Introduction

• Prostate cancer is the most common cancer in men, and the 4^th most common cause of death for men in England and Wales.
• The lifetime risk for prostate cancer in men is about 1 in 6 – compared to 1 in 8 for breast cancer in women
• It is a disease strongly associated with age. In post-mortem examination 30% of men over 50, and 80% of men over 80 have histological evidence of prostate cancer. Many of these instances are “sub-clinical” and will never be diagnosed
• Most cancers are slow growing, but some are much more aggressive and carry a much worse prognosis
• Rates of prostate cancer are particularly low in Asians, and particularly high in African Americans and Scandinavians.
• The tumours are usually adenomas and are usually located in the peripheral prostate
• Spread is most commonly to bones and lymph nodes. Prostate cancer is unusual in that it often causes an increased bone density- osteosclerosis (most cancers cause decreased bone density).
• Prostate cancer is also unusual because morbidity and mortality when diagnosed with the disease are not affected by age.

Epidemiology & Aetiology

• Prostate cancer is rare before the age of 40, and prevalence increases with age.
  • Mean age of diagnosis is 66
  • The age of presentation in metastatic disease is older than this and the mean age of death from prostate cancer is 80
  • Given the ageing population in the developed world it is estimated that number of cases of prostate cancer will increase in the coming decades
• Accounts for about 25% of all cancer in men
• Lifetime risk is about 1 in 6
• There is also a genetic factor – similar to that in breast cancer, so if someone in your family has the disease, then you are also more likely to have it.
  • Risk >2x if one first degree relative
• Average life-expectancy after diagnosis is approximately 5-10 years – the disease is very slow to progress.
• Some evidence suggests that a lower intake of animal fat and increased intake of fresh fruit and vegetables decreases the risk of prostate cancer

Clinical features

• Haematuria
• Haematospermia
• Incontinence
• Perineal or suprapubic pain
• Impotence
• Rectal pain and tenesmus (sensation of needing to defecate)
• Symptoms of metastatic spread – particularly to the bones (weight loss and bony pain, spinal cord compression, lymph node enlargement)
• Abnormal prostate on DRE
  • Irregular
  • Hard
  • Assymetrical
  • Adhesion to surrounding tissue
  • Nodules
• Lower urinary tract symptoms (LUTS) are commonly associated with benign prostatic hyperplasia (BPH),but symptoms may be present in advanced prostate cancer, and typically this would cause urinary obstruction. LUTS include:
  • Urinary frequency (particularly noticeable at night)
  • Poor flow of urine
  • Urgency
  • Urge incontinence
  • Sensation of incomplete emptying
• Urinary tract infection

Differential Diagnosis

• Benign Prostatic Hyperplasia
• Prostatitis
• Haematuria differentials
  • UTI
  • Renal stones
  • Bladder cancer

Screening programs

• These are controversial. Treatment of asymptomatic patients will result in serious morbidity (such as incontinence and sexual dysfunction) and there is little evidence that it improves overall outcomes at a population level. There is no recommendation for screening in the UK or Australia.
• Instead, it is recommended to discuss the pros and cons of screening on an individual patient basis and allow the patient to decide if they wished to be screened.
• The RACGP Red Book has a useful resource on explaining PSA screening to patients. Summarising that document, for every 1000 patients screened
  • 1 life will be saved (4 will die as opposed to 5), BUT
  • 87 men will undergo biopsy with no disease detected (false negative)
  • 28 men will need hospitalisation for treatment of complications of a biopsy
  • 10 will have impotence, urinary incontinence or decal incontinence as a result of biopsy
  • 0.5 men will have an MI as a result of treatment

When to investigate

PSA may be performed as part of screening, as described above.

NICE guidelines also recommend considering PSA and DRE in men with any of the following:

• Any LUTS
• Erectile dysfunction
• Visible haematuria (aka frank haematuria)

Investigations

• PSA – prostate specific antigen – this likely to be markedly raised in metastatic disease (>16ng/ml), but may only be slightly raised or normal in early disease.
  • “Normal” level is not always clearly defined. My local hospital lab reports normal as <6 ng/ml, although most urologists would consider results of >3 ng/ml as worthy of monitoring and repeat testing. Many urologist now also use age related reference ranges in clinical practice:
    • Age <49 – <2.5ng/ml
    • Age 50-59 – <3.5 ng/ml
    • Age 60-69 – <4.5 ng/ml
    • Age 70+ – <6.5 ng/ml
  • Many factors, both physiological (e.g. pressure from bicycle riding) and pathology (e.g. prostatitis, prostate cancer and BPH) can cause a raised PSA
  • It is also possible have a normal PSA and still have prostate cancer
  • In prostate cancer, the long-term risk is associated with the PSA level:
    • Low risk – PSA <10 ng/ml
    • Medium risk – PSA 10-20 ng/ml
    • High risk – PSA >20 ng/ml
  • In a single raised results in a low risk patient, repeating the test in a few weeks is reasonable
  • Comparing “free” and “total” PSA can also give a clue as to the origin of the raised PSA. Prostate cancer produces more “bound” PSA (i.e. bound to pother proteins in the blood) compared to other causes of raised PSA. In patients with a raised PSA of an unclear cause, requesting a “Free and Total PSA” test can help to differentiate the cause. A free PSA level of <15% is highly suspicious for prostate cancer. 
  • PSA velocity – refers to the rate at which the PSA is increasing. An increase of >0.75ng/ml in <2 years is considered significant for prostate cancer
• DRE – digital rectal examination – this can detect physical abnormalities of the prostate.
  • A normal prostate is “walnut sized” and smooth, with a palpable central sulcus
  • BPH may cause a smooth, generalised enlargement of the prostate
  • A soft boggy, tender prostate can indicate prostatitis
  • A hard, craggy prostate is suspicious for prostate cancer
  • In recent years, DRE in primary care has declined with an increase in reliance on the PSA test
  • There is some debate in many sources about whether or not performing a DRE can alter a PSA result. Some guidelines suggest not performing a DRE on same day as a PSA test, but the consensus amongst most experts is that DRE does not raise the PSA
• Urinalysis including MC+S
  • Helps to differentiate urinary tract and bladder abnormalities
• Transrectal ultrasound of prostate (TRUS), often with biopsy. The ultrasound is useful because it gives a more accurate estimation of size than a DRE, and can also help stage any tumour present. You may also want to examine the upper renal tract for signs of dilation.
  • “Classical” finding – hypodechoic area in there peripheral prostate
• MRI – is becoming more commonly used to assess the level of disease in the prostate after diagnosis. In some circumstances (often in patient treated with a watchful waiting approach it can replace recurrent TRUS biopsies for monitoring of known cancers
• 10-15% of TURP surgeries will uncover a cancer when it is only suspected to be BPH.
• Bone metastasis can be seen on X-ray as osteoscleoritc lesions.

Spread

• Bones – particularly the axial skeleton– these are detected with radionuclide bone scans
• Lymph nodes (obturator, internal iliac and presacral nodes)
• Bladder
• Rectum
• Seminal vesicles

Staging and Grading

Staging refers to the spread of the tumour from the local site, to peripheral tissues. Grading refers to the histological findings – in particular how well differentiated the cells appear.

Staging and grading the tumour is important for delivering the most appropriate treatment. There are multiple systems used. The TNM system is often used for staging, and the Gleason grading system is often used for grading. A higher score is associated with a worse prognosis. Prostate cancers are often heterogeneous (i.e. they show multiple different types of abnormal cell growth). In the Gleason system, the two most common types of growth are analysed, a score is assigned to each, and the score is added together. There are 5 grades of tissue – Grade 1 to 5. The lowest possible score is 2, and the highest is 10. A score of 10 indicates the most poorly differentiated cells and thus the most advanced cancer development.

• For example, if the two most common types of cells are Gleason 3 and Gleason 4, then the Gleason score is 7 (3+4).
• Gleason score 4 or less – ten-year risk of progression – 25%
• Gleason 5-7 – ten-year risk of progression – 50%
• Gleason 8+ – ten year risk of progression – 75%

Since 2014, the WHO has recommended the ISUP – International Society of Urological Pathology scoring system – usually abbreviated to ISUP-WHO score. This incorporates the Gleason score into its outcomes, and makes an important differentiation between two types of Gleason 7 (3+4 and 4+3) which previously were grouped together:

• Grade 1 – Gleason 2-6
• Grade 2 – Gleason 7 (3+4)
• Grade 3 – Gleason (4+3)
• Grade 4 – Gleason 8
• Grade 5 – Gleason 9-10

Stages of cancer spread are detailed below (images courtesy of Cancer Research UK):

Treatment

Patients should be counselled about the risks of treatment – including erectile dysfunction and urinary incontinence.

“Watchful waiting” – i.e. – no active management, repeating PSA and DRE at regular intervals – is suitable in up to 45% of cases. These patients are typically asymptomatic, with local prostate cancer with no spread, discovered on PSA screening. These are often the patients with “die with prostate cancer” (from another cause), rather than “die from prostate cancer”. 

As the period of watchful waiting advances, monitoring periods can be increased if there is no evidence of disease spread.

• Radical prostatectomy – this may be considered in patients with no evidence of metastatic disease if they have shown disease progression during surveillance, or are symptomatic, or have high chance of metastasis, or in younger patients with an otherwise long life expectancy. It involves the complete removal of the prostate, seminal vesicles, and surrounding connective tissue. Often, a local lymph node dissection is all performed. It can be performed ‘open’ or laparoscopically. The cure rate is 90% for tumours confined to the prostate. At 12 months, the incontinence rate is 7%, and sexual dysfunction rate is 30%. Operative mortality is higher in elderly patients, but overall is roughly 0.5%. Other side effects include DVT, lymphocoele and urethral stricture.
  • After treatment the PSA level is monitored. It should reduce to almost 0 after a radical prostatectomy. If it does not, this is a sign that the cancer has metastasised.
  • Studies measuring the effectiveness of surgery as opposed to that of ‘watching and waiting’ in non-metastatic prostate cancer found that surgery did reduce mortality from prostate cancer, but not overall mortality (i.e. patients still died of something else – and so overall survival was not increased)
• Radiotherapy – this, along with prostatectomy are the only curative treatments for prostate cancer. This is more suitable for elderly patients, although many younger and generally fit patient may chose it as an alternative to surgery. There are no randomised control trial comparing surgery with radiotherapy. There are two types of this treatment:
  • External beam radiotherapy – this uses high energy x-rays from outside the body. There is a risk of impotence and proctitis, sometimes with rectal bleeding and soiling that requires surgery to correct.
  • Patients may als be given androgen suppression therapy along with this treatment as an adjuvant, and this has been shown to boost intermediate outcomes.
  • Brachytherapy – this is where radioactive ‘seeds’ are planted in the prostate. The benefit of this is that the radiation is less likely to affect the surrounding tissues, and thus there are fewer side effects. There are two types of brachytherapy:
    • Temporary high dose seeds –these tend to be used for patients with a more advanced prostate cancer, as they deliver a high dose of radiation. This may be used in conjunction with external beam radiotherapy.
    • Permanent low dose seeds – this is effective in early prostate cancer.
    • The brachytherapy treatments have a lower chance of developing erectile dysfunction, and problems voiding. Whilst these problems may still develop in some patients, often they correct themselves in the long term.
    • External beam radiotherapy and brachytherapy may be used in conjunction with each other
• Androgen suppression – this is the main treatment for non-localised disease. About 80% of patients will show a sustained response to this treatment, but it can take 24-36 months for the response to appear. The quicker the PSA returns to the normal range, the better the prognosis. This treatment can take several forms:
  • Androgen suppression drugs – e.g. bicalutamide
  • Luteinising hormone releasing hormone antagonists – e.g. goserelin, leuprorelin, triptorelin – these stop the release of luteinising hormone, and thus the production of testosterone.
    • For patients on these treatments, measure PSA every 3 months
    • Consider osteoporosis treatments for patients on these drugs
  • Castration – should be offered to all men with metastatic disease as an alternative to anti-LHRH agents – however any men refuse this treatment method.
• Non-hormonal chemotherapy is not usually helpful.
• Finasteride – a 5α-reductase drug, this may be given prophilactically to at risk patients to reduce the risk of developing cancer. It inhibits the production of dihydrotestosterone from testosterone and thus prevents growth of the prostate, however there is a high risk of sexual dysfunction.

References

• Murtagh’s General Practice. 6th Ed. (2015) John Murtagh, Jill Rosenblatt
• Prostate Cancer – Patient.info
• Prostate Specific Antigen – RACGP

Related Articles

• Anatomy and Development of The Urinary Tract
• Benign Prostatic Hyperplasia – BPH
• Catheterisation
• Erectile Dysfunction
• Haematuria