Germ cell tumours are the most common malignancies of the male gonads, which is in significant contrast to the epithelial-stromal tumours of the female gonads. With the exception of spermatocytic seminoma, all of these tumours may occur in the ovary as well, albeit at much lower frequency.
Epidemiology
Germ cell tumours in adult men are uncommon but are increasing in incidence. It is the most common malignancy of young adult men with a median age of diagnosis of 34. Classical seminomas, the most common type, are typically diagnosed 10 years later than non-seminomas which may represent their less aggressive features.
There is a large geographical variation in incidence, with the highest rates in northern Europe (Norway, Sweden, Denmark and Germany) and New Zealand Maoris (7-8/100,000). Lowest rates occur in other non-European groups of Africa and Asia (2/100,000).
An important epidemiological features of germ cell tumours is that men born in Scandinavia during World War II had a very low incidence. This suggests that causative factors occur early in life or during foetal development.
Aetiology and Pathogenesis
Given the increased frequency of germ cell tumours in the male gonads versus the female gonads, the continual turnover of gametes in the testis is thought to be of significant importance in the pathogenesis of male germ cell tumours.
- Cryptoorchidism is an extensively studied and commonly associated factor, with a 3.5 increase in relative risk. In the event of a single undescended testis, the normal testis is also at elevated risk of malignancy.
- There is a suggestion that hypospadias and inguinal hernia are also risks but there is less evidence available
- Intrauterine growth restriction is associated with an increased risk of testicular cancer in case-control studies
- There is limited evidence for causes in adult life, although there is an association with low physical activity and high socio-economic class.
- Immunosuppression may increase the likelihood of developing testicular cancer
- Male infertility is associated with a 9.3 relative risk of developing malignancy.
- There is limited evidence regarding the theory of exposure to maternal oestrogens during development in the womb.
- About 1-2% of germ cell tumours have a hereditary component to their aetiology. Children of a men with a germ cell tumour have a relative risk of 2 for developing a tumour themselves.
There appears to be no difference in the aetiology of seminomatous and non-seminomatous germ cell tumours.
Pathogenesis
Whatever the initiator/s of germ cell malignancy are, there seems to be a high association with intratubular germ cell neoplasia, unclassified. The prevelance of this condition matches the expected incidence of germ cell malignancy; with <1% of normal men affected, 2-3% of men with cryptoorchidism, and 5% of men with a previously diagnosed germ cell malignancy in the contralateral testis.
Natural History
The natural history is dependent on the subtype of germ cell tumour.
- Seminomas typically remain localised or spread to lymph nodes. The most commonly involved nodes are in the para-aortic region, and further spread may occur to the mediastinum and left supraclavicular fossa. They may occasionally become more aggressive and spread haematogenously to the lungs. Less commonly involved organs include brain, liver and bone.
- Non-seminomas are usually more aggressive and spread haematogenously to similar sites.
Clinical Presentation
Symptoms
Most patients present with a painless swelling in the affected testis. Occasionally other symptoms may be present such as pain or 'dragging' feelings. Advanced disease presents with symptoms related to the site of spread; such as abdominal or back pain for para-aortic nodes. Incidental abnormalities on blood tests or imaging may also lead to diagnosis in asymptomatic patients.
Signs
Examination usually reveals a firm, enlarged testis. Advanced cases may be fixed to the scrotum. The remaining examination may be normal although lymph nodes in the supraclavicular fossa or axilla may be palpable. Gynaecomastia may develop in non-seminomatous germ cell tumours.
Imaging
Scrotal ultrasound has a sensitivity close to 100% for the detection of a testicular mass.
CT imaging of the chest and abdomen is a vital staging investigation.
Bloods
There are two important tumour markers, which are typically not elevated for seminoma:
- Alpha fetoprotein (AFP) is elevated in teratomas and yolk sac tumours.
- β-human chorionic gonadotrophin (β-hCG) is produced by tumours that contain syncytiotrophoblastic components.
Lactate dehydrogenase (LDH) is not a specific marker but indicates tumour burden.
Tumour Features
Summary of Germ Cell Tumours
There are a number of germ cell tumours; the table below summarises the important similarities and differences:
| Germ Cell Tumour | Macroscopic | Microscopic | IHC | Genetics | Markers | Prognosis |
|---|---|---|---|---|---|---|
| Classical Seminoma | Homogenous, tan-pink, no haemorrhage |
Uniform, rounded cells with prominent nucleoli. |
PLAP +ve C-KIT +ve CD117 +ve OCT4 +ve CD30 -ve |
AFP -ve β-hCG uncommon |
Usually localised. 99% curability |
|
| Spermatocytic Seminoma |
Soft, well circumscribed, bulging, mucoid surface |
Three populations: 1) Round cells, varied size 2) Small dark cells, high NCR 3) Giant cells, may have multiple nuclei Minimal stroma |
None useful | All tumours have an extra chromosome 9. No specific genes known |
N/A | Never metastasises |
| Embryonal carcinoma | Tan, granular, foci of haemorrhage or necrosis common |
Solid or papillary architecture. Cells usually large and polygonal with large nuclei. Poorly defined borders. May also have syncytiotrophoblast cells |
CD30 +ve OCT4 +ve TP53 +ve >50% PLAP focal |
Metastasises early Pure form worse than mixed tumour |
||
| Yolk Sac Tumour | Tan-grey, mucinous or gelatinous |
Multiple patterns seen, often several per tumour: 1) Microcystic (common) 2) Macrocystic 3) Solid 4) Glandular/alveolar 5) Endodermal sinus 6) Papillary 7) Myxomatous 8) Polyvesicular 9) Hepatoid 10) Enteric Glomeruloid bodies are pathognomic of yolk sac tumours |
AFP +ve CK +ve |
Aneuploidy common | AFP | Stage and AFP dependent |
| Choriocarcinoma | Extensive haemorrhage | Needs cells resembling all components of the placenta (eg. cytotrophoblast, syncytiotrophoblast, intermediate trophoblast). |
β-hCG positive staining | Often present with widespread metastases |
||
| Teratoma | Cystic regions | Contain tissue representing all 3 embryonal tissues. Mature elements (similar to adult tissues), immature elements (small round blue cells). Mature elements may develop their own malignancy (eg adenoca) |
Benign in children Malignant after puberty |
|||
| Mixed Germ Cell Tumour |
Intratubular Germ Cell Neoplasia
The presumed precursor lesion to most germ cell tumours, seen in about 85% of patients with a germ cell malignancy.
Macroscopic Features
IGCN is not visible macroscopically.
Microscopic Features
The germ cells in IGCN lie along the basement membrane, replacing the normal spermatogonia. They are significantly larger and have a much paler cytoplasm. The abnormal cells may extend through the rete testis into the epididymis.
Classical Seminoma
For a discussion of spermatocytic seminoma see the germ cell tumours in the elderly topic.
Seminoma is (fortunately) the most commonly diagnosed germ cell tumour of young adults.
Macroscopic Features
The tumour usually enlarges the testis, but invasion through the tunica vaginalis, epididymis or spermatic cord is uncommon. The tumour is usually tan or pink, soft, and usually homogenous. Uncommonly the tumour may be lobulated. Regions of necrosis may be visible.
Microscopic Features
The cells forming the classical seminoma are uniform, rounded cells arranged in sheets or clusters. The cells are usually pale pink with a single nucleus and prominent nucleoli. Fibrosis is commonly present around the tumour. Rarely, the growth pattern may be cribriform. In about 7% of cases syncytiotrophoblastic cells may be preset as large, multinucleated cells.
Syncytiotrophoblastic cells in seminoma do not convey a worse prognosis, even if β-hCG is produced and detectable. It is important to exclude a non-seminomatous germ cell tumour however!
Immunohistochemistry
Placental alkaline phosphatase (PLAP) and C-Kit have positive staining in 85-100% of seminomas and are commonly used markers. Other stains can be used to differentiate seminoma from its more aggressive mimic, embryonal carcinoma.
Serum markers
AFP should never be elevated; if this occurs it suggest the tumour has transformed into a teratoma or embryonal carcinoma. β-hCG can be elevated with no change in prognosis; however choriocarcinoma should be excluded as a diagnosis. LDH can indicate the burden of disease.
Prognostic Factors
The most important
Tumours > 4 cm (24 vs 13% relapse)
Invasion of rete testis (23 vs 14% relapse)
For stage I tumours, lymphovascular invasion has no impact on relapse rates for classical seminoma. Non-seminomatous germ cell tumours with lymphovascular invasion have a much higher rate of recurrence and this increases the stage to T2.
Embryonal Carcinoma
Comprises about 2-10% of germ cell tumours in young adults. It is commonly seen as a component in mixed germ cell tumours (80%). Like seminoma, they usually present with a painless swelling, but the age of onset is about 10 years early on average.
Macroscopic Appearance
Tumours are frequently smaller than seminomas (about 4 cm). Unlike seminoma, they frequently invade the tunica albuginea, rete testis, epididymis and spermatic cord. The tumour is usually soft, white-grey and may contain haemmorhagic foci and necrosis.
Microscopic Appearance
Embryonal carcinoma has a number of microscopic growth patterns, containing undifferentiated cells that have an epithelial appearance. This is similar to the early embryo, explaining the title of 'embryonal carcinoma'.
The nucleus and cytoplasm of cells is more variable than seminoma, and the cytoplasmic appearances vary widely (clear, granular, eosinophilic or basophilic). Lymphovascular invasion is common.
Immunohistochemistry
CD30 is commonly positive in embryonal carcinoma. TP53 and AFP are also seen in some tumours.
Growth Patterns
Embryonal carcinoma may spread to lymph nodes like seminoma, but commonly develops haematogenous spread to the lungs. Pure embryonal carcinoma tends to be more aggressive.
Serum Markers
β-hCG may be elevated in embryonal carcinoma with syncytiotrophoblastic cells present (similar to seminoma). AFP may be elevated in tumours with a mixed pattern. LDH is used to measure disease burden.
Yolk Sac Tumour
Yolk sac tumours are seen in both infants and young adults. For a discussion of infantile testicular germ cell tumours, click here.
In adults, yolk sac tumour is usually seen as a component of a mixed germ cell tumour.
Macroscopic Appearance
Pure yolk sac tumours are usually solid, soft and pale grey. Necrosis and haemorrhage may be seen.
Microscopic Appearance
Yolk sac tumours have a variety of appearances. Most tumours have a number of these patterns:
- Microcystic/reticular pattern consists of a honeycombed meshwork of cells with prominent vacuoles.
- Macrocystic pattern consists of numerous spaces surrounded by malignant cells
- Solid pattern contains polygonal cells with a clear cytoplasm, similar to seminoma.
- Glandular/alveolar pattern
- Endodermal sinus pattern is diagnostic of yolk sac tumour, consisting of a stalk of connective tissue, central capillary and lined by cuboidal epithelium
- Papillary, glandular, alveolar, hepatoid, polyvesicular, enteric or myxomatous patterns are also seen.
Immunohistochemistry
Yolk sac tumours often stain positively for AFP and low molecular weight cytokeratins.
Serum Markers
AFP is an important prognostic marker in yolk sac tumours
Choriocarcinoma
A malignancy formed by syncytiotrophoblastic, cytotrophoblastic and intermediate trophoblastic cells. Pure forms make up less than 1% of germ cell tumours in men. Mixed germ cell tumours with choriocarcinoma as a component make up 8% of germ cell tumours.
Macroscopic Features
Choriocarcinomas are usually haemorrhagic with a surrounding rim of viable tan tumour.
Microscopic Features
There are three cell components:
- Syncytiotrophoblastic cells (multinucleated cells with deeply staining cytoplasm)
- Cytotrophoblastic cells (single nucleus, pale cytoplasm)
- Intermediate trophoblastic cells (similar to but larger than cytotrophoblastic cells)
These cells are arranged together, often with significant amounts of necrosis and haemorrhage.
Imunohistochemistry
Malignant cells typically stain with β-hCG, inhibin and epithelial membrane antigen.
Growth Patterns
This aggressive tumour typically presents with haematogenous spread. Symptoms commonly include haemoptysis, headache or backache from metastatic lesions.
Teratoma
Teratoma makes up 2-7% of all germ cell tumours and 47-50% of mixed germ cell tumours. It is more common in children. A teratoma contains tissue from all three germinal layers (endoderm, mesoderm, ectoderm).
Macroscopic Features
Unlike other germ cell tumours, teratomas are usually firm and irregular. They may have cystic components or other mature tissues such as hair or teeth.
Microscopic features
Various tissue types may be present. Squamous epithelium, glandular formation and neural tissues are common. 'Organoid' structures may form. Muscular tissue is the most common mesoderm component. Primitive foetal tissue may also develop.
Immunohistochemistry
A broad spectrum of stains are used for teratoma, based on the tissue types generated. AFP is often positive.
Growth Patterns
Adult teratoma is metastatic in about 1/3rd of patients.
Mixed Germ Cell Tumour (Tumours of more than one histological type [mixed forms])
Mixed germ cell tumours are the most common germ cell tumour in males after seminoma, making up 32-45% of these malignancies. They can contain any of the germ cell tumours mentioned above, including seminoma.
Macroscopic Features
The tumour is usually soft but heterogenous. Teratomatous elements may be firm or cystic. When cut, the tumour has a heterogenous colour with areas of necrosis and haemorrhage.
Microscopic Features
Tumours show a mix of the germ cell tumours above. The most commonly included forms are embryonal carcinoma and teratoma (47%). Yolk sac tumours occur in 41%.
Immunohistochemistry
The immunohistochemical stains used are the same as for the germ cell tumours above. AFP and hCG are useful in defining specific areas of the tumour.
Growth Patterns
Growth depends on the tumour types present. Most tumours spread to retroperitoneal lymph nodes and occasionally to the lungs; those with choriocarcinoma components often metastasise earlier to the brian or bone.
Staging
The TNM system is used to stage testicular malignancy. Importantly, there are only three levels of overall stage (I, II, III) and serum markers are also considered in the staging system (S stage).
T Stage
T0 - No evidence of primary tumour
Tis - Intratubular Germ Cell Neoplasia
T1 - Tumour limited to testis/epididymis; no invasion into tunica vaginalis; no lymphovascular invasion
T2 - As for T1 but with lymphovascular invasion or involvement of tunica vaginalis
T3 - Invasion of spermatic cord
T4 - Invasion of scrotum
N Stage
N0 - No regional node involvement
N1 - Lymph node metastases, less than 2 cm AND no more than 5 nodes involved
N2 - Lymph node metastases, 2 - 5 cm, OR more than 5 nodes involved
N3 - Lymph node metastases > 5 cm
M Stage
M0 - No distant metastasis
M1a - Non-regional lymph node or lung metastases
M1b - Other metastases
S Stage
| Stage | β-hCG | AFP | LDH |
|---|---|---|---|
| S0 | Not elevated | Not elevated | Not elevated |
| S1 | < 5,000 | < 1,000 | < 1.5 × normal |
| S2 | 5,000 - 10,000 | 1,000 - 10,000 | 1.5 - 10 × normal |
| S3 | > 10,000 | > 10,000 | > 10 × normal |
Final Stage
| Stage | T stage | N stage | M stage | S stage |
|---|---|---|---|---|
| 0 | Tis | N0 | M0 | S0 |
| IA | T1 | N0 | M0 | S0 |
| IB | T2-4 | N0 | M0 | S0 |
| IS | Any | N0 | M0 | S1-3 |
| IIA | Any | N1 | M0 | S0-1 |
| IIB | Any | N2 | M0 | S0-1 |
| IIC | Any | N3 | M0 | S0-1 |
| IIIA | Any | Any | M1a | S0-1 |
| IIIB | Any | Any | M1a | S2 |
| IIIC | Any | Any | M1a | S3 |
| IIIC | Any | Any | M1b | Any |
