mediastinum. Presenting features include:

  • Chest radiograph findings, often incidental
  • Tracheal deviation with resulting stridor
  • Superior Vena cava syndrome

Cervical involvement (5%) produces the following symptoms:

  • Horner’s syndrome (ptosis, miosis, anhydrosis)
  • Tracheal compression

Paravertebral tumors can occur due to the invasion of the spinal cord by abdominal or thoracic tumors, through the neural foramina. This can result in:

  • Epidural spinal cord compression, an oncologic emergency, causing pain, motor and sensory deficits and loss of bowel and bladder control.
  • Nerve root compression and other fairly non-specific neurological symptoms which can make diagnosis in young children difficult
  • Congenital Horner syndrome in infants which requires a detailed work-up (VMA and HVA measurement, examination for abdominal and thoracic masses)

Neuroblastomas are associated with several paraneoplastic syndromes including:

  • Opsoclonus-myoclonus-ataxia—occurring in 1-3% and likely autoimmune in origin
  • VIP secretion--leading to diarrhea and hypokalemia

Metastases occur via both lymphatic and hematogenous routes.

Regional lymph node involvement is found in 35% of children with localized disease.

Hematogenous spread most often occur to bone, bone marrow, skin and liver.

  • Bone—bone pain (esp. with ambulation) and in the younger child limp or irritability.       Infiltration of periorbital bones may produce periorbital ecchymosis, ptosis and proptosis.           
  • Bone marrow—blood cunt abnormalities and fever
  • Liver—hepatomegaly
  • Skin—nontender papules and subcutaneous nodules           

Diagnosis

Most often, neuroblastoma is discovered as a mass on an ultrasound, radiograph, CT, MRI, or during a physical exam. Increasingly obstetrical ultrasonography is being used to diagnose neuroblastomas present prenatally.

If neuroblastoma is suspected, multiple lab tests should be ordered.
In addition to standard serum chemistries and LFT’s, a CBC should be ordered to look for anemia, and urine should be checked for               catecholamines (VMA, HVA), that can be produced by the tumor.
Tumor markers are elevated in 95% of patients with neuroblastoma.
The tumor should be assessed by CT or MRI, and a metastatic workup including bone scan should be done as well. If possible, the tumor should be biopsied and assessed for cytogenic and molecular markers.

International consensus panel has agreed on the minimum criteria for establishing a diagnosis of neuroblastoma, which require one of the following:

  • An unequivocal histologic diagnosis from tumor tissue by light microscopy with or without immunohistochemistry, electron microscopy, or increased urine or serum catecholamines or metabolites.
  • Evidence of metastases to bone marrow on an aspirate or trephine biopsy with concomitant elevation of urinary or serum catecholamines or their metabolites.

Staging

There are three staging systems for neuroblastoma, the Evans System, the St. Jude System, and the International Staging System. The International Neuroblastoma Staging System is now universally used to stage neuroblastomas. The INSS staging system is as follows:

Stage 1- Localized tumor confined to the area of origin, with complete gross excision, lymph nodes microscopically negative.

Stage 2-The tumor extends beyond the structure of origin, but does not cross the midline, with (2B) or without (2A) ipsilateral lymph node involvement.

Stage 3-Tumor extends beyond the midline, with or without bilateral lymph node involvement.

Stage 4-Tumor disseminated to distant sites, such as bone, bone marrow, liver, skin or lymph nodes.

            Stage 4S—Special category reserved for infants under 1 year of age which carries a much better prognosis. Localized primary tumor (as defined for stage 1 or 2) with dissemination limited to skin, liver or bone marrow (mets to cortical bone are excluded from this category).

Screening

  • Several groups have attempted to develop screening programs for neuroblastomas using urinary catecholamines, given the much better prognosis of this tumor when detected at a younger age.
  • The screening programs led to more neuroblastomas being diagnosed in the screened population most of which were low-stage tumors with favorable biologic features.
  • There was no decrease in the incidence of high-risk tumors in children beyond the age of screening and no decrease in mortality in the screened population compared to controls.
  • Consequently, screening of infants for neuroblastomas with urinary catecholamines is currently not recommended, though may be considered if there is a family history.

Treatment:

In general, key factors influencing clinical behavior of neuroblastomas include tumor stage, age at diagnosis, pathologic risk classification and cyto and molecular genetics. Together these factors are used to stratify patients into low, intermediate, and high-risk groups that determine treatment strategies. Treatment for neuroblastoma uses a multifaceted approach, with a combination of surgery, chemotherapy and radiotherapy.

  • For low-risk disease, surgery is a primary modality, however low risk tumors that are difficult to resect require additional chemo or radiation therapy. Furthermore for a subset of patients in the 4S stage, observation is an option due to high rate of spontaneous regression.
  • For intermediate-risk disease, combined modality approach of surgery plus chemotherapy is standard. Chemotherapy is used and can sometimes convert an unresectable tumor to a resectable one. The most commonly used chemotherapeutic agents are cyclophosphamide, displatin, doxorubicin, carboplatin and ifosfamide. Radiotherapy is an adjunct to chemotherapy in specific situations such as with spinal cord compression or in older patients with node positive disease.
  • For high-risk disease aggressive combined modality approaches are typically employed including surgical resection and high-dose chemotherapy with stem-cell rescue as well as radiation therapy.

Outcome

Outcome is dependent on the stage, tumor characteristics and therapy administered. Overall disease free survival for stage 1 and 2 disease is between 75 and 95%. Patents older than 1 year of age with stage 4 disease have a very poor prognosis. The overall cure rate for neuroblastoma is about 55%.

 References

  1. Alexander, F. Neuroblastoma. Urologic Clinics of North America. 2000; 27(3):383-392.
  2. Woods, William G., et al. Screening of infants and mortality due to neuroblastoma. New England Journal of Medicine 346.14 (2002): 1041-1046.
  3. Broecker, B. Non-Wilms Renal Cell Tumors in Children. Urologic Clinics of North America. 2000; 27(3): 463-469.
  4. Maris, John M. Recent advances in neuroblastoma. New England Journal of Medicine 362.23 (2010): 2202-2211.
  5. Maris J. et al  Neuroblastoma.  Lancet 2007 369:2106

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