Nilay M. Gandhi, MD
Arthur L. Burnett, II, MD, MBA, FACS
BASICS
DESCRIPTION
• Heterogeneous malignancy arising from neural crest elements along the sympathetic chain with a broad spectrum of clinical behavior
• International Neuroblastoma Staging System (INSS) (1)
– Stage 1: Localized tumor, completely excised, ipsilateral lymph nodes (LN) (–)
– Stage 2a: Localized tumor, incompletely excised, ipsilateral LN (–)
– Stage 2b: Localized tumor with/without complete excision, ipsilateral LN (+), enlarged contralateral LN (–)
– Stage 3: Unresectable unilateral tumor crossing midline or localized unilateral tumor with contralateral LN (+)
– Stage 4: Any primary tumor with metastasis to distant LN, bone, liver, skin, or bone marrow
– Stage 4s: Localized primary tumor (stage 1, 2a, 2b) metastasis limited to liver, skin, and/or bone marrow in infant <1 yr
EPIDEMIOLOGY
Incidence
• 3rd most common childhood cancer (after leukemia and brain tumors)
– Most common solid extra-cranial tumor in children
– Most common cancer in infants <1 yr of age
• Comprises 6–10% of all childhood neoplasms
– 1 in 7,000 live births
– 750 new cases/yr
50% incidence in children <2 yr of age (highest incidence in 1st yr of life)
Peak age 0–4 yr (median 18–24 mo)
More common in Caucasian male infants
Prevalence
• 10.5 per 1 million children <15 yr of age
• Accounts for 15% of all pediatric cancer fatalities
RISK FACTORS
• Risk in sibling or offspring is <6%
• Maternal factors:
– Folate deficiency (increased incidence)
– Gestational diabetes mellitus
• Environmental factors implicated but not confirmed (2)
– Paternal exposure to electromagnetic fields
– Prenatal exposure to alcohol, pesticides, or phenobarbital
– Potential relationship with assisted pregnancies
• Genetic factors:
– Increased incidence in Turner’s syndrome
Genetics
• Majority are sporadic
– 1–2% familial (autosomal dominant 20%)
20% bilateral adrenal or multifocal tumors
Germline mutation in ALK gene
• Aneuploidy = favorable prognosis
• N-MYC amplification (20% patients), chromosome
1p deletion (25–35%), loss of 11q
heterozygosity (35–45%) = adverse prognosis
PATHOPHYSIOLOGY
• Determined by tumor site origin, metastasis, and presence of paraneoplastic syndromes
• Likely failure of persistent primitive ganglion cells to respond to normal signals
• Spinal cord, sympathetic ganglia involvement:
– Urinary retention, constipation, extremity paresis, Horner syndrome
• Presence of metastasis:
– Fever, lethargy, weight loss, bony pain, pallor
• Bone metastasis (older children)
• Liver metastasis (younger children)
• Active biochemical products:
– 90% produce catecholamines
Paroxysmal hypertension (HTN), palpitation, flushing, headache
– Homovanillic acid (HVA) in poorly differentiated tumors
– Vanillylmandelic acid (VMA) in well-differentiated tumors
ASSOCIATED CONDITIONS
• Other disorders of neural crest derived cells
– Hirschsprung disease
– Neurofibromatosis type 1
– Congenital central hypoventilation syndrome
GENERAL PREVENTION
• Screening with urinary catecholamines is not effective (Japan, Canada, Germany)
– Increased diagnosis, no impact on survival
– Majority low-grade, spontaneously resolve
• Genetic counseling indicated if family history
DIAGNOSIS
HISTORY
• Early satiety, poor appetite, vomiting
– Possible partial bowel obstruction due to intra-abdominal mass
• Unexplained weight loss, anorexia, fever, pallor, irritability suggests metastatic disease
• Urinary frequency/retention, constipation:
– Extrinsic compression of pelvic organs/nerves from presacral mass
• Poor truncal balance, jerky muscle movements, or uncontrolled eye movement
– Acute myoclonic encephalopathy (2%)
Toxic byproducts/autoimmune phenomenon
• Extremity weakness, sensory deficits
– Paravertebral tumor compressing spinal cord
• Pain in skull and long bones from metastasis
• Pallor/anemia (bone marrow involvement in 50% of patients)
• Bleeding diathesis (from liver metastasis)
• Paroxysmal HTN, sweating, headaches, palpitations
– <5% patients (catecholamines sequestered within intracellular vacuoles)
• Watery diarrhea, hypokalemia due to VIP secretion
PHYSICAL EXAM
• Abdominal mass
– 65% retroperitoneal, 40% adrenal
• HTN (rare, due to catecholamine release)
• Metastasis present in 70% at diagnosis
– Raccoon’s eyes
Upper eyelid hemorrhage (periorbital metastasis)
– Bluish/erythematous subcutaneous nodules
Skin metastasis, “blueberry-muffin” spots
• Acute myoclonic encephalopathy
– Rapid eye movements (opsoclonus), jerky extremities (myoclonus)
– Cerebellar ataxia, dysphasia, intellectual deficit
– Autoimmune phenomenon
– 70–80% with prolonged neurologic impairment (ACTH/steroid therapy)
• Unilateral Horner’s syndrome
– Ptosis, loss of papillary dilation, unilateral anhydrosis
– Tumor compression on sympathetic ganglia
• Extremity paresis, sensory deficits
– Paravertebral tumor compressing spinal cord
DIAGNOSTIC TESTS & INTERPRETATION
Lab
• 24-hr urinary VMA and HVA
– Elevated in 90–95% of patients
• CBC: Anemia suggests bone marrow involvement
• PT/PTT: Elevation suggests liver involvement
• Ferritin: Elevation in advanced disease
– 40–50% of patients (must be >3 standard deviations)
Imaging
• Ultrasound (1st choice for children with palpable abdominal mass)
• Whole-body CT
– Evaluate primary tumor, regional extent, distant metastasis
– Intratumoral calcification and/or vascular encasement distinguishes from Wilms tumor
• Whole-body MRI
– Evaluate intraspinal tumor extension, delineate major vessels
• Bone scan (radionuclide, not skelet al)
• Iodine123 MIBG
– Determine extent of disease, assess tumor recurrence
Diagnostic Procedures/Surgery
• Open/laparoscopic biopsy for pathologic tissue diagnosis
• Bone marrow aspirate/biopsy
– 2 marrow aspirates (bilateral iliac crests) + 2 core biopsies recommended
– 70% positive aspirates
Future research into neuroblastoma-specific immunocytology of marrow aspirates
Pathologic Findings
• Gross: Solid/cystic vascular, poorly encapsulated purple mass
• Histology:
– Small round blue cells
Mitosis-Karyorrhexis index is prognostic
– Homer–Wright pseudorosettes
• Histopathologic markers:
– N-MYC
– DNA ploidy
– Shimada classification (stroma poor/rich)
Stroma-poor (based on age, histologic maturation, mitotic rate)
Stroma-rich (nodular, intermixed, well differentiated)
• Neuron-specific enolase (NSE) staining is specific for neuroblastoma
• Periodic acid-Schiff (PAS) staining can distinguish sarcomas
DIFFERENTIAL DIAGNOSIS
• Ganglioneuroma (benign form)
• Ganglioneuroblastoma (intermediary between ganglioneuroma and neuroblastoma)
• Intra-abdominal mass in childhood:
– Wilms tumor
– Pheochromocytoma
– Rhabdomyosarcoma
– Lymphoma
– Teratoma
– Ewing sarcoma
– Rare primary neoplasms of liver and pancreas
TREATMENT
GENERAL MEASURES
• Multimodal treatment approach involving surgery, chemotherapy, radiotherapy, and/or bone marrow or stem cell transplantation
• Nearly all stage 4s patients spontaneously resolve (observation)
• INSS surgical stage and more recently the International Neuroblastoma Risk Group (INRG) pretreatment system dictates treatment (3)
MEDICATION
First Line (4)
• Low risk: None unless surgical failure
– Cyclophosphamide, Adriamycin, and Cisplatin/VM-26 in low-dose cycles
• Intermediate risk: Induction with Cyclophosphamide and Adriamycin with or without radiotherapy
• High risk: Cyclophosphamide, Adriamycin, VM-26, Doxorubicin, Cisplatin, Etoposide in various combinations
Second Line
• Intermediate risk: Cisplatin/VM-26
• High risk: Alternative use of above-listed combinations
SURGERY/OTHER PROCEDURES
• Low risk (stages 1, 2, or 4s with age <1 yr or >1 yr with favorable pathology):
– Surgery is curative
– Chemotherapy indicated if recurrence, N-MYC amplification, or unfavorable histology
• Intermediate risk (stage 3 age <1 yr or >1 yr with favorable pathology, or stage 4 <1 yr):
– Surgery + multiagent chemotherapy
• High risk (stage 2 with age >1 yr with unfavorable histopathology, or stage 3, 4, 4s with N-MYC amplification regardless of age):
– Intensive chemotherapy with or without bone marrow ablation and repeated surgery
ADDITIONAL TREATMENT
Radiation Therapy
• Reserved for primary or secondary chemotherapy failures in low-risk patients
• Utilized for local control in bulky stage 3 or advanced stage 4
– Avoid if spinal cord compression due to adverse effects on spine growth
• Intraoperative radiation therapy not better than external beam irradiation
Additional Therapies
Bone marrow transplantation
Complementary & Alternative Therapies (5)
• 13-cis-retinoic acid improves 5-yr overall survival (OS) in children with advanced stage disease after transplantation or intensive chemotherapy
• Iodine131 MIBG targeted delivery for metastatic disease
• Anti-GD2 antibodies (research pending)
ONGOING CARE
PROGNOSIS
• Dependent on risk status
– Low risk: Resection is curative, 97% 5-yr OS
– Intermediate risk: neoadjuvant chemo followed by >50% resection, 70–90% 5-yr OS
– High risk: Neoadjuvant chemo 4 cycles (restage after 2 cycles), >50% resection, radiation, peripheral stem cell transplant, monoclonal Ab, 20–40% 5-yr OS
• Better survival in nonadrenal primary tumors
• Shimada classification
– Stroma-poor: <10% survival
COMPLICATIONS
• Dumbbell neuroblastoma with spinal cord compression
– Best treated with chemotherapy
– Neurosurgical intervention only for emergent decompression
• Associated with tumor presentation and with treatment modalities
FOLLOW-UP
Patient Monitoring
• Low risk:
– Imaging + lab markers 1–2 mo after therapy, every 6 mo for 5 yr, then annually after 5 yr
• Intermediate risk:
– Imaging + lab markers 1–2 mo after therapy, every 1–3 mo for 1st yr, then every 4–6 mo for 2–5 yr, then annually after 5 yr
• High risk:
– Imaging + lab markers 1–2 mo after therapy, every 1–3 mo for 5 yr, every 6 mo after 5 yr
Patient Resources
• National Cancer Institute (http://www.cancer.gov/cancertopics/types/neuroblastoma)
• National Cancer Comprehensive Network
(http://www.nccn.com/living-with-cancer/265-neuroblastoma.html)
REFERENCES
1. Brodeur GM, Seeger RC, Barrett A. International criteria for diagnosis, staging, and response to treatment in patients with neuroblastoma. J Clin Oncol. 1988;6(12):1874–1881.
2. Park JR, Eggert A, Caron H. Neuroblastoma: Biology, prognosis, and treatment. Pediatr Clin North Am. 2008;55(1):97–120.
3. Montclair T, Brodeur GM, Ambros PF, et al. The International Neuroblastoma Risk Group (INRG) staging system: An INRG Task Force report. J Clin Oncol. 2009;27(2):298–303.
4. Maris JM. Recent advances in neuroblastoma. NEJM. 2010;362:2201–2211.
5. Wagner LM, Danks MK. New therapeutic targets for the treatment of neuroblastoma. J Cell Biochem. 2009;107(1):46–57.
ADDITIONAL READING
• Matthay KK, George RE, Yu AL. Promising therapeutic targets in neuroblastoma. Clin Cancer Res. 2012;18(10):2740–2753.
• Wylie L, Philpott A. Neuroblastoma progress on many fronts: The neuroblastoma research symposium. Pediatr Blood Cancer. 2012;58(4):649–651.
See Also (Topic, Algorithm, Media)
• Abdominal mass, newborn/child, urologic considerations
• Neuroblastoma Image 
• Pheochromocytoma
• Wilms tumor (nephroblastoma)
CODES
ICD9
• 194.0 Malignant neoplasm of adrenal gland
• 197.7 Malignant neoplasm of liver, secondary
• 198.5 Secondary malignant neoplasm of bone and bone marrow
ICD10
• C74.90 Malignant neoplasm of unsp part of unspecified adrenal gland
• C78.7 Secondary malig neoplasm of liver and intrahepatic bile duct
• C79.52 Secondary malignant neoplasm of bone marrow
CLINICAL/SURGICAL PEARLS
• Most common malignancy in infants <1 yr.
• INSS stage determines optimum treatment modality.
• Urine HVA and VMA are diagnostic.
• N-MYC associated with poor prognosis.
• Neuroblastoma requires a minimum of 5-yr follow-up.