Primary Mediastinal Nonseminomatous Germ Cell Tumour

Primary mediastinal nonseminomatous germ cell tumour is a malignant germ cell tumour of the anterior mediastinum with yolk sac tumour, embryonal carcinoma, choriocarcinoma or teratomatous elements, alone or mixed. It has a poorer prognosis than testicular nonseminomatous tumours and always falls in the poor risk group.

It accounts for about 40% to 50% of primary mediastinal germ cell tumours and about 1% to 3% of all germ cell tumours. It affects men aged 20 to 35, and is rare in women and in children (where it presents at younger ages).

About 20% of patients have Klinefelter syndrome (47,XXY). Haematological malignancy (acute myeloid leukaemia, myelodysplastic syndrome, histiocytic sarcoma) develops in about 2% to 6%, from a clonal origin shared with the germ cell tumour.

Pathophysiology. Isochromosome 12p is typical. Yolk sac elements secrete AFP, and choriocarcinoma and syncytiotrophoblastic elements secrete beta-hCG. Teratomatous elements can undergo somatic type malignant transformation.

Behaviour. Disease is bulky at diagnosis and spreads early to lung, liver, brain, bone and nodes. Five year survival is about 40% to 50% with cisplatin based chemotherapy and surgery. Raised markers after treatment, non-pulmonary visceral metastases and haematological malignancy worsen outcome.

• Chest pain, cough, dyspnoea, fever, weight loss, haemoptysis and superior vena cava syndrome.
• Gynaecomastia from raised hCG.
• Cytopenias or leucocytosis from marrow involvement or haematological malignancy.
• Neurological deficits with brain metastases (choriocarcinoma, very high hCG).

Red flags.

• Superior vena cava syndrome, stridor or respiratory failure.
• Haemoptysis or haemothorax from tumour bleeding (choriocarcinoma).
• Tumour lysis (rising potassium, urate, phosphate and creatinine) after the first cycle.
• Neutropenic sepsis during chemotherapy.
• Headache, seizure or focal deficit.

• CT of chest, abdomen and pelvis: large heterogeneous anterior mediastinal mass with necrosis, cystic areas, fat and calcification (teratoma) and vascular invasion.
• Serum AFP, beta-hCG and lactate dehydrogenase before treatment. AFP over 1,000 ng/mL or very high hCG with a typical mass supports the diagnosis when biopsy is unsafe, and chemotherapy can start without biopsy in an unstable patient.
• Core biopsy when stable: immunohistochemistry (glypican-3, SALL4, AFP, OCT3/4, CD30, hCG, cytokeratin).
• Testicular ultrasound, karyotype and FBC (Klinefelter syndrome, haematological disorders), MRI brain, and bone marrow examination when counts are abnormal.
• FBC, creatinine, uric acid, potassium, phosphate, liver tests, audiometry, lung function with DLCO, and sperm banking.

Differential diagnosis.

• Mediastinal seminoma
• Lymphoma and thymic carcinoma
• Thymoma
• Metastatic testicular nonseminomatous tumour
• Sarcoma and small cell carcinoma
• Mature teratoma

Treatment is chemotherapy first, followed by resection of residual disease.

First line 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. Tumour lysis laboratory tests are added for the first cycle.
• 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 (primary prophylaxis).
• Tumour lysis prophylaxis with intravenous hydration and urate lowering therapy before the first cycle. Test for G6PD deficiency before rasburicase.
• Very high hCG or bulky tumours: start with a reduced first cycle (etoposide and cisplatin) in a monitored setting.

Surgery. Resection of all residual disease after marker normalisation, by an experienced thoracic team (median sternotomy, with lung, pericardium or phrenic nerve resection as needed). Pathology of the residue (necrosis, mature teratoma or viable carcinoma) directs further therapy. Viable cancer is followed by 2 further cycles of cisplatin based chemotherapy. Persistently raised AFP or hCG after chemotherapy indicates viable disease and needs salvage chemotherapy before surgery.

Salvage therapy (relapse or incomplete response).

• 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, especially in the first relapse.

Monitoring. Markers and CT every 4 to 6 weeks during chemotherapy, then every 2 to 3 months in year 1, every 3 months in year 2, then 6 monthly to year 5. Lifelong surveillance for haematological malignancy (FBC), cardiovascular risk and endocrine late effects.

Referral and escalation.

• Same day referral to a germ cell tumour centre on suspicion, before biopsy or delay.
• Urgent chemotherapy for superior vena cava syndrome with raised markers and a typical mass.
• Haematology review for any cytopenia or abnormal film.

Special groups.

• Klinefelter syndrome: endocrine review for hypogonadism, and counselling.
• Children and adolescents: treat at a paediatric oncology centre with weight adjusted cisplatin based regimens.
• Women: rare, and treated with the same chemotherapy.
• Fertility: sperm banking before the first cycle (it is often not possible in an emergency, so cryopreservation after the first cycle is discussed).
• Pregnancy in partners: contraception during and for 6 months after chemotherapy.