Mediastinal Yolk Sac Tumour

Mediastinal yolk sac tumour is a malignant germ cell tumour of the anterior mediastinum with yolk sac (endodermal sinus) differentiation, alone or as part of a mixed tumour. It secretes AFP and has a poor prognosis among germ cell tumours.

It is the commonest non-seminomatous germ cell tumour component in the mediastinum, with pure forms making up about 5% to 20% of mediastinal nonseminomatous tumours. Peak age is 15 to 35, and boys and young men are mostly affected. It is a very rare cause of mediastinal tumour in children, in whom the sacrococcygeal region and testis are commoner.

Klinefelter syndrome is associated, and haematological malignancy (acute myeloid leukaemia, myelodysplastic syndrome, histiocytic sarcoma) develops in about 2% to 6% of mediastinal germ cell tumours, most often with yolk sac elements.

Pathophysiology. Yolk sac cells recapitulate extraembryonic structures, with reticular, microcystic, solid, glandular and hepatoid patterns, Schiller-Duval bodies and hyaline globules. Tumours express AFP, glypican-3, SALL4 and cytokeratin, and are OCT3/4 and CD30 negative.

Behaviour. The tumour is bulky and spreads early to lung, liver, bone and nodes. Five year survival is about 40% to 55% with cisplatin based chemotherapy and surgery. Slow marker decline during chemotherapy, extrapulmonary metastases and incomplete resection predict poor outcome.

• Chest pain, cough, dyspnoea, weight loss, fever and hoarseness.
• Superior vena cava obstruction, pleural or pericardial effusion and haemoptysis.
• Cytopenias or abnormal blood film when haematological malignancy is present.

• CT of the chest, abdomen and pelvis: heterogeneous anterior mediastinal mass with necrosis, haemorrhage and cystic components.
• Serum AFP (often over 1,000 ng/mL), beta-hCG and lactate dehydrogenase before treatment. The AFP half life is 5 to 7 days and decline during chemotherapy is tracked.
• Biopsy: Schiller-Duval bodies, glypican-3 and SALL4 positive, AFP stain positive in a subset, CD117 and CD30 negative. Markedly raised AFP with a typical mass supports starting chemotherapy without biopsy in an unstable patient.
• Testicular ultrasound, karyotype, FBC and film, MRI brain, and bone marrow examination for unexplained cytopenias.
• Baseline creatinine, liver tests, audiometry, lung function with DLCO, and sperm banking.

Differential diagnosis.

• Mediastinal embryonal carcinoma, choriocarcinoma and teratoma
• Mediastinal seminoma
• Thymoma and thymic carcinoma
• Hepatoid carcinoma and metastatic hepatocellular carcinoma (AFP raised)
• Lymphoma and sarcoma
• Metastatic testicular yolk sac tumour

Chemotherapy. Cisplatin based combination for 4 cycles.

• Bleomycin, etoposide and cisplatin, every 21 days for 4 cycles: bleomycin 30 units IV on days 1, 8 and 15; etoposide 100 mg/m2 IV daily on days 1 to 5; cisplatin 20 mg/m2 IV daily on days 1 to 5 with hydration and magnesium and potassium supplements; maximum bleomycin 360 units over 4 cycles (lifetime ceiling 400 units), cisplatin 100 mg/m2 each cycle; monitoring: FBC, creatinine, potassium and magnesium before each cycle, audiometry, neuropathy, respiratory symptoms and chest imaging for bleomycin toxicity (stop for any pulmonary toxicity), avoid high inspired oxygen concentrations during anaesthesia, markers before each cycle; adjustment: give cisplatin only when creatinine clearance is 60 mL/min or more, reduce bleomycin as creatinine clearance falls under 60 mL/min and avoid when under 30, etoposide 75% of the dose when creatinine clearance is 15 to 50 mL/min and 50% when under 15, reduce for hepatic impairment.
• Alternative when bleomycin is contraindicated: 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 24 to 72 hours after chemotherapy, with tumour lysis prophylaxis (hydration and urate lowering therapy) before the first cycle.
• Children are treated in paediatric oncology centres with cisplatin based regimens dosed by weight, with dose reduction under 10 kg.

Surgery. Resection of all residual disease after chemotherapy, once markers are normal. Persistently raised AFP indicates viable tumour, and salvage chemotherapy is given before surgery.

Salvage therapy.

• Paclitaxel, ifosfamide and cisplatin: paclitaxel 175 mg/m2 IV over 3 hours on day 1, ifosfamide 1.2 g/m2 IV daily on days 1 to 5 with mesna, 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, neuropathy, audiometry, neurological status; 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, give cisplatin only when creatinine clearance is 60 mL/min or more, reduce paclitaxel for hepatic impairment, premedicate against hypersensitivity.
• High dose chemotherapy with autologous stem cell rescue at a specialist centre.

Monitoring. AFP, hCG and CT every 4 to 6 weeks during treatment, then every 2 to 3 months in year 1, every 3 months in year 2, then 6 monthly to year 5. FBC at each visit for haematological malignancy, with lifelong cardiovascular and endocrine surveillance.

Referral and escalation.

• Referral to a germ cell tumour centre on suspicion.
• Same day oncology for superior vena cava syndrome, respiratory compromise or neutropenic sepsis.
• Haematology review for any cytopenia, since haematological malignancy changes prognosis and therapy.

Special groups.

• Klinefelter syndrome: endocrine follow up and counselling.
• Children: weight adjusted regimens and late effect surveillance (hearing, renal function, fertility).
• Fertility: sperm banking before the first cycle.