Mediastinal Teratoma with Malignant Transformation

Mediastinal teratoma with malignant transformation is a germ cell tumour of the anterior mediastinum in which a non-germ-cell malignancy (somatic type malignancy) arises within teratomatous tissue. The transformed component is usually a sarcoma, adenocarcinoma or primitive neuroectodermal tumour, and it determines behaviour and treatment more than the germ cell origin does.

Mediastinal germ cell tumours form 1% to 4% of all germ cell tumours. Somatic type malignancy is reported in a minority of testicular teratomas and in a larger share of mediastinal non-seminomatous tumours. Most patients are men aged 20 to 40.

Klinefelter syndrome (47,XXY) is associated with mediastinal non-seminomatous germ cell tumours. Haematological malignancy of shared clonal origin (acute myeloid leukaemia, myelodysplastic syndrome) can accompany them.

Pathophysiology. Teratomatous elements contain tissue from all three germ layers, and a mature element can acquire further genetic change and become malignant. Isochromosome 12p is often retained in the transformed clone, which shows that it descends from the germ cell tumour.

Transformed histologies. Rhabdomyosarcoma, angiosarcoma, leiomyosarcoma, adenocarcinoma (often intestinal type), squamous carcinoma and primitive neuroectodermal tumour are the commonest. Each responds poorly to cisplatin based chemotherapy for germ cell tumours.

Behaviour. Tumours are bulky and invade the pericardium, great vessels, lung and chest wall. Markers (AFP and beta-hCG) are often normal or only mildly raised, because the malignant element does not secrete them. Prognosis is poor unless resection is complete.

• Chest pain, cough, dyspnoea, fever, weight loss and superior vena cava obstruction from a large anterior mass.
• Pleural and pericardial effusions, and haemoptysis when the tumour invades the lung or bronchus.
• Rupture into the bronchus or pleura can cause expectoration of hair or sebaceous material, pneumonitis or empyema.
• Growth of the mass during or after chemotherapy with normal markers raises the question of growing teratoma syndrome or of malignant transformation.

Red flags.

• Superior vena cava syndrome, stridor or respiratory failure.
• Pericardial tamponade.
• Sudden chest pain with dyspnoea after rupture.

• CT of the chest, abdomen and pelvis with contrast: heterogeneous anterior mediastinal mass with fat, calcification, cystic change and a solid enhancing nodule, often with invasion of adjacent structures. MRI helps define pericardial, cardiac and vascular involvement.
• Serum AFP, beta-hCG and lactate dehydrogenase before any treatment.
• Image directed core biopsy of the solid enhancing component (not the cystic part) with several cores. Immunohistochemistry selects the transformed lineage: desmin and myogenin (rhabdomyosarcoma), CD31 and ERG (angiosarcoma), CDX2 and cytokeratin 20 (intestinal type adenocarcinoma), cytokeratin and p63 (squamous carcinoma), and SALL4 and OCT3/4 for germ cell elements.
• Testicular ultrasound, karyotype, FBC and film, and MRI of the brain when metastases are suspected.
• Baseline creatinine, liver tests, audiometry, lung function with DLCO and echocardiography before chemotherapy, and sperm banking.
• FDG-PET is used to detect viable disease after chemotherapy.

Differential diagnosis.

• Mature teratoma and growing teratoma syndrome
• Mediastinal non-seminomatous germ cell tumour, seminoma, yolk sac tumour and embryonal carcinoma
• Thymoma and thymic carcinoma
• Lymphoma
• Primary mediastinal sarcoma
• Sarcomatoid carcinoma and metastatic testicular teratoma

Complete surgical resection of all disease is the basis of cure, because the transformed element is relatively resistant to chemotherapy. Treatment is planned by a germ cell tumour and sarcoma team.

Surgery. Resection by median sternotomy or clamshell incision, with resection of involved pericardium, pleura, lung, phrenic nerve and vascular structures as needed, after chemotherapy for any germ cell component. Incomplete resection leads to early local recurrence.

Chemotherapy for the germ cell component (raised markers or viable germ cell tumour).

• Bleomycin, etoposide and cisplatin: bleomycin 30 units IV on days 1, 8 and 15, etoposide 100 mg/m2 IV daily on days 1 to 5 and cisplatin 20 mg/m2 IV daily on days 1 to 5 with hydration and magnesium and potassium supplements, every 21 days for 4 cycles; maximum bleomycin 360 units over 4 cycles (lifetime ceiling 400 units) and 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.
• Pegfilgrastim 6 mg subcutaneously once, 24 to 72 hours after each cycle; maximum 6 mg each cycle; monitoring: FBC, bone pain; adjustment: none for renal or hepatic impairment, omit within 14 days before the next cycle.

Chemotherapy for the transformed component. Regimens follow the transformed histology.

• Sarcoma (rhabdomyosarcoma, leiomyosarcoma, angiosarcoma, undifferentiated pleomorphic sarcoma): doxorubicin 75 mg/m2 total each cycle (25 mg/m2 daily on days 1 to 3) with ifosfamide 10 g/m2 total (2.5 g/m2 daily on days 1 to 4) IV, with mesna at a total of 60% to 100% of the ifosfamide dose and pegfilgrastim 6 mg subcutaneously 24 to 72 hours after chemotherapy, every 3 weeks for up to 6 cycles; maximum doxorubicin cumulative working ceiling 450 mg/m2 and ifosfamide 10 g/m2 each cycle; monitoring: FBC, creatinine, urinalysis for haematuria, neurological status (ifosfamide encephalopathy), echocardiography; 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, reduce doxorubicin for hepatic impairment (bilirubin 20 to 51 micromol/L by 50%, 53 to 85 micromol/L by 75%, over 85 micromol/L avoid).
• Adenocarcinoma and squamous carcinoma are treated with a regimen for that carcinoma, planned by a medical oncologist. Primitive neuroectodermal tumour is treated with an Ewing type regimen at a sarcoma centre.

Radiotherapy. Postoperative radiotherapy to the mediastinum (50 to 60 Gy in 25 to 30 fractions) is considered after incomplete resection or for a sarcoma with positive margins, balancing risks to lung, heart and spinal cord.

Relapse. Salvage chemotherapy by histology, re-resection when feasible, and high dose chemotherapy with stem cell rescue for the germ cell component in specialised centres.

Monitoring. CT of the chest every 3 months for 2 years, then every 6 months to year 5, with AFP and beta-hCG at each visit. FBC for haematological malignancy. Lifelong cardiovascular, endocrine and fertility follow up.

Referral and escalation.

• Referral to a germ cell tumour centre with sarcoma expertise before biopsy or surgery.
• Same day oncology for superior vena cava syndrome, tamponade or neutropenic sepsis.
• Haematology review for any cytopenia or abnormal film.

Special groups.

• Klinefelter syndrome: endocrine review for hypogonadism.
• Fertility: sperm banking before the first cycle.
• Smokers and older adults: higher bleomycin lung toxicity, so use etoposide and cisplatin without bleomycin when lung function is limited.
• Pregnancy in partners: contraception during chemotherapy and for 6 months after.