Mediastinal Embryonal Carcinoma

Mediastinal embryonal carcinoma is a malignant germ cell tumour of the anterior mediastinum with primitive epithelial cells growing in sheets, glands and papillae. Pure forms are rare, and embryonal carcinoma usually occurs as a component of mixed germ cell tumours.

It forms a small part of primary mediastinal nonseminomatous germ cell tumours. It affects men aged 15 to 40, with very rare cases in women and children.

Associations are Klinefelter syndrome and, rarely, haematological malignancy of clonal origin.

Pathophysiology. Isochromosome 12p is typical. Cells express OCT3/4, SOX2, CD30, SALL4 and cytokeratin, and are negative for CD117, D2-40 and glypican-3 (yolk sac). AFP is normal or mildly raised, and beta-hCG is raised in a minority.

Behaviour. The tumour invades locally and metastasises early (lung, liver, brain, bone, nodes). Five year survival is about 40% to 50% with cisplatin based chemotherapy and surgery. It is always in the poor risk group for mediastinal primaries.

• Chest pain, cough, dyspnoea, fever and weight loss.
• Superior vena cava obstruction, pleural or pericardial effusion and haemoptysis.
• Gynaecomastia when hCG is raised.

• CT of the chest, abdomen and pelvis: large, heterogeneous anterior mediastinal mass with necrosis and invasion of adjacent structures.
• Serum AFP, beta-hCG and lactate dehydrogenase before treatment.
• Core biopsy with immunohistochemistry: OCT3/4, SOX2 and CD30 positive, CD117 negative. A broad panel is needed to separate it from lymphoma, carcinoma and sarcoma.
• Testicular ultrasound, karyotype, FBC and film, MRI brain, creatinine, liver tests, audiometry, lung function with DLCO, and sperm banking.

Differential diagnosis.

• Mediastinal seminoma (CD117 positive, CD30 negative)
• Yolk sac tumour, choriocarcinoma and mixed germ cell tumour
• Anaplastic large cell lymphoma and Hodgkin lymphoma (CD30 positive)
• Thymic carcinoma and large cell carcinoma of lung
• Metastatic testicular embryonal carcinoma
• Sarcoma and small cell carcinoma

Management is chemotherapy followed by resection of residual disease.

Chemotherapy.

• 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 before the first cycle.

Surgery. Resection of residual disease after chemotherapy once markers are normal. Pathology of the residue (necrosis, teratoma or viable carcinoma) determines further treatment, and viable cancer needs 2 further cisplatin based cycles.

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. Markers 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 for haematological malignancy, and lifelong cardiovascular and endocrine surveillance.

Referral and escalation.

• Germ cell tumour centre referral on suspicion.
• Same day oncology for superior vena cava syndrome, respiratory compromise or neutropenic sepsis.

Special groups.

• Klinefelter syndrome: endocrine follow up.
• Fertility: sperm banking before the first cycle.
• Children and adolescents: paediatric oncology centre with weight adjusted therapy.