• One of the strongest relationships between age and any human malignancy ^[4].
• Aging is the MOST important risk factor ^[1].
• Rare before age 40 ^[4].
• The mechanism: with ageing, there is cumulative exposure to androgens, accumulation of somatic mutations, epigenetic changes, chronic inflammation, and telomere shortening in prostatic epithelial cells.

• Blacks > Caucasians > Asians ^[4].
• African-American men have the highest incidence and mortality worldwide — they develop cancer earlier, present with higher-grade disease, and have worse outcomes even after adjusting for socioeconomic factors. This is thought to reflect both genetic susceptibility and differences in androgen metabolism.
• Asian men (including Hong Kong Chinese) historically have lower rates, but this gap is narrowing with westernisation ^[4].

• 2× risk if 1 first-degree relative affected; 4.5× risk if 2 first-degree relatives affected ^[4].
• Risk is higher if the affected relative was diagnosed at a young age.
• 5–10% of prostate cancers are hereditary ^[4].

• BRCA1 and BRCA2 mutations ^[1][4]:
  • BRCA2 is a stronger risk factor for prostate cancer than BRCA1 ^[1].
  • BRCA2 carriers have ~3–8× increased risk and tend to develop more aggressive, higher-grade disease.
  • These are tumour suppressor genes involved in homologous recombination DNA repair. When both alleles are lost (germline mutation + somatic "second hit"), DNA damage accumulates → malignant transformation.
  • BRCA mutations also confer sensitivity to PARP inhibitors (e.g., olaparib) — a therapeutic target in metastatic castration-resistant prostate cancer (mCRPC).
• Other heritable mutations: ATM, CHEK2, Lynch syndrome (HNPCC = hereditary non-polyposis colorectal cancer) ^[4].
• TMPRSS2-ETS fusion gene: present in ~50% of prostate cancers ^[2]. TMPRSS2 is an androgen-regulated gene; when fused with ETS family transcription factors (e.g., ERG), it drives androgen-dependent overexpression of oncogenic transcription factors.

• Growth of prostate cancer is stimulated by androgens ^[4].
• The role of 5α-reductase inhibitors (finasteride, dutasteride) is debated — they reduce overall prostate cancer incidence but there was concern about increasing high-grade cancer detection (likely a detection bias rather than a true increase) ^[4].

• Obesity: small increased risk ^[4] — likely through altered hormonal milieu (higher oestrogen from aromatisation, insulin resistance, IGF-1 signalling).
• Regular physical exercise decreases risk ^[4].

• Evidence is generally weak ^[4].
• Potentially protective: selenium, lycopene (tomatoes), vitamin E, green tea, possibly coffee ^[4].
• Potentially harmful: dietary fat (linked to obesity), isoflavonoids (soybean products — note: this is debated) ^[4].
• High animal fat intake may increase risk; high vegetable intake may be protective ^[1].

• Smoking is listed as a risk factor ^[1][2] — associated with higher-grade disease and worse prognosis rather than significantly increased incidence.

• Chronic prostatitis/inflammation: may contribute to carcinogenesis through oxidative stress and proliferative inflammatory atrophy (PIA) → prostatic intraepithelial neoplasia (PIN) → carcinoma sequence.

• Commonly used system for classifying histologic characteristics of prostate cancer ^[1].
• Developed by Donald Gleason in the 1960s–70s, based entirely on architectural pattern (how glands are arranged), NOT nuclear features.
• The pathologist identifies the primary (most prevalent) pattern and the secondary (second most prevalent) pattern, each graded 1–5.
• Gleason score = primary pattern + secondary pattern (range: 2–10) ^[1].
• Gleason 8–10 is considered high-grade ^[1].

In modern practice (2014 ISUP modified Gleason), patterns 1 and 2 are essentially never assigned on needle biopsy — the minimum Gleason score on biopsy is 3+3 = 6.

The ISUP (International Society of Urological Pathology) introduced Grade Groups to simplify Gleason scoring and better stratify prognosis:

^[2][4]

• Incidental findings: abnormal DRE, elevated PSA ^[2]
• Increasingly, prostate cancer is detected before symptoms develop because of routine or opportunistic PSA testing.

Obstructive LUTS are late findings because cancer arises in the peripheral zone ^[2].

LUTS occur when the cancer grows large enough to compress the urethra or invade the bladder neck/trigone:

Voiding (Obstructive) Symptoms:

• Hesitancy (difficulty initiating micturition) — the enlarged prostate compresses the prostatic urethra, increasing urethral resistance
• Weak stream / decreased force — same mechanism
• Intermittency (stop-start stream) — detrusor struggles against obstruction
• Straining to void
• Terminal dribbling
• Incomplete emptying
• Urinary retention (acute or chronic) — complete obstruction

Storage (Irritative) Symptoms:

• Frequency and urgency — secondary detrusor overactivity from chronic obstruction, or direct tumour invasion of the bladder wall/trigone irritating detrusor muscle
• Nocturia — same mechanism
• Urge incontinence

Note: These symptoms are indistinguishable from BPH on history alone. You cannot differentiate BPH from prostate cancer based on LUTS pattern — that's why DRE and PSA are essential.

• Haematuria / haemospermia ^[2] — cancer eroding into the prostatic urethra or ejaculatory ducts, disrupting blood vessels.
• Haemospermia (blood in the semen) is usually benign, but new-onset haemospermia in an older man should raise suspicion for prostate cancer.

• New-onset erectile dysfunction ^[2] — may indicate local invasion of the neurovascular bundles (of Walsh) that run posterolateral to the prostate and are responsible for cavernous nerve-mediated erection.

• Perineal/pelvic pain — perineural invasion (prostate cancer has a particular tropism for perineural invasion) or direct extension into pelvic floor muscles
• Rectal symptoms (tenesmus, rectal bleeding — rare because Denonvilliers' fascia acts as a barrier between the prostate and rectum)
• Ureteric obstruction → hydronephrosis → flank pain, renal impairment — from local extension into the trigone/ureteric orifices or bulky pelvic lymphadenopathy compressing ureters
• Lower limb oedema — bulky pelvic lymphadenopathy compressing iliac veins or lymphatics

Metastatic sites: bone (vertebra via Batson's venous plexus), liver, adrenal ^[2]

• Bone pain (most common symptom of metastatic prostate cancer):
  • Persistent, dull, deep ache, often in the lower back, pelvis, hips
  • Worse at night (unlike mechanical back pain)
  • Pathophysiology: osteoblastic metastases stimulate periosteal nerve stretching and local inflammation
• Pathological fractures — weakened bone (despite being osteoblastic, the new bone is structurally disorganised and weak)
• Spinal cord compression (oncological emergency):
  • Back pain → progressive lower limb weakness → sensory level → urinary retention/incontinence
  • From vertebral body collapse or epidural tumour extension compressing the spinal cord
• Bone marrow failure (pancytopenia) — extensive marrow infiltration by metastatic disease (leukoerythroblastic blood film)
• Constitutional symptoms: weight loss, fatigue, anorexia — cytokine-mediated cancer cachexia
• Hypercalcaemia — less common in prostate cancer than in other bone-metastasising cancers because osteoblastic lesions tend to sequester calcium rather than release it (in fact, prostate cancer patients may even be hypocalcaemic from avid bone uptake)

DRE is the single most important physical examination for prostate cancer.

DRE findings in prostate cancer (only 25% of cancers are palpable) ^[2]:

• Asymmetrically enlarged prostate
• Hard, irregular nodule (in contrast to BPH, which is smooth, firm, and rubbery with a symmetrically enlarged gland)
• Loss of the midline sulcus (the normal median groove between the two lobes is obliterated by tumour)
• Fixed (cannot be moved — suggests extracapsular extension)
• Surface may be nodular or craggy

Why only 25% palpable? Because:

1. Many cancers are small (T1c — detected by PSA, not palpable)
2. Anterior tumours (20–30%) are beyond the reach of the examining finger
3. DRE can only assess the posterior and lateral aspects of the prostate

• Palpable bladder — if urinary retention has developed from obstruction
• Lower limb lymphoedema — bulky pelvic lymphadenopathy
• Bony tenderness — metastatic bone disease (percussion tenderness over spine)
• Neurological signs — if spinal cord compression (upper motor neuron signs below the level of compression: hyperreflexia, upgoing plantars, sensory level, urinary retention)
• Cachexia — advanced/metastatic disease
• Pallor — anaemia from bone marrow infiltration or chronic disease

These are strategies to improve PSA accuracy when the total PSA is in the equivocal range, where the pre-test probability of cancer is only ~20–25%:

DRE: insensitive (cannot detect small cancers and cancers in other areas) and non-specific (30% PPV only) ^[4]

DRE can theoretically obtain T staging ^[4]: T1 (impalpable), T2 (palpable, confined), T3 (extracapsular — firm extension beyond gland), T4 (fixed to pelvic wall/invading adjacent structures).

Limitations ^[1]:

• Stage T1 cancers are by definition non-palpable
• Only detects tumours in the posterior and lateral aspects of the prostate
• Cannot detect anterior zone tumours (20–30% of cancers)
• Traditional cutoff for PSA ≥ 4 with DRE: Sensitivity = 59%, Specificity = 94%, PPV = 5–30% ^[1]

• Check MSU 1 week prior to procedure; treat UTI if positive ^[2]
• 12-core systematic biopsy with labelling from different areas of the prostate ^[2][4] — this samples all zones systematically
• Plus targeted biopsies of any MRI-suspicious lesion (PI-RADS 3–5)
• Labelling cores by location is important because it guides resection margin planning in subsequent prostatectomy ^[4]

Bleeding (haematuria and haematospermia), pain, infection/sepsis and urinary retention are the main biopsy complications. Rates vary with route and definitions; do not combine the senior-note figures of “3% overall” and “25% fever” as one cohort. Fever after biopsy requires prompt assessment for infection.

Multiparametric (mp) MRI uses multiple imaging sequences to characterise prostate tissue ^[1]:

PI-RADS (Prostate Imaging — Reporting and Data System) v2.1 Scoring:

Principle: bone-seeking radiopharmaceuticals (99mTc-MDP) are analogues of calcium/phosphate that are adsorbed onto bone surface. Adsorption rate is affected by osteoblastic activity and vascularity ^[12].

This is why bone scan is excellent for detecting prostate cancer metastases (which are osteoblastic) but may miss purely osteolytic lesions (e.g., multiple myeloma). The superscan pattern — intense symmetric bone uptake with absent renal activity — indicates widespread metastatic disease and should not be confused with a "normal" scan ^[12].

Why does this work? Grade Group 1 (Gleason ≤ 6) prostate cancer has an extremely low risk of metastasis or cancer-specific death within 10–15 years. The "cost" of radical treatment (incontinence, erectile dysfunction) outweighs the marginal survival benefit in this group. AS allows intervention only when the biology declares itself as more aggressive.

^[4]

• Palliative intent for old fragile patients ^[3]
• Offer palliative treatment for symptoms or impending complications; consider earlier ADT selectively for aggressive progression. A single high PSA is not a universal trigger
• Limited life expectancy reduces the opportunity to benefit from radical treatment; interpret trial outcomes using the enrolled risk group and follow-up, rather than claiming that treatment never improves survival
• Risk of disease progression to require palliative intervention is approximately 40–50% over 10 years, but many will die of other causes first

• Primarily localised cT1–2 disease; selected locally advanced M0 disease after multidisciplinary review
• Confirmed histological diagnosis ^[1]
• Life expectancy > 10 years ^[1]
• Patients fully counselled and aware of possible complications and alternative treatment options ^[1]
• PSA ≥20 or Grade Group 4–5 does not automatically exclude surgery. Selected high-risk M0 patients can undergo RP as part of multimodal management after appropriate staging and counselling. MRI may show the primary cancer; “negative MRI” is not an eligibility requirement. EAU treatment guideline.

• Life expectancy < 10 years (no survival benefit from surgery)
• Unfit for general anaesthesia
• T4 disease (fixed tumour invading rectum, levators, pelvic wall — technically not resectable)
• Extensive nodal or distant metastatic disease (surgery alone will not be curative)
• Patient preference against surgery

Open (retropubic/perineal), laparoscopic, or robotic — none has clearly shown superiority over others ^[4], though robotic-assisted laparoscopic prostatectomy is now the most widely used approach worldwide due to improved ergonomics, 3D visualisation, and possibly lower blood loss.

Open, laparoscopic and robotic approaches remain options; surgeon experience and patient selection matter, and access varies.

• Resection of: prostate, prostatic urethra, seminal vesicles, part of vas deferens ^[4]
• ePLND when indicated by nodal risk samples external iliac, obturator and internal iliac basins. It improves pathological staging; a routine survival benefit from dissection itself is unproven. “Up to the aortic bifurcation” is not the standard extended pelvic template.

Three surgical goals ^[1]:

1. Excise cancer completely with a clear margin
2. Maintain continence by preserving the external sphincter — the external urethral sphincter sits at the prostatic apex and must be carefully preserved during apical dissection
3. Maintain potency by sparing autonomic nerves in the neurovascular bundles — cavernous nerves lie immediately posterolateral to the prostatic capsule ^[1]

Nerve-sparing technique may be used in most patients to ↓ risk of erectile dysfunction, but is contraindicated if there is high risk of extracapsular extension ^[4] — because the neurovascular bundles abut the prostatic capsule, and preserving them in the setting of T3a disease risks leaving cancer behind.

Positive margins, extraprostatic extension and seminal-vesicle invasion increase recurrence risk. Many patients with undetectable postoperative PSA can have PSA surveillance with early salvage RT; selected very high-risk cases may merit adjuvant RT. pN1 decisions incorporate nodal burden, pathology and postoperative PSA, with observation or ADT ± RT selected by the MDT.

After RP, biochemical recurrence is commonly defined as PSA ≥0.2 ng/mL confirmed on repeat testing; after RT, the Phoenix definition is nadir +2 ng/mL. These definitions are not instructions to delay useful salvage therapy: AUA/ASTRO/SUO advises salvage RT at PSA ≤0.5, with earlier treatment considered for high-risk recurrence. A negative PSMA PET must not by itself withhold prostate-bed salvage RT. Salvage guideline.

Post-op care: Foley catheter should be placed for ≥ 7 days post-op ^[4] to allow the vesicourethral anastomosis to heal.

• Localised or locally advanced disease ^[4]
• Older patients ^[2] — avoids surgical risks
• Alternative to RP for any localised disease (patient preference)
• Adjuvant after RP for positive margins or pT3 disease
• Salvage after biochemical recurrence post-RP

• Unfavourable intermediate risk: RT generally combines with 4–6 months ADT; favourable intermediate-risk patients may receive RT without ADT after individual assessment
• Adjuvant ADT × 2–3 years if high-risk localised or locally advanced ^[4]

Why combine ADT with RT? ADT causes tumour shrinkage (cytoreduction) → smaller radiation target; it also induces apoptosis in cancer cells, making them more radiosensitive; and it controls micrometastatic disease systemically. Randomised trials (e.g., EORTC 22863, RTOG 9202) have shown significant survival benefit from adding long-term ADT to RT in high-risk disease.

Prostate cancer cells depend on androgen receptor (AR) signalling for survival and proliferation. Testosterone (mainly from testes) is converted to DHT (by 5α-reductase) in the prostate → DHT binds AR → activates transcription of pro-survival genes. Remove the androgen signal → cancer cells undergo apoptosis. This is the basis of ADT, first demonstrated by Charles Huggins (Nobel Prize, 1966).

> 90% of male hormones (testosterone) originate from the testes; < 10% (DHEA, DHEA-S, androstenedione) originate from the adrenals ^[1]

Side effects of testosterone-lowering agents ^[1]:

This is newly diagnosed metastatic disease that has NOT yet been treated with ADT (or is still responding to ADT).

The modern approach ^[3][4]:

• Traditional approach: ADT monotherapy first → add others if CRPC ^[2] — this is outdated
• New approach: upfront combination therapy ^[2][3] — multiple landmark trials (CHAARTED, LATITUDE, STAMPEDE, ENZAMET, TITAN, ARASENS) have proven that upfront intensification dramatically improves survival

Treatment by metastatic volume ^[3]:

Why treat the primary tumour with RT in low-volume disease? The STAMPEDE trial showed that in patients with low metastatic burden, adding radiotherapy to the prostate (while on systemic ADT) improved overall survival — likely because the primary tumour is a source of ongoing seeding of metastatic clones.

Definition of CRPC ^[4]:

• Castrate level of testosterone ( < 50 ng/dL) — i.e., the patient IS on ADT
• PLUS disease progression defined as:
  • Biochemical progression: 3 consecutive rises in PSA 1 week apart with 2 × 50% increase over nadir and one PSA > 2 ng/mL
  • Radiological progression: ≥ 2 new bone lesions on bone scan or enlarging soft tissue lesion
  • Symptomatic progression alone is NOT sufficient to diagnose CRPC ^[4]

Mechanism: either tumour cells becoming testosterone-independent or autonomous androgen secretion ^[4] — through AR gene amplification, AR splice variants (AR-V7), intracrine androgen synthesis, or activation of alternative growth pathways.

Treatment of CRPC ^[4]: Usually continue ADT + add 2nd-line treatment:

• Mechanism: Although prostate cancer arises in the peripheral zone (and therefore causes LUTS late), large tumours or those with central/transitional zone extension eventually compress or invade the prostatic urethra and bladder neck → increased urethral resistance → voiding difficulty → ultimately acute urinary retention (AROU).
• Clinical presentation: Progressive voiding LUTS (hesitancy, weak stream, incomplete emptying) → AROU (inability to void, suprapubic pain, palpable distended bladder)
• Management: Urethral catheterisation; if failed, suprapubic catheter; may consider TURP to relieve obstruction ^[4] (palliative TURP — note that this does NOT cure the cancer, it simply debulks the intraprostatic component to relieve the obstruction)

• Mechanism: Cancer invading the bladder trigone or ureteric orifices → unilateral or bilateral ureteric obstruction → hydronephrosis → obstructive nephropathy → post-renal AKI ^[11]. Alternatively, bulky pelvic lymphadenopathy can extrinsically compress the ureters.
• Clinical presentation: May be silent (bilateral chronic partial obstruction → gradual renal impairment detected on bloods); or acute with flank pain if sudden complete obstruction
• Key point: Post-renal disease is rapidly reversible if recognised early, but prolonged obstruction progresses to tubulointerstitial fibrosis (i.e., irreversible intrinsic renal disease) ^[11]
• Management: Ureteric stenting (retrograde via cystoscopy, or antegrade via percutaneous nephrostomy) to relieve obstruction; treat underlying cancer

• Mechanism: Tumour eroding into the prostatic urethra or ejaculatory ducts disrupts vascular integrity → blood in the urine or semen
• Haematuria or haemospermia ( < 1%): uncommon, can also be due to BPH ^[4]
• Management: Usually conservative (tumour-directed treatment will reduce bleeding); severe haematuria may require bladder irrigation, cystoscopy with fulguration, or palliative RT

• Direct extension: stromal invasion through prostatic capsule → urethra, bladder base, seminal vesicles ^[4]
• Rectal invasion is rare because Denonvilliers' fascia acts as a natural barrier between the prostate and rectum, but can occur in T4 disease → tenesmus, rectal bleeding, fistula formation
• Neurovascular bundle invasion → new-onset erectile dysfunction (cavernous nerves immediately posterolateral to prostate capsule)
• Lower limb lymphoedema → lymphoedema due to pelvic lymphadenopathy or lymph node metastases ^[4]; bulky inguinal/pelvic nodes obstruct lymphatic drainage

Vertebral metastasis is the commonest metastatic site ^[4]. Reason: Batson's plexus connects prostatic venous plexus to internal vertebral plexus ^[4].

This is an oncological emergency that demands immediate recognition and treatment. Delay of even hours can result in irreversible paraplegia.

• Epidemiology: prostate cancer accounts for ~20% of all malignant cord compression ^[15]; > 90% vertebral, especially thoracic ^[15]
• Routes of spread: haematogenous (most common), direct invasion, lymphatics ^[15]
• Presentation: bone pain and tenderness → motor/sensory symptoms → sphincter disturbance (late) ^[15]
  • The classic sequence is: back pain (often the first symptom, present for weeks before neurological signs) → radiculopathy (band-like pain in a dermatomal distribution) → motor weakness (upper motor neuron pattern below the level: spasticity, hyperreflexia, upgoing plantars) → sensory level (loss of sensation below the compression) → sphincter dysfunction (urinary retention, faecal incontinence — this is a LATE sign and indicates severe cord damage)
• Investigations ^[15]:
  • MRI of the entire spine: confirm extradural compressive lesion
  • Important to image the entire spine because 33% have multilevel involvement ^[15]
  • Plain X-ray: may show osteolytic/osteoblastic lesions, vertebral collapse, pedicle erosion (the "winking owl" sign — loss of one pedicle on AP view)
• Management ^[15]:
  • Dexamethasone 4 mg IV Q6H if neurological symptoms present — reduces peritumoral oedema and buys time
  • Surgical decompression + stabilisation followed by RT if unstable spine
  • RT alone if stable spine OR unfavourable prognosis

• Liver metastases: hepatomegaly, deranged LFTs, RUQ pain, jaundice (late) ^[4]
• Lung metastases: usually asymptomatic (incidental CXR/CT finding); late: cough, haemoptysis, breathlessness ^[16]
• Adrenal metastases: usually asymptomatic; rarely symptomatic adrenal insufficiency ^[16]
• Disseminated intravascular coagulation (DIC): uncommon but reported in advanced prostate cancer; the mechanism involves release of tissue factor and procoagulant substances from tumour cells