Testicular Mixed Germ Cell Tumour

Description

Mixed germ cell tumours (MGCTs) are a subgroup of non-seminomatous testicular germ cell tumours, characterised by the presence of two or more germ cell components within the same tumour. The components may include seminoma, embryonal carcinoma, yolk sac tumour, teratoma, or choriocarcinoma. Like other testicular tumours, MGCTs primarily occur in the testicles but can occasionally arise in extragonadal sites such as the mediastinum, retroperitoneum, or pineal gland in the brain.

Pathogenesis

The exact pathogenesis of MGCTs is not clearly understood. However, they are believed to originate from germ cell neoplasia in situ (GCNIS), a precursor lesion of invasive germ cell tumours. From the GCNIS cells, the tumour diversifies into various germ cell components, leading to the mixed nature of the tumour.

Epidemiology, Risk Factors & Associations

Mixed germ cell tumours account for around 60-70% of all germ cell tumours, making them not only the most common type of germ cell tumour but also the most prevalent non-seminomatous germ cell tumour (40-50%). They typically present in the peak age group for germ cell tumours, which is 15-35 years.

Risk factors include:

• Cryptorchidism (Undescended Testis): This is a significant risk factor for all testicular tumours, including MGCTs, with a 3-5 times increased risk compared to the general population.
• Family History of Testicular Cancer: Men with a brother or father affected by testicular cancer are at a significantly higher risk.
• Previous History of Testicular Cancer: Men who have had testicular cancer in one testis are at an increased risk of developing a tumour in the other testis.
• Klinefelter Syndrome: Men with this chromosomal disorder have an approximately 50 times increased risk of testicular germ cell tumours, including MGCTs.
• Infertility: Men with infertility issues are at a higher risk, as there is an association between impaired spermatogenesis and the development of testicular germ cell tumours.

Clinical Features

Patients with mixed germ cell tumours commonly present with a painless testicular swelling or lump. Occasionally, acute pain may occur due to haemorrhage or infarction within the tumour. Symptoms related to metastatic disease, such as back pain (from retroperitoneal lymph node metastasis) or respiratory symptoms (from lung metastasis), can also occur. Gynaecomastia may be seen in some cases due to hormonal secretion by certain components of the tumour, particularly choriocarcinoma.

Complications

Possible complications include metastasis, which most commonly involves the retroperitoneal lymph nodes, lungs, and less commonly, the liver, bones, and brain. Long-term complications can also arise from treatment, including infertility from chemotherapy or radiotherapy, and psychological distress.

Subtypes

Subtypes of MGCTs are determined by the germ cell components present. The most common combinations include seminoma and embryonal carcinoma, seminoma and teratoma, and embryonal carcinoma and teratoma. Rarer components such as yolk sac tumour and choriocarcinoma can also be present.

• Seminoma and Embryonal Carcinoma: These are seen together in about 30-40% of MGCTs. Seminomas are typically more slow-growing and less aggressive than embryonal carcinomas.
• Seminoma and Teratoma: This combination occurs in around 20-30% of MGCTs. The presence of a teratoma component may increase the likelihood of post-treatment residual masses.
• Embryonal Carcinoma and Teratoma: Approximately 15-25% of MGCTs feature both these components. This combination often presents with a more aggressive clinical course due to the nature of embryonal carcinoma.
• Yolk Sac Tumour Component: This element is less common, found in about 5-10% of MGCTs. However, when present, yolk sac tumour tends to significantly increase the serum alpha-fetoprotein (AFP) level.
• Choriocarcinoma Component: This is the rarest component, seen in less than 1% of MGCTs. Despite its rarity, choriocarcinoma is highly aggressive and is associated with elevated serum beta-human chorionic gonadotropin (β-HCG) levels.

Pathological Features

Histopathology

On gross examination, mixed germ cell tumours typically appear as heterogeneous masses with areas of necrosis and haemorrhage. Histologically, the different components of the tumour can be identified by their characteristic features:

• Seminoma: Large cells with clear cytoplasm, separated by thin fibrous septa with lymphocytic infiltrate.
• Embryonal Carcinoma: High-grade cells with large nucleoli, often with a glandular or papillary structure.
• Yolk Sac Tumour: Schiller-Duval bodies (resembling a glomerulus), microcystic or reticular pattern, and positive staining for AFP.
• Teratoma: Differentiation into somatic tissue types (ectodermal, mesodermal, and endodermal).
• Choriocarcinoma: Presence of cytotrophoblasts and syncytiotrophoblasts, and positive staining for beta-hCG.

Serology

• Alpha-fetoprotein (AFP): Elevated levels are seen when a yolk sac tumour or embryonal carcinoma component is present. AFP is not usually elevated in pure seminomas, so an elevated AFP level is suggestive of a non-seminomatous component such as MGCT.
• Beta-human chorionic gonadotropin (beta-hCG): This can be raised in seminomas, choriocarcinomas, and to a lesser extent, embryonal carcinomas. Elevated beta-hCG levels can cause symptoms such as gynaecomastia due to its cross-reactivity with luteinising hormone receptors.
• Lactate dehydrogenase (LDH): This can be elevated in germ cell tumours and may act as a surrogate marker for tumour burden.

Radiological Features

General Features

• Typically present as a testicular mass, often with areas of haemorrhage, necrosis, or cystic degeneration.
• Typically heterogenous in appearance due to the mixed histological components.

Ultrasound

• Usually first-line imaging modality for evaluation of a testicular mass.
• MGCTs appear as mixed echogenic lesions.
• Some components such as teratomas can cause shadowing due to calcification.

MRI

• Heterogeneous signal intensity can be seen on both T1 and T2-weighted images, reflecting the mixed components.
• High T1 signal from haemorrhagic components or fat in teratoma can help to suggest the diagnosis.

CT

• This is typically used for staging, to evaluate retroperitoneal lymph nodes and potential distant metastasis.

Grading and Staging

The American Joint Committee on Cancer (AJCC) and the International Germ Cell Cancer Collaborative Group (IGCCCG) have provided staging systems for testicular germ cell tumours. These consider the size and extent of the primary tumour, involvement of lymph nodes and presence of distant metastasis, along with serum levels of tumour markers.

Differential Diagnosis

• Pure Seminoma: This is differentiated from MGCTs by the lack of heterogeneity in both histological and radiological features. Serum AFP is not elevated in pure seminomas.
• Leydig Cell Tumour: These tumours are typically smaller and may show signs of androgen secretion, which is not seen in MGCTs. They also do not elevate serum AFP or beta-hCG.
• Metastasis to the Testis: Testicular metastases are rare but can mimic primary germ cell tumours. A known primary malignancy and systemic symptoms can help in differentiating.
• Orchitis: This is an inflammatory condition which can cause testicular swelling. However, it typically presents with pain, erythema, and systemic symptoms such as fever.

Management

• A radical inguinal orchiectomy is generally performed for diagnosis and treatment.
• Depending on the stage, adjuvant treatment may include surveillance, chemotherapy, or radiotherapy.
• The specific components present in the MGCT may influence treatment, as certain components such as teratomas and choriocarcinomas can be more resistant to certain treatments.
• Regular follow-up with physical examination, tumour markers, and imaging is important for early detection of recurrence.