Central Nervous System Germinoma

Central nervous system germinoma is a germ cell tumour of the pineal or suprasellar region (and sometimes basal ganglia) that resembles testicular seminoma and is highly sensitive to chemotherapy and radiotherapy. Over 90% of patients with localised disease are cured, and treatment aims to reduce radiation dose and late effects.

It forms about 1% to 3% of paediatric brain tumours in Western countries and up to 10% in East Asia. Peak age is 10 to 20 years. Pineal tumours are commoner in boys and suprasellar tumours are more often seen in girls.

Klinefelter syndrome, Down syndrome and NF1 are associated. Bifocal tumours (pineal and suprasellar together) are typical and count as one localised disease, not as metastasis.

Pathophysiology. Tumour cells resemble primordial germ cells and express OCT3/4, SALL4, PLAP and CD117 (KIT). KIT and RAS-MAPK signalling mutations are frequent. Syncytiotrophoblastic cells may secrete low levels of beta-hCG.

Behaviour. Disease spreads along the ventricles and the CSF, so ventricular radiotherapy is used even for localised tumours. Pure germinoma has an excellent prognosis, while mixed germ cell tumours need more intensive treatment.

• Pineal region: headache, vomiting and papilloedema from obstructive hydrocephalus, Parinaud syndrome (upgaze palsy, convergence retraction nystagmus, light near dissociation).
• Suprasellar region: diabetes insipidus (often the first sign, with polyuria and polydipsia), visual field loss, growth failure, delayed or precocious puberty, hypopituitarism.
• Basal ganglia: hemiparesis, cognitive decline and behavioural change.

Red flags.

• Falling consciousness from acute hydrocephalus.
• Hyponatraemia or hypernatraemia from untreated diabetes insipidus or adrenal insufficiency.

• MRI of the brain and whole spine with gadolinium: well defined enhancing mass in the pineal or suprasellar region (or both), with hydrocephalus.
• Serum and CSF AFP and beta-hCG (germinoma: AFP normal, beta-hCG normal or mildly raised, with CSF beta-hCG under 50 IU/L). AFP over the upper limit of normal indicates a non-germinomatous component.
• Lumbar CSF cytology 2 or more weeks after surgery when safe, or before surgery when safe.
• Biopsy (stereotactic or endoscopic) when markers are normal. A pure germinoma with typical imaging and marker profile may be treated after biopsy confirmation, and tumour markers cannot replace biopsy when AFP is normal.
• Endocrine assessment: sodium, osmolality, urine osmolality, cortisol, thyroid function, prolactin, IGF-1, gonadotropins and sex steroids. Visual fields and acuity.
• Baseline audiometry, creatinine and echocardiography before chemotherapy.

Differential diagnosis.

• Non-germinomatous germ cell tumour and teratoma
• Pineal parenchymal tumours (pineocytoma, pineoblastoma)
• Craniopharyngioma, low grade glioma and pituitary tumour
• Langerhans cell histiocytosis and lymphocytic hypophysitis

Treatment of hydrocephalus. Endoscopic third ventriculostomy with biopsy at the same operation, or an external ventricular drain, when needed before definitive treatment.

Chemotherapy followed by reduced dose radiotherapy. A response to chemotherapy allows whole ventricular radiotherapy at a reduced dose.

• Carboplatin with etoposide: carboplatin 600 mg/m2 IV on day 1 with etoposide 100 mg/m2 IV daily on days 1 to 3, every 21 days for 4 cycles; maximum carboplatin 600 mg/m2 and etoposide 300 mg/m2 each cycle; monitoring: FBC, creatinine, magnesium, audiometry; adjustment: recalculate carboplatin from measured GFR, reduce by 25% for neutrophils under 0.5 x 10^9/L or platelets under 25 x 10^9/L, give etoposide at 75% of the dose when creatinine clearance is 15 to 50 mL/min and 50% when under 15, reduce for hepatic impairment

Radiotherapy. Whole ventricular radiotherapy 24 Gy in 15 fractions with a boost to the primary tumour (to a total of 40 Gy) for localised disease responding to chemotherapy. Craniospinal radiotherapy (24 Gy with a boost) for disseminated disease. Radiotherapy alone (whole ventricular 24 Gy and boost 16 Gy) is an alternative in patients unfit for chemotherapy.

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 when the pituitary axes fail. Hydrocortisone replacement is adjusted for stress (stress dosing) and monitored by a paediatric or adult endocrinologist.

Surgery. Limited to biopsy, hydrocephalus treatment and resection of residual teratomatous elements. Radical resection is not needed.

Monitoring. MRI of the brain and spine every 3 months for 2 years, then every 6 months to year 5, then yearly. Annual endocrine, visual and neurocognitive review for life. Sodium and fluid balance monitoring.

Referral and escalation.

• Paediatric or adolescent and young adult neuro oncology referral at diagnosis.
• Emergency admission for acute hydrocephalus, severe hypernatraemia or adrenal crisis.

Special groups.

• Children: weight adjusted doses, with endocrine and growth follow up.
• Women and girls: fertility counselling and ovarian protection.
• Klinefelter syndrome: endocrine follow up.