Cancer

Updated 25 August 2014

Testicular Cancer

Testicular cancer is the most common malignancy in 15 – 35 year old males. The vast majority of testicular cancer (95%) develops from the germinal cells of the testes.

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Summary

  • Testicular cancer is the most common malignancy of males aged 15 – 35 years.
  • The incidence of testicular cancer is on the increase.
  • Most testicular cancers present with a painless lump in the scrotum.
  • Testicular cancer spreads to the lymph glands around the aorta.
  • More than 90% of all patients with testicular cancer of all stages are cured from their disease.
  • The treatment of testicular cancer can lead to infertility.
  • A small subgroup of patients do badly despite intensive treatment.

Description

Testicular cancer is the most common malignancy in 15 – 35 year old males. The vast majority of testicular cancer (95%) develop from the germinal cells of the testes. These germ cell tumours are divided into two sub-groups: seminomas and non-seminomas.

Less than 5% of testicular tumours are the non-germ cell tumours and include rarities such as Leydig cell tumours, Sertoli cell tumours and gonadoblastomas and will not be discussed further. In this article the term testicular cancer will refer to germ cell testicular tumours.

The incidence of testicular cancer shows marked variation among different countries, races and socio-economic groups. The disease is most common in Scandinavia and rare in Africa.

The cause of testicular cancer is unknown. Carcinoma in situ (CIS) is believed to be the precursor of seminoma and non-seminoma. Men with undescended testicles have a 5–10 times increased risk of developing testicular cancer, compared to the general population. Five percent of patients who have had a testicular cancer develop a second cancer on the other side.

Testicular cancer typically presents with a painless lump in the testis. Left untreated, the tumour cells can spread via the lymphatic pathways to the retroperitoneal glands around the aorta at the level of the kidneys. Later spread via the blood stream to the lungs, liver, bone and brain can occur. Most patients have disease confined to the testis or the regional lymph glands at presentation.

Many testicular cancers produce tumour markers. These are proteins overproduced by the tumour cells and can be measured in the blood.  They can be useful in the diagnosis, staging and monitoring of treatment.

Testicular cancer is one of the most treatable cancers. The vast majority of patients, including those with widespread metastatic disease, are cured by modern day chemotherapy and/or radiotherapy. The treatment regimes, however, are not without complications and despite the excellent overall results, a small group of poor prognosis patients do badly despite intensive therapy.

Cause

The exact cause of testicular cancer is unknown. The clinical evidence suggests that congenital (born with), environmental and genetic factors play a role.

Testicular cancer develops from the primitive germ cells of the testes. During development the germ cell may be affected by environmental factors, resulting in disturbed differentiation (cell development). Factors that may interfere with normal germ cell development include cryptorchidism (undescended testicle), genetic predisposition or chemical carcinogenesis.

Statistical analysis indicates that one third of patients with germ cell testicular tumours are genetically predisposed to the condition. The marked variation in incidence among different race groups also points to the possible role of genetic factors. On the molecular genetic level all germ cell tumours (including carcinoma in situ) exhibit increased copies of part or all of the short arm of chromosome 12, suggesting that modification of one or more genes mapped to this chromosome play a crucial role in the development of testicular cancer. It is not clear how and when modification of this gene takes place.

The incidence of testicular cancer has increased fourfold over the last five decades. During the same period an apparent decrease in semen quality and an increase in genital abnormalities, such as hypospadia (a penile malformation) and undescended testicles, have been observed. The higher incidence of testicular cancer in men with testicular atrophy, undescended testes and infertility, suggests a common environmental factor as the most likely link between these genital abnormalities.

Symptoms

Testicular cancer can be completely asymptomatic in its early stage. Most testicular tumours present with a painless lump or swelling of the testis, noted by the patient or his sexual partner. 30-40% of patients complain of a dull ache or heaviness in the scrotum or lower abdomen. Acute pain is the presenting symptom in ±10% of patients.

Approximately 10% of patients present with symptoms or signs due to the spread of tumour to organs outside of the testes. Spread to the lymph glands can present with a mass in the abdomen or the neck. Large glands in the abdomen can cause abdominal pain, nausea, vomiting and loss of appetite. Lung metastases lead to shortness of breath and cough. Bone involvement causes bone pain.

Prevalence

Testicular cancer is the most common malignancy in the 15-35 year old age group in males. The incidence of testicular cancer shows marked variation among different countries, races and socio-economic classes. Scandinavian countries report 6.7 new cases per 100,000 males annually, compared to 3.7 per 100,000 in the USA and 0.8 per 100,000 males in Japan. The lifetime probability of developing testicular cancer is 0.2% (or 1 in 500) for a white male in the USA. The incidence among blacks in the USA is a quarter that of whites.

Within a given race group individuals in the higher socio-economic classes have approximately twice the incidence of those in the lower classes.

Testicular cancer appears to be on the increase. The current incidence in the USA is twice what it was in the 1930s. Similar trends have been noted in Denmark. There is no epidemiological data available for South Africa. The disease is common among whites and people of mixed race, but exceedingly rare among South African blacks.

Course

Testicular cancer develops in the primordial germ cell. The pre-malignant (non-invasive) stage of the disease is called carcinoma in situ (CIS). The tumour grows as a hard painless lump in the testicle. The testes have a thick capsule that acts as a natural barrier to tumour spread. Direct local spread beyond the capsule of the testes is rare.

Testicular cancer typically spreads via the lymphatic pathways in an organised step-wise manner. Due to its embryological development, the lymphatic drainage of the testes is to the lymph glands around the aorta and vena cava at the level of the kidneys. These para-aortic lymph glands are the first to be involved in the spread of testicular cancer.

From here the cancer may spread to the iliac lymph glands in the pelvis, and to the mediastinal glands in the chest and then on to the glands in the neck. With advanced disease, blood borne spread takes place to various other organs. The sites involved in decreasing frequency include lung, liver, brain, bone, kidney, adrenal gland and spleen.

Most testicular cancers are fast growing, with doubling times ranging from 10 to 30 days. Patients left untreated, and those unfortunate enough to suffer treatment failure, demise rapidly, usually within 2-3 years.

Testicular cancer is seldom allowed to run its natural course in clinical practice. Very few patients refuse modern day treatment, which has been spectacularly successful in curing this disease, even in the presence of widespread metastases.

Risk Factors

Although there is no known cause for testicular cancer, definitive risk factors have been identified:

Proven

  • Undescended testicles
  • Previous history of testicular cancer
  • Presence of carcinoma in situ (the precursor of testes cancer)
  • Oestrogen administration to mother during pregnancy
  • Brother or father with testicular cancer
  • Male infertility

Possible

  • Trauma
  • Mumps-associated atrophy of testes

Of all the known risk factors, undescended testicle has the strongest association with cancer formation. A patient with an undescended testicle has a 5-10 times increased risk of developing a testicular cancer, compared to the general male population.

Approximately 0.08% of men suffer from cryptorchidism (undescended testicle). Seven to 10% of all testicular tumours develop in patients with a history of cryptorchidism. Interestingly enough, 5-10% of these cancers develop in the opposite “normal” descended testicle.

The relative risk is greater for high (intra abdominal) undescended testicles, compared to lower (groin level) undescended testicles. The standard practice of surgically placing the undescended testes in the scrotum at an early age does not reduce the risk of later development of testicular cancer. However, it does ensure that the testes are in a position where early detection of tumour formation is possible.

A patient with one testicular tumour has a 5% chance of a cancer on the other side, which can be present at the same time, or develop later. Overall, 2-3% of all testicular cancers occur bilaterally, either simultaneously or successively.

In these high risk groups with a history of undescended testicle or a previous testicular cancer, the opposite “normal” testes can be biopsied for the presence of carcinoma in situ. Carcinoma in situ (CIS) or Intra-tubular Germ Cell Neoplasia (ITGN) is the non-invasive precursor of testicular cancer.

All germ cell testicular cancers are believed to develop from CIS. If CIS is present in the “normal” opposite testicle, the chance of developing cancer in that testicle is 50% over 5 years. However, if CIS is absent, then the chance of developing a testicular cancer is almost negligible. CIS can be diagnosed on a small (3mm) testicular biopsy. It can be treated with a local dose of radiotherapy that destroys the CIS, but preserves the hormonal function of the testes. CIS only develops in late adolescence and cannot be tested for before the age of ±18 years.

Someone with a brother with testes cancer has a 10 fold increased risk of developing cancer himself, while having a father with the disease carries a four fold increased risk for the son.

Oestrogen administration to the mother during pregnancy carries a 3-5 times increased risk of subsequent testicular cancer development in the male offspring. This may be an indirect effect, via the increased incidence of undescended testicle cause by maternal oestrogen administration.

Minor trauma is often the event that uncovers a previously unnoticed testicular tumour. A cause and effect relationship has never been proven in humans.

Small, abnormal (atrophic) testicles seem to be at greater risk of developing cancer. The incidence of testicular cancer is relatively high among infertile men. Mumps-associated atrophy, however, has never been proven to be a risk factor.

When to see a doctor

You need to see a doctor urgently in case of:

  • A lump or hardness detected in the testicle itself
  • Unexplained enlargement of the testicle
  • Unexplained pain, ache or swelling within the scrotum

High risk patients need to be especially vigilant in the case of:

  • Undescended testes
  • Previous history of testicular tumour
  • Brother or father with testicular tumour
  • Infertile men

Many benign conditions can present with a lump in the scrotum and may be mistaken for a testicular tumour. A skilled clinical examination and an ultrasound scan where necessary can almost always distinguish between these various conditions. With testicular tumours the lump or hardness is confined to the testicle itself, whereas most of the other conditions present with lumps separate from the testes.

Conditions which can present with a mass (lump) in the scrotum:

  • Epididymal cyst: fluid collection in drainage tubes of testis
  • Epididymytis: infection of epididymis
  • Inguinal hernia
  • Torsion of testicle
  • Hydrocele: fluid collection around the testis
  • Hematocele: trauma resulting in blood around the testis
  • TB of epididymis or testis
  • Mumps orchitis

Visit preparation

There is no specific preparation necessary for the first visit in a suspected case of testicular cancer.

The physician will take a thorough history and perform a clinical examination. If he suspects a testicular cancer he will probably take some blood samples for serum tumour marker levels, and arrange for an ultrasound scan of the scrotum.

Ultrasound is very effective in diagnosing or disproving testicular tumours. If the clinical and radiological findings confirm a mass within the testes, the next step is usually the removal of the testicle via an incision in the groin (see treatment).

Diagnosis

The diagnosis of testes cancer is based on a medical history, physical examination and some confirmatory special tests.

History

Most patients present with a history of a lump, swelling or hardness detected in the testicle. 10% of patients present with scrotal pain, and a further 10% present with symptoms related to metastatic spread (see symptoms).

Physical examination

The most common physical finding is that of a painless, non-tender lump within the testicle. Occasionally only a firm enlargement of the testicle is felt. 70-80% of patients present with disease confined to the testis. Only some of the 20-30%, who already have disease beyond the testicle at presentation, will have clinical evidence of this spread.

Spread to the abdominal lymph nodes is felt as a mass in the upper abdomen. Occasionally enlarged glands can be felt in the neck. Spread to other organs does not take place in the absence of prior lymphatic spread.

Liver enlargement, bone involvement or lung metastases are rarely detected clinically at the initial presentation.

Initial special investigations

  • Ultrasound scrotum
  • Serum tumour markers: Alphafetoprotein (AFP) and human chorionic gonadotropin (HCG)

Ultrasound of the scrotum is an excellent test to define the site and nature of scrotal masses. Almost all solid masses of the testes itself are cancerous. Almost all scrotal masses not arising from the testes are benign.

Tumour markers are substances produced by tumours, which can be measured in the blood, thereby indicating the presence and extent of a tumour. Most non-seminomatous germ cell tumours produce AFP and/or HCG. 5-10% of patients with pure seminoma produce elevated levels of HCG. Tumour markers are useful in diagnosis, staging and monitoring of response to treatment. The initial tumour marker levels also provide important prognostic information that may impact on choice of further treatment.

Excision of testicle by radical orchidectomy (see treatment)

The diagnosis of testicular cancer is confirmed by removing the testicle via an incision in the groin and sending the specimen for histological analysis. After the diagnosis has been confirmed, the next steps are a series of staging investigations to determine the presence and extent of spread of disease.

Staging Investigations

  • Chest X-ray
  • CT scan of abdomen and pelvis
  • Tumour markers (HCG and AFP)

The subsequent management following orchidectomy will depend on the nature of the primary tumour and the stage (extent) of spread of disease. The CT scan is performed to detect spread to the lymph glands around the aorta and to identify liver metastases.

A chest X-ray will detect 90% of lung metastases. If the tumour marker levels were elevated prior to removal of the testicle they are repeated. Tumour markers which remain elevated after removal of the testis indicate the presence of residual disease.

Staging

A number of staging systems are in use throughout the world. This complicates the comparison of data from different sentra. The Royal Marsden Hospital system is widely used and is simple and easy to understand. It is also widely used in South Africa.

  • Stage I - Tumour confined to the testes
  • Stage II - Tumour spread to para-aortic lymph glands
  • Stage IIa - Glands less than 2cm
  • Stage IIb - Glands 2-5cm
  • Stage IIc - Glands more than 5cm
  • Stage III - Lymph gland involvement in chest or neck
  • Stage IV - Spread outside of lymph glands, i.e. to lung, liver, bone or brain

Treatment of the primary tumour

The primary tumour is treated by radical inguinal orchidectomy. An incision is made in the groin and the spermatic cord carrying the testicular blood vessels is tied off. The testes and its coverings are removed en bloc. The testicle is not removed via the scrotum because this can lead to spread to the scrotal skin and the lymph glands of the groin.

The orchidectomy specimen is sent for histological analysis to determine the type of testicular tumour, i.e. seminoma or non-seminoma. Subsequent treatment will depend on the type and stage of disease.

Most of the treatment options affect fertility. This needs to be discussed with the patient prior to commencing treatment. If appropriate, semen should be preserved for possible future assisted reproduction.

Subsequent treatment

Stage I Seminoma (confined to testes)
The standard treatment is radiotherapy to the para-aortic lymph glands and to the pelvic glands on the side of the tumour. Seminomas are exquisitely sensitive to radiotherapy. The relapse rate is 3-5% and overall survival is 92 – 99%.

Surveillance is an alternative to initial adjuvant radiotherapy. This involves regular follow up with CT scans and Chest X Rays and only irradiating if and when nodes become apparent. The relapse rate on surveillance is 20%. Thus, 80% of patients are cured by orchidectomy alone and will receive unnecessary radiation under standard treatment regimes. The 20% who relapse do so mainly at the para-aortic nodes.

Results of radiation treatment following relapse are good.

A third option in stage I seminoma is a course of Carboplatin chemotherapy. Results with Carboplatin are good and it is a reasonable option for patients with moderate to high risk seminoma who do not want radiotherapy.

Stage IIa Seminoma
The standard treatment is radiotherapy to the para-aortic glands and the pelvic glands on the side of the tumour. 10% of patients relapse post radiotherapy and overall survival is 96%.

Stage IIb, IIc, III and IV Seminoma
The standard treatment is chemotherapy with 4 cycles of Etoposide and Cisplatin. The overall survival is 85%. For patients with widespread disease beyond the lymph glands and lungs the survival is 57%. Fortunately most seminomas present with disease confined to the testicle.

Stage IIb and IIc are sometimes treated with radiotherapy but 18% of IIb and 38% of IIc cases will relapse after this treatment.

Stage I Non-seminoma
The standard treatment is different in the UK and the USA. In the UK (and SA) most patients are treated by regular surveillance. 70% are cured by orchidectomy alone and 30% will relapse. Most relapses take place within 5-6 months and most of these have elevated tumour marker levels. Relapse is treated very effectively with chemotherapy. The overall survival exceeds 95%.

In the USA the standard treatment is a retroperitoneal lymph node dissection. This is a major operation involving surgical removal of all the lymph glands around the aorta and vena cava. Results of retroperitoneal lymph node dissection are excellent with a 96% overall survival. Only the small number of patients who relapse are subjected to chemotherapy.

The major disadvantage of this treatment protocol is that 70% of patients undergo a major operation unnecessarily.

Primary chemotherapy after orchidectomy is a third option in stage I non-seminoma. This avoids the anxiety associated with surveillance, but 50 - 70% of patients who would have been cured by orchidectomy alone receive unnecessary chemotherapy. It may be a good option for high risk patients who are not suitable for surveillance due to social or other reasons.

Stage II, III and IV Non-seminoma
Chemotherapy is standard treatment for non-seminoma that has spread beyond the testes. Most regimes are based on 4 cycles of Bleomycin, Etoposide and Cisplatin. The results of chemotherapy depend on the nature and extent of disease.

Patients with disease confined to the lymph glands and lungs and with only moderately elevated tumour markers are regarded as a good prognostic group. They comprise 84% of all cases of metastatic non-seminoma. The overall survival following chemotherapy is 75 – 90%. The remaining 16% are those patients with spread beyond the lymph glands and the lungs and marked elevation of tumour markers.

The prognosis of this subgroup is poor with a 5 year survival of 40 – 50%.

Side effects

Orchidectomy
The loss of one testicle is not a major problem, provided that the opposite testis is normal. Cosmesis is seldom a problem, but if necessary a testicular prosthesis can be inserted into the empty scrotal sac.

Retroperitoneal lymph node dissection
Historically this operation used to lead to retrograde ejaculation (ejaculationof sperm into the bladder) due to damage to the sympathetic nerves. This caused functional infertility. Modern day modifications to the surgical technique have greatly reduced the incidence of this problem.

Radiotherapy
The total radiation dose is low, leading to minor degrees of nausea and vomiting only. Radiotherapy to the para-aortic and pelvic nodes inevitably causes some scatter irradiation to reach the testicle, despite testicular shielding during treatment. If the testis receives less than 1 Gray of radiation the chances of recovery is more or less 100%. A dose of 6-8 Gray to the testicle leads to permanent infertility.

Chemotherapy
Cisplatin causes azoospermia (absence of sperm) in most patients. This usually recovers after 3-4 years. Cisplatin and Ifosfomide are both toxic to the kidneys. Most of the chemotherapeutic agents cause nausea and vomiting. This side effect can normally be combated very effectively with anti-nausea medication. All chemotherapeutic agents tend to suppress the bone marrow. Hair loss is the rule rather than the exception. The risk of developing secondary cancer is increased in patients who have had chemotherapy or radiation, but fortunately the incidence is low.

Future trends

Most patients with testicular cancer are cured from their disease. The various treatment regimens, however, are not without complications. One area of current interest involves the treatment of good prognosis patients. It may be possible to reduce the doses or to eliminate some of the chemotherapeutic agents in some of these patients without compromising survival.

The role of careful surveillance programmes are becoming more popular in order to reduce unnecessary side effects from treatment.

The other main area of research involves high risk poor prognosis patients. This small group of patients currently do badly despite very intensive chemotherapeutic and radiotherapy regimes. Dose-intensive chemotherapy, with very high doses of chemotherapy and blood stem cell support, provides only a modest improvement in results at the cost of severe side effects. Dramatic improvement will probably depend on the development of new chemotherapeutic agents and novel therapeutic approaches.

Prevention

It is not possible to prevent the development of testes cancer. All men should examine their testicles regularly for swellings or lumps. It is debatable whether men with undescended testicles or previous testicular cancers should have biopsies of their testes to rule out CIS. Carcinoma in situ is the precursor to testicular cancer and if detected it can be treated successfully with radiation. This destroys the CIS but preserves the hormonal function of the testes.

As with all cancer earlier treatment leads to improved outcome. Testicular cancer is fast growing, and any man with a suspicious lump in his testes should not delay seeking professional help.

Previously reviewed by Dr Pieter J le Roux MBChB, FRCS(Eng), FRCSI, FCS(SA)Urol.

Reviewed by Dr David Eedes, Oncologist, February 2011

 

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