Neuroblastoma

BASICS

Most common tumor of infants and one of the most common tumors of children ‚

DESCRIPTION

A neoplasm developed from immature sympathetic ganglion cells of neural crest origin that may arise anywhere along the sympathetic chain or in the adrenal medulla ‚

Sites of disease
- Adrenal medulla, 40%
- Sympathetic ganglia
  - Abdominal, 25%
  - Thoracic, 15%
  - Cervical, 5%
  - Pelvic, 5%
- Other, 10%
Metastasis: lymphatic and hematogenous to bone, bone marrow, liver, skin, dura, orbits

EPIDEMIOLOGY

Third most common pediatric malignancy
Most common tumor in infants <1 year of age; accounts for 8 " “10% of all childhood cancers and 15% of all childhood oncologic deaths
Predominant age at diagnosis
- Within first 5 years of life: 90%
- Children in the first year of life: 30%
- Between ages 1 and 4 years: 50%
- Median age 17.3 months
Predominant sex: males > females (1.2:1)
Predominant race: white > black (1.7:1 for males, 1.9:1 for females)
Screening: no impact on mortality (60% regress spontaneously)

Incidence

From birth to age 1 year in the United States: 52.1 cases/million children/year
From age 1 to 4 years in the United States: 19.1 cases/million children/year
First 15 years of life in the United States: 9.8 cases/million children/year
In 2006, there were 700 new cases of neuroblastoma diagnosed in the United States.

ETIOLOGY AND PATHOPHYSIOLOGY

Genetics

80% of tumors have genetic abnormalities.
Genetic alterations associated with aggressive tumor behavior and poor outcomes (1)
- Deletions in short arm of chromosome 1p36
- Unbalanced gain of long arm of chromosome 17 (trisomy 17q)
- Polymorphism at chromosome 6p22
- N-Myc amplification on chromosome 2 (20 " “25%)
- Anaplastic lymphoma kinase (ALK) gene associated with hereditary neuroblastoma
Genetic alterations associated with better outcomes: 11q23, 14q
DNA ploidy: Hyperdiploidy in infants <1 year of age is associated with excellent long-term survival; diploidy is associated with treatment failure.
Familial cases (1 " “2%)
- Median age at diagnosis: 9 months
- Autosomal dominant inheritance with incomplete penetrance

RISK FACTORS

Maternal phenytoin or opiates
Folate deficiency
Opsoclonus myoclonus syndrome
- 50% have neuroblastoma.
Beckwith-Wiedemann syndrome
Pancreatic islet cell dysplasia
Fetal alcohol syndrome
Hirschsprung disease
Family history of neuroblastoma
Neurofibromatosis type 1
Congenital central hypoventilation syndrome
Gestational diabetes mellitus

DIAGNOSIS

HISTORY

Abdominal pain and distension
General malaise
Weight loss
Anemia
Failure to thrive
Bone pain/weakness/paresthesias/loss of bladder or bowel function due to spinal cord compression
Fever
Diarrhea due to vasoactive intestinal peptide
Flushing, sweating, irritability

PHYSICAL EXAM

Abdominal mass (50 " “75%): hard, fixed, tender
Hypertension (25%)
Skin nodules: firm, bluish red, nontender, central blanching with surrounding erythema (33%)
Horner syndrome (ptosis, miosis, enophthalmos, heterochromia of iris) and superior vena cava syndrome with thoracic neuroblastoma
Orbital ecchymosis/proptosis (panda eyes) with orbital metastasis (15%)
Respiratory distress
Dysphagia due to esophageal compression
Paraplegia and cauda equina syndrome (hourglass lesion on MRI)
Cerebellar ataxia (chaotic nystagmus): dancing eye syndrome

DIFFERENTIAL DIAGNOSIS

Suprarenal: Wilms tumor and hepatoblastoma
Thoracic: lymphoma, teratoma, infection

Initial Tests (lab, imaging)

Labs:
- CBC and platelet count (can suggest bone metastasis)
- CMP, Mg, PO4
- 24-hour or spot urine for catecholamines, including epinephrine, norepinephrine, dopamine, metanephrines, vanillylmandelic acid, homovanillic acid, and vanillylglycolic acid (85% secrete catecholamine metabolites)
- Uric acid and serum ferritin
- Lactate dehydrogenase (LDH) level (high levels >1,500 IU/L, associated with poor outcome)
- Serum neuron-specific enolase (levels >100 ng/mL associated with poor outcome)
- GD2 monoclonal antibody levels
- Assay for vasoactive intestinal polypeptide
Imaging, diagnostic and/or staging
- Ultrasound " ”prenatal or diagnostic
- Chest/abdominal x-rays " ”stippled calcifications
- CT with IV contrast with delays to evaluate primary tumor and evaluate for metastasis. Obtain head CT if proptosis present.
- 131I metaiodobenzylguanidine (MIBG) scintigraphy (most sensitive and specific) with potassium iodide, methimazole, and thyroxine for thyroid protection
- Skeletal survey (with orbital views) and bone scan (to stage tumor/rule out metastasis)
- MRI (to evaluate for spinal canal invasion)
- PET scan occasionally indicated
- Myelogram for neurologic symptoms

Diagnostic Procedures/Other

Bilateral iliac crest bone marrow biopsy
Tumor biopsy (open or laparoscopic)

Test Interpretation

Diagnosis confirmed by the following:
- Primary tumor histology " ”small, round blue cells with positive tumor markers, or
- Metastatic histology (rosettes) with positive catecholamines
Specimen tested for synaptophysin, chromogranin, S100 antigen, and neuron-specific enolase
The International Neuroblastoma Pathology Classification (INPC) recognizes two histologic classes:
- Favorable histology: poorly differentiated neuroblastoma with low or intermediate mitosis-karyorrhexis index (MKI), differentiating neuroblastoma and low MKI tumors in younger patients, ganglioneuroblastoma, and/or ganglioneuroma regardless of age
- Unfavorable histology: undifferentiated or high MKI tumors, poorly differentiated and intermediate MKI tumors at any age, any grade and differentiation tumor in children >5 years, and/or nodular ganglioneuroblastoma regardless of age
Immature tumors tend to be large, red, lobular, soft, and friable.
Mature tumors are fibrous and contain calcification, hemorrhage, necrosis, cysts, rosettes, and nerve filaments.
International Neuroblastoma Staging System (INSS)
- Stage 1: localized tumor with complete resection, with or without microscopic residual disease; negative nonadherent nodes
- Stage 2A: localized tumor with incomplete gross excision, negative lymph nodes
- Stage 2B: localized tumor with or without complete excision, positive ipsilateral nonadherent lymph nodes; negative contralateral nodes
- Stage 3: tumor extending across midline; localized tumor with positive contralateral nodes; or midline tumor with bilateral extension or bilateral lymph node involvement (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 <18 months

TREATMENT

GENERAL MEASURES

Children 's Oncology Group risk stratification (1)[A]: Patients are stratified to low, intermediate, and high risk based on INSS stage, age, N-myc status, INPC classification, and DNA ploidy for therapy.
- Low-risk disease (stages 1, 2A, 2B with favorable characteristics)
  - Observation (for perinatal neuroblastoma with small adrenal tumors (1)[A])
  - Surgery alone
  - Chemotherapy with or without surgery for symptomatic disease or unresectable progressive disease
- Intermediate-risk disease (stages 3 and 4) with favorable characteristics
  - Chemotherapy with or without surgery
  - Surgery or observation (in infants)
  - Radiation therapy (only for emergent therapy)
- High-risk disease (stages 2A/2B, 3, and 4) with unfavorable characteristics
  - Chemotherapy, surgery, SCT, radiation therapy, and anti-GD2 antibody ch14.18, with interleukin-2/GM-CSF and 6 months of 13-cis-retinoic acid (2)[A]
- Stage 4S disease
  - Observation with supportive care (for asymptomatic patients with favorable tumors)
  - Chemotherapy (for symptomatic patients, young infants, or unfavorable tumors)
Surgical resection
- Arterial monitoring for hypertension due to catecholamine release
- Stages 1 and 2: Attempt complete resection.
- Stages 3 and 4: Biopsy followed by four cycles of chemotherapy and then evaluation with a second-look operation and resection.
- Stage 3 tumors but not stage 4 tumors have a 5-year survival benefit from gross total resection versus subtotal resection (3)[A]
- Tumors are highly vascular, prone to hemorrhage, and frequently necrotic with a pseudocapsule.
- Laparoscopic resection is a reasonable approach for low-/intermediate-risk patients and in selected high-risk patients with tumors ≤5 cm and in the absence of vascular encasement (4)[B].
Patients with neurologic deficits may require urgent laminotomy prior to resection of primary tumor.
Radiation therapy for low or intermediate risk is reserved for symptomatic life- or organ-threatening tumor bulk unresponsive to chemotherapy.

MEDICATION

First Line

Carboplatin + etoposide
Cyclophosphamide + doxorubicin + vincristine
Cisplatin
Ifosfamide (with mesna)
Topotecan ‚ ± cyclophosphamide
Dacarbazine
Peptichemio
Teniposide

Second Line

Immunotherapy using antiganglioside (anti-GD2) monoclonal antibodies is standard of care for the treatment of high-risk metastatic neuroblastoma (5)[A].
Biologic agents targeting tumor microenvironment
Radioimmunotherapy with 131I MIBG in high-risk disease
In patients with high-risk neuroblastoma, myeloablative therapy followed by autologous peripheral blood stem cell transplant results in significantly better overall survival (~59%) (6)[A].

INPATIENT CONSIDERATIONS

Admission Criteria/Initial Stabilization
Inpatient workup and treatment until stable and induction chemotherapy completed ‚

ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

Patient Monitoring

For low-risk patients stratified to observation, follow-up with ultrasound. An enlarging neoplasm necessitates operative intervention.
Followup perioperatively and then every 3 months for first year, every 4 months for second year, every 6 months for third year, then at least annually
Follow-up with CT or MRI every 3 to 6 months, then annually
For high-risk tumors, multiagent chemotherapy every 3 to 4 weeks for four courses, then reevaluate with bone marrow or second-look operation

PATIENT EDUCATION

Long-term outlook
Possibility of second malignancy
Side effects of treatment

PROGNOSIS

5-year survival rate by age at diagnosis are as follows:
- Age <1 year: 87%
- Age 1 to 14 years: 65%
Overall 5-year survival rate is 73.6%.
- Stage 1: expected survival ~100%
- Stage 2: survival 75%
- Stage 3: survival 43%
- Stage 4: survival 15%
- Stage 4S: survival 70 " “80%
Survival for those presenting with opsoclonus and nystagmus is nearly 90%.
Cervical, pelvic, and mediastinal tumors: favorable prognosis
DNA hyperdiploidy, high CD44, and elevated neurotrophin Trk-A indicate a favorable prognosis.
Serum LDH level <1,500 IU/mL may indicate improved survival rate.
N-Myc amplification (>10), increased bcl-2, 17q gain, 1p deletion, Trk-B amplification, elevated P-glycoprotein, elevated telomerase, elevated GD2, and unfavorable histology indicate worse prognosis.
Neuron-specific enolase level >100 ng/mL correlates with metastatic disease and reduced survival.
Spontaneous regression (1)[A]
- May occur in a small proportion of patients and is not completely understood
- Incidence of spontaneous regression is 10 to 100 times greater than for any other human cancer.

COMPLICATIONS

Nausea, vomiting, and diarrhea
Alopecia
Bone marrow and immune suppression
Hemorrhagic cystitis
Antidiuretic hormone secretion
Local tissue necrosis
Cardiac and renal toxicity
Hearing loss
Graft-versus-host disease
Second neoplasms
Scoliosis
Delayed growth and maturation
Horner syndrome
Nerve injury with high mediastinal tumors

REFERENCES

11 National Cancer Institute. Neuroblastoma Treatment " “for health professionals (PDQ ‚ ®). http://www.cancer.gov/types/neuroblastoma/hp/neuroblastoma-treatment-pdq.22 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;27(7):1007 " “1013.33 Mullassery ‚ D, Farrelly ‚ P, Losty ‚ PD. Does aggressive surgical resection improve survival in advanced stage 3 and 4 neuroblastoma? A systematic review and meta-analysis. Pediatr Hematol Oncol. 2014;31(8):703 " “716.44 Kelleher ‚ CM, Smithson ‚ L, Nguyen ‚ LL, et al. Clinical outcomes in children with adrenal neuroblastoma undergoing open versus laparoscopic adrenalectomy. J Pediatr Surg. 2013;48(8):1727 " “1732.55 Yu ‚ AL, Gilman ‚ AL, Ozkaynak ‚ MF, et al. Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N Engl J Med. 2010;363(14):1324 " “1334.66 Yal ƒ § ‚ B, Kremer ‚ LC, Caron ‚ HN, et al. High-dose chemotherapy and autologous haematopoietic stem cell rescue for children with high-risk neuroblastoma. Cochrane Database Syst Rev. 2010;(5):CD006301.

ADDITIONAL READING

Du ‚ L, Liu ‚ L, Zhang ‚ C, et al. Role of surgery in the treatment of patients with high-risk neuroblastoma who have a poor response to induction chemotherapy. J Pediatr Surg. 2014;49(4):528 " “533. ‚

CODES

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
C74.91 Malignant neoplasm of unsp part of right adrenal gland
C74.92 Malignant neoplasm of unspecified part of left adrenal gland

ICD9

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

SNOMED

neuroblastoma (disorder)
adrenal neuroblastoma (disorder)
Malignant tumor of mediastinum
Abdominothoracic neuroblastoma
Pelvic neuroblastoma
malignant retroperitoneal tumor (disorder)

CLINICAL PEARLS

Tumor behavior is highly variable; some regress spontaneously, whereas others are very aggressive with high mortality.
Treatment of neuroblastoma is determined almost entirely by protocol based on the Children 's Oncology Group risk stratification.
Survival for advanced tumors has improved slightly with multimodality therapy.

Home

Erectile Dysfunction

Doctor123.org