Non-Germinomatous Central Nervous System Germ Cell Tumour

Non-germinomatous central nervous system germ cell tumours are a group of malignant intracranial germ cell tumours that include yolk sac tumour, embryonal carcinoma, choriocarcinoma, immature teratoma and mixed tumours. They need intensive chemotherapy and radiotherapy, and prognosis is worse than for pure germinoma.

They form about 1% to 2% of paediatric brain tumours in Western countries, with a peak age of 10 to 20 years and male predominance. The pineal region is commonest, then the suprasellar region and basal ganglia.

Klinefelter syndrome is associated with intracranial non-germinomatous tumours. Mixed tumours with a germinoma component fall in the non-germinomatous group for treatment.

Pathophysiology. Isochromosome 12p, KIT and RAS-MAPK signalling mutations are common. Yolk sac elements secrete AFP, and syncytiotrophoblastic and choriocarcinoma elements secrete beta-hCG. Embryonal carcinoma expresses CD30 and OCT3/4.

Behaviour. Tumours spread along the CSF, and may haemorrhage (choriocarcinoma). Five year survival is about 70% to 90% for tumours with mildly raised markers and about 40% to 60% for those with very high AFP or choriocarcinoma or yolk sac tumour histology.

• Pineal region: obstructive hydrocephalus, Parinaud syndrome.
• Suprasellar region: diabetes insipidus, visual loss, hypopituitarism, precocious puberty (with hCG secretion in boys).
• Basal ganglia: hemiparesis and cognitive decline.
• Acute neurological deterioration from tumour haemorrhage.

Red flags.

• Acute hydrocephalus with falling consciousness.
• Intratumoural haemorrhage in choriocarcinoma.

• MRI of the brain and whole spine with gadolinium: heterogeneous enhancing mass with cysts, haemorrhage and calcification.
• Serum and CSF AFP and beta-hCG before any procedure. AFP over 10 ng/mL or beta-hCG over 100 IU/L (serum or CSF) in a typical location defines a non-germinomatous tumour, and biopsy may be omitted when markers are unequivocal and the patient is at risk with surgery.
• Biopsy or resection when markers are normal or equivocal, with immunohistochemistry (AFP, hCG, OCT3/4, CD30, SALL4, glypican-3).
• CSF cytology 2 or more weeks after surgery.
• Endocrine assessment, visual fields, audiometry, echocardiography and creatinine before chemotherapy. Testicular ultrasound and chest and abdominal imaging when an extragonadal primary is possible.

Differential diagnosis.

• Germinoma
• Pineoblastoma and pineal parenchymal tumours
• Teratoma (mature or immature) and mixed tumours
• Atypical teratoid rhabdoid tumour and metastatic gonadal tumour

Management combines chemotherapy, radiotherapy and surgery for residual disease.

Hydrocephalus. Endoscopic third ventriculostomy or an external drain before treatment when needed.

Chemotherapy (cisplatin based).

• Etoposide, ifosfamide and cisplatin: etoposide 75 mg/m2 and ifosfamide 1.2 g/m2 IV daily on days 1 to 5 with mesna, and cisplatin 20 mg/m2 IV daily on days 1 to 5, every 21 days for 4 cycles; maximum cisplatin 100 mg/m2 each cycle; monitoring: FBC, creatinine, magnesium, urinalysis, neurological status, audiometry; adjustment: avoid ifosfamide when eGFR is under 30 mL/min/1.73 m2 and reduce by about 25% to 50% when it is 30 to 59, stop for grade 2 neurotoxicity, give cisplatin only when creatinine clearance is 60 mL/min or more, etoposide 75% of the dose when creatinine clearance is 15 to 50 mL/min and 50% when under 15.
• Pegfilgrastim 6 mg subcutaneously once, 24 to 72 hours after each cycle; maximum 6 mg each cycle; monitoring: FBC, bone pain; adjustment: none for renal or hepatic impairment, omit within 14 days before the next cycle.

Radiotherapy. Craniospinal radiotherapy 30.6 Gy in 17 fractions with a boost to the primary site (to 54 Gy), or whole ventricular radiotherapy for localised tumours with a good response, after chemotherapy. Proton therapy is preferred in children where available.

Surgery. Second look resection for residual masses after chemotherapy, especially when markers have normalised, since teratomatous tissue is resistant to chemotherapy. Growing teratoma syndrome (enlarging mass with normal markers) needs resection.

Endocrine management.

• Diabetes insipidus: desmopressin 100 micrograms orally twice daily (or 10 to 20 micrograms intranasally once or twice daily), titrated to urine volume and serum sodium; maximum 1200 micrograms orally each day; monitoring: serum sodium within 3 to 7 days of starting or changing the dose and then regularly, fluid balance and weight; adjustment: avoid when creatinine clearance is under 50 mL/min, avoid with loop diuretics, allow a short daily period of polyuria to reduce the risk of hyponatraemia, use lower doses in older adults
• Adrenal and thyroid replacement are started as pituitary function fails.

Relapse. Re-resection, high dose chemotherapy with stem cell rescue, and re-irradiation in selected patients, at specialist centres.

Monitoring. MRI of the brain and spine with AFP and beta-hCG every 4 to 8 weeks during treatment, then every 3 months for 2 years and every 6 months to year 5. Audiometry, renal function and endocrine surveillance for life.

Referral and escalation.

• Referral to a paediatric or adolescent and young adult neuro oncology centre with germ cell tumour expertise.
• Emergency admission for hydrocephalus, haemorrhage, neutropenic sepsis or electrolyte disturbance.

Special groups.

• Children: weight adjusted therapy with hearing, renal and growth follow up.
• Klinefelter syndrome: endocrine follow up.
• Fertility: sperm banking before chemotherapy when feasible.