In its early stages, neuroblastoma can be readily cured with surgery; in some circumstances, it can spontaneously regress or mature to a benign ganglioneuroma.
In the more common advanced stages, it frustrates clinicians and it is frequently a progressive and relentless disease (11).
NATURAL HISTORY
Neuroblastoma, along with ganglioneuroma and ganglioneuroblastoma, may arise initially from any site along the sympathetic nervous system.
The most common site of origin is the adrenal medulla (30% to 40%) or the paraspinal ganglia in the abdomen or pelvis (25%).
Thoracic (15%) and head-and-neck primary tumors (5%) are slightly more common in infants than in older children.
More than 70% of patients with neuroblastoma have metastatic disease at presentation; the most frequent sites are the lymph nodes, bone, bone marrow, skin (or subcutaneous tissues), and liver.
The lung and central nervous system are rarely sites of metastatic involvement (11).
CLINICAL PRESENTATION
Pain is the most common presenting symptom, frequently due to bone, liver, or bone marrow metastases or local visceral invasion by the primary tumor.
Other symptoms may include weight loss, anorexia, malaise, and fever.
Respiratory distress may accompany massive hepatomegaly, especially in infants with stage IV-S disease.
Horner’s syndrome can accompany a primary tumor originating in the neck.
Spinal cord compression with paralysis of the lower extremities can accompany the so-called dumbbell-shaped tumor that extends from its origin along the sympathetic ganglia through the adjacent neural foramina.
Orbital metastases cause proptosis and ecchymosis.
DIAGNOSTIC WORKUP
The diagnosis of neuroblastoma must be established by pathologic evaluation.
Tumor tissue may be obtained from the suspected primary tumor site or involved lymph nodes, by excision (if the tumor is resectable) or incisional biopsy.
Bone marrow aspirate and biopsy frequently show metastatic tumor deposits that can establish the diagnosis.
Pathologic evaluation of bone marrow is a requirement for staging. Neuroblastoma in bone marrow appears in clumps and pseudorosettes, but the absence of pseudorosettes does not eliminate the possibility of neuroblastoma (11).
Laboratory studies include measurement of urinary catecholamines and their metabolites; either homovanillic acid or vanillylmandelic acid (metabolites of dopa/norepinephrine and epinephrine, respectively) is elevated in more than 90% of patients with stage 4 neuroblastoma.
A vanillylmandelic acid/homovanillic acid ratio exceeding 1.5 is associated with a favorable prognosis in patients with metastatic neuroblastoma.
Anemia secondary to bone marrow involvement can be evaluated with a complete blood count.
Serum ferritin, lactate dehydrogenase, and other liver functions should be assayed routinely.
Imaging studies assist in staging and planning an approach to therapy. The specific imaging workup depends on the location of the primary tumor.
Neck and chest tumors can be easily evaluated by computed tomography (CT).
Abdominal or pelvic masses are often initially evaluated by abdominal ultrasound or CT.
Unlike Wilms’tumor, which originates from the kidney and causes calyceal distortion, neuroblastoma often displaces a normal kidney inferiorly and laterally. X-ray studies show intrinsic speckled calcifications in 85% of neuroblastomas.
CT of the abdomen with intravenous contrast is more sensitive than intravenous pyelogram and provides more information about lymph node or hepatic metastases and tumor resectability.
Magnetic resonance imaging (MRI) scans are replacing the routine use of CT in evaluation of suspicious thoracic or abdominal masses. Although MRI cannot demonstrate intratumoral calcifications, it allows better evaluation of blood vessel encasement, intraspinal extension (dumbbell tumors), diffuse hepatic replacement, and bone marrow involvement (11). Each of these findings improves staging accuracy and facilitates the decision-making process regarding appropriate surgical interventions (25).
A Radiology Diagnostic Oncology Group study is evaluating the merits of various imaging studies in the workup and follow-up evaluation of neuroblastoma (24). Radionuclide bone scans are helpful in determining the extent of metastatic disease because neuroblastoma has a predilection for bony metastases.
Metaiodobenzylguanidine (MIBG) is concentrated by neurosecretory granules of both normal and neoplastic tissues of neural crest origin. MIBG labeled with either131I or123I has a sensitivity of 85% to 90% and specificity of nearly 95% in the detection of metastatic neuroblastoma (20).
The long-acting somatostatin analog octreotide, labeled with123I, has been used to image neuroblastoma, with a sensitivity comparable to that of131I MIBG (17).The expression of somatostatin receptors by neuroblastoma tissues is a favorable prognostic factor.
STAGING
The most commonly used staging system is the International Neuroblastoma Staging System (INSS), initially published in 1988. It is based on clinical, radiographic, and surgical findings (1).
The INSS integrates many of the concepts of previous staging systems promoted by the Children’s Cancer Group and Pediatric Oncology Group (POG) (17) and unifies them into a single system (Table 47-1).
TABLE 47-1 Neuroblastoma Staging Systems
Evans and D’Angio
Pediatric Oncology Group
International Staging System
Stage
Stage A
Stage 1
Tumor confined to the organ or structure of origin.
Complete gross resection of primary tumor, with or without microscopic residual. Intracavitary lymph nodes, not adhered to and removed with primary (nodes adhered to or within tumor resection may be positive for tumor without upstaging patient to stage C), histologically free of tumor. If primary is in abdomen or pelvis, liver histologically free of tumor.
Localized tumor with complete gross excision, without microscopic residual disease; representative ipsilateral lymph nodes negative for tumor microscopically (nodes attached to and removed with the primary tumor may be positive).
Stage II
Stage B
Stage 2A
Tumor extending in continuity beyond the organ midline. Regional lymph nodes on the ipsilateral side may be involved.
Grossly unresected primary tumor. Nodes and liver same as stage A.
Localized tumor with incomplete gross excision; representative ipsilateral nonadherent lymph nodes negative for tumor microscopically.
Stage III
Stage C
Stage 2B
Tumor extending in continuity beyond the midline. Regional lymph nodes may be involved bilaterally.
Complete or incomplete resection of primary. Intracavitary nodes not adhered to primary histologically positive for tumor. Liver as in stage A.
Localized tumor with or without complete gross excision, with ipsilateral nonadherent lymph nodes positive for tumor. Enlarged contralateral lymph nodes must be negative microscopically.
Stage IV
Stage D
Stage 3
Remote disease involving the skeleton, bone marrow, soft tissue, and distant lymph node groups, etc. (see stage IV-S).
Any dissemination of disease beyond intracavitary nodes (i.e., extracavitary nodes, liver, skin, bone marrow, bone).
Unresectable unilateral tumor infiltrating across the midlinea, with or without regional lymph node involvement; or localized unilateral tumor with contralateral regional lymph node involvement; or midline tumor with bilateral extension by infiltration (unresectable) or by lymph node involvement.
Stage IV-S
Stage DS
Stage 4
Patients who would otherwise be stage I or II, but who have remote disease confined to liver, skin, or bone marrow (without radiographic evidence of bone metastases on complete skeletal survey).
Infants <1 year of age with stage IV-S disease (see Evans and D’Angio)
Any primary tumor with dissemination to distant lymph nodes, bone, bone marrow, liver, skin, and/or other organs (except as defined for stage 4S).
Stage 4S
Localized primary tumor as defined for stages 1, 2A, or 2B with dissemination limited to skin, liver, and/or bone marrowb (limited to infants <1 year of age).
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