Neuroblastoma

Neuroblastoma: Excerpt from The 5-Minute Pediatric Consult

Edward F. Attiyeh, MD

Neuroblastoma - BASICS

Neuroblastoma - description

• Neuroblastoma is the most common extracranial solid tumor of childhood and the most common malignancy of infancy.
• It is derived from neural crest cells and can arise anywhere along the sympathetic chain of the peripheral nervous system, most commonly in the adrenal medulla.
• Neuroblastoma has the highest rate of spontaneous regression of any human malignancy; however, in most cases, it is one of the most aggressive cancers of childhood.
• Neuroblastoma should be distinguished from ganglioneuroma and ganglioneuroblastoma, which show features of differentiation or maturation.
• The International Neuroblastoma Staging System (INSS) is the current staging system:
  • Describes localized tumors (stages 1 and 2), more extensive primary tumors (stage 3), and metastatic tumors (stage 4)
  • Stage 4S (“Special”) describes a distinct group of infants <365 days old who have a small primary mass with dissemination limited to the liver, skin, and/or <10% of the bone marrow.
• Risk grouping relies on patient age, tumor stage, MYCN amplification status, Shimada histopathology status, and tumor ploidy. In general:
  • Low-risk groups have localized disease and do not have MYCN amplification.
  • High-risk groups have disseminated disease (often involving the bones, bone marrow, liver, and/or skin) as well as unfavorable biologic characteristics (e.g., MYCN amplification).

Neuroblastoma - epidemiology

• Most children are <5 years of age at diagnosis.
• ~50% of children have disseminated disease at diagnosis.
• Male/Female ratio 1.1:1
• More common in whites
• Most primary tumors are in the abdomen.

Neuroblastoma - prevalence

Neuroblastoma accounts for ~7–10% of all childhood cancers.

Neuroblastoma - incidence

About 800 new cases per year in the US (10 per million children per year)

Neuroblastoma - risk factors

Neuroblastoma - genetics

Neuroblastoma can rarely (~1%) show a genetic predisposition (autosomal dominant with variable penetrance).

Neuroblastoma - pathophysiology

• One of the “small round blue cell” tumors of childhood
• Tumor growth causes mass effect:
  • Nerve/Cord compression
  • Renal artery stenosis
• Bone metastases cause pain: Characteristic involvement of the bony orbit
• Bone marrow metastases may cause cytopenias.
• Amplification of the MYCN proto-oncogene is present in ~20% of tumors.
• There has not been a tumor suppressor gene identified: Many candidate tumor suppressor genes may lie in genomic regions frequently lost in neuroblastomas (e.g., 1p, 3p, and 11q).

Neuroblastoma - etiology

No known etiology or causative environmental exposures.

Neuroblastoma - associated conditions

• Neuroblastoma has been found to occur along with:
  • Neurofibromatosis type I
  • Hirschsprung disease
  • Central congenital hypoventilation syndrome
• This suggests that a dysregulated development of peripheral nervous system may play a role in neuroblastoma initiation.

Neuroblastoma - DIAGNOSIS

Neuroblastoma - signs & symptoms

Presenting signs and symptoms depend on the primary site of the tumor and the degree of dissemination.

Neuroblastoma - history

• General appearance, activity level, appetite:
  • Patients with localized, low-risk disease may be very well-appearing (i.e., tumor is an incidental finding on imaging study).
  • Patient with disseminated, high-risk disease typically appear ill.
• Based on tumor location:
  • Thoracic:
    • Chest pain
    • Cough
    • Respiratory distress
  • Abdominal:
    • Pain
    • Swelling
  • Bone marrow:
    • Fatigue (anemia)

Neuroblastoma - physical exam

• Abdomen:
  • Abdominal mass is usually firm, fixed, irregular, and frequently crosses the midline.
  • Abdominal distention with or without tenderness
  • Signs of bowel obstruction: Anorexia, vomiting, low stool output
  • Hypertension (renal artery compression)
  • Genital and lower extremity edema from obstruction of venous and lymphatic drainage
• Cervical/Thoracic mass (posterior mediastinal):
  • Respiratory distress or stridor with thoracic masses
  • Horner syndrome with cervical or high thoracic masses: Ptosis, myosis, and anhydrosis
  • Superior vena cava syndrome with large mediastinal tumors
• Paraspinal mass:
  • Vertebral body involvement and nerve root compression
  • Bladder and bowel dysfunction, paraplegia, and back pain secondary to spinal cord compression
• Metastatic disease:
  • Liver: Hepatomegaly
  • Bone:
    • With or without bony pain
    • Periorbital ecchymoses
    • Proptosis
  • Bone marrow:
    • Cytopenias
    • Pain from marrow expansion
  • Lymph nodes: Adenopathy
  • General:
    • Fever
    • Irritability
    • Failure to thrive

Neuroblastoma - tests

Neuroblastoma - lab

• CBC: Decreased hemoglobin, platelets, and/or WBC counts may indicate bone marrow involvement.
• Electrolytes, liver function tests, and renal function tests in anticipation of starting chemotherapy
• Urine catecholamine metabolites are typically elevated: Homovanillic acid (HVA) and vanillylmandelic acid (VMA)

Neuroblastoma - imaging

• Imaging study of the suspected primary tumor site (generally an ultrasound or CT scan; MRI may be necessary for paraspinal tumors): Calcification suggests neuroblastoma.
• Metaiodobenzylguanidine (MIBG) scan:
  • MIBG is taken up by 90% of neuroblastomas.
  • Radioisotope-labeled MIBG can detect both bone and soft tissue involvement.
• Bone scan to evaluate for bony metastasis: Only necessary if the tumor is not MIBG-avid

Neuroblastoma - diag proced-surgery

• Tumor biopsy
• Bilateral bone marrow aspirates and biopsies

Neuroblastoma - differencial diagnosis

• Abdominal masses:
  • Wilms tumor
  • Lymphoma
  • Germ-cell tumor
  • Hepatoblastoma
  • Pancreaticoblastoma
• Thoracic masses:
  • Lymphoma (usually non-Hodgkin)
  • Leukemia with bulky disease
  • Germ-cell tumors
• “Small round blue cell tumors”:
  • Non-Hodgkin lymphoma
  • Ewing sarcoma
  • Peripheral primitive neuroectodermal tumors (PNET)
  • Rhabdomyosarcoma

Neuroblastoma - TREATMENT

Neuroblastoma - general measures

Treatment protocols are based on risk classification:

• Patients with low-risk disease, such as stage 1 or 4S with favorable biologic features, may undergo spontaneous regression or only require surgery.
• Patient with intermediate-risk disease receive 2–8 cycles of outpatient chemotherapy.
• Patients with high-risk disease, such as stage 4 or MYCN amplified, receive a combination of surgery, high-dose chemotherapy requiring stem cell rescue, radiation therapy, and biologic response modification therapy.

Neuroblastoma - special therapy

Neuroblastoma - radiotherapy

• Radiation therapy is used for control of local disease or for palliation.
• Total body irradiation may be a component of high-dose therapy prior to stem cell transplant.

Neuroblastoma - medication

• Multiagent chemotherapy typically includes a combination of vincristine, cyclophosphamide, doxorubicin, cisplatin, carboplatin, etoposide (VP-16), and/or topotecan.
• High-dose myeloablative chemotherapy is followed by autologous stem cell transplant.
• 13-cis-retinoic acid induces differentiation of neuroblastoma cells and improves patient survival following stem cell transplant.

Neuroblastoma - surgery

• Total surgical resection at the time of diagnosis may be attempted but not if it would involve significant morbidity.
• Neoadjuvant chemotherapy results in smaller tumors that make a future resection attempt more straightforward.

Neuroblastoma - FOLLOW UP

Referral to a pediatric oncologist is essential before any diagnostic procedures or therapeutic interventions.

Neuroblastoma - prognosis

• Adverse prognostic factors:
  • Age >18 months
  • Advanced stage (especially stage 4 metastatic disease)
  • MYCN amplification (very powerful marker of poor outcome)
  • Unfavorable histology
  • Diploid tumor genome (primarily in infants)
  • Loss of heterozygosity at chromosome arms 1p or 11q
• These factors serve to stratify children at diagnosis as either at low, intermediate, or high risk of relapse. These risk groups predict survival:
  • Low- and intermediate-risk patients have excellent outcomes (>80–90% survival).
  • High-risk patients have poorer outcomes (30–50% survival) despite aggressive therapy.

Neuroblastoma - complications

Paraneoplastic syndromes:

• Vasoactive intestinal peptide (VIP) syndrome:
  • Neuroblastoma may secrete VIP, which causes watery diarrhea, abdominal distention, and electrolyte imbalances.
  • Usually resolves with removal of the tumor
• Opsoclonus-myoclonus-ataxia (2–4%):
  • Associated with chaotic eye movements (dancing eyes) and myoclonic jerks (dancing feet) with or without cerebellar ataxia
  • Up to 80% of patients have long-term neurologic deficits.
  • Likely due to autoimmune effect of antineural antibodies
  • Specific therapy includes high-dose steroids and intravenous immunoglobulin (IVIG).
• Symptoms of catecholamine excess are rare.

Neuroblastoma - patient monitoring

• On therapy:
  • Frequent laboratory evaluations to monitor for effects of chemotherapy:
    • Marrow suppression
    • Organ toxicity
  • Disease re-evaluation prior to surgery or stem cell transplant:
    • Imaging
    • Bone marrow evaluation
• Off therapy:
  • Close follow-up for 2–3 years after completion of therapy for disease recurrence.
    • Imaging of site of primary tumor
    • Urine catecholamine metabolites
  • Late effects of chemotherapy and radiation therapy require close monitoring.

Neuroblastoma - bibliography

1. Attiyeh EF, London WB, Mosse YP, et al. Chromosome 1p and 11q deletions and outcome in neuro-blastoma. N Engl J Med. 2005;353:2243–2253.
2. Brodeur AE, Brodeur GM. Abdominal masses in children: Neuroblastoma, Wilms tumor, and other considerations. Pediatr Rev. 1991;12:196–206.
3. Kuroda T, Saeki M, Honna T, et al. Late complications after surgery in patients with neuroblastoma. J Pediatr Surg. 2006;41(12):2037–2040.
4. Caty MG, Shamberger RC. Abdominal tumors in infancy and childhood. Pediatr Surg. 1993;40:1253–1271.
5. Finklestein JZ. Neuroblastoma: The challenge and the frustration. Hematol Oncol Clin North Am. 1987;1:675–694.
6. Grupp SA, Stern JW, Ross AA, et al. Tandem high dose therapy in rapid sequence for children with high-risk neuroblastoma. J Clin Oncol. 2000;18:2567–2575.
7. Lee KL, Ma JF, Shortliffe LD. Neuroblastoma: Management, recurrence, and follow-up. Urol Clin North Am. 2003;30:881–890.

Neuroblastoma - CODES

Neuroblastoma - icd9

194.0 Malignant neoplasm of adrenal gland

Neuroblastoma - FAQ

• Q: Are siblings of children with neuroblastoma at increased risk for neuroblastoma compared with the general population?
• A: No, except in rare families with a known history of neuroblastoma (<1%).
• Q: Can neuroblastoma spontaneously regress?
• A: Yes; however, this is usually seen only in children younger than 1 year with lower stage disease or in infants with stage 4S disease.
• Q: What are the biggest risks during therapy?
• A: As with all intensive chemotherapy regimens, the risk of infection is high. This is especially true during the autologous stem cell transplant phase.
• Q: What therapy is available to patients who either fail to go into remission or relapse following aggressive therapy?
• A: There is no curative therapy after disease recurrence in neuroblastoma. However, the disease can be controlled with phase 1 or 2 therapies for many years, maintaining a good quality of life for patients.

Book Source Details

• Book Title: The 5-Minute Pediatric Consult
• Author(s): M. William Schwartz MD; et al.
• Year of Publication: 2008
• Copyright Details: The 5-Minute Pediatric Consult, Copyright © 2008 Lippincott Williams & Wilkins.

More About Retinoblastoma

• Back to disease: Retinoblastoma: Introduction
• Next Book Extract About Retinoblastoma: Retinoblastoma (The 5-Minute Pediatric Consult)
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Copyright notice for book excerpts: Copyright © 2008 Lippincott Williams & Wilkins. All rights reserved.

More About This Book: Title: The 5-Minute Pediatric Consult Authors: M. William Schwartz MD; et al. Publisher: Lippincott Williams & Wilkins Copyright: 2008 ISBN: 0-7817-7577-9

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