At a Glance

Neuroblastoma is a malignant tumor of post ganglionic sympathetic neurons that presents in children, usually before 3 years of age, and is the second most common solid tumor of childhood (after brain tumors). It results in the over production of catecholamines, but hypertension or signs of increased sympathetic activity are uncommon. Most neuroblastomas present with mass effects, depending on the location of the primary or metastatic tumors.

The abdomen is the most common primary site of neuroblastomas, either in the adrenal gland or upper abdomen, but tumors can also present in the chest, neck, or pelvic region and possibly in the central nervous system or other parts of the sympathetic autonomic system. Metastases can be widespread, involving the bone marrow, bone, lymph nodes, liver, skin, testis, intracranium, or orbits.

Neuroblastomas are well known for the ability to regress or mature into benign tumors but are potentially aggressive malignancies resisting multiple therapies.

Continue Reading

Classic signs and symptoms encompass mass, systemic, paraneoplastic, and secretory effects and include:

abdominal mass with pain, constipation, or urinary obstruction

proptosis, periorbital ecchymosis (raccoon eyes), or Horner syndrome due to mass effects

back pain or spinal mass, weakness, scoliosis, bone pain with anemia or hematopoietic changes as a sign of marrow involvement

thoracic or liver involvement with respiratory symptoms

skin papules or nontender nodules that blanch with a surrounding halo on pressure

fever, weight loss, and irritability as systemic signs

secretory diarrhea from production of vasoactive intestinal polypeptide (VIP), a paraneoplastic syndrome

opsoclonus myoclonus ataxia, also a paraneoplastic syndrome

heterochromia iridis (varying colors of the iris)

hypertension from catecholamine production

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

Urinary vanillylmandelic acid (VMA) or homovanillic acid (HVA), either in 24-hour or random collections with creatinine measurement as a reference, are the mainstay biochemical screening tests. However, normal values do not rule out the diagnosis and a single positive test does not confirm the diagnosis. Other disorders that cause elevated catecholamines may affect the tests and small or early tumors may have normal results.

Urine VMA and HVA reference ranges are age dependent, so the performing laboratory’s ranges must be consulted for interpretation.

Supplementary tests to confirm a diagnosis or provide additional evidence for equivocal results and a high clinical suspicion are subsequently listed. Urine catecholamine testing may also be considered a mainstay test by some.

Urine VMA and HVA can also be used to follow patients with known neuroblastoma for response to treatment or recurrences.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

For urine HVA or VMA results, L-Dopa taken less than 24 hours before testing may elevate results and increased values may be seen with other neural crest tumors, including pheochromocytoma or in nonspecific conditions causing elevated catecholamines. Elevated VMA results may also be seen with hypertension.

What Lab Results Are Absolutely Confirmatory?

Diagnostic criteria include:

definitive tissue diagnosis based on usual light microscopy and with possible electron microscopy or immunohistochemical studies

increased urine or serum catecholamines or their metabolites, usually combined measurement of urinary VMA and HVA and metastatic lesions confirmed by tissue diagnosis or biochemical testing

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

Several auxiliary or adjunct tests may be performed if the urine VMA and HVA tests are normal or equivocal.

Urine (random or 24-hour) free/fractionated catecholamines or plasma free/fractionated catecholamines can be performed. A disproportionate elevation of one or more catecholamines, especially dopamine, supports the diagnosis of neuroblastoma.

Chromogranin A may provide supporting evidence of a tumor or assist in monitoring treated patients.

Neuron-specific enolase (NSE) levels may be high and correlate with tumor mass or metabolic activity. Elevated levels may support the diagnosis of suspected neuroblastoma or help in monitoring treated patients.

Additional follow-up tests to help stratify tumor risk factors for progression are available and include genetic testing, such as MYCN oncogene amplification by fluorescence in situ hybridization(FISH) or DNA analysis, cytogenetic tests, or gene sequencing to correlate with patterns of risk and outcome. These tests are available at reference labs but may not be U.S. Food and Drug Administration (FDA) approved.

Ferritin and lactate dehydrogenase (LDH) levels that decline have been followed to document good response to treatment.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

Catecholamine tests can be affected by many factors. The laboratory performing the test for specific factors should be consulted, but the following should be considered:

Environmental or patient conditions leading to increased levels, such as temperature, noise, postural changes, stresses, hypertension, hypotension, decreased blood volume (e.g., diuretics), hypoglycemia, exercise, or stress of venipuncture, should be considered.

Reference values depend on age and, for plasma, whether the patient was supine or standing when the specimen was taken.

Recent nicotine exposure or caffeine intake may elevate results.

Drugs, such as some antidepressants and cocaine, drug or alcohol withdrawal, and other drugs that might be metabolized to catecholamines should be considered.

Many other drugs might interfere with specific methods, so the laboratory should be consulted.

Plasma catecholamines are labile, so specimen procurement and handling should follow strict guidelines.

Chromogranin A assays can be affected by drugs, such as proton pump inhibitors (e.g., omeprazole) that stimulate neuroendocrine secretion, so those drugs should be discontinued before testing. Hepatic metabolism and renal excretion affect chromogranin A disposition, so liver and renal dysfunction may have altered levels. The assays are immunometric, so many factors can affect them, including cross reactions with heterophile antibodies, the “hook effect,” and standardization of results. One should consult with the performing laboratory for questions.

NSE is also an immunometric assay, so it can have the variables previously noted for chromogranin A. For each test, the same laboratory should be used for trending, so results are comparable. Hemolysis, proton pump inhibitors, and liver and renal failure can also affect results. All results must be considered in clinical context.