Ganglioneuroblastoma

Ganglioneuroblastoma is a tumour of the sympathetic nervous system that lies between neuroblastoma and ganglioneuroma, with both neuroblastic and mature ganglion cell (Schwannian stroma rich) components. Behaviour ranges from benign (intermixed type) to aggressive (nodular type), so subtype and molecular risk decide treatment.

Neuroblastic tumours are the commonest extracranial solid tumour of childhood, with about 10 to 12 cases in 1,000,000 children each year. Ganglioneuroblastoma forms about 5% to 10% of them. Median age is 5 to 7 years, older than for neuroblastoma, and tumours arise in the adrenal gland, posterior mediastinum, retroperitoneum and pelvis.

Associations are familial neuroblastoma (ALK and PHOX2B germline variants), neurocristopathies (Hirschsprung disease, congenital central hypoventilation syndrome) and neurofibromatosis type 1. Most cases are sporadic.

Pathophysiology. Tumours arise from sympathoadrenal neural crest cells. Adverse molecular features are MYCN amplification, segmental chromosome changes (11q loss, 1p loss, 17q gain), ALK mutation or amplification, and TERT rearrangement. The Schwannian stroma rich component is benign and does not show MYCN amplification, but a nodular component can.

Histological subtypes. Intermixed ganglioneuroblastoma (over 50% Schwannian stroma, with scattered neuroblasts) has favourable histology. Nodular ganglioneuroblastoma has a discrete neuroblastic nodule within a stroma rich background and can be favourable or unfavourable by age, differentiation and mitosis karyorrhexis index.

Risk stratification. Age, stage (image defined risk factors), histology, MYCN, 11q status and ploidy place patients in very low, low, intermediate or high risk groups. Localised intermixed tumours have over 95% survival, while high risk disease survives about 50%.

• Many tumours are asymptomatic and found on chest imaging or abdominal examination.
• Mass effects: cough, dyspnoea, dysphagia (thoracic), abdominal pain or distension, constipation or urinary symptoms (pelvic).
• Catecholamine or vasoactive intestinal peptide secretion: sweating, hypertension, flushing, secretory diarrhoea with hypokalaemia.
• Spinal canal extension of a paravertebral tumour (dumbbell tumour): back pain, weakness, sphincter dysfunction.
• Metastatic disease: bone pain, limp, periorbital ecchymoses, pallor and fever.
• Paraneoplastic opsoclonus myoclonus syndrome.

Red flags.

• Acute cord compression with weakness or sphincter loss.
• Respiratory compromise from a large thoracic mass.

• Ultrasound then MRI (preferred for spinal extension and image defined risk factors) or CT of the primary site, with chest CT.
• Urinary catecholamine metabolites (vanillylmandelic acid, homovanillic acid) in a spot urine sample, raised in about 90%.
• Biopsy or resection for histology, with MYCN amplification, ALK, 11q and ploidy testing on tumour tissue. Immunohistochemistry (PHOX2B, synaptophysin, S100 for stroma).
• Staging: MIBG scintigraphy (or FDG-PET for MIBG-negative disease), bone marrow aspirates and trephines in suspected metastatic disease, and imaging of the whole spine when canal extension is suspected.
• Baseline FBC, creatinine, liver tests, audiometry and echocardiography before chemotherapy.
• Germline testing (ALK, PHOX2B) for familial disease, syndromic features or multifocal tumours.

Differential diagnosis.

• Neuroblastoma and ganglioneuroma
• Nephroblastoma (Wilms tumour), hepatoblastoma and adrenocortical tumour
• Phaeochromocytoma and paraganglioma
• Lymphoma and rhabdomyosarcoma
• Neurogenic tumours (schwannoma, neurofibroma)

Management is set by risk group at a paediatric oncology centre.

Low risk and intermixed localised tumours. Surgery alone (complete resection when safe) or observation with imaging and catecholamine follow up. Many residual tumours mature without treatment.

Intermediate risk tumours. Resection after a short course of multi-agent chemotherapy for unresectable or symptomatic tumours or those with unfavourable histology. Chemotherapy regimens and doses are set by the paediatric oncology team and depend on weight and age.

High risk tumours (nodular unfavourable, MYCN-amplified, metastatic). Multimodal therapy: induction chemotherapy, surgery, high dose consolidation with stem cell rescue, radiotherapy to the primary site and residual metastases, and post-consolidation immunotherapy with differentiation therapy.

• Differentiation therapy after consolidation: isotretinoin 160 mg/m2 orally each day in 2 divided doses with food for 14 days then 14 days off, for 6 cycles after consolidation (5.33 mg/kg each day for children under 12 kg); maximum 160 mg/m2 daily; monitoring: lipids, liver tests, calcium, skin and mucosal dryness, dry eyes, mood, pregnancy test in adolescents; adjustment: reduce by 50% for grade 3 toxicity, stop for severe hypercalcaemia or hepatotoxicity, avoid vitamin A supplements and tetracyclines, prevent pregnancy

Spinal canal extension. Chemotherapy first for neurological deficits (avoid laminectomy where possible), with surgery for refractory cases.

Supportive care. Antiemetics, central line care, nutritional support, infection prophylaxis, and management of hypertension and diarrhoea from secretory tumours.

Monitoring. MRI or CT every 3 months for 1 to 2 years, then every 6 months, with urinary catecholamine metabolites. Late effects: hearing loss, renal and cardiac toxicity, growth, endocrine deficiency, infertility and second cancers.

Referral and escalation.

• Urgent referral to a paediatric oncology centre for any child with a suspected sympathetic tumour.
• Same day assessment for cord compression, respiratory compromise or fever with neutropenia.

Special groups.

• Infants: reduced doses by weight and observation more often chosen for small tumours.
• Adolescents and adults (rare): treated by a neuroblastoma specialist team with the same risk adapted approach.
• Familial or syndromic cases: genetic counselling and surveillance of relatives.