Testicular Seminomas

Testicular seminoma is the most common testicular cancer, seen in young to middle-aged males, classically characterised by uniform, large cells with clear cytoplasm, raised LDH and a homogenous hypoechoic mass on ultrasound.

Description

Seminomas are a subtype of testicular germ cell tumours (TGCTs), originating from germ cells of the seminiferous tubules in the testis. Characterised by their slow growth and tendency to remain localised, they account for approximately 50% of all TGCTs and are considered among the most treatable and curable cancers, particularly if caught in the early stages.

Extragonadal seminomas are relatively rare and can be found in locations such as the mediastinum, retroperitoneum, and pineal gland in the brain. These tumours generally behave in a similar way to their testicular counterparts and the treatment approach is similar as well.

Pathogenesis

Seminomas are a type of germ cell tumour primarily originating in the testes. These neoplasms are characterised by their origin from germ cells, with the majority occurring in the testes due to their role as the main site of germ cell residence in the male body. However, due to the potential migration of germ cells during embryonic development, seminomas may also develop in extragonadal locations such as the mediastinum, retroperitoneum, and the pineal gland in the brain. These instances are comparatively rare, but exhibit similar characteristics and behaviours to their testicular counterparts. As one of the two main types of testicular cancer, seminomas are notable for their relatively slow growth rate and high responsiveness to treatment, even when diagnosed at advanced stages.

Testicular seminomas originate from germ cells within the testes, specifically the primordial germ cells or gonocytes. The exact pathogenesis is not entirely understood; however, it is believed to start with the development of precursor lesions known as intratubular germ cell neoplasia (IGCN), which progress to invasive germ cell tumours. Genetic abnormalities, such as isochromosome 12p and mutations in genes like KIT, often accompany this progression.

Epidemiology, Risk Factors & Associations

• Seminomas are the most common form of testicular cancer, accounting for about 40-50% of all cases.
• Typically present in males aged 30-50 years (20-30 per 100,000 population), slightly older than the peak incidence of non-seminomas.

Risk factors include

• Cryptorchidism (Undescended Testis): This is one of the most significant risk factors for developing seminoma, increasing the risk by approximately 3-6 times. Around 10% of testicular cancer cases are linked to cryptorchidism. Importantly, this risk remains elevated even after surgical correction.
• Family History of Testicular Cancer: A man’s risk of developing a seminoma is increased by up to 10 times if a first-degree relative (brother or father) has had testicular cancer.
• Previous Testicular Cancer: A man who has been diagnosed with testicular cancer has a 12-18 times higher risk of developing a tumour in the other testis.
• Infertility is associated with higher risk of developing testicular cancer, including seminomas.
• Genetic conditionsL
  • Klinefelter Syndrome: Men with Klinefelter syndrome, characterised by an extra X chromosome (47,XXY), have a 20-50 times higher risk of developing germ cell tumours, including seminomas.
  • Down Syndrome: There is also evidence suggesting an increased risk of testicular cancer, including seminomas, in men with Down syndrome.
  • Testicular Dysgenesis Syndrome (TDS): TDS refers to a spectrum of conditions including cryptorchidism, hypospadias, poor semen quality and testicular germ cell cancer. The dysregulation of the sex-determining region Y (SRY) and mutations in the RNA-binding motif protein (RBMY) have been proposed to underlie TDS.
• HIV Infection, especially those with acquired immunodeficiency syndrome (AIDS), are at slightly increased risk.
• Socioeconomic Status: Testicular cancer, including seminomas, is more common in men with higher socioeconomic status. The reasons for this correlation are unclear but could be related to different lifestyle and health-seeking behaviours.
• Occupational Exposure: Certain chemical exposures, including those to certain pesticides and those in the leather industry, may be linked to a slightly higher risk of testicular cancer.
• Smoking: Some research suggests that long-term heavy smoking may slightly increase the risk of testicular cancer.

Clinical Features

• Most seminomas present as a painless testicular enlargement or mass, which is typically discovered incidentally by the patient.
• Less commonly, patients may experience discomfort or a dragging sensation in the scrotum.
• On examination, the tumour is usually firm and does not transilluminate.
• A small proportion of patients may present with symptoms of metastatic disease, such as back pain or respiratory symptoms.

Complications

Potential complications include infertility due to treatment, metastatic disease, hormonal imbalances due to impaired testicular function, psychological distress, and the potential for secondary malignancies from treatment-related effects.

Subtypes

Seminomas are generally classified into two subtypes: classic seminomas and spermatocytic seminomas. The classic seminoma is more common and is associated with younger age, whereas spermatocytic seminoma is less common and typically presents in older patients.

Classical Seminomas (Typical)

• This subtype is the most common, comprising about 85% of all seminomas.
• Classical seminomas are most often diagnosed in men aged between 30 and 50 years.
• Histologically, they are characterised by sheets of large, uniform tumour cells separated by fibrous septa with a significant lymphocytic infiltrate.
• Tumour cells in classical seminomas have a clear or pale cytoplasm with a large, centrally located nucleus and prominent nucleoli.
• An important feature of classical seminomas is the presence of interspersed non-neoplastic cells, known as syncytiotrophoblasts, which can produce human chorionic gonadotropin (hCG).
• Despite these cells, the levels of hCG tend to remain low or normal in classical seminomas, which can be helpful in distinguishing them from other germ cell tumours.

Spermatocytic Seminomas

• This subtype is less common, accounting for about 2% of all seminomas.
• Spermatocytic seminomas typically present in older men, with a median age at diagnosis of 65 years, and are considered to be a more benign variant of seminoma.
• The histological appearance of spermatocytic seminomas is distinctive, with a tripartite population of cells: small, medium, and large. These tumours lack the lymphocytic infiltrate seen in classical seminomas.
• An important feature distinguishing spermatocytic seminomas from classical seminomas is the absence of syncytiotrophoblast cells, and consequently, hCG levels are not elevated in these tumours.
• Spermatocytic seminomas have a favourable prognosis, and metastatic disease is exceedingly rare.

Pathological Features

Histopathology

Classical Seminoma

• On histopathology, these are comprised of sheets of large, uniform tumour cells, also known as seminoma cells, separated by fibrous septa.
• These tumour cells exhibit clear or pale cytoplasm with a large, centrally located nucleus and prominent nucleoli.
• There is usually a significant lymphocytic infiltrate, and the presence of interspersed non-neoplastic cells, known as syncytiotrophoblasts, is a key feature.

Spermatocytic Seminoma

• In spermatocytic seminomas, the histological features are different.
• These tumours demonstrate a tripartite population of cells – small, medium, and large, providing a clear contrast to the uniform appearance of classical seminoma cells.
• They lack the lymphocytic infiltrate seen in classical seminomas and the syncytiotrophoblast cells are absent.

Serology

• Serologically, seminomas are associated with elevated levels of certain markers in the blood.
• Classical seminomas can produce human chorionic gonadotropin (hCG) due to the presence of syncytiotrophoblast cells. However, the levels of hCG tend to remain low or normal in classical seminomas.
• In contrast, spermatocytic seminomas do not lead to elevated hCG levels due to the absence of syncytiotrophoblast cells.

Biochemistry

• Seminomas typically do not produce AFP (Alpha-Fetoprotein), and an elevated AFP is suggestive of a non-seminomatous germ cell tumour or a mixed germ cell tumour with a component of yolk sac tumour or embryonal carcinoma.
• LDH (lactate dehydrogenase) can be elevated in seminomas and is used as a marker of tumour burden and in the assessment of prognosis.

Genetics

• Genetic predisposition plays a critical role in the development of seminomas.
• Patients with a history of testicular dysgenesis, including cryptorchidism, have a higher risk of developing seminomas. This condition is associated with mutations in the INSL3 gene and its receptor RXFP2.
• Familial clusters of testicular germ cell tumours have led to the identification of the TGCT1 susceptibility locus on chromosome Xq27, though the specific gene and mutation have yet to be identified.
• Other genetic factors include mutations in genes associated with spermatogenesis, DNA repair, and telomerase function. These mutations contribute to the risk of seminoma, although they are not specifically associated with seminomas.
• Seminomas are typically diploid or near diploid, and they show a gain of the short arm of chromosome 12 (12p) in nearly all cases.
• This is in contrast to most solid tumours, which are aneuploid. This diploid or near-diploid status may explain why seminomas are highly sensitive to radiation and chemotherapy compared with other solid tumours.

Radiological Features

General Features

• Imaging characteristics of seminomas reflect their uniform cellular nature.

US

• Typically well-defined, homogeneously hypoechoic intratesticular solid mass without calcification or tunica invasion
• Rarely shows necrosis or cystic changes

CT

• Seminomas can show as a well-defined, heterogeneous, hypoattenuating mass.
• Lymph node enlargement, particularly in the retroperitoneum, may be present in cases of metastatic disease.

MRI

• T1: Hypointense
• T2: Hyperintense
• DWI: Restricted diffusion.

NM

• PET: Increased FDG uptake

Differential Diagnosis

• Non-seminomatous Germ Cell Tumour (NSGCT): The presence of elevated Alpha-Fetoprotein (AFP) levels is a distinguishing feature of NSGCTs, as seminomas do not produce AFP. NSGCTs are more heterogeneous in appearance radiologically, with mixed cystic and solid components, compared to the typically homogenous seminomas.
• Leydig Cell Tumour: Leydig cell tumours are often smaller and show characteristic signs of hypersecretion of testosterone such as precocious puberty in children or gynaecomastia in adults. They may also cause pain, unlike seminomas which are typically painless. Histologically, Leydig cell tumours are distinguished by the presence of Reinke crystals. They demonstrate characteristic gold-yellow to brown cut surface on gross pathology due to their lipoid content.
• Secondary Testicular Lymphoma: This is the most common testicular cancer in older men. Testicular lymphoma can be distinguished from seminoma by characteristic clinical features such as systemic lymphoma symptoms (fevers, night sweats, weight loss), elevated LDH, and often bilateral testicular involvement. Pathologically, lymphomas contain lymphoid cells rather than germ cells and B-cell markers on immunohistochemistry.
• Testicular Metastases: They typically present as multiple lesions and may be bilateral. The patient’s known primary malignancy and systemic symptoms can assist in differentiating from seminomas.
• Epidermoid Cyst of Testis: This is a benign lesion. Radiologically, it can show the ‘onion ring’ appearance with alternating hypo- and hyperintense concentric rings on T2-weighted MRI. It does not elevate serum tumour markers, differentiating it from seminomas.
• Adenomatoid Tumour: These are benign neoplasms that occur within the tunica albuginea and epididymis. They are usually asymptomatic, small (less than 2cm), and are often incidental findings. The lack of increased tumour markers and systemic symptoms help distinguish adenomatoid tumours from seminomas.
• Tuberculous Orchitis: This rare condition can mimic a testicular tumour. Key distinguishing factors include a history of tuberculosis, systemic symptoms (such as fever and weight loss), and the presence of granulomas on histopathology.

Management

Management is usually initiated by urology with a radical inguinal orchiectomy, providing both diagnosis and treatment. Depending on the stage and risk group, adjuvant treatment may include surveillance, chemotherapy, or radiotherapy. Seminomas are very responsive to radiotherapy. Long-term follow-up is required due to the potential for late recurrence.