Health is Wealth

Lab studies
• General laboratory studies should be routinely obtained in children suspected of having neuroblastoma.
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o A CBC count should be obtained to determine if the child has anemia, which typically does not occur until the tumor has become widely disseminated.
o Once dissemination occurs, abnormalities in findings of coagulation studies (prothrombin time [PT], activated partial thromboplastin time [aPTT]) may secondary to liver involvement. Thrombocytopenia due to overwhelming bone marrow involvement may also be present.
o The erythrocyte sedimentation rate, a nonspecific acute-phase reactant, is elevated in classic neuroblastoma.
• Specific laboratory studies should be obtained when the diagnosis of neuroblastoma is considered.
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o Metabolic tumor by-products are useful as diagnostic inclusion criteria for detecting neuroblastoma.
o Elevated metabolic catecholamine by-products can be detected in the urine of patients with neuroblastoma.
o Phenylalanine and tyrosine are catecholamine precursors, which are converted through a sequence of enzymatic events to dihydroxyphenylalanine (DOPA), dopamine, norepinephrine, and epinephrine.
o DOPA and dopamine are metabolized into their final product, homovanillic acid (HVA), while norepinephrine and epinephrine are metabolized into vanillylmandelic acid (VMA).
o Ninety percent of neuroblastoma tumors secrete these by-products. This fact becomes clinically relevant because children with dedifferentiated tumors excrete higher levels of HVA than VMA. This occurs because dedifferentiated tumors have lost the final enzymatic pathway that converts HVA to VMA. A low VMA-to-HVA ratio is consistent with a poorly differentiated tumor and indicative of a poor prognosis.
o Neuroblastoma cells lack the enzyme that converts norepinephrine to epinephrine. Despite this fact, elevated levels of norepinephrine are not identified in the serum of patients with neuroblastoma. This might be explained by at least 2 processes—(1) norepinephrine may be catabolized within the tumor; or (2) tyrosine hydrolase, the initial enzyme in catecholamine synthesis, is subject to a negative feedback loop by norepinephrine. For either or both reasons, norepinephrine does not reach detectable serum levels.
o A LaBrosse VMA spot test may be used to screen patients in certain institutions. It is economical but has low sensitivity and specificity.
o High-performance liquid chromatography has a much lower false-positive rate and is more sensitive than the LaBrosse VMA spot test, but its only drawback is that it is more expensive and is therefore often used only to confirm a positive result on spot test.
• Nonspecific tumor markers can be identified in patients with neuroblastoma.
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o Neuron-specific enolase (NSE), lactic dehydrogenase (LDH), and ferritin are markers useful in the identification of active disease, as well as in prognostication.
o Approximately 96% of patients with metastatic neuroblastomas demonstrate an elevated NSE level, which has been associated with a poor prognosis.

Imaging studies
Radiographic assessment is recommended in all infants and children with an abdominal mass. The standard diagnostic imaging modalities include plain abdominal radiography (kidneys, ureters, bladder [KUB]), renal/bladder ultrasonography, bone scintigraphy, and CT scanning or MRI.
• KUB most commonly reveals finely stippled calcifications of the abdomen or posterior mediastinum.
• Renal/bladder ultrasonography improves the diagnostic evaluation and is probably the single best imaging modality to obtain. Ultrasonography is noninvasive and provides relevant information regarding the laterality, consistency, and size of the mass.
• Abdominal CT scanning or MRI usually follows ultrasonography. Both of these studies are more invasive, in that they require general sedation for young children. The benefit is that they enhance the ultrasonographic findings by providing information about regional lymph nodes, vessel invasion, and distant metastatic disease.
• Bone scintigraphy and a skeletal survey to detect cortical bone disease are helpful in the diagnosis of neuroblastoma. Metaiodobenzylguanidine (MIBG) is a compound taken up by catecholaminergic cells that competes for uptake even in neuroblastoma cells. In this way, MIBG is quite sensitive and specific in the detection of metastasis to bones and soft tissue, with highest sensitivity (91-97%) in the detection of bone deposits. Bone scintigraphy using 99Tc diphosphonate and a skeletal bone survey to detect cortical bone disease are essential if MIBG scintigraphy results are negative in the bone. MIBG is recommended for re-assessment both during and after therapy in high-risk patients with MIBG-avid disease at diagnosis.
• Expression of somatostatin (SS) receptors has been described in neuroblastoma cell lines and tumors. Studies have shown that these tumors can be successfully targeted with radioactive SS analogs as a method of detection. Currently, the indication for radio-labeled SS analog in children with neuroblastoma is not well-defined because this method is less sensitive than MIBG scan (64% vs 94%). However, because neuroblastoma SS receptors are associated with favorable clinical and biological prognostic factors, radio-labeled SS analog could provide valuable information. In fact, improved survival has been found in patients with SS receptor–positive neuroblastoma. However, more studies need to be performed to confirm the benefits of SS receptor scanning.