COMMON CANCERS

Cancer of the prostate gland

Epidemiology
Prostate cancer is diagnosed in about 30,000 and 200,000 men each
year in the UK and USA, respectively. These figures have risen
steadily over the last 20 years. This statistic should be interpreted
with caution because of increased detection due to the prostatespecific antigen (PSA) serum test (though an increase in clinically significant cancer appears to have occurred). Prostate cancer
kills more than 9,000 men in the UK each year.
There is significant variation in the incidence of clinical
prostate cancer worldwide. It is relatively high in northern
Europe and North America, intermediate in southern Europe and
South America, and low in the Far East and Asia. The highest
incidences are found in African-American men and the lowest in
Chinese men.

Thomas Swallow
Simon Chowdhury
Roger S Kirby

Abstract
Prostate cancer constitutes a major health problem. It is estimated that the
lifetime risk of western men having prostate cancer is about 30%, with the
risk of dying from the cancer being 3%. Increasing age is the strongest predeterminant for the development of prostate cancer. Virtually all cancers are
adenocarcinomas, the grade being indicated by the Gleason score. Often,
there are no presenting symptoms. Investigations such as serum
prostate-specific antigen (PSA), digital rectal examination and biopsies
via a transrectal ultrasound probe are required for diagnosis. Staging, if
required, consists of magnetic resonance imaging or computed tomography for locally advanced disease and/or a bone scan for detection of
bony metastases. Management depends largely on the stage of the
disease. For localized prostate cancer, radical prostatectomy can offer
a cure. Adverse consequences include erectile dysfunction and incontinence. Prostate cancer is also radiosensitive and treatment can be given
as external-beam radiotherapy or in the form of brachytherapy. Hormonal
therapy, such as luteinizing hormone-releasing hormone analogues and
anti-androgens, is used in locally advanced and metastatic disease.
Hormones do not cure but slow the progression of the cancer. Follow-up
consists of PSA surveillance and other therapeutic options can be considered if the PSA starts to rise. Cytotoxic chemotherapy is increasingly
being used for hormone-escaped prostate cancer. The survival rate at 10
years may be as high as 90% for a well-differentiated, localized prostate
cancer.

Aetiology and risk factors

A direct cause of prostate cancer has not been discovered, but
several risk factors have been identified.
Familial: several studies have shown the prevalence of prostate
cancer within certain families. This familial or hereditary form of
cancer is characterized by either:

three successive generations being affected with the
disease

a clustering of three or more men with the disease in
a nuclear family

two men with early-onset prostate cancer (i.e. age <55
years) in the same family.
The hereditary form of prostate cancer starts about 10 years
before that of the sporadic type. No single gene has been found
(although the HPC-1 gene has been implicated), nor has the
influence played by the environment on the expression of HPC-1
been identified.

Keywords brachytherapy; Gleason score; hormonal therapy; prostate

cancer; prostatectomy; PSA; radiotherapy

Age is the strongest predetermining factor for the development of

prostate cancer. It is rarely found in men aged under 50 years,
but it is increasingly common with advancing age. The probability of prostate cancer developing in a man aged under 40 years
is 1 in 10,000; it is 1 in 8 for men aged 60e79 years.

Prostate cancer is becoming an increasingly significant international health problem; it may soon overtake lung cancer as the
leading cause of cancer-related mortality in men in developed
countries. For a western male, the lifetime risk of:

developing microscopic prostate cancer is 30%

developing clinical disease is 10%

death from the disease is 3%.

Diet appears to have a significant influence on the risk and

prevention of prostate cancer. The amount of dietary fat
consumed seems to be a risk factor for the development of
prostate cancer. The diet is rich in dairy products and red meat in
areas with a high incidence (e.g. USA). Studies have indicated
that vitamins E and D, as well as the trace element selenium, may
protect against prostate cancer.

Thomas Swallow MRCS is a Clinical Research Fellow in Urology at

St Georges Hospital, London, UK. Conflicts of interest: none declared.

Testosterone and its main metabolite, dihydrotestosterone, are

the principal hormones regulating the growth and function of the
prostate gland. Cancer of the prostate is rarely found in castrated
men. Conversely, relatively high concentrations of circulating
testosterone have been found in African-American men, possibly
explaining their higher incidence of prostate cancer compared to
Caucasian men.

Simon Chowdhury MRCP is a Consultant Medical Oncologist specializing

in the treatment of prostate cancer at Guys Hospital, London, UK.
Conflicts of interest: none declared.
Roger S Kirby FRCS(Urol) is a Honorary Professor of Urology at
St Georges Hospital, and University College London, London, UK.
Conflicts of interest: none declared.

MEDICINE 40:1

Other risk factors have been suggested, including vasectomy,

environmental (e.g. exposure to cadmium) and viral factors.

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2011 Published by Elsevier Ltd.

COMMON CANCERS

Pathology

the routine measurement of PSA is not present in the UK. The

advantages would be:

an initial increase in incidence rates as more cancers are
detected, followed by a fall as they are treated

detection of the disease at earlier stages and decrease in
mortality from advanced disease

an increase in relative survival rate as compared to other
causes of death

detection of disease at a younger age and at lower
concentrations of PSA.
The disadvantages include the:

number of false-positives e the PSA test lacks specificity,
and the concentration may be high due to other causes
(e.g. infection (prostatitis), benign prostatic hyperplasia
(BPH), acute urinary retention, vigorous digital rectal
examination)

number of false-negatives e the PSA test lacks sensitivity,
and the concentration may be within the typical normal
range even in the presence of cancer

potential identification and subsequent treatment of clinically irrelevant disease.
The upper limit of normal PSA is usually 4 ng/ml, but this value
will include some patients with BPH and some with prostate
cancer. The PSA increases with age, so the value must be adjusted
for age. Further refinements of the PSA have been employed.

The speed of rise of PSA concentration (PSA velocity)
during the year before the diagnosis of cancer is strongly
associated with the risk of death from prostate cancer.

The ratio of free:total concentration of PSA can indicate
whether a rise is due to BPH or cancer. A value of less than
18% suggests cancer and biopsy is indicated.

Over 95% of prostate cancers are adenocarcinomas; the

remainder are neuroendocrine tumours or sarcomas. Characteristic prostate adenocarcinoma cells have hyperchromatic,
enlarged nuclei with prominent nucleoli and abundant cytoplasm. The basal cell layer is absent in prostate cancer, but
present in normal glands and the glands of benign prostatic
hyperplasia. Prostate cancer is often multifocal. About 70% are
found in the peripheral zone, 20% originate in the transition
zone, and 10% are within the central zone.
Prostatic intraepithelial neoplasia (PIN) is the precursor of
prostate cancer. Cells show similar characteristics to those of
prostate cancer cells, but the basal cell layer is present. PIN is
often found adjacent to areas of prostate cancer, and its identification in biopsy specimens in the absence of cancer warrants
further investigation for concurrent invasive carcinoma.

Grading and staging

Prostate cancer is graded using the Gleason grading system, which
is based on the microscopic appearance of the glandular architecture of the prostate. The system is in two parts: a grade between
1 and 5 is given to the most dominant pattern; then a grade between
1 and 5 is given to the second commonest pattern. The two are
added together to give the Gleason score. Thus, a Gleason score
ranges from 2 to 10 and is usually fully annotated (e.g. 3 4 7).
The grade indicates the degree of glandular differentiation: grade 1
indicates a well-differentiated tumour, whereas grade 5 is a poorly
differentiated tumour. The Gleason score gives an indication of
prognosis and tumour progression.
The staging of prostate cancer is assessed using a number of
diagnostic tools, including digital rectal examination, bone
scintigraphy and MRI. Not all are essential in every case; the
decision is guided by the concentration of PSA in serum, Gleason
score and the clinical stage. Imaging is often unnecessary in
patients who are at low risk of metastases using these
parameters.

The digital rectal examination is an essential part of the urological examination, enabling the size of the prostate gland to be
assessed, and nodules or lumps to be detected. The digital rectal
examination alone can determine the need for further investigation. The cancer can be staged by assessing whether the tumour
extends to the seminal vesicles or invades adjacent structures.
Transrectal ultrasound and biopsy are indicated if cancer is
suspected because of a raised PSA and the findings of the digital
rectal examination. This procedure is done under local anaesthesia and biopsies of the prostate are taken via a transrectal
ultrasound probe. Ultrasound-guided biopsy:

provides more accurate staging than the digital rectal
examination

allows lesions to be identified

enables the volume of the prostate gland to be measured.
Biopsies are taken with a Tru-Cut needle and 6e12 cores are
removed. This process samples a small percentage of the prostate
gland, but the urologist or radiologist can focus on taking samples
from lesions that feel or look suspicious on ultrasound. Occasionally, despite a high PSA, the biopsies are negative for cancer,
or PIN is found. Most urologists recommend repeat biopsies or
even saturation biopsies (20 biopsies are taken) if suspicion
remains high. In general, transrectal ultrasound and biopsies have
a low morbidity. Infection is seen in less than 5% (provided antibiotic prophylaxis is used) and less than 2% have significant
bleeding. Anticoagulants should be stopped before biopsy.

Tumour progression
The likelihood of local extension outside the prostate capsule,
invasion into the seminal vesicle, and nodal and distant metastases increases with increasing PSA, tumour volume and Gleason
score. Invasion into the seminal vesicle is associated with nodal
and distant spread. The obturator lymph node chain is the most
common site for lymphatic spread. Metastatic spread usually
involves non-regional lymphatics and the axial skeleton.

Diagnosis
Early low-grade prostate cancer is usually asymptomatic. Locally
advanced or metastatic disease is usually the cause if men
present with symptoms. Local growth can cause obstructive or
irritative urinary symptoms. Metastatic spread can present as
bone pain and even compression of the spinal cord. The main
investigations to diagnose prostate cancer are discussed below.
PSA: most cancers are discovered by routine measurement of
PSA in serum. A screening programme for prostate cancer and

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COMMON CANCERS

Other investigations

Incidence of death from prostate cancer: watchful waiting

versus radical prostatectomy
Cumulative incidence of death
from prostate cancer (%)

MRI or CT of the pelvic area is indicated if biopsies are positive

for adenocarcinoma. This gives anatomical information about
the local extension of the cancer and lymph node involvement,
which is important if a radical prostatectomy is considered.
Whole-body bone scintigraphy is carried out if the PSA is
over 10 ng/ml. This gives information on bony metastases that
may influence management.
New molecular studies are available that may negate the need
for prostate biopsies. A specific urine sample assay can detect
PCA3, a gene that is overexpressed in prostate cancer tissue. A
prostate massage is done so that prostate cells are shed; these are
then caught via a urine sample for analysis.

Watchful waiting
Radical prostatectomy

30
20
10
0

Number at risk
Radical
347
prostatectomy
Watchful waiting 348

Differential diagnosis
Induration of the prostate, apparent on digital rectal examination,
is also associated with prostatitis, previous transurethral resection
of the prostate, needle biopsy or prostatic calculi. The main
differential diagnoses are BPH, prostatic calculi and prostatitis.

4
6
Years of follow-up

10

343

332

284

210

118

341

326

279

198

104

Source: Bill-Axelson A, Holmberg L, Ruutu M et al. Scandinavian Prostate

Cancer Group Study No. 4. Radical prostatectomy versus watchful waiting in
early prostate cancer. New Engl J Med 2005; 352: 197784. Reproduced with
permission.

Management

Figure 1

Localized prostate cancer

Watchful waiting/active surveillance may be the most appropriate course for men aged over 70 years and/or those with
significant co-morbidity, particularly if the cancer is low volume
and the Gleason score is low. Careful follow-up with regular
digital rectal examination and monitoring of PSA is important.
Counselling and implementation of active treatment should
occur if the cancer progresses.

advanced disease. Pelvic lymph nodes can be included in the

treatment field. Advances in radiotherapy have led to the radiation beam being focused on the prostate gland. This has led to
fewer adverse effects, but proctitis, rectal bleeding and haematuria can occur. There is also a 1e3% risk of incontinence. In
carefully selected patients, external-beam radiotherapy offers
a 15-year overall survival, similar to that seen after radical
prostatectomy. Radiotherapy may be combined with hormonal
therapy and two trials have shown improved overall survival in
high-grade and locally advanced disease with the use of prolonged androgen deprivation therapy (see below) following
radiotherapy. The cancer cannot usually be treated by surgery if
recurrence occurs. One study has revealed a doubling of incidence of rectal carcinoma in patients treated with external-beam
radiotherapy, so post-treatment rectal bleeding should be
investigated.

Radical prostatectomy (Figure 1) has the advantage of removing

the entire prostate gland, which reduces the risk of disease
recurrence. The procedure is commonly done through a horizontal or vertical incision on the lower abdomen. Laparoscopic
and robot-assisted laparoscopic removal of the prostate are
becoming more common. Particular care is taken to preserve the
delicate nerves on either side of the prostate; this reduces the risk
of impotency. The seminal vesicles are removed with the prostate gland. The urethra is then anastomosed to the base of the
bladder. The obturator lymph nodes are sampled. A catheter is
left for 2 weeks while the urethra and bladder heal. A recent
randomized controlled clinical trial showed a significant
improvement in mean survival in patients treated by radical
prostatectomy compared to those managed by watchful waiting,
and a 50% reduction in the development of metastases.
Erectile dysfunction may result in up to 50% of patients, but can
be greatly improved with phosphodiesterase-5 inhibitors. Stress
incontinence is seen in 2e3% and almost invariably improves
with pelvic floor exercises, physiotherapy and/or anticholinergics.
Careful histopathological examination of the whole tumour
specimen can identify patients at higher risk of recurrence, which
can be reduced by postoperative radiotherapy.

Brachytherapy is the deployment of radioactive seeds directly

into the prostate gland. It can be done as a two-stage (two visits
to hospital; to be measured and then implanted with the seeds)
or a one-stage procedure. Brachytherapy can be combined with
external-beam radiotherapy in patients considered at high risk of
recurrence. Brachytherapy is most suitable for patients with
smaller, lower-risk cancers and for men with small or mediumsized prostate glands. Long-term tumour control from mature
series appears to be equivalent to prostatectomy and externalbeam radiotherapy. Without careful case selection, the predominant complication is the occurrence of obstructive urinary
symptoms, including the need for prolonged catheterization.
Sexual function is thought to be better preserved after brachytherapy compared to surgery and radiotherapy.

External-beam radiotherapy: radiation therapy provides

a definitive treatment approach for localized and locally

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COMMON CANCERS

Locally advanced prostate cancer

Hormonal therapy
Analogues of luteinizing hormone-releasing hormone
(LHRHa) are usually given as a depot injection every 3 months.
They act by over-stimulating LHRH receptors in the pituitary gland
and, via negative feedback, stop the release of luteinizing hormone
from the pituitary gland. The concentration of circulating testosterone is reduced to a castration level. These agents reduce the size
of the cancer and slow progression, but do not eradicate the
disease. The main adverse effects of androgen deprivation therapy
(ADT) are hot flushes, sweats, and reduced libido. Patients may
also notice reduced muscle mass, reduced strength and weight
gain. A proportion of patients suffer reduced bone mineral density
and there is known to be an increased risk of non-traumatic fractures, so men at risk of osteoporosis should be carefully monitored
or treated with bisphosphonates where necessary.
Anti-androgens block the action of testosterone on the prostate gland. Adverse effects include breast enlargement and
soreness. They can also cause mild stomach upset and damage
the liver. They do not have such a profound effect as LHRHa on
potency and libido. Anti-androgens slow the progression of, but
do not cure prostate cancer.

LHRHa and anti-androgens in combination confer complete

testosterone blockade. It is not clear whether this combination
therapy significantly increases the time to progression or overall
survival. Combination therapy is probably best suited to
younger, relatively fit men with advanced prostate cancer
because it may result in a longer period before disease
progression.
Follow-up: most patients have regular measurement of PSA.
After radical prostatectomy, the PSA should remain at zero if all
the cancer has been removed. In locally advanced and metastatic
disease treated with hormones, it should fall to very low levels
initially.
Castrate-refractory prostate cancer
Prostate cancer eventually becomes insensitive to hormone
ablation and the PSA begins to rise (castrate-refractory prostate
cancer). This rise is often accompanied by clinical symptoms,
particularly bone pain. Whole-body bone scintigraphy must be
repeated to see if the cancer has spread. This is an area that is
changing rapidly and therapeutic options that have been shown
to benefit the patient include:

modifying existing hormonal therapy (e.g. abiraterone)

cytotoxic chemotherapy (e.g. docetaxel)

bone-directed therapies (e.g. bisphosphonates, monoclonal
antibodies to RANK-ligand, radioisotopes)

palliative radiotherapy.
Most of these treatments have shown a small benefit in the late
stages of disease and it is hoped that, by using them earlier in the
treatment of locally advanced and metastatic disease, they will
have a greater effect.

Metastatic prostate cancer

About 70% of men with metastatic prostate cancer die from their
cancer within 5 years. Progression can be delayed for several
years by the treatments discussed below.
Bilateral orchidectomy is the surgical removal of both testicles
so that testosterone is no longer produced. Prosthetic testes can
be inserted for a better cosmetic appearance. A subcapsular
orchidectomy (only the cells of the testes are removed and the
capsule is left) can be done. The main adverse effects are hot
flushes, loss of libido and impotence. About 80% of men respond
to this treatment, which slows disease progression for about 18
months.

Prognosis
The natural history of prostate cancer is highly dependent on
stage, grade, co-morbidity and age. The survival rate at 10 years
for a well-differentiated, localized prostate cancer may be as high
as 90%; for a poorly differentiated tumour it drops to 60% or
less. Prostate cancer is one of the few solid cancers that is readily
curable, if it is detected early.
A

LHRHa: the response to this treatment in metastatic cancer is

about 80%, and benefits last for 18e36 months. A large rise in
circulating testosterone may be seen when the injection is first
given, causing bone pain and even spinal cord stenosis; antiandrogens are given to protect against this tumour flare.
Newer LHRH antagonists (e.g. degarelix) do not cause a surge
and may have a role in emergency situations e such as newly
diagnosed cancer presenting with cord compression.

MEDICINE 40:1

FURTHER READING
Kirby RS, Partin A, Feneley M, Parsons K, eds. Prostate cancer: principles
and practice. London: Taylor and Francis, 2005.

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2011 Published by Elsevier Ltd.