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Section A

Case Study

Mr MP, a 66 year-old, retired council worker, attended clinic for his biannual active
surveillance check-up. Mr MP has been monitored for a raised prostate specific antigen
(PSA) level, caused by prostate cancer, for 16 years. He was initially found to have a raised
PSA through a blood test, after he presented with worsening urinary symptoms, including:
slow urinary flow, increased frequency and mild nocturia. The patient also commented that
he had no pain on urination but often experienced hesitancy and a feeling that he had not
100% emptied his bladder.
Over this period of 16 years, Mr MPs PSA level has increased from 2ng/ml to 10ng/ml with
his most recent PSA being 9.4ng/ml (normal PSA levels for men in their 60s is up to
4ng/ml
1
). This is only a small elevation in PSA level but biopsies have continued to show the
presence of cancer within the prostate; Mr MPs most recent biopsy showed a Gleason
score of 6, indicating the cancer cells are slow-growing
1
.
Mr MP had surgery 2 years ago for inguinal and umbilical hernias but has no other relevant
medical history. He is currently taking over-the-counter painkillers (ibuprofen and
paracetamol) for a sore shoulder and half a sleeping tablet each night, as he has been
having violent dreams over the last 2 months. On further discussion, Mr MP believes that
these dreams stem from the ongoing stress he has been experiencing since his diagnosis.
He further mentioned that he was worried about developing incontinence and sexual
dysfunction, especially if this resulted from surgery, and therefore stressed that he did not
want any invasive treatment for his cancer until absolutely necessary. Apart from these
dreams, the patient expressed that his diagnosis had not affected his daily life.




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Epidemiology & Aetiology of Prostate Cancer

Prostate cancer (PC) is the most common type of cancer in men and the second leading
cause of cancer mortality in males in Europe and the USA
2
. In 2008, an estimated 324,000
men were diagnosed with PC in Europe and around 899,000 men worldwide
3
. Approximately
1 in 9 men will be diagnosed with this form of cancer in their lifetime, with a 2-3% lifetime risk
of dying from the disease
2
.
It is estimated that the health and economic cost of PC is around 800m a year in the UK
4
;
three-quarters of this relating to the diagnosis, treatment and care of patients with PC, and
the remaining quarter relating to the economic losses from premature deaths and patients
taking time off when they are unable to work (as shown in Table 1)
4
.
Incidence figures have risen drastically in the previous two decades, however much of this
has been due to the increased use of prostate-specific antigen (PSA) screening. The PSA
tests have led to the diagnosis of many more cancers, including some which may not have
presented clinically within the lifetimes of the patients concerned
5
. Autopsy data from males
dying from other causes have shown that the true prevalence of PC is actually far higher
than these incidence figures but in most men the disease remains latent during their life
2
.
The aetiology of PC is complex but many risk factors for its development have been
established.

Age is a well-known risk factor for the development of PC. It is very rare below the
age of 50, accounting for only 0.1% of cases. However, over 75% of cases are
diagnosed in men over 65
3
.

Healthcare and environmental factors have been found to correlate with an
increased incidence of PC. The USA, Australia and Scandinavia have the highest
rates and Japan and the Far East, the lowest. This data reflects the healthcare
practices (e.g increased use of PSA testing) and environmental factors (such as
pollution, infection and diet) of the population
2
.
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Diets high in fat, high in red meat (especially barbecued) and low in vegetables have
been linked to the highest rates of PC. Diet is often related to the country of origin (as
indicated above) e.g. the Japanese population consume less fat than the American
population, and they have a lower incidence of PC
2
.

Family history of PC also presents an increased risk of developing the disease.
Having a first-degree relative diagnosed with PC doubles the risk of PC
6
.

Testosterone is the main hormone controlling the growth and function of the
prostate. Cancer is rarely found in castrated men or those suffering from familial
congenital testosterone metabolism defects, such as 5-alpha-reductase deficiency
2
.
As well as this, higher testosterone levels have been found in the African-American
population, possibly indicating why the increased incidence of PC in this population
when compared to Caucasian men
6
.

Psychosocial Aspects of PC

It is not only the physical symptoms of PC that need to be addressed, but also the wide-
array of psychological issues that the patient may experience. Psychological and social
issues develop in between 30-50% of PC patients. This is irrespective of the severity of their
disease and the treatment they receive
7
. Depression, anxiety and stress, often seen as a
response to the pain, sexual dysfunction and urinary problems that are seen in PC, can
develop at any point in the timeline of the disease.

Anxiety
The types of anxiety seen with patients with PC vary, but it is thought that at any given time
20-60%
8
of PC patients suffer from the issue, with 30-40% of patients complaining that their
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anxiety is affecting their daily lives
9
. It can affect the patient at any stage: during testing for
PC (including PSA testing), at the time of diagnosis, as well as before and during treatment
8
.
It seems that PSA levels are the basis of a significant amount of anxiety for a PC patient. An
abnormal PSA level can be caused by a number of mechanisms and therefore the
uncertainty of a diagnosis can cause stress. Thereby, it was found that anxiety reduced even
when a diagnosis of PC was given, as the uncertainty was removed
10
.

Depression
Depression is strongly correlated to pain and fatigue, symptoms often seen in the late stages
of PC. As well as this, erectile dysfunction & urinary incontinence, complications that many
men diagnosed with PC fear, have a clear link with depressive symptoms
9
.
Interestingly, in studies comparing psychological distress in men with PC and their partners,
it was suggested that the partners risk of depressive symptoms is as high or higher that the
patients
11
, clearly showing how PC can affect, not just the patient, but their family, friends
and surrounding others.

As such, when treating PC, irrespective of stage, the physician needs to consider the family
as well as social and psychological perspectives before making any decisions about a
treatment plan. A multi-disciplinary approach, including urologists, psychiatrists and
psychologists, is required, in order to treat the physical and psychological aspects that are
causing the patients depression and anxiety and address the concerns of carers and loved
ones.







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Section B

The majority (>95%) of prostate tumours are adenocarcinomas arising from prostatic
epithelial cells
12
. However, it is important to recognise the rarer histologies; carcinoid
tumours, large prostatic duct carcinomas, small-cell undifferentiated cancer etc, as certain
therapies will be less effective against these
12
. The peripheral zone of the prostate, located
at the back of the prostate gland, (shown in Figure 1
12
) is the most common area for an
adenocarcinoma to develop, with about 70-75% of PCs occuring here
13
.

PC and PIN

Cancer is generally thought of as a multi-step process; a continuous series of genetic and
cellular events render the tumour increasingly malignant. This can be seen in PC, through
the development of pre-malignant lesions, which may present many years before an
invasive carcinoma develops
14
, and that are now recognized to lead to the development of
PC
15
. These pre-malignant lesions are known as prostatic intraepithelial neoplasia or PIN.
PIN is defined as the presence of cytologically atypical or dysplastic epithelial cells within
architecturally benign-appearing glands and acini
12
(an example of PIN is given in Figure
2
12
). It represents neoplasia that has not yet invaded through the basement membrane.

Molecular Basis

The molecular determinants of PC are an essential area of research and have been under
intense investigation for many years. The main areas of research I will discuss are: mutation
of genes involved with prostate gland development (NKX3.1) as well as activation (Myc) and
loss of tumour-suppression (PTEN& RB).



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NKX3.1
The NKX3.1 gene is located on chromosome 8p21. It has been found that this region
displays heterozygous loss in 50% of primary PC patients and 80% loss in those with
metastatic disease
15
. As well as this, in mouse models, loss of the NXK3.1 gene (a gene that
acts as a transcription factor involved in organogenesis, but also has tumour-suppressing
effects) alongside Myc over expression (discussed below), results in the development of PIN
and eventually micro-invasive cancer
16
.
These two pieces of evidence are strongly suggestive that the NKX3.1 gene plays an
important part in the development of PC.

Myc
The proto-oncogene Myc is a transcription factor that regulates gene expression in many
biological processes. Myc is located on chromosome 8q24,a locus that is often amplified in
PC patients (around 30%)
15
. Mouse models have shown that, in mice with engineered
Super-Lo, Lo or Hi levels of Myc expression, all groups spontaneously developed PIN
and the Lo and Hi groups developed invasive disease. This suggested that Myc over-
expression alone could cause tumour formation
17
.

PTEN (P13K pathway)
Phosphatidylinositol 3-kinase (P13K) through a complex cascade of reactions (shown in
Figure 3
18
) activates AKT, a protein kinase involved with cell proliferation, transcription and
cell migration. This AKT activation is regulated by PTEN.
PTEN is a tumour suppressor, acting in the opposite way to P13K, dephosphorylating PIP3
to PIP2 and reducing AKT activation. It has been found that a loss of a single PTEN allele,
leaving AKT unregulated, can start the development of early stage PC (70% of primary PCs
have a haploid loss of PTEN) and loss of the second allele, alongside other genetic
mutations, leads to the development of invasive disease
19
.


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RB
p130 retinoblastoma (RB) protein is a tumour suppressor; its loss is associated with many
epithelial cancers. The proteins function is to regulate cell-cycle progression and in the
context of cancer, its absence causes the cell cycle to run abnormally, leading to
uncontrolled cell proliferation
20
. RB loss was found in over 70% of castrate-resistant PC
specimens and it has been found that an RB loss signature is associated with poor cancer
prognosis
15
.

Clinical Presentation

The clinical presentations of PC are a result of the invasive growth of the tumour, its spread
to regional lymph nodes and its transport, via the blood, to other sites.
Early stage PC is mostly diagnosed through a routine blood test, as the patient is usually
asymptomatic at this time. At later stages, urinary symptoms may begin to occur. Local
tumour growth can disrupt the urethra or the bladder neck, and may also push into the
trigone area of the bladder. This can lead to obstructive or irritative symptoms
21
, including
increased urinary frequency including nocturia, retaining urine, difficulty passing urine
(straining or stop/start), dysuria and haematuria. It is important that the relevant
investigations are done to ensure these symptoms are not caused by benign prostatic
hyperplasia (BPH).
PC most often spreads to bone
21
and this often presents as localised bone pain, commonly
in the back due to vertebral metastases. Pathological fracture and peripheral
lymphadenopathy are other common presentations
14
.

Conclusion

PC does not have a single cause. Its initiation is most likely caused by a complex array of
genetic mutations, many of which are still being researched. In the near future, with the
increased use of whole-genome sequencing it is hoped that we will be possess the ability to
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determine precisely what mutations or losses are seen in a given patients prostate tumour,
allowing us to treat the precise abnormality. Until then, the onus lies with the physician, and
the development of individualised treatment plans, to deal with and treat, not only the
physical symptoms of the disease but the important psychological issues that may arise.