Testicular cancer

More than 95% of testicular tumours arise from the germ cells. Testicular germ cell tumours can be subdivided into seminoma and non-seminomatous germ cell tumours (NSGCTs). Of the germ cell tumours, about 50% are seminomas and 50% are non-seminomas.

Since the introduction of combination chemotherapy in the 1970s, survival rates for testicular cancer have risen every year to cure rates of over 95%¹ .

Classification

Testicular cancers are defined based on their cell type. 2016 updated World Health Organization (WHO) histopathological classification characterises testicular cancers accordingly² .

• Germ cell tumours.

• Derived from germ cell neoplasia in situ (GCNIS):
  

  • Seminoma.

  • Embryonal carcinoma.

  • Yolk sac tumour, post-pubertal type.

  • Trophoblastic tumour.

  • Teratoma, post-pubertal type.

  • Teratoma with somatic-type malignancies.

  • Mixed germ cell tumours.

• Germ cell tumours unrelated to GCNIS including spermatocytic tumour, yolk sac tumour, pre-pubertal type, Mixed germ cell tumour, pre-pubertal type.

• Sex cord/stromal cell tumours including Leydig cell tumour, Sertoli cell tumour, granulosa cell tumour.

• Thecoma/fibroma group of tumours.

• Other sex cord/gonadal stromal tumours.

• Tumours containing both germ cell and sex cord/gonadal stromal - eg, gonadoblastoma

• Miscellaneous non-specific stromal cell tumours including tumours of paratesticular structures

Epidemiology

• Testicular cancer is a rare cancer, with an annual incidence rate of 1.5 cases/100,000 men (world adjusted). In Western Caucasian populations in recent decades³ .

• Testicular cancer is the most common solid tumor among males aged 15-34 years. The age-adjusted annual incidence in the USA is 5.6 cases per 100,000 persons, with a peak of 14.6 cases per 100,000 persons aged 30-34 years⁴ . Incidence is known to be rising⁵ .

• The incidence of testicular cancer varies by ethnic origin, with the highest rates reported in developed countries and the lowest in developing countries. The highest incidence rates of testicular cancer are in Norway (11.8 per 100,000) and the lowest are in India (0.5 per 100,000) and Thailand (0.4 per 100,000)⁶ .

• Testicular cancer can occur at any age but is most common between the ages of 15 and 40 years. Testicular tumours are the most common malignancy in men aged between 20 and 35 years.

• Testicular tumours are far more common in adults than in children. Seminoma is rare in boys younger than 10 years of age but is the most common testicular tumour in men older than 60 years.

Risk factors

These include⁴ :

• Cryptorchidism or testicular maldescent.

• Klinefelter's syndrome.

• Family history.

• Male infertility (increases risk by a factor of three).

• Low birth weight, young maternal age, young paternal age, multiparity, breech delivery.

• Infantile hernia.

• Height - taller men are more at risk of developing germ cell tumours.

Of the factors associated with the risk of developing germ cell tumours of the testis, cryptorchism and malignancy in the contralateral testis are by far the strongest.

Testicular microlithiasis, vasectomy, and scrotal trauma are not risk factors for testicular cancer^{4 7} .

Genetic factors⁸

Many malignancies are due to genetic damage. This genetic damage may be caused in the intrauterine environment for tumours of testis and breast. Virtually all testicular tumours display an abnormality on chromosome 12. Up to 20% of men may carry the testicular germ cell tumour 1 (TGCT1) gene on their X chromosome. Possession of this gene may increase risk of testicular malignancy by up to 50 times. It may also be involved in families with a history of cryptorchism, and families of men who develop bilateral disease are also more likely to carry this gene.

Presentation

Symptoms

• More than 95% present with a lump in the body of the testis, which is usually painless. See the separate Lumps in the Groin and Scrotum article.

• Testicular pain and/or abdominal pain.

• Dragging sensation.

• Recent history of trauma; it is probably the trauma that leads the man to examine himself and find the tumour rather than being the cause of malignant change.

• Hydrocele.

• Gynaecomastia from beta human chorionic gonadotrophin (beta-hCG) production.

• Metastasis - seminomas metastasise to para-aortic nodes and produce back pain; teratomas undergo blood-borne spread to the liver, lung, bone and brain.

Signs

• A lump is palpable in nearly all cases.

• Whereas the normal testis is rather delicate and the inflamed testis is very tender, the malignant testis tends to lack the normal level of sensation.

• Lymphatics from the scrotum drain to the inguinal nodes but from the testes they go deeper. Hence, inguinal lymph nodes are unlikely to be enlarged.

Patients presenting with a swelling in the scrotum should be examined carefully and an attempt made to distinguish between lumps arising from the testis and other intrascrotal swellings. An ultrasound scan should be performed to make a distinction.

Differential diagnosis²

• Epididymo-orchitis.

• Torsion.

• Lymphoma.

• Other scrotal lumps - eg, hydrocele, haematocele, epididymal cyst, hernia.

• Infection - eg, tuberculosis, syphilis, mumps.

Investigations⁶

Investigations should not delay referral. Patients should be referred urgently to be seen within two weeks if malignancy is suspected. Pre-operative investigations should include assay of tumour markers, bilateral testicular ultrasound, and CXR.

• Diagnosis is usually confirmed by ultrasound.

• Tissue histology can follow an inguinal orchidectomy.

• Disease can be staged by thoraco-abdominal CT scanning.

• Elevation of tumour markers supports the diagnosis but normal marker levels do not exclude testicular cancer and these markers are raised in other cancers and some benign conditions:
  

  • Alpha-fetoprotein (AFP) is produced by yolk sac elements but not produced by seminomas.

  • Beta-hCG is produced by trophoblastic elements and so there may be elevated levels both in teratomas and in seminomas.

Staging of testicular tumours¹⁰

• I - no evidence of disease outside the testis.

• IM - as above but with persistently raised tumour markers.

• II - infradiaphragmatic nodal involvement.
  

  • IIA - maximum diameter <2 cm.

  • IIB - maximum diameter 2-5 cm.

  • IIC - maximum diameter >5-10 cm.

  • IID - maximum diameter >10 cm.

• III - supradiaphragmatic and infradiaphragmatic node involvement:
  

  • Abdominal nodes A, B, C, as above.

  • Mediastinal nodes M+.

  • Neck nodes N+.

• IV - extralymphatic metastases:
  

  • Abdominal nodes A, B, C, as above.

  • Mediastinal or neck nodes as for stage III.

  • Lungs:
    

    • L1 <3 metastases.

    • L2 multiple metastases <2 cm maximum diameter.

    • L3 multiple metastases >2 cm in diameter.

  • Liver involvement H+.

  • Other sites specified.

Management¹⁰

Management is dependent on the type of tumour and stage⁶ . Approximately 90% of patients classified as having a good prognosis achieve a durable complete remission with treatment. Even metastatic disease should be seen as potentially curable. When treating young adults with a highly curable disease, possible long-term toxicity of treatment is an important consideration. Following confirmation of a germ cell tumour, all patients should be referred to a specialist centre for the management of testicular tumours.

• Where possible, a radical orchidectomy should be performed. A testicular prosthesis should be offered to all patients. When appropriate, sperm storage should be offered to men who may require chemotherapy or radiotherapy.

• Patients with metastases where the diagnosis is not in doubt (high tumour markers and the presence of a testicular mass) should be referred for immediate chemotherapy.

Management of stage 1 disease

• Seminoma:
  

  • 80% to 85% are stage I at diagnosis⁴ . Among men with a stage I seminoma, 83% to 85% are free from relapse five years after orchiectomy alone; therefore, surveillance without additional therapy is preferred.

• Stage I NSGCT and mixed seminoma/NSGCT:
  

  • Patients with stage I NSGCT or mixed seminoma/NSGCT of the testis with no high-risk features (blood vessel and/or lymphatic invasion) should be managed by surveillance following inguinal orchidectomy.

  • In low-risk patients under surveillance, CT scanning at three and 12 months post-orchidectomy is recommended.

  • Two courses of adjuvant bleomycin, etoposide and cisplatin (BEP) chemotherapy should be offered to patients with stage I NSGCT or mixed seminoma/NSGCT of the testis following inguinal orchidectomy if high-risk features are present or if the patient is unable or unwilling to comply with a policy of surveillance.

Carcinoma in situ (CIS)

Of all patients with unilateral testicular tumours, approximately 2-5% have CIS in their contralateral testis. CIS develops into invasive malignancy in 70% of the cases in seven years and probably all patients over a longer period of time. CIS can be successfully treated with a low dose of radiotherapy or unilateral orchidectomy.

Management of metastatic disease

• Seminoma:
  

  • Stage II seminomas are treated with adjuvant therapy (radiotherapy or cisplatin-based chemotherapy, which usually includes etoposide⁴ .

  • For patients with stage IIC and IID seminoma, chemotherapy is the recommended initial treatment.

  • Patients with stage III and IV seminoma should be treated with cisplatin-based chemotherapy. In patients with stage III and IV seminoma, carboplatin should only be used as an alternative to cisplatin in exceptional circumstances.

• NSGCT:
  

  • Patients with good-prognosis metastatic NSGCT should receive three cycles of BEP chemotherapy. (The International Germ Cell Consensus Classification (IGCCC) prognostic grouping is mainly based on the presence on the site of the primary, presence of non-pulmonary metastases and levels of tumour markers.)

  • Patients with good-prognosis metastatic NSGCT and in whom bleomycin is contra-indicated should receive chemotherapy with etoposide and cisplatin.

  • Standard initial chemotherapy for patients with intermediate and poor-risk germ cell tumours is four courses of BEP.

Management of residual masses after chemotherapy

• Patients with NSGCT who have residual masses after chemotherapy and whose markers have normalised should be treated by complete excision.

• Patients with seminoma who have residual masses following chemotherapy can generally be managed by a policy of observation rather than radiotherapy.

Other

• Counselling and support organisations.

• Fertility issues and sperm storage (semen quality is reduced after orchidectomy and samples should be taken before surgery).

• Testicular prosthesis should be offered to all patients.

• Follow-up visits for early detection and treatment of relapse during the first 5-10 years.

Complications

• Most survivors of testicular cancer regain a normal quality of life. Some patients become hypogonadal after orchidectomy and fertility may be reduced after chemotherapy.

• Peripheral neuropathy, Raynaud's phenomenon, and hearing loss caused by chemotherapy may persist for years.

• After chemotherapy 2.0- to 3.7-fold increased risks for cancers of the small intestine, bladder, kidney and lung have been observed¹¹ .

• There is an increased risk of cardiac events¹² . The increased risk of cardiovascular disease and a second cancer is similar to the risk seen from long-term smoking.

• Overall quality of life scores are similar to those in the general population, but anxiety associated with fear of recurrence, economic worries, alcohol misuse, and sexual difficulties are common in survivors.

• Late relapse (new tumour growth more than two years after at least three cycles of chemotherapy) occurs in 2-3% and does not have a good response to chemotherapy.

Prognosis¹

There has been decline in mortality rates reported in Western countries. The prognosis is dependent on stage, tumour type and presence of low, medium or high levels of markers.

• If the tumour is diagnosed early, over 95% of men are cured and treatment can be less intensive.

• For NSGCTs, the overall results are less favourable than for seminomas.

• Choriocarcinomas have the worst prognosis of any of the testicular malignancies.

Early detection

Public information campaigns have encouraged men to check for any scrotal lumps regularly and to see a GP if they have any concerns. Patients with increased clinical risk factors for testicular cancer, including a family history of testicular cancer, undescended testis (cryptorchidism) or testicular atrophy should be informed of their potential increased risk of testicular cancer, along with potential benefits and harms associated with screening.