Primary Mediastinal Seminoma

Primary mediastinal seminoma is a germ cell tumour of the anterior mediastinum with the histology of testicular seminoma, in the absence of a testicular primary. It is highly chemosensitive and curable in most patients.

It forms about 3% to 4% of germ cell tumours, and about one third of primary mediastinal germ cell tumours. It occurs in men aged 20 to 40 (median about 30), and is very rare in women.

It is not associated with Klinefelter syndrome, unlike mediastinal non-seminomatous tumours. Cryptorchidism and familial germ cell tumour are risk factors for testicular tumours and are not established here.

Pathophysiology. Tumours are thought to arise from primordial germ cells that arrested along the midline migration path. Cells show isochromosome 12p and KIT mutation, with OCT3/4, SALL4, CD117 and D2-40 positivity.

Serum markers. AFP is normal in pure seminoma (a raised value indicates a non-seminomatous component). Beta-hCG is raised in 10% to 30% (usually under 200 IU/L), and lactate dehydrogenase is often raised in proportion to tumour volume.

Behaviour. The tumour is large at diagnosis (often over 10 cm), with local invasion and metastasis to nodes, lung, liver and bone. Five year survival with cisplatin based chemotherapy is about 80% to 90%. A raised AFP or non-pulmonary visceral metastases lower survival.

• Chest pain, cough, dyspnoea, fever, weight loss and hoarseness.
• Superior vena cava obstruction (about 10% to 20%), pericardial effusion and pleural effusion.
• Gynaecomastia with raised hCG, and back pain from bone metastases.

• CT of chest, abdomen and pelvis: large lobulated anterior mediastinal mass, relatively homogeneous with mild enhancement.
• Serum AFP, beta-hCG and lactate dehydrogenase before any treatment.
• CT-directed core biopsy or mediastinoscopic biopsy: sheets of uniform cells with clear cytoplasm and a lymphocytic infiltrate, with OCT3/4, SALL4, CD117 and D2-40 positive and CD30 negative.
• Testicular ultrasound in all men to exclude a testicular primary (including a burnt out lesion), and examination of the testes.
• FBC, creatinine, liver tests, audiometry, lung function with DLCO before bleomycin, and sperm banking before chemotherapy.
• FDG-PET is used after chemotherapy for residual masses.

Differential diagnosis.

• Mediastinal non-seminomatous germ cell tumour (raised AFP)
• Lymphoma (Hodgkin and primary mediastinal B-cell)
• Thymoma and thymic carcinoma
• Metastatic testicular seminoma (testicular primary)
• Sarcoidosis and tuberculous lymphadenopathy
• Intrathoracic goitre

Chemotherapy. Cisplatin based combination for 3 cycles (4 cycles when non-pulmonary visceral metastases are present).

• Bleomycin, etoposide and cisplatin, every 21 days: 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 270 units over 3 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 (age over 40 with lung disease, smoking): etoposide 100 mg/m2 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, potassium and magnesium before each cycle, audiometry, neuropathy, markers; adjustment: 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, reduce for hepatic impairment.
• Growth factor support (pegfilgrastim 6 mg subcutaneously 24 to 72 hours after chemotherapy) for febrile neutropenia.

Residual mass. Assess with CT and FDG-PET 6 or more weeks after chemotherapy. A residual mass over 3 cm that is PET negative is observed. A PET-positive or enlarging mass needs biopsy or resection (surgery is difficult because of fibrosis). Routine radiotherapy to the mediastinum is not given.

Relapse. Salvage chemotherapy with ifosfamide, paclitaxel and cisplatin, or high dose chemotherapy with autologous stem cell rescue, at a specialist centre.

Monitoring. Examination, serum markers and CT of the chest every 3 to 4 months in year 1, every 6 months in year 2, then annually to year 5. Lifelong cardiovascular risk review, testosterone and fertility follow up, and surveillance for second cancers.

Referral and escalation.

• Urgent referral to a germ cell tumour centre on suspicion, before biopsy.
• Same day oncology for superior vena cava syndrome, with chemotherapy started urgently once the diagnosis is secure.

Special groups.

• Fertility: sperm banking before the first cycle.
• Smokers and older adults: higher bleomycin lung toxicity, so use etoposide and cisplatin.
• Africa and low resource settings: late presentation is common, and the curability with cisplatin based therapy justifies referral for treatment.