eMedicine Specialties > Urology > Cancer, Wilms Tumor and Neuroblastoma

Neuroblastoma: Workup

Author: Byron D Joyner, MD, Associate Professor, Department of Urology, University of Washington School of Medicine; Consulting Staff, Program Director, Department of Surgery, Division of Pediatric Urology, Children's Hospital and Regional Medical Center
Coauthor(s): Natalya Lopushnyan, Yale University School of Medicine
Contributor Information and Disclosures

Updated: Dec 4, 2007

Workup

Laboratory Studies

• General laboratory studies should be routinely obtained in children suspected of having neuroblastoma.
  • 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.
  • 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.
  • 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.
  • Metabolic tumor by-products are useful as diagnostic inclusion criteria for detecting neuroblastoma.
  • Elevated metabolic catecholamine by-products can be detected in the urine of patients with neuroblastoma.
  • Phenylalanine and tyrosine are catecholamine precursors, which are converted through a sequence of enzymatic events to dihydroxyphenylalanine (DOPA), dopamine, norepinephrine, and epinephrine.
  • DOPA and dopamine are metabolized into their final product, homovanillic acid (HVA), while norepinephrine and epinephrine are metabolized into vanillylmandelic acid (VMA).
  • 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.
  • 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.
  • A LaBrosse VMA spot test may be used to screen patients in certain institutions. It is economical but has low sensitivity and specificity.
  • 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.
  • Neuron-specific enolase (NSE), lactic dehydrogenase (LDH), and ferritin are markers useful in the identification of active disease, as well as in prognostication.
  • 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.

Diagnostic Procedures

• The biopsy is the sine qua non in the diagnostic evaluation of neuroblastoma. To confirm the diagnosis of neuroblastoma, histologic evidence of neural origin or differentiation is required. Samples of tumor tissue can be viewed via light or electron microscopy or via immunohistochemistry. Another option is to sample bone marrow, a frequent metastatic site for neuroblastoma.
• The literature is confusing in terms of the number of bone marrow aspirates or biopsies needed to diagnose neuroblastoma. Recently, an international committee on neuroblastoma staging recommended obtaining 2 bone marrow aspirates and 2 biopsies, 1 from each posterior iliac crest.
• The issue of biopsies might become obsolete because immunocytology of marrow aspirates may offer the single best source of diagnostic information. Recently, a large body of published work has addressed the use of immunocytochemical and polymerase chain reaction (PCR)–based technologies to detect neuroblastoma cells and neuroblastoma-specific transcripts such as tyrosine hydroxylase and disialoganglioside (GD2) synthase in marrow or blood samples. This method is used to assess minimal disease during the course of treatment. Although these techniques can greatly increase sensitivity, whether this increased sensitivity provides prognostic information about the likelihood of relapse is still unclear.

Histologic Findings

The 3 distinct histologic patterns of the neurocristopathies include neuroblastoma, ganglioneuroblastoma, and ganglioneuroma. They represent a spectrum of maturation and dedifferentiation. The typical neuroblastoma is characterized by small uniform cells that contain dense hyperchromatic nuclei and scant cytoplasm. A neuritic process called neuropil is pathognomonic of all except the most primitive neuroblastoma. Homer-Wright pseudorosettes are clusters of neuroblasts surrounding areas of eosinophilic neuropil and are observed in 15-50% of patients. If identified, they are diagnostic of neuroblastoma.

The minimal diagnostic criteria for diagnosing neuroblastoma have been established by an international group of conferees and corresponding participants. These criteria include (1) unequivocal pathologic diagnosis or (2) unequivocal bone marrow (syncytia) and elevated levels of urinary catecholamine metabolic by-products. Both of these diagnostic criteria require a histopathologic diagnosis.

Staging

At least 6 different staging systems for neuroblastoma exist. Historically, each staging system represents a temporal improvement in the understanding of the tumor. However, the presence of so many systems has not only confounded the literature but also complicated the comparison of studies between institutions. Twenty years ago, the International Neuroblastoma Staging System (INSS) was established to provide a uniform staging system.

The INSS is a clinical, radiographic, and surgical appraisal of children with neuroblastoma. The system combines many of the most important diagnostic criteria from each of the staging systems and includes initial distribution and surgical resectability of the tumor. Arabic numerals are used to distinguish this staging system from other systems.

• Stage 1 is characterized by a localized tumor with complete gross excision, with or without microscopic residual disease. Representative ipsilateral lymph nodes that test negative for tumor are present microscopically (nodes attached to and removed with the primary tumor may test positive).
• Stage 2A is characterized by a localized tumor with incomplete gross excision; representative ipsilateral nonadherent lymph nodes that test negative for tumor are present microscopically.
• Stage 2B is characterized by a localized tumor with or without complete gross excision, with ipsilateral nonadherent lymph nodes that test positive for tumor. Enlarged contralateral lymph nodes must test negative microscopically.
• Stage 3 is an unresectable unilateral tumor infiltrating across the midline, with or without regional lymph node involvement; a localized unilateral tumor with contralateral regional lymph node involvement; or a midline tumor with bilateral extension by infiltration (unresectable) or by lymph node involvement. The midline is defined as the vertebral column. Tumors that originate on one side and cross the midline must infiltrate to or beyond the opposite side of the vertebral column.
• Stage 4 is any primary tumor disseminated to distant lymph nodes, bone, bone marrow, liver, skin, and/or other organs (except as defined for stage 4S).
• Stage 4S (S = special)
  • Stage 4S is characterized by a localized primary tumor (as defined for stage 1, 2A, or 2B), with dissemination limited to skin, liver, and/or bone marrow (limited to infants aged <1 y).
  • Marrow involvement should be minimal (ie, <10% of total nucleated cells identified as malignant via bone biopsy or bone marrow aspirate).
  • More extensive bone marrow involvement is considered stage 4 disease.
  • The results of the MIBG scan (if performed) should be negative for disease in the bone marrow.
  • Stage 4S is the most unusual group, comprising approximately 5% of patients with neuroblastoma.
  • This stage occurs in infants younger than 12 months and is characterized by hepatomegaly, subcutaneous nodules, and a positive result on bone marrow biopsy.
  • Everything else being equal, these children would normally be classified as having stage 1 or 2 disease; however, disease in this special group of infants almost always spontaneously regresses. Nonetheless, infants younger than 2 months frequently develop extensive and rapidly progressive intrahepatic expansion of neuroblastoma that can result in respiratory compromise.
  • The 5-year survival rate in patients with stage-4S disease is 75%.

According to the INSS, the neuroblastoma can be diagnosed based on either (1) characteristic histopathologic findings of tumor or presence of tumor cells in a bone marrow aspirate or biopsy sample or (2) elevated urinary catecholamine levels.

Specific requirements to stage neuroblastoma include (1) bone marrow aspirates and biopsy samples, (2) body CT scan (excluding head, if not clinically indicated), (3) bone scan, and (4) MIBG scintigraphy.

Stage for stage, infants with neuroblastoma have a better prognosis than older children. In fact, statistically, age is the most significant clinical prognosticator for neuroblastoma. Forty percent of infants (<1 y) have localized neuroblastoma, compared with 20% of children older than 1 year. Additionally, nearly 70% of children older than 1 year have disseminated neuroblastoma, compared with less than 25% of infants.

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