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).¹ Of the germ cell tumours, about 45% are seminomas and 50% are non-seminomas. The non-germ cell tumours include Leydig cell tumours, Sertoli cell tumours and sarcomas. Since the introduction of combination chemotherapy in the 1970s, survival rates for testicular cancer have risen every year to cure rates of over 95%.²

Classification

British Testicular Tumour Panel Classification:^1,3

• Seminomas.
• Teratomas, which are subdivided into:
  • Teratoma differentiated.
  • Malignant teratoma intermediate.
  • Malignant teratoma undifferentiated.
  • Malignant teratoma trophoblastic (choriocarcinoma is the most lethal form and it is the least common at 1% of the non-seminomatous type).
• Yolk sac tumours:
  • Yolk sac tumours are also known as endodermal sinus tumours and are the most common prepubertal germ cell tumours.
  • They may be benign but they are most often malignant.
  • Most require surgery and chemotherapy because of their aggressive nature but the overall prognosis is excellent.

Epidemiology

• Testicular cancer is a relatively rare cancer with an incidence of 7.0 per 100,000 population. The lifetime risk of developing testicular cancer is about 1 in 199 for men in the UK.²
• There has been a steady increase in incidence over previous decades in industrialised countries.⁴
• Testicular cancer can occur at any age but is most common between the ages of 15 and 35 years. Testicular tumours are the most common malignancy in men aged between 20 and 35 years.⁵
• There is also secondary peak in incidence after age 60.⁵
• Testicular tumours are far more common in adults than in children.⁶ Seminoma is rare in boys younger than 10 years of age but is the most common testicular tumour in men older than 60.⁵

Risk factors

Risk factors include:

• Cryptorchidism or testicular maldescent.⁴
• Klinefelter's syndrome.⁴
• Family history.⁴
• Male infertility (increases risk by a factor of three).⁷
• Low birthweight, young maternal age, young paternal age, multiparity, breech delivery.⁸
• Infantile hernia.
• Height - taller men are more at risk of developing germ cell tumours.⁹
• Testicular microlithiasis (small intratesticular calcifications seen on ultrasound).¹⁰

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.

Genetic factors

Many malignancies are due to genetic damage. This genetic damage may be caused in the intrauterine environment for tumours of testis and breast.¹¹ Virtually all testicular tumours display an abnormality on chromosome 12.^12,13 Up to 20% of men may carry the testicular germ cell tumour 1 (TGCT1) gene on their X chromosome.¹⁴ 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.¹⁵

Presentation

Symptoms

• Painless lump; see separate article Lumps in the Groin and Scrotum.
• 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 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.¹

Differential diagnosis

• Epididymo-orchitis.
• Torsion.
• Lymphoma.
• Other scrotal lumps, e.g. hydrocele, haematocele, epididymal cyst, hernia.
• Infection, e.g. tuberculosis, syphilis, mumps.

Investigations

Investigations should not delay referral. Patients should be referred urgently to be seen within two weeks if malignancy is suspected. Preoperative investigations should include assay of tumour markers, bilateral testicular ultrasound, and CXR.¹

• Diagnosis is usually confirmed by ultrasound.
• Tissue histology can follow an inguinal orchidectomy.⁴
• Disease can be staged by thoraco-abdominal CT scanning.
• Tumour markers are useful in staging and assessing response to treatment:
  • 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 in both teratomas and seminomas.
  • Lactate dehydrogenase (LDH) should also be measured, especially in advanced tumours.⁴

Royal Marsden staging of testicular tumours:¹

• 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.

Management¹

Management is dependent on the type of tumour and stage (see Scottish Intercollegiate Guidelines Network (SIGN) guidelines for individual treatment recommendations).¹ Approximately 90% of patients classified as having a good prognosis achieve a durable complete remission with treatment.¹⁶ Even metastatic disease should be seen as potentially curable.¹⁷ When treating young adults with a highly curable disease, possible long-term toxicity of treatment is an important consideration.¹⁸ Following confirmation of a germ cell tumour, all patients should be referred to a specialist centre for the management of testicular tumours.

• Where possible, an inguinal 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:
  • Post-orchidectomy management options include surveillance, single-dose adjuvant carboplatin and adjuvant radiotherapy.
• 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)

• Men with testicular cancer have an increased risk of CIS of the opposite testicle.
• Patients with a testicular cancer who are 30 years old or less and have a small (<12 ml) contralateral testis should be considered for biopsy of the contralateral testis to diagnose CIS. If CIS is identified, subsequent management should be in a specialist centre.
• Patients with biopsy-proven CIS of the contralateral testis have the options of surveillance, prophylactic orchidectomy and adjuvant radiotherapy.

Management of metastatic disease

• Seminoma:
  • In stage IIA seminoma, both chemotherapy and radiotherapy treatment options should be considered.
  • 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).¹⁹
• Testicular prosthesis should be offered to all patients.

Complications

• Infertility may precede treatment or result from it.
• Treatment toxicity of radiotherapy.
• Treatment toxicity of chemotherapy.
• Short-term (e.g. neutropenia, nausea and vomiting, alopecia, fatigue and sepsis).
• Long-term (e.g. lung damage with bleomycin, nerve, hearing and renal damage with cisplatin, avascular necrosis).

Prognosis

This is dependent on stage, tumour type and presence of low, medium or high levels of markers.¹

• Seminoma is highly curable when detected early. The 5-year survival rate is around 95% with Stage I disease and 85-90% with Stage 2 disease.
• For non-seminomatous germ cell tumours, the results are less favourable, with a 5-year survival rate of 86% for Stage I disease. The corresponding survival rate for teratocarcinomas is only 70%.
• Choriocarcinoma has a dismal prognosis, with nearly no patients surviving five years after their presentation. 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.

Document references

1. Management of adult testicular germ cell tumours, Scottish Intercollegiate Guidelines Network - SIGN (March 2011)
2. Cancer Statistics, Cancer Research UK
3. Testicular Tumours, Surgical Tutor
4. Guidelines on Testicular Cancer, European Association of Urology (2011)
5. Sachdeva K et al, Testicular Cancer, Medscape, Aug 2011
6. Ross JH, Kay R; Prepubertal testis tumors. Rev Urol. 2004 Winter;6(1):11-8. [abstract]
7. Walsh TJ, Croughan MS, Schembri M, et al; Increased risk of testicular germ cell cancer among infertile men. Arch Intern Med. 2009 Feb 23;169(4):351-6. [abstract]
8. Cook MB, Graubard BI, Rubertone MV, et al; Perinatal factors and the risk of testicular germ cell tumors. Int J Cancer. 2008 Jun 1;122(11):2600-6. [abstract]
9. Chia VM, Quraishi SM, Graubard BI, et al; Insulin-like growth factor 1, insulin-like growth factor-binding protein 3, and testicular germ-cell tumor risk. Am J Epidemiol. 2008 Jun 15;167(12):1438-45. Epub 2008 Apr 11. [abstract]
10. Coffey J, Huddart RA, Elliott F, et al; Testicular microlithiasis as a familial risk factor for testicular germ cell tumour. Br J Cancer. 2007 Dec 17;97(12):1701-6. Epub 2007 Oct 30. [abstract]
11. Grotmol T, Weiderpass E, Tretli S; Conditions in utero and cancer risk. Eur J Epidemiol. 2006;21(8):561-70. Epub 2006 Sep 13. [abstract]
12. Testicular Tumours, Online Mendelian Inheritance in Man (OMIM).
13. Houldsworth J, Korkola JE, Bosl GJ, et al; Biology and genetics of adult male germ cell tumors. J Clin Oncol. 2006 Dec 10;24(35):5512-8. [abstract]
14. Testicular Germ Cell Tumour 1 (X-linked), Online Mendelian Inheritance in Man (OMIM).
15. Testicular Cancer Research; Testicular cancer research, CancerHelp UK
16. Feldman DR, Bosl GJ, Sheinfeld J, et al; Medical treatment of advanced testicular cancer. JAMA. 2008 Feb 13;299(6):672-84. [abstract]
17. Kopp HG, Kuczyk M, Classen J, et al; Advances in the treatment of testicular cancer. Drugs. 2006;66(5):641-59. [abstract]
18. Gilbert DC, Van As NJ, Huddart RA; Reducing treatment toxicities in the management of good prognosis testicular germ cell tumors. Expert Rev Anticancer Ther. 2009 Feb;9(2):223-33. [abstract]
19. Liguori G, Trombetta C, Bucci S, et al; Semen quality before and after orchiectomy in men with testicular cancer. Arch Ital Urol Androl. 2008 Sep;80(3):99-102. [abstract]

Internet and further reading

• Orchid, Fighting Male Cancer