Basics
Description
- Neuroblastoma is a "small round blue cell tumor " of childhood which arises from developing neural crest cells in the sympathetic nervous system.
- The clinical behavior of neuroblastoma is amazingly diverse. Some tumors undergo maturation into benign ganglioneuroma or even spontaneously regress without therapy, whereas others inexorably progress despite intensive treatment.
- Behavior of neuroblastoma tumors can often be predicted by combining clinical features (age, stage) with pathologic/molecular features (histologic characteristics, tumor ploidy, MYCN amplification, 1p, and 11q23 status).
- Integrating clinical and molecular features allows for appropriate risk stratification so that treatment can be tailored to the risk of recurrence. Current risk stratification identifies three separate groups of patients with different prognoses and treatment strategies:
- Low-risk patients: localized tumors and/or favorable clinical and molecular features
- Intermediate-risk patients: more extensive primary tumor or regional disease or unfavorable clinical and molecular features
- High-risk patients: patients >18 months with metastatic disease or unfavorable molecular features
Epidemiology
- The median age at diagnosis is 19 months, with 89% of cases diagnosed younger than 5 years of age. Fewer than 5% of patients are diagnosed older than 10 years of age.
- The male:female ratio is 1.1:1.
- The majority of tumors arise in the retroperitoneum, with the adrenal gland being the single most common location.
Incidence
About 800 new cases per year in the United States (10 per million children per year)
Prevalence
- Accounts for 8 " 10% of all childhood cancer, making it the most common extracranial solid tumor and the most common cancer overall during the first 2 years of life
- Accounts for 15% of all pediatric cancer deaths
- Occurs in 1 per 7,000 live births
Risk Factors
Genetics
- Most cases arise spontaneously. One percent are familial (autosomal dominant) and are usually associated with ALK mutations.
- Patients with associated congenital central hypoventilation syndrome often have PHOX2B mutations.
Pathophysiology
Tumor growth can cause symptoms in multiple ways:
- Neurologic: nerve or cord compression from paraspinal tumors
- Hypertension: from renal artery distortion or occasionally from excessive catecholamine release
- Pain: from metastatic bone disease
- Pancytopenia: from marrow disease
Etiology
No known etiology or causative environmental exposures
Commonly Associated Conditions
May occur along with other disease that have dysregulation of the peripheral nervous system, such as neurofibromatosis type I, Hirschsprung disease, or central congenital hypoventilation syndrome
Diagnosis
History
- Patients with low-risk disease often appear well and the tumor is discovered incidentally on exam or imaging studies for other reasons.
- High-risk patients often are ill-appearing with obvious symptoms related to tumor location:
- Abdominal pain or distension
- Painful bone metastases causing limp
- Orbital bone metastases causing swelling or discoloration (raccoon eyes)
- Paraspinal tumors causing weakness, pain, or bowel/bladder symptoms
- Marrow involvement causing pallor and fatigue, petechiae
- Some patients may have paraneoplastic syndromes causing opsoclonus/myoclonus/ataxia related to antineuronal antibodies or excessive diarrhea related to vasoactive intestinal peptide (VIP) secretion.
Physical Exam
- Exam findings depend on primary tumor site and extent of dissemination.
- Patients with disseminated disease often have fever and/or worsening nutritional status.
- Patients with abdominal disease may have bulky firm abdominal mass, and hypertension may occur from renal artery distortion or rarely catecholamine release. The liver may be massively enlarged, particularly in patients with stage 4S disease in the 1st year of life.
- Patients with thoracic tumors may have Horner syndrome, and occasionally, respiratory symptoms from airway compression.
- Patients with paraspinal tumors with invasion into the spinal canal may have weakness and/or radicular pain.
- Bone metastases may have associated proptosis, soft tissue swelling, or discoloration from venous stasis.
- Regional or distant nodes may be enlarged, particularly in the supraclavicular region.
- Bluish firm skin nodules may be seen in infants.
- Pallor or petechiae from marrow metastases
Diagnostic Tests & Interpretation
Lab
- CBC
- Decreased hemoglobin, platelets, and/or WBC may indicate marrow involvement.
- Lactic dehydrogenase (LDH)
- Often elevated with large or metastatic tumors
- Urine catecholamines (homovanillic acid [HVA], vanillylmandelic acid [VMA])
- Can be done on spot urine samples
- Elevated in 90% of patients
Imaging
- CT or MRI
- To evaluate primary tumor site
- Calcification quite common in neuroblastoma
- Metaiodobenzylguanidine (MIBG)
- Most specific test for neuroblastoma
- Uptake seen in primary tumor and metastases in 90% of patients
- Bone scan done if tumor is not avid on MIBG.
- Alternatively, fluorodeoxyglucose-18 positron emission tomography (FDG-PET) scan may also identify tumor in MIBG-negative patients.
Diagnostic Procedures/Other
- Tumor biopsy is usually required, unless there is metastatic tumor in bone marrow coupled with elevated urine HVA/VMA.
- Tumor tissue usually expresses neuroendocrine markers (synaptophysin, neuron-specific enolase [NSE]) and often contains neuropil.
- The determination of favorable vs. unfavorable histology is made based on degree of differentiation, presence of stroma, mitotic/karyorrhectic index, and age of patient.
- Neuroblastomas are immature; ganglioneuroblastomas have some maturity but are still malignant, whereas ganglioneuromas are fully mature and benign.
- Bilateral bone marrow aspirates and biopsies help complete staging.
- The International Neuroblastoma Staging System (INSS) is the current staging system:
- Stage 1: completely resected localized tumor
- Stage 2: incompletely resected localized tumor (2A) or with regional node involvement (2B)
- Stage 3: unresectable tumor crossing midline or contralateral regional lymph node involvement
- Stage 4: dissemination to nodes, bone marrow, liver, skin (except 4S)
- Stage 4S: <1 year old, with stage 1 " 2 primary tumor and metastases limited to liver, skin, or bone marrow
Differential Diagnosis
- Abdominal masses: Wilms tumor, germ cell tumor, hepatoblastoma, abdominal sarcoma, or lymphoma
- Thoracic masses: lymphoma, leukemia, germ cell tumor
- "Small round blue cell tumors of childhood " : non-Hodgkin lymphoma, rhabdomyosarcoma, Ewing sarcoma/peripheral neuroectodermal tumor (PNET)
Treatment
- Treatment is based on risk stratification using age 18 months, stage, DNA ploidy, favorable vs. unfavorable histology, MYCN amplification, and loss of heterozygosity (LOH) 1p/11q.
- Low-risk tumors
- Treatment is surgery alone, generally without adjuvant chemotherapy.
- Selected patients with stage 4S disease may never even require surgery and may be closely observed without therapy.
- Intermediate-risk tumors
- Treatment generally uses 2 " 8 cycles of outpatient chemotherapy, performing surgical resection when appropriate.
- Chemotherapy includes carboplatin, etoposide, doxorubicin, and cyclophosphamide.
- Selected patients may also receive topotecan or cis-retinoic acid.
- High-risk tumors
- Treatment involves multiple cycles of intense induction chemotherapy, with surgical resection of primary tumor done when appropriate.
- Treatment is then consolidated with high-dose chemotherapy and autologous peripheral blood stem cell transplant.
- Following recovery, they receive irradiation to the primary tumor site, as well as any metastatic sites that were slow to respond to induction therapy. Finally, patients receive multiple cycles of cis-retinoic acid coupled with anti-GD2 antibody, which targets the GD2 protein that is ubiquitously expressed on neuroblastoma cells.
- Chemotherapy used during induction consists of vincristine, doxorubicin, cyclophosphamide, cisplatin, and etoposide. High-dose chemotherapy often involves carboplatin, etoposide, and melphalan. Newer regimens are testing the use of busulfan and melphalan.
Ongoing Care
Follow-up Recommendations
Referral to a pediatric oncologist is essential before any diagnostic procedures or therapeutic interventions.
Patient Monitoring
- On therapy
- Laboratory monitoring for myelosuppression and organ function
- Disease reevaluation with imaging and bone marrow testing prior to surgery and stem cell transplant
- Off therapy
- Close follow-up for disease recurrence up to 5 years after completion of therapy, using imaging and urine catecholamine measurement
- Monitoring for late effects of cancer therapy, especially in young growing children
Prognosis
- Adverse prognostic factors
- Age >18 months
- Advanced stage
- MYCN gene amplification
- Unfavorable histology
- Diploid tumor genome (primarily infants)
- LOH at chromosome arms 1p or 11q
- Expected outcomes with current therapy
- Low-risk disease: >90% 3-year event-free survival
- Intermediate risk: approximately 85% 3-year event-free survival
- High-risk: approximately 30 " 50% 3-year event-free survival
Complications
Treatment-related complications (see "Cancer Therapy Late Effects " chapter)
- Growth delays
- Renal insufficiency
- Hearing loss
- Hypothyroidism
- Second malignancy
- Cardiac dysfunction
- Infertility
Additional Reading
- Maris JM. Recent advances in neuroblastoma. N Engl J Med. 2010;362(23):2202 " 2211. [View Abstract]
- Park JR, Eggert A, Caron H. Neuroblastoma: biology, prognosis, and treatment. Hematol Oncol Clin North Am. 2010;24(1):65 " 86. [View Abstract]
Codes
ICD09
- 194.0 Malignant neoplasm of adrenal gland
- 158.0 Malignant neoplasm of retroperitoneum
- 164.9 Malignant neoplasm of mediastinum, part unspecified
- 195.2 Malignant neoplasm of abdomen
- 195.1 Malignant neoplasm of thorax
ICD10
- C74.90 Malignant neoplasm of unsp part of unspecified adrenal gland
- C48.0 Malignant neoplasm of retroperitoneum
- C38.3 Malignant neoplasm of mediastinum, part unspecified
- C76.3 Malignant neoplasm of pelvis
- C74.92 Malignant neoplasm of unspecified part of left adrenal gland
- C74.91 Malignant neoplasm of unsp part of right adrenal gland
SNOMED
- 432328008 neuroblastoma (disorder)
- 281562007 adrenal neuroblastoma (disorder)
- 363494000 Malignant tumor of mediastinum
- 281566005 Abdominothoracic neuroblastoma
- 281564008 Pelvic neuroblastoma
- 363420003 malignant retroperitoneal tumor (disorder)
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, but this is usually seen only in children <1 year of age 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 high-risk neuroblastoma. However, some patients can have meaningful stabilization of disease with therapeutic MIBG administration or other experimental therapies.