Prostate cancer

Prostate cancer is a malignant tumour of the glandular cells of the prostate. It is the second most common cancer in the UK and the most common cancer in men in the UK. Approximately 1 in 8 men are diagnosed with prostate cancer in their lifetime. It is so common in fact that approximately 80% of men over the age of 80 have cancer cells present in their prostate. .

🦴 Anatomy and Pathophysiology physiology

There are certain factors that are believed to contribute to the aetiology of prostate cancer (although the exact mechanisms are not fully understood). Let’s look at 4 of these factors that may play a role:

1. Genetics - a positive family history increases the risk of prostate cancer. Mutations in genes such as BRCA1, BRCA2, HOXB13 and many more have associations with the disease. Lynch syndrome (associated with MLH1, MSH2, MSH6 and PMS2) is also associated with prostate cancer.
2. Ethnicity - Afro-Caribbean groups have higher incidences.
3. Hormonal factors - although the evidence is not clear-cut, there seems to be a role of androgens and the development of prostate cancer. Individuals who take anabolic steroids also are at higher risk.
4. High fat diet - this is shown (albeit with weak evidence) to have implications in the disease.

Let’s quickly recap the prostate gland:

The prostate gland is located between the bladder and the base of the penis. It is a walnut sized accessory gland that envelopes the prostatic urethra.

There are 4 main zones of the prostate to be aware of:

1. Anterior fibromuscular zone - found anteriorly and is made of irregular connective tissue and smooth muscle.
2. Peripheral zone - found in the lateral sections of the prostate and makes up 70% of the glandular tissue (it is also the main area where prostatic cancer arises).
3. Central zone - found centrally and surrounds the ejaculatory ducts that enter the prostate. It makes up 25% of the glandular tissue of the prostate.
4. Transitional zone - this surrounds the prostatic urethra. It contains mucosal glands and is the main site for BPH to occur.

The most common site for prostate cancer to develop is the peripheral zone as it is predominantly glandular tissue and the most common type of prostate cancer is an adenocarcinoma (cancer of glandular tissue). Other sites where prostate cancer arises are the transitional zone and central zone.

The disease often spreads to the seminal vesicles, followed by bladder neck and then the lymphatics (lymphatic spread initially occurs to the obturator nodes). Spread to the seminal vesicles is associated with distant disease.

🔢 Classification and types

1. Adenocarcinoma - this is the most common type of prostate cancer. It can be subdivided into 2 types - the cells that make up the glands and the cells that line the ducts.
1. Acinar adenocarcinoma - this makes up 93% of all prostate cancers. It refers to the cancer arising from the actual glandular cells of the prostate.
2. Ductal adenocarcinoma - this is when the cancer arises from the cells lining the ducts of the prostate. It is the more aggressive variant of adenocarcinoma.
2. Transitional cell/urothelial carcinoma - this is when the cancer starts in the bladder lining and then spreads to the prostate. Rarely, it may start in the prostate and spread to the neck of the bladder.
3. Squamous cell carcinoma - this is when there is replacement of the glandular epithelial cells with multi-layered cells that have squamous differentiation (i.e. squamous metaplasia). It is more aggressive than adenocarcinoma.
4. Small cell carcinoma - a type of neuroendocrine cancer. It is also more aggressive than adenocarcinoma.

There are even rarer variants of cancer that may occur in the prostate such as sarcoma of the prostate and lymphoma of the prostate.

⚠️ Risk factors

• Increasing age
• Obesity
• Afro-Carribean ethnicity
• Family history

😷 Presentation

Presentation of the disease differs depending on the stage of the disease. It is often asymptomatic which leads to late detection. This is due to the disease occurring in the peripheries of the prostate which does not cause any obstructive symptoms.

Locally advanced prostate cancer may lead to obstructive symptoms such as:

• Voiding LUTS - problems relating to bladder outlet obstruction that make it more difficult to pass urine.
• Weak stream
• Hesitancy - delayed urine flow despite feeling the urge to urinate
• Intermittency - this is when the flow starts and stops and varies in its flow rate.
• Incomplete emptying - the inability to fully empty the bladder leading to chronic retention of urine.
• Straining
• Haematuria
• Haematospermia
• Rectal tenesmus
• Pelvic pain or testicular pain
• Bone metastasis
• Back and bone pain
• Cauda equina syndrome - saddle anaesthesia, incontinence (urinary and/or faecal), urinary retention, sexual dysfunction.

☝

Digital rectal examination (DRE) findings:

On DRE, an abnormal prostate may be felt. A normal prostate should be smooth, symmetrical with a notable median sulcus. An abnormal DRE is when there is:

• Asymmetry
• Nodular prostate
• Indurated (hard) prostate
• Absent median sulcus

As the DRE only assesses the posterior wall of the prostate, abnormalities in the middle or anterior portions of the prostate go undetected.

🔍 Investigations

• Comprehensive history
• Urine dipstick - may be positive for blood.
• Digital rectal examination - if the prostate feels malignant on DRE → refer using 2 week wait cancer pathway.
• Prostate-specific antigen (PSA) - if the PSA level is above the age-specific PSA threshold → refer using 2 week wait cancer pathway.
• LFTs - bones produce ALP and so a raised ALP may indicate bony metastasis.

🗣

Imaging:

• 🥇 Pre-biopsy prostate MRI - a multi-parametric MRI (mpMRI) is now recommended as the first-line investigation for suspected localised prostate cancer. We can score the results on a Likert scale as follows:

Likert score	Likelihood of prostate cancer:
1	Very low suspicion
2	Low suspicion
3	Equivocal
4	Probable cancer
5	Definite cancer

• CT scan and bone isotope scans - if metastasis is suspected.

🏆 For confirmation of diagnosis, the gold-standard is to take a biopsy of prostatic tissue. This can be achieved using 2 methods:

1. Transperineal biopsy - this is preferred due to the lower risk of infection. It is offered to men with a Likert score ≥3. It can be done freehand (guided by ultrasound and mpMRI) or can be done using a template (template biopsy).
2. Transrectal ultrasound-guided biopsy (TRUS biopsy) - this involves sampling the prostate transrectally using ultrasound guidance once again.

If there is a negative biopsy but persistent/rising PSA or a suspicious DRE → repeat prostate biopsy.

🔢 Grading

After the initial biopsy, the prostate cancer is given a grade known as the Gleason score. The Gleason score is given based on the morphological features of the prostatic tissue. The scores range from 1 (normal tissue) to 5 (very poorly differentiated cells). The grades 1 and 2 are not deemed as cancerous, so technically the scores range from 3-5. The score is calculated by adding together the two most common grades of cells that are seen on the sample. This means scores range from 6 (3+3) to 10 (5+5). The higher the score the worse the prognosis.

Gleason scores are not used in isolation to determine the prognosis. Instead it is used in conjunction with the PSA levels and TNM staging.

🧰 Management

Depending on the grade and stage of prostate cancer, the treatment involve expectant management, radiotherapy, brachytherapy, hormonal therapy, surgery, chemotherapy.

🧰

Management of prostate cancer:

• Watchful waiting

This is used for patients who are not suitable or do not wish to receive curative treatment. These patients will have deferred use of hormone therapy but no other interventions (such as surgery or radiotherapy) will be offered.

It is suitable for older men, patients with significant comrbidities and patients with slow progressing tumours (who are likely to die due to causes other than their prostate cancer while not suffering significant morbidity from their prostate cancer).

• Active surveillance

Active surveillance differs from watchful waiting as it defers the use of curative methods (as opposed to simply hormonal therapy). Prostate biopsies may be repeated along with PSA levels in order to reassess the prognostic risk of the patient. The idea of active surveillance is to avoid over treatment and to only treat when the risk surpasses a certain threshold.

• Surgical options
• Radical prostatectomy - this involves removal of the entire prostate and both seminal vesicles. It is useful when the cancer is confined to the prostate.

Complications of surgery include:

• Erectile dysfunction - this occurs due to damage to the pelvic splanchnic nerves during surgery as well as losing prostatic fluid. The testes continue to produce sperm but they will be reabsorbed back into the body. An orgasm is still possible but it will be dry and lack ejaculate.
• Urinary incontinence - this is due to damage of the external urethral sphincter that lays beneath the prostate.
• Bilateral orchidectomy - this is essentially surgical castration. It is more of a hormonal therapy to reduce the amount of androgens circulating to reduce cancer growth.

• Radiotherapy options
• External beam radiotherapy (EBRT)

Complications of EBRT include:

1. Proctitis - this is due to the radiation affecting the rectum. Symptoms include pain, altered bowel habits, rectal bleeding, discharge. One may use prednisolone suppositories to reduce the inflammation.
• Brachytherapy - this involves the implantation of metal seeds into the prostate to deliver continuous targeted radiotherapy to the prostate.

Complications of brachytherapy include:

1. Cystitis or proctitis
2. Erectile dysfunction
3. Urinary incontinence
4. Increased risk of rectal or bladder cancer
5. Diarrhoea

• Hormonal therapy options

The aims of hormonal therapy is to reduce the amount of androgens present that stimulate the cancer to grow. It is often used in combination with radiotherapy or alone in cases of advanced disease.

Options for hormonal therapy include:

1. 🥇 Goserelin (Zoladex) or leupoprelin (Prostap) - these are GnRH agonists. It is given as a 3 monthly injection. It leads to an initial surge of testosterone levels but over time with chronic administration the testosterone levels decline.
2. Bicalutamide - this is an androgen receptor blocker.
3. Degarelix - this is a GnRH antagonist.
4. Enzalutamide or abiraterone - these are newer hormone therapies known as maximum androgen blockers (MABs).

Adverse effects of hormonal therapies include:

5. Hot flushes
6. Sexual dysfunction
7. Gynaecomastia
8. Fatigue
9. Osteoporosis