Mixed Germ Cell Tumour of the Testis

Mixed germ cell tumour is a testicular cancer that contains two or more germ cell histologies in the same tumour. It is the commonest form of testicular germ cell tumour, making up about 40 to 50% of cases.

Peak age is 20 to 35 years. The usual combinations are embryonal carcinoma with teratoma and yolk sac tumour, or embryonal carcinoma with seminoma. Overall cure is over 90%.

Any nonseminomatous element places the tumour in the nonseminomatous group, even when seminoma is the largest part.

Pathophysiology. The tumour arises from germ cell neoplasia in situ and carries isochromosome 12p. Germ cell neoplasia in situ is found in the contralateral testis in about 5%, and a second tumour in the other testis occurs in about 2 to 3%.

Risk factors are cryptorchidism, previous germ cell tumour, a family history, infertility and testicular atrophy.

Behaviour follows the most aggressive component. Embryonal carcinoma and choriocarcinoma spread early, and teratoma resists chemotherapy.

Markers:

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

A raised AFP with seminoma only histology means a nonseminomatous component was not sampled, and the tumour is managed as nonseminomatous.

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

Stage I relapse risk rises with lymphovascular invasion (the main factor) and a predominance of embryonal carcinoma.

A painless or mildly painful testicular mass, sometimes with a short history. Metastatic disease causes back pain, cough, dyspnoea, haemoptysis, a neck or abdominal mass, gynaecomastia and weight loss. Brain metastases cause headache, seizures or focal deficits.

A young man with an unexplained retroperitoneal or mediastinal mass, lung nodules, or a markedly raised hCG or AFP needs testicular examination and ultrasound.

• Scrotal ultrasound of both testes: a heterogeneous mass with calcification, cystic areas and microlithiasis.
• AFP, beta-hCG and lactate dehydrogenase before orchidectomy, repeated after it until normal.
• CT of chest, abdomen and pelvis with contrast. MRI of the brain when hCG is over 5000 IU/L, lung or bone metastases are present, or neurological symptoms occur.
• Pathology: each component with its percentage, lymphovascular invasion, rete testis invasion, pT stage and germ cell neoplasia in situ. Immunostains: OCT3/4 and CD117 (seminoma), CD30 (embryonal carcinoma), AFP and glypican-3 (yolk sac), beta-hCG (trophoblast).
• Pre-treatment: semen analysis, testosterone, creatinine clearance, audiometry, lung function with carbon monoxide transfer factor, HIV and hepatitis tests.

Differential diagnosis.

• Pure seminoma
• Pure embryonal carcinoma, yolk sac tumour or teratoma
• Testicular lymphoma
• Sex cord stromal tumour
• Epididymo orchitis or abscess
• Extragonadal germ cell tumour
• Burned out testicular tumour

• Offer sperm banking before orchidectomy or any treatment.
• Radical inguinal orchidectomy with high ligation of the cord. Never biopsy through the scrotum.
• Stage I:
  • Without lymphovascular invasion: surveillance, with relapse in about 15 to 20%.
  • With lymphovascular invasion: surveillance (relapse about 40 to 50%), 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: BEP for 3 cycles (good risk) or 4 cycles (intermediate and poor risk).
  • 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).
  • VIP for 4 cycles when bleomycin is contraindicated: 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.
  • 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. Give pegfilgrastim 6 mg subcutaneously once each cycle 24 hours after chemotherapy in poor risk disease or after neutropenic complications. Neutropenic fever needs intravenous antibiotics within 60 minutes.
  • Cisplatin needs creatinine clearance over 60 mL/min. Stop bleomycin for cough, dyspnoea or falling transfer factor, avoid it in eGFR under 60 or lung disease, and limit inspired oxygen during anaesthesia.
• Residual masses over 1 cm after chemotherapy with normal markers: surgical resection of all sites, since about 40% contain teratoma and about 10% contain viable cancer. PET-CT is not reliable in this setting.
• Relapse: salvage chemotherapy with 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, at a specialist centre.
• Late effects: hearing loss, neuropathy, kidney impairment, Raynaud phenomenon, secondary cancers, cardiovascular disease, hypogonadism and infertility.

Monitoring. Surveillance: clinical review with markers every 2 to 3 months in year 1, every 3 to 4 months in year 2, then every 6 months to year 5, with CT of the abdomen at about 3 and 12 months. After chemotherapy: markers and review every 1 to 3 months in year 1, then spaced out, with CT at 3 to 6 months and as directed. Yearly testosterone, lipids, glucose and blood pressure, and testicular self-examination of the other testis.

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