Testicular Choriocarcinoma

Testicular choriocarcinoma is a highly malignant germ cell tumour made of syncytiotrophoblast and cytotrophoblast cells that secrete beta-hCG. Pure choriocarcinoma is rare, under 1% of testicular germ cell tumours, and trophoblastic elements occur in about 8% of mixed tumours.

It is the most aggressive germ cell tumour. It spreads early by the blood to the lung, liver, brain, bone and gastrointestinal tract, often when the testicular primary is small or non-palpable.

Pathophysiology. The tumour arises from germ cell neoplasia in situ and carries isochromosome 12p. Histology shows sheets of cytotrophoblast and syncytiotrophoblast, with extensive haemorrhage and necrosis.

Immunostaining is positive for beta-hCG, inhibin and cytokeratin, and negative for OCT3/4 and CD30.

Marker: beta-hCG is very high, often over 50 000 IU/L, with a half life of about 24 to 36 hours. Raised hCG causes gynaecomastia and, by cross-reaction with the thyroid stimulating hormone receptor, hyperthyroidism.

Because of fragile new vessels, choriocarcinoma bleeds. Haemorrhage into metastases (lung, brain, gastrointestinal tract, retroperitoneum) can cause sudden deterioration, especially in the first days of chemotherapy (choriocarcinoma syndrome).

Prognosis falls with high hCG and non-pulmonary visceral metastases. Most patients fall in the poor risk group, with five year survival of about 50 to 70%.

Presentation is usually with metastatic disease: haemoptysis, dyspnoea, chest pain, back or abdominal pain, gastrointestinal bleeding, headache, seizures or focal neurological deficit from brain haemorrhage, and weight loss. Gynaecomastia and thyrotoxic features (tremor, weight loss, palpitations). The testis may be normal or only mildly enlarged, and may have a tiny nodule or scar.

Brain, lung or gastrointestinal haemorrhage and respiratory failure are the main emergencies.

• Beta-hCG (often over 50 000 IU/L), AFP and lactate dehydrogenase. Check thyroid function. A very high hCG with a normal testicular ultrasound still needs the testis to be examined and imaged for a burned out primary.
• Scrotal ultrasound: a small or heterogeneous mass with haemorrhage and calcification, or no mass.
• CT of chest, abdomen and pelvis with contrast, and MRI of the brain in all patients, since brain metastases are frequent.
• Haemoglobin, clotting screen, liver and kidney function, and blood group and crossmatch, because bleeding is likely.
• Pathology after orchidectomy when safe. In an unstable patient with a characteristic picture and markedly raised hCG, chemotherapy can start before orchidectomy.
• Before chemotherapy: semen analysis, creatinine clearance, audiometry and lung function (when feasible), and HIV and hepatitis tests.

Differential diagnosis.

• Mixed germ cell tumour with trophoblastic elements
• Seminoma with raised hCG
• Embryonal carcinoma
• Extragonadal germ cell tumour
• Metastatic carcinoma from another site
• Gestational trophoblastic disease (rare in men) or hCG-secreting non-germ cell cancers
• Laboratory artefact (phantom hCG, hook effect at very high levels)

• Offer sperm banking if time and condition allow, and do not delay urgent chemotherapy for it.
• Stabilise first: oxygen, transfusion of red cells and platelets to keep platelets over 50 x 10^9/L, correction of coagulopathy, and treatment of thyrotoxicosis if present (propranolol 10 to 40 mg orally three times daily, or carbimazole 20 to 40 mg daily).
• Radical inguinal orchidectomy once stable, with high ligation of the cord, or after the first cycle of chemotherapy when the patient is too unwell.
• Chemotherapy in a specialist oncology centre, started promptly:
  • For extensive disease or respiratory compromise, a low dose induction, such as cisplatin 20 mg/m2 and etoposide 100 mg/m2 on days 1 and 2, then full BEP, may lower the risk of fatal haemorrhage.
  • BEP for 4 cycles every 21 days: bleomycin 30 units intravenously on days 1, 8 and 15, etoposide 100 mg/m2 on days 1 to 5, and cisplatin 20 mg/m2 on days 1 to 5 with hydration (1 to 2 L of saline before and after, plus magnesium and potassium). Use VIP for 4 cycles (etoposide 75 mg/m2, ifosfamide 1.2 g/m2 and cisplatin 20 mg/m2 on days 1 to 5, with mesna totalling 60 to 100% of the ifosfamide dose) when bleomycin is contraindicated or lung disease is severe.
  • Antiemetics for high emetic risk: ondansetron 8 mg, dexamethasone 12 mg and aprepitant 125 mg on day 1, then aprepitant 80 mg on days 2 and 3 with dexamethasone 8 mg on days 2 to 4.
  • Give filgrastim 5 micrograms/kg subcutaneously daily from 24 hours after chemotherapy, or pegfilgrastim 6 mg once each cycle, since poor risk disease needs full dose intensity. Neutropenic fever needs intravenous antibiotics within 60 minutes.
  • Cisplatin needs creatinine clearance over 60 mL/min. Stop bleomycin for lung toxicity, and limit inspired oxygen during anaesthesia.
• Brain metastases: chemotherapy plus whole brain radiotherapy (about 30 Gy in 10 to 15 fractions), or surgery or stereotactic radiosurgery for limited lesions.
• Residual masses over 1 cm after chemotherapy with normal markers: surgical resection.
• Relapse: salvage chemotherapy (TIP or VeIP) or high dose carboplatin and etoposide with stem cell rescue, at a specialist centre.
• Late effects: hearing loss, neuropathy, kidney impairment, secondary cancers, hypogonadism and infertility.

Special groups. Patients with very high hCG and large volume disease need an intensive care bed early, with bleeding precautions and close respiratory monitoring.

Monitoring. beta-hCG should fall by at least half every 2 to 3 days in the first weeks. Markers before each cycle, then every 1 to 3 months for the first year, with imaging after chemotherapy and at intervals set by oncology.

Referral and escalation. Immediate referral to a specialist oncology centre. Urgent escalation for haemoptysis, neurological deficit, gastrointestinal bleeding, respiratory failure or neutropenic fever.