A. Epidemiology

1. Most common extracranial solid tumor of childhood
2. Accounts for 7% of malignancies in patients <15 years
3. Accounts for ~15% of pediatric oncology deaths
4. Spontaneous regression does occur in ~5% (usually disseminated, Stage IVS)
5. Screening infants at 6 months of age increases detection and reduces mortality [8]
6. Catecholamine screening detected 215 neuroblastoma cases per 1 million births in Japan [8]
7. Long term survival <40% for high risk clinical phenotype
8. Variable presentation

B. Etiology

1. Sympathetic ganglion (adrenal or sympathetic chain) derived tumor
2. Derived from neural crest cells
3. Tumors usually secrete excess catecholamines which can be used for screening [8]
4. Most tumors (65%) occur in abdomen; ~50% of these in the adrenal gland
5. Other common sites are neck, chest, pelvis

C. Genetics

1. Loss of heterozygosity (LOH) or loss of chromosome (chr) 1p36 is predictor of unfavorable outcome [2,3]
2. N-Myc
   1. N-Myc amplification is central to evaluation of risk
   2. N-myc amplification and duplication of chr 17q are unfavorable [3]
   3. Both N-myc and MRP are independent, strong risk factors for poor outcome [4]
   4. N-myc amplification correlates with multidrug resistance protein (MRP) levels [4]
   5. Specific chr 6p22 alleles are associated with N-myc amplifcation and relapse [9]
3. Unbalanced chr 11q LOH associated with poor progression free survival [2]
4. Any gain of function of chr arm 17q is highly unfavorable to outcome [5]
5. Chr 6p22 locus associated with clinically aggressive (metastatic) disease [9]
6. ~1% of patients have family history with unclear chromosomal association
7. TP53 (p53), CDKN2A and ras pathways are intact in most tumors

D. Symptoms

1. Highly variable depending on location of tumor and any paraneoplastic effects
2. Localized Tumors
   1. ~40% present with localized disease
   2. Occur from intra-adrenal mass to growth anywhere along sympathetic (paraspinal) chain
   3. Main symptoms due to local mass effects
   4. Horner's syndrome (ptosis, meiosis, anhidrosis) can occur with cervical chain disease
   5. Paraspinal tumors in thoracic, abdominal and pelvic regions in ~10% of patients
   6. Paraspinal tumors can invade neural foramina causing nerve root or cord compression
3. Nasal Mass [6]
   1. Congestion
   2. Obstruction may be associated with loss of smell, sinusitis
4. Paraneolastic Syndromes
   1. Secretion of vasoactive intestinal polypeptide (VIP) causes gatrointestinal (GI) symptoms
   2. GI symptoms include watery diarrhea, abdominal pain, distension, vomiting
   3. Opsoclonus-myoclonus syndrome (OMS) in ~3% fo neuroblastoma
   4. OMS includes rapid eye movements, ataxia, irregular muscle movements
5. Metastatic Disease
   1. ~50% of patients present with hematogenous metastasis
   2. Typical sites include cortical bone, bone marrow, liver, non-continguous lymph nodes
   3. Particular predisposition to metastasize to bony orbit with periorbital ecchymoses (raccoon eyes), proptosis, or both
   4. Bone marrow replacement with marro insufficiency/failure can occur
   5. Compression of renal artery can lead to hyper-reninemic hypertension
   6. Pheochromocytoma-like symptoms are rare
   7. Stage 4S (S=special) in ~5% of patients, with small localized primary tumors with metastases to skin, liver, or bone marrow, almost always spontaneously regress

1. Radiography
   1. Plain Radiographs: calcification occurs in ~50%
   2. On intravenous pyelogram (IVP), see displaced / deformed kidney
   3. Computerized Tomography (CT) - good at assessing bone invasion, involvement, and evaluation of tumors in abdomen, pelvis or mediastinum
   4. MRI - best overall assessment of tumors in parapsinal area, essential when assessing intra-foraminal (spinal cord) extenesion and potential for compression
   5. MIBG (metaiodobenzylguanidine) scintigraphy is preferred method for assessment of primary tumor and metastatic disease (concentrated in 90% of neuroblastomas)
2. Definitive diagnosis required tissue with defined histopathologic evalation
   1. Stroma rich neuroblastoma - prominent Schwann cells and ganglion cells
   2. Stroma poor neuroblastoma - densely packed small round "blue" cells (prominent nuclei) with scant cytoplasm
   3. Cells positive for tyrosine hydroxylase and other specific markers
3. Bone marrow involvement should be assessed with bilateral bone marrow aspirates, biopsies

F. Staging - INSS System (Panel, Ref [1])

1. Stage 1
   1. Localized tumors with complete gross excision ± microscopic residual disease
   2. Representative ipsilateral non-adherent LN negative for tumor microsopically
2. Stage 2A
   1. Localized tumors with incomplete gross excision
   2. Representative ipsilateral non-adherent LN negative for tumor microsopically
3. Stage 2B
   1. Localized tumors ± negative gross excision
   2. Representative ipsilateral LN positive for tumor
   3. Enlarged contralateral LN should be negative microsopically
4. Stage 3
   1. Unresectable unilateral tumor infiltrating across midline ±LN involvement; OR
   2. Localized unilateral tumor with contralateral regional LN involvement; OR
   3. Midline tumor with bilateral extension by infiltration (unresectable) or LN involvement
5. Stage 4: any primary tumor with dissemination to distant LN, bone, bone marrow, liver, skin or other organs, except as defined in 4S
6. Stage 4S (Special): localized primary tumor in infants <1 year (Stage 1, 2A, or 2B) with dissemination limited to skin, liver or bone marrow with <10% malignant

G. Risk Groups and Survival

1. Depend on Stage and several other parameters
2. Stage 1 are all low risk
3. Stage 2A or 2B
   1. Low risk: non-amplified N-Myc, >50% resection
   2. Intermediate: non-amplified N-Myc, biopsy only or <50% resection
   3. High: amplified N-Myc
4. Stage 3
   1. Intermediate Risk: non-amplified N-Myc with age <365 days or with age >357 days and favorable histology
   2. High Risk: amplified N-Myc or non-amplified N-Myc and unfavorable histology
5. Stage 4
   1. Intermediate Risk: non-amplified N-Myc with age <365 days, or with age >357-547 days and favorable histology
   2. High Risk: all others
6. Stage 4S
   1. Low Risk: age <365, non-amplified N-Myc, favorable histology, asymptomatic
   2. High Risk: amplified N-Myc
   3. Intermediate Risk: all others
7. Prognosis
   1. Low risk ~90% 12 year survival
   2. Intermediate risk ~80% 12 year survival
   3. High risk ~25% 12 year survival

H. Therapy [7]

1. Multi-modality therapy is generally used
2. Extensive, often difficult surgical resection - often delayed after chemotherpay
3. Chemotherapy
   1. Induction combination chemotherapy with cisplatin, etoposide, doxorubicin, vincristine, vincristine
   2. Topotecan and cyclophosphamide for relapsed disease
   3. Intensive chemotherapy + radiotherapy with bone marrow transplantation
   4. Stem cell susually harvested induction therapy in preparation for consolidation
   5. Consolidation is to eliminate any remaining cells after induction
   6. Consolidation usually uses myelablative cytotoxic agents with stem cell rescue
   7. Myeloablation with autologous stem cell rescue improves disease-free intervals
   8. Addition of 13-cis-retinoic acid to high risk patients improves survival following stem cell transplantation [7]
4. Radiation therapy
   1. Usually to primary tumor and various metastatic sites
   2. External beam radiation used in most cases

References

1. Maris JM, Hogarty MD, Bagatell R, Cohn SL. 2007. Lancet. 369(9579):2106
2. Attiyeh EF, London WB, mosse YP, et al. 2005. NEJM. 353(21):2243
3. Caron H, van Sluis P, de Kraker J, et al. 1996. NEJM. 334(4):225
4. Norris MD, Bordow SB, Marshall GM, et al. 1996. NEJM. 334(4):231
5. Bown N, Cotterill S, Lastowska M, et al. 1999. NEJM. 340(25):1954
6. Cunningham MJ, Lin DT, Curry WT Jr., et al. 2007. NEJM. 356(26):2721 (Case Record)
7. Matthay KK, Villablanca JG, Seeger RC, et al. 1999. NEJM. 341(16):1165
8. Hiyama E, Iehara T, Sugimoto T, et al. 2008. Lancet. 371(9619):1173
9. Maris JM, Mosse YP, Bradfield JP, et al. 2008. NEJM. 358(24):2585