Neuroblastoma – Causes, Symptoms, Diagnosis, Treatment and Ongoing care

Basics

Most common tumor of infants and most common extracranial solid tumor of children

Description

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 diseaseStage 2A: Localized tumor with incomplete gross excision, ipsilateral lymph node negativeStage 2B: Localized tumor with or without complete excision, ipsilateral lymph nodes positive; contralateral lymph nodes negativeStage 3: Unresectable tumor extending across midline, or localized tumor with positive contralateral lymph nodes, or midline tumor with bilateral extension unresectableStage 4: Any primary tumor with distant metastasesStage 4S: Localized primary tumor with dissemination limited to skin, liver, and/or bone marrow in infants <1 year of ageAmplification of n-myc oncogene (poor prognosis)Normal DNA ploidy: Worse prognosis than hyperdiploidySites of disease: Adrenal medulla 40–60%Retroperitoneal sites 20%Mediastinum 10%Pelvis 2–6%Neck 2%System(s) affected: Endocrine/Metabolic; Nervous

Epidemiology

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 newbornPredominant sex: Males > Females (1.2:1)The most common tumor in infants <1 year of age in the USAccounts for 6–10% of all childhood cancers, but 15% of all childhood oncologic deaths4th most common pediatric malignancy

Incidence

27.8 cases/million children/year for 1st 5 years of life in the US8.7 cases/million in children/year for 1st 15 years of life in the USDenmark: 1/12,000–14,000 live birthsJapan: 1/15,000–18,749 infants1/7,000 live births in the US and the UK (1)[C]

Risk Factors

Beckwith–Wiedemann syndromePancreatic islet cell dysplasiaMaternal phenytoin treatmentFetal alcohol syndromeHirschsprung diseaseFamily history

Genetics

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]

Etiology

Genetic abnormalities in 80% of cases

Diagnosis

Physical Exam

50–60% present with metastatic disease.Abdominal mass (50–75%)Weight lossAnemiaFailure to thriveAbdominal pain and distensionBone painFeverDiarrheaHypertension (25%)Horner syndrome (ptosis, miosis, enophthalmos, heterochromia of iris)Orbital ecchymosis (panda eyes)Respiratory distressDysphagiaParaplegiaCauda equina syndromeFlushing, sweating, irritabilityCerebellar ataxia (chaotic nystagmus): Dancing eye syndrome

Diagnostic Tests & Interpretation

Lab

CBC and platelet countLiver function studiesRenal function studiesUrinary catecholamines, including dopamine, vanillylmandelic acid, and homovanillic acid (85% secrete catecholamine metabolites)Uric acid levelCreatinine levelMagnesium levelCalcium levelLactate dehydrogenase (LDH) level (high levels, >1500 IU/l, associated with poor outcome)ElectrolytesBilirubin, aspartate aminotransferase, and alanine aminotransferase levelsGd2 monoclonal antibody levelsSerum neuron-specific enolase (levels >100 ng/mL associated with poor outcome)Serum ferritinBone marrow aspirationAssay for vasoactive intestinal polypeptide

Imaging

Chest radiographSkeletal survey (including orbital views)Bone scanCT or MRI of neck, chest, abdomen, or pelvis, depending on the location of tumor; also to evaluate for metastatic diseasePET scanMIBG scintigraphyMyelogram may be indicated for neurologic symptoms.

Diagnostic Procedures/Surgery

Myelogram if neededBone marrow aspirationTumor biopsy (open preferred over needle biopsy due to better tissue sample for multiple studies)

Pathological Findings

Small, dark, round cellsImmature tumors tend to be large, red, lobular, soft, friableMature tumors are fibrous, contain calcification, hemorrhage, necrosis, cysts, rosettes, and nerve filaments.May be neuroblastoma, ganglioneuroblastoma, or benign ganglioneuroma, depending on cell maturityFavorable histology: Stroma-rich, well-differentiated. and intermixed tumorsUnfavorable histology: Stroma-rich nodular and stroma-poor, undifferentiated tumors

Differential Diagnosis

RhabdomyosarcomaWilms tumorsOther tumors of neck, chest, abdomen, pelvisHydronephrosis

Treatment

Medication

First Line

CyclophosphamideMelphalanVincristineDacarbazineTeniposideEtoposideDoxorubicin (Adriamycin)CisplatinPeptichemioCarboplatinIfosfamide (with mesna to protect against hemorrhagic cystitis)TopotecanImmunotherapy using antiganglioside monoclonal antibodiesContraindications: 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.

Second Line

By protocolOndansetron (Zofran), dronabinol (Marinol), metoclopramide (Reglan), and others for nausea control

Additional Treatment

General Measures

Radiation therapy in children >1 year of age with stage 3 diseaseRadioimmunotherapy with hematopoietic stem cell rescueChemotherapy for stage 2 and greater

Additional Therapies

See General Measures.

Surgery/Other Procedures

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 decompressionStages 4, 4S: Resection of primary tumor and chemotherapyMyeloablative therapy followed by bone marrow transplantation considered in stages 3 and 4Current 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.

In-Patient Considerations

Admission Criteria

Inpatient workup and treatment until stable and induction chemotherapy completed

Ongoing Care

Follow-Up Recommendations

Patient Monitoring

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.

Diet

No special diet

Patient Education

Patient and family education regarding long-term outlookPossibility of 2nd malignancySide effects of treatment

Prognosis

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.

Complications

NauseaVomitingAlopeciaBone marrow suppressionImmunosuppressionHemorrhagic cystitisAzotemiaDiarrheaAntidiuretic hormone secretionLocal tissue necrosisMyocardiopathyRenal toxicityHearing lossHypocalcemiaHypomagnesemiaGraft versus host disease

References

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.

Additional Reading

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.

Codes

ICD9

158.0 Malignant neoplasm of retroperitoneum164.9 Malignant neoplasm of mediastinum, part unspecified194.0 Malignant neoplasm of adrenal gland191.9 Malignant neoplasm of brain, unspecified site

Snomed

281560004 neuroblastoma of brain (disorder)281562007 adrenal neuroblastoma (disorder)281563002 thoracic neuroblastoma (disorder)432328008 neuroblastoma (disorder)

Clinical Pearls

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.