Neuroblastoma – Causes, Symptoms, Diagnosis, Treatment and Ongoing care
Most common tumor of infants and most common extracranial solid tumor of children
A neoplasm of neural crest origin that may arise anywhere along the sympathetic ganglion chain or in the adrenal medulla:
- Stage 1: Localized tumor with complete resection, with or without microscopic residual disease
- Stage 2A: Localized tumor with incomplete gross excision, ipsilateral lymph node negative
- Stage 2B: Localized tumor with or without complete excision, ipsilateral lymph nodes positive; contralateral lymph nodes negative
- Stage 3: Unresectable tumor extending across midline, or localized tumor with positive contralateral lymph nodes, or midline tumor with bilateral extension unresectable
- Stage 4: Any primary tumor with distant metastases
- Stage 4S: Localized primary tumor with dissemination limited to skin, liver, and/or bone marrow in infants <1 year of age
- Amplification of n-myc oncogene (poor prognosis)
- Normal DNA ploidy: Worse prognosis than hyperdiploidy
- Sites of disease:
- Adrenal medulla 40–60%
- Retroperitoneal sites 20%
- Mediastinum 10%
- Pelvis 2–6%
- Neck 2%
- System(s) affected: Endocrine/Metabolic; Nervous
- Predominant age:
- 90% occur in 1st 8 years of life.
- 30% occur in children in the 1st year of life.
- 50% occur between ages 1 and 4 years.
- Most common intra-abdominal malignancy in the newborn
- Predominant sex: Males > Females (1.2:1)
- The most common tumor in infants <1 year of age in the US
- Accounts for 6–10% of all childhood cancers, but 15% of all childhood oncologic deaths
- 4th most common pediatric malignancy
- 27.8 cases/million children/year for 1st 5 years of life in the US
- 8.7 cases/million in children/year for 1st 15 years of life in the US
- Denmark: 1/12,000–14,000 live births
- Japan: 1/15,000–18,749 infants
- 1/7,000 live births in the US and the UK (1)[C]
- Beckwith–Wiedemann syndrome
- Pancreatic islet cell dysplasia
- Maternal phenytoin treatment
- Fetal alcohol syndrome
- Hirschsprung disease
- Family history
- Familial cases reported (1–2%):
- The median age at diagnosis of familial cases is 9 mo (median age at diagnosis of sporadic cases is 18 mo) (2)[B].
- Follows an autosomal dominant pattern of inheritance (2)[B]
- Genetic abnormalities in 80%
- Deletions in short arm of chromosome 1p36 or 11q23, unbalanced gain of long arm of chromosome 17 (all of these genetic alterations result in aggressive tumor behavior and poor outcome) (2)[B]
- Amplification of n-myc oncogene occurs on chromosome 2 (poor prognostic sign, present in ∼20–25%).
- Cellular DNA ploidy (hyperdiploidy in infants <1 year of age is associated with excellent long-term survival, diploidy in the same age group is associated with treatment failure) (1)[C]
Genetic abnormalities in 80% of cases
- 50–60% present with metastatic disease.
- Abdominal mass (50–75%)
- Weight loss
- Failure to thrive
- Abdominal pain and distension
- Bone pain
- Hypertension (25%)
- Horner syndrome (ptosis, miosis, enophthalmos, heterochromia of iris)
- Orbital ecchymosis (panda eyes)
- Respiratory distress
- Cauda equina syndrome
- Flushing, sweating, irritability
- Cerebellar ataxia (chaotic nystagmus): Dancing eye syndrome
Diagnostic Tests & Interpretation
- CBC and platelet count
- Liver function studies
- Renal function studies
- Urinary catecholamines, including dopamine, vanillylmandelic acid, and homovanillic acid (85% secrete catecholamine metabolites)
- Uric acid level
- Creatinine level
- Magnesium level
- Calcium level
- Lactate dehydrogenase (LDH) level (high levels, >1500 IU/l, associated with poor outcome)
- Bilirubin, aspartate aminotransferase, and alanine aminotransferase levels
- Gd2 monoclonal antibody levels
- Serum neuron-specific enolase (levels >100 ng/mL associated with poor outcome)
- Serum ferritin
- Bone marrow aspiration
- Assay for vasoactive intestinal polypeptide
- Chest radiograph
- Skeletal survey (including orbital views)
- Bone scan
- CT or MRI of neck, chest, abdomen, or pelvis, depending on the location of tumor; also to evaluate for metastatic disease
- PET scan
- MIBG scintigraphy
- Myelogram may be indicated for neurologic symptoms.
- Myelogram if needed
- Bone marrow aspiration
- Tumor biopsy (open preferred over needle biopsy due to better tissue sample for multiple studies)
- Small, dark, round cells
- Immature tumors tend to be large, red, lobular, soft, friable
- Mature tumors are fibrous, contain calcification, hemorrhage, necrosis, cysts, rosettes, and nerve filaments.
- May be neuroblastoma, ganglioneuroblastoma, or benign ganglioneuroma, depending on cell maturity
- Favorable histology: Stroma-rich, well-differentiated. and intermixed tumors
- Unfavorable histology: Stroma-rich nodular and stroma-poor, undifferentiated tumors
- Wilms tumors
- Other tumors of neck, chest, abdomen, pelvis
- Doxorubicin (Adriamycin)
- Ifosfamide (with mesna to protect against hemorrhagic cystitis)
- Immunotherapy using antiganglioside monoclonal antibodies
- Contraindications: See the manufacturer’s information for each drug.
- Precautions: See the manufacturer’s information for each drug.
- Significant possible interactions: See the manufacturer’s information for each drug.
- By protocol
- Ondansetron (Zofran), dronabinol (Marinol), metoclopramide (Reglan), and others for nausea control
- Radiation therapy in children >1 year of age with stage 3 disease
- Radioimmunotherapy with hematopoietic stem cell rescue
- Chemotherapy for stage 2 and greater
See General Measures.
- Surgical resection may be complete, incomplete, or biopsy only: For stage 1, excision only.
- If resection incomplete or biopsy, then chemotherapy followed by 2nd-look operation (reduction of tumor size may allow complete resection at second operation).
- Dumbbell extension through vertebral foramina, chemotherapy alone vs laminectomy and decompression
- Stages 4, 4S: Resection of primary tumor and chemotherapy
- Myeloablative therapy followed by bone marrow transplantation considered in stages 3 and 4
- Current Children’s Oncology Group risk stratification (1)[C]:
- Low-risk disease treated with surgery alone: Includes stage 1, 2A, 2B with favorable histology, and 4S with normal NMYC and favorable histology.
- Intermediate-risk disease treated with chemotherapy, surgery, and local radiation: Includes stage 3 with normal NMYC amplification and favorable histology, stage 4 with normal NMYC, and stage 4S with unfavorable histology.
- High-risk disease treated with chemotherapy, surgery, and bone marrow transplant or stem cell rescue: Includes stage 2B with unfavorable histology, stage 3 with amplified NMYC and unfavorable histology, stage 4 with amplified NMYC and >1 year of age, and stage 4S with amplified NMYC.
- All children require central venous access for chemotherapy.
Inpatient workup and treatment until stable and induction chemotherapy completed
- Multiagent chemotherapy every 3–4 weeks for 4 courses, then reevaluate with bone marrow or 2nd-look operation.
- Follow every 3 months for 1st year, every 4 months for 2nd year, every 6 months for 3rd year, then at least yearly.
- Follow with CT or MRI every 3–6 months initially, then yearly.
No special diet
- Patient and family education regarding long-term outlook
- Possibility of 2nd malignancy
- Side effects of treatment
- Overall survival 58% (3)[C]:
- Stage 1: Expected survival ∼100%
- Stage 2: Survival 75%
- Stage 3: Survival 43%
- Stage 4: Survival 15%
- Stage 4S: Survival 70–80%
- Normal DNA ploidy, NMYC amplifications, and/or unfavorable histology indicate worse-than-usual prognosis for the same tumor.
- Infants <1 year of age have better outcome.
- Patients with cervical, pelvic, and mediastinal tumors have better prognosis than those with retroperitoneal, paraspinal, or adrenal tumors.
- Survival for those presenting with opsoclonus (uncontrolled, multidirectional eye movements) and nystagmus is nearly 90% (seen especially in mediastinal tumors in infants <1 year of age).
- Neuron-specific enolase level >100 ng/mL correlates with advanced disease and reduced survival.
- Serum LDH level <1,500 IU/mL may indicate improved survival rate.
- In patients with high-risk neuroblastoma, myeloablative therapy followed by autologous bone marrow transplant result in significantly better overall survival (about 59%) (2)[B].
- Spontaneous regression in Stage 4S (2)[B]:
- Spontaneous regression may occur in a small proportion of patients and is not completely understood.
- The incidence of spontaneous regression in neuroblastoma is 10–100 times greater than for any other human cancer.
- Bone marrow suppression
- Hemorrhagic cystitis
- Antidiuretic hormone secretion
- Local tissue necrosis
- Renal toxicity
- Hearing loss
- Graft versus host disease
1. Weinstein JL, Katzenstein HM, Cohn SL. Advances in the diagnosis and treatment of neuroblastoma. Oncologist. 2003;8:278–92.
2. Matthay KK, Reynolds CP, Seeger RC, et al. Long-Term Results for Children With High-Risk Neuroblastoma Treated on a Randomized Trial of Myeloablative Therapy Followed by 13-cis-Retinoic Acid: A Children’s Oncology Group Study. J Clin Oncol. 2009.
3. Grosfeld JL, et al. Neuroblastoma in the 1st year of life: Clinical and biologic factors influencing outcome. Sem Pediatr Surg. 1993;2:37–46.
Mullassery D, Dominici C, Jesudason EC, McDowell HP, Losty PD et al. Neuroblastoma: contemporary management. Arch Dis Child Educ Pract Ed. 2009;94:177–85.
Pearson AD, Pinkerton CR, Lewis IJ, et al. High-dose rapid and standard induction chemotherapy for patients aged over 1 year with stage 4 neuroblastoma: a randomised trial. Lancet Oncol. 2008;9:247–56.
Yalçin B, Kremer LC, Caron HN, van Dalen EC et al. High-dose chemotherapy and autologous haematopoietic stem cell rescue for children with high-risk neuroblastoma. Cochrane Database Syst Rev.2010;5:CD006301.
- 158.0 Malignant neoplasm of retroperitoneum
- 164.9 Malignant neoplasm of mediastinum, part unspecified
- 194.0 Malignant neoplasm of adrenal gland
- 191.9 Malignant neoplasm of brain, unspecified site
- 281560004 neuroblastoma of brain (disorder)
- 281562007 adrenal neuroblastoma (disorder)
- 281563002 thoracic neuroblastoma (disorder)
- 432328008 neuroblastoma (disorder)
- Survival has improved slightly with multimodality therapy, and it is hoped that bone marrow transplant/stem cell rescue will further improve survival in the future.
- The treatment of neuroblastoma is determined almost entirely by protocol based on tumor stage, NMYC amplification, and histology findings.