Nonseminomatous Germ Cell Tumour

Nonseminomatous germ cell tumour is a group of testicular cancers that includes embryonal carcinoma, yolk sac tumour, teratoma, choriocarcinoma and mixed tumours.

Mixed tumours that contain seminoma and nonseminomatous elements are treated as nonseminomatous disease.

It makes up about 40 to 50% of testicular germ cell tumours and is the commonest form in men aged 15 to 35. About 60 to 70% present at stage I, and the overall cure rate is over 90%, even in metastatic disease.

Pathophysiology. Risk factors are cryptorchidism, previous germ cell tumour, a family history, infertility, and testicular atrophy. All germ cell tumours carry the isochromosome 12p, and arise from germ cell neoplasia in situ.

Tumour markers:

• AFP (yolk sac component), with half life of 5 to 7 days.
• Beta-hCG (syncytiotrophoblastic cells), with half life of about 24 to 36 hours.
• Lactate dehydrogenase, reflecting tumour bulk.

Marker categories after orchidectomy:

• S1: AFP under 1000 ng/mL, hCG under 5000 IU/L, lactate dehydrogenase under 1.5 times the upper limit.
• S2: AFP 1000 to 10 000 ng/mL, hCG 5000 to 50 000 IU/L, or lactate dehydrogenase 1.5 to 10 times the limit.
• S3: AFP over 10 000 ng/mL, hCG over 50 000 IU/L, or lactate dehydrogenase over 10 times the limit.

Prognostic groups in advanced disease:

• Good: testicular or retroperitoneal primary, no non-pulmonary visceral metastases and S1 markers. Five year survival about 95%.
• Intermediate: testicular or retroperitoneal primary, no non-pulmonary visceral metastases and S2 markers. About 80 to 85%.
• Poor: mediastinal primary, non-pulmonary visceral metastases, or S3 markers. About 50 to 70%.

Spread is through lymphatics to the retroperitoneum, and by blood to lung, liver, brain and bone.

Painless testicular mass or swelling, sometimes with pain. Metastatic disease causes back pain, cough, dyspnoea, haemoptysis, neck mass, abdominal mass, gynaecomastia, and headache or neurological signs from brain metastases. A young man with unexplained retroperitoneal or mediastinal mass, lung nodules, or markedly raised hCG or AFP needs a testicular examination and ultrasound, since an extragonadal or burned out primary is possible.

• Scrotal ultrasound: a heterogeneous mass with calcification, cystic areas and microlithiasis.
• AFP, beta-hCG and lactate dehydrogenase before orchidectomy, and repeated after it until normal, to define stage and prognostic group.
• CT of chest, abdomen and pelvis with contrast. MRI of the brain for hCG over 5000 IU/L, lung or bone metastases, or neurological symptoms.
• Pathology: histological components (percentages), lymphovascular invasion, rete testis involvement, pT stage and germ cell neoplasia in situ. Lymphovascular invasion marks high risk stage I disease.
• Pre-treatment: semen analysis, testosterone, creatinine clearance, audiometry, lung function with carbon monoxide transfer factor, HIV and hepatitis tests.

Differential diagnosis.

• Seminoma
• Testicular lymphoma
• Sex cord stromal tumour
• Epididymo orchitis or abscess
• Extragonadal germ cell tumour
• Burned out testicular tumour
• Metastasis from another cancer

• Offer sperm banking before orchidectomy or any treatment.
• Radical inguinal orchidectomy with high ligation of the cord. Never biopsy through the scrotum.
• Stage I:
  • Low risk (no lymphovascular invasion): surveillance, with relapse in about 15 to 20%.
  • High risk (lymphovascular invasion): surveillance (relapse about 40 to 50%), or adjuvant BEP for 1 cycle (relapse about 2 to 3%), or nerve sparing retroperitoneal lymph node dissection.
• Stage IIA or IIB with normal markers: nerve sparing retroperitoneal lymph node dissection or BEP for 3 cycles. With raised markers: primary chemotherapy.
• Stage IIC and III: chemotherapy for good risk with BEP for 3 cycles (or EP for 4), and for intermediate or poor risk with BEP for 4 cycles.
  • BEP is repeated 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 replacement).
  • VIP for 4 cycles when bleomycin is contraindicated: etoposide 75 mg/m2 on days 1 to 5, ifosfamide 1.2 g/m2 on days 1 to 5 and cisplatin 20 mg/m2 on days 1 to 5. Add mesna (total dose 60 to 100% of the ifosfamide dose) and hydration.
  • 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.
  • Do not reduce doses for neutropenia.
  • Use filgrastim 5 micrograms/kg subcutaneously daily from 24 hours after chemotherapy, or pegfilgrastim 6 mg once each cycle 24 hours after the last dose, in poor risk disease, VIP, or after neutropenic complications.
  • Neutropenic fever needs intravenous antibiotics within 60 minutes (for example piperacillin-tazobactam 4.5 g every 6 hours, adjusted to renal function).
  • Bleomycin cautions: stop for cough, dyspnoea or falling transfer factor, and avoid in eGFR under 60 or lung disease. Limit inspired oxygen during anaesthesia.
  • Cisplatin needs creatinine clearance over 60 mL/min, with monitoring of creatinine, magnesium, potassium, hearing and neuropathy.
• Residual masses over 1 cm after chemotherapy with normal markers: surgical resection (retroperitoneal lymph node dissection or resection of lung or other lesions), since about 40% contain teratoma and about 10% contain viable cancer. PET-CT is not reliable in nonseminomatous disease.
• Relapse or marker rise: salvage chemotherapy at a specialist centre.
  • TIP: paclitaxel 250 mg/m2 over 24 hours on day 1, ifosfamide 1.5 g/m2 and cisplatin 25 mg/m2 on days 2 to 5, with mesna.
  • Or VeIP.
  • Or high dose carboplatin and etoposide with stem cell rescue.
• Brain metastases: chemotherapy with whole brain radiotherapy or surgery or stereotactic treatment.
• Late effects: hearing loss, neuropathy, Raynaud, kidney impairment, secondary leukaemia (with cumulative etoposide over 2 g/m2), cardiovascular disease, hypogonadism and infertility.

Monitoring.

• Stage I surveillance: clinical review with markers every 2 to 3 months in year 1, every 3 to 4 months in year 2, every 6 months to year 5, with CT of the abdomen at about 3 and 12 months (more often in high risk disease).
• After chemotherapy: markers and clinical review every 1 to 3 months in year 1, then spaced out, with CT at 3 to 6 months and then as directed.
• Yearly testosterone, lipids, glucose and blood pressure.

Referral and escalation. Refer to urology, then to a specialist oncology centre for all stages. Urgent referral for symptomatic metastases, hCG over 50 000 IU/L, brain metastases, or neutropenic fever.