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 are cured from their disease
The treatment of testicular cancer can lead to infertility
A small subgroup of patients do badly despite intensive treatment
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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. These germ cell tumours are divided into seminomas and
non-seminomas.
Non germ cell tumours (less than 5% of testes tumours) 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 as
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 lump in the testis. The cancer
spreads via the lymphatic pathways to the retroperitoneal glands around the
aorta at the level of the kidneys. Later spread takes place to the lungs,
liver, bone and brain. Most patients have disease confined to the testis or the
regional lymph glands at presentation.
Many testicular cancers produce tumour markers. These substances can be
measured in the blood and are useful in diagnosis, staging and monitoring of
treatment.
The results of the treatment of testes cancer are spectacular. 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 primordial germ cells of the testes.
During development the primordial germ cell may be affected by environmental
factors, resulting in disturbed differentiation. 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 in 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 and undescended
testicles, have been observed. The higher incidence of testes cancer in men
with testicular atrophy, undescended testes and infertility, indicates 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. 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 testes 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)
Estrogen administration to
mother during pregnancy
Brother or father with
testes 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, as 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 testes 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 testes 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
Need to see a doctor urgently:
A lump or hardness detected
in the testicle itself
Unexplained enlargement of
testicle
Unexplained pain, ache or
swelling within scrotum
High risk patients who need to be especially vigilant:
Undescended testes
Previous history of testes
tumour
Brother or father with
testes tumour
Infertile men
Many benign conditions can present with a lump in the scrotum and may be
mistaken for a testes 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)
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 according to histology and stage
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 of the treatment of testicular cancer
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.
Retroperitoneal lymph node dissection
Historically this operation used to lead to retrograde ejaculation 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 in the treatment of testicular cancer
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 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.
Reviewed by Dr Pieter J le Roux MBChB, FRCS(Eng), FRCSI, FCS(SA)Urol.
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