Carcinoma of the Prostate

Carcinoma of the prostate is the commonest visceral malignancy in elderly men and a perennial NEET PG favourite because it bridges urology, oncology and pathology. Mastery of Gleason/ISUP grading, PSA interpretation, the predilection for osteoblastic bone metastases and the logic of androgen deprivation therapy will reliably fetch you marks.

Definition & overview

Prostate cancer is a malignant neoplasm arising overwhelmingly (>95%) as acinar adenocarcinoma from the glandular epithelium of the prostate. Its biological behaviour ranges from indolent, autopsy-discovered "latent" cancers to aggressive, rapidly metastasising disease.

Key anatomical fact that underlies clinical behaviour:

• Peripheral zone — origin of ~70% of carcinomas; palpable on digital rectal examination (DRE); explains why cancer is felt as a hard posterior nodule.
• Transition zone — origin of benign prostatic hyperplasia (BPH) and ~20% of cancers.
• Central zone — least often involved (~5%).

High-yield: Carcinoma typically arises in the peripheral zone (felt on DRE), whereas BPH arises in the transition (periurethral) zone (causes early voiding symptoms). This is why early prostate cancer is often asymptomatic while BPH causes obstruction early.

Epidemiology & risk factors

Most important non-modifiable risks:

Risk factor	Note
Age	Strongest risk factor; rare before 50, incidence rises steeply thereafter
Ethnicity	Highest in African-American men; lowest in Asians
Family history	First-degree relative doubles risk; BRCA2 (and BRCA1) carriers — aggressive disease
Hereditary syndromes	BRCA2, Lynch syndrome (HNPCC), HOXB13 mutation
Diet/obesity	High animal fat, metabolic syndrome — weaker associations

Androgens (testosterone → dihydrotestosterone via 5-alpha-reductase) are permissive but not causative — the cancer is androgen-dependent, which is the entire rationale for hormonal therapy.

Pathology, Gleason score & ISUP grading

Histology is the single highest-yield topic. The Gleason grading system is based purely on the architectural (glandular) pattern, NOT nuclear features, graded 1–5 (well to poorly differentiated). Patterns 1 and 2 are essentially no longer assigned.

The Gleason score = primary (most predominant) pattern + secondary (second most common) pattern, ranging from 6 to 10 in clinical practice. On needle biopsy, if a high-grade pattern is present even as a minor (tertiary) component, it is incorporated.

High-yield: Gleason grading is based on architecture/glandular pattern, not cytology. The lowest practical score is 3+3 = 6.

The 2014 ISUP (Grade Group) system, now standard, simplifies prognostication:

ISUP Grade Group	Gleason score	Interpretation
1	≤6 (3+3)	Low risk, indolent
2	7 (3+4)	Predominantly well-formed glands
3	7 (4+3)	Predominantly poorly-formed (worse than 3+4)
4	8 (4+4, 3+5, 5+3)	High grade
5	9–10	Highest grade, worst prognosis

High-yield: Gleason 3+4 (Group 2) has a clearly better prognosis than 4+3 (Group 3) — the primary (first) number carries more weight because it is the dominant pattern.

Useful immunohistochemistry: malignant glands lose the basal cell layer → negative for basal markers p63 and high-molecular-weight cytokeratin (34βE12), and are positive for AMACR (P504S/racemase) and PSA/PSMA. Perineural invasion is characteristic but not pathognomonic.

Clinical features

Early, organ-confined disease is usually asymptomatic — detected by raised PSA or an incidental DRE nodule. Symptoms, when present, indicate locally advanced or metastatic disease:

• Lower urinary tract symptoms (LUTS) — hesitancy, poor stream, frequency (overlap with BPH).
• Haematuria, haematospermia.
• Bone pain — especially lower back / lumbosacral spine and pelvis from osteoblastic metastases; the classic presentation.
• Pathological fracture, spinal cord compression (oncological emergency).
• Lower-limb oedema (pelvic nodal obstruction), renal failure from ureteric obstruction.

High-yield: An elderly man with low back pain + sclerotic (osteoblastic) vertebral lesions is prostate cancer until proven otherwise. Prostate and breast (and rarely carcinoid) classically give osteoblastic secondaries; most other cancers (lung, kidney, thyroid) are osteolytic.

Prostate cancer metastasises to the vertebral column preferentially via the valveless Batson's vertebral venous plexus, bypassing the caval system — a favourite single-best-answer.

Diagnosis & investigations

PSA (prostate-specific antigen)

PSA is a kallikrein-family serine protease produced by prostatic epithelium; it is organ-specific but NOT cancer-specific — also raised in BPH, prostatitis, urinary retention, after DRE/catheterisation/cycling and ejaculation.

• Traditional cut-off 4 ng/mL (age-specific ranges exist).
• Refinements to improve specificity:

Parameter	Concept	Suggests cancer
PSA density	PSA ÷ prostate volume	>0.15
PSA velocity	Rate of rise over time	>0.75 ng/mL/year
Free:total PSA ratio	Free PSA fraction	Low ratio (<10–18%) favours cancer
Age-specific PSA	Higher cut-offs with age	—

High-yield: A low free:total PSA ratio points to malignancy (cancer binds more PSA to proteins → less free PSA). PSA is best as a monitoring/follow-up marker: after radical prostatectomy it should become undetectable (<0.2 ng/mL).

Imaging & biopsy — the diagnostic pathway

Suspicion (raised PSA / abnormal DRE) → multiparametric MRI (mpMRI) prostate → MRI-targeted + systematic transrectal/transperineal biopsy → histology + Gleason/ISUP → staging (bone scan ± CT/PSMA-PET).

• mpMRI is now done before biopsy; lesions are scored by PI-RADS (v2.1), 1–5 — PI-RADS ≥3 prompts biopsy and improves detection of clinically significant cancer.
• Biopsy is the definitive diagnostic step (TRUS-guided or transperineal); transperineal has lower sepsis risk.
• Investigation of choice for bone metastasis = technetium-99m (⁹⁹ᵐTc-MDP) radionuclide bone scan, showing multiple "hot spots." A negative bone scan is unusual if PSA <10–20 ng/mL.
• PSMA PET-CT (⁶⁸Ga-PSMA) is increasingly the most sensitive staging tool for nodal/distant disease and biochemical recurrence.
• Transrectal ultrasound (TRUS): cancer is classically hypoechoic in the peripheral zone (but many are isoechoic).

High-yield: Bone scan is the investigation of choice for skeletal metastases; PSMA-PET is the most sensitive modern staging/recurrence modality.

Staging

TNM staging governs treatment:

• T1 — clinically inapparent (T1a/b incidental on TURP; T1c = needle biopsy for raised PSA, impalpable).
• T2 — confined to prostate (palpable).
• T3 — through capsule (T3a) / seminal vesicle (T3b).
• T4 — fixed or invades adjacent structures (bladder neck, rectum, pelvic wall).

Risk stratification (D'Amico) combines T-stage, PSA and Gleason/ISUP:

Risk group	PSA	Gleason / ISUP	T stage
Low	<10	≤6 / GG1	≤T2a
Intermediate	10–20	7 / GG2–3	T2b
High	>20	≥8 / GG4–5	≥T2c–T3

Management — the core algorithm

Treatment depends on risk group, life expectancy and patient preference.

Localised disease

1. Active surveillance — preferred for low-risk (ISUP 1) disease with low volume; monitor PSA, repeat DRE/MRI/biopsy. Avoids overtreatment of indolent cancer.
2. Radical prostatectomy — removal of prostate + seminal vesicles ± pelvic lymph nodes (open, laparoscopic or robot-assisted). Curative for organ-confined disease in men with >10-year life expectancy.
3. Radical radiotherapy — external beam (EBRT) or brachytherapy (radioactive seed implantation, e.g. Iodine-125), often combined with ADT in intermediate/high risk.

High-yield: Watchful waiting ≠ active surveillance. Active surveillance = curative-intent monitoring of low-risk young/fit patients with intent to treat on progression. Watchful waiting = symptom-directed palliation in elderly/comorbid patients with limited life expectancy.

Radical prostatectomy vs radiotherapy

Feature	Radical prostatectomy	Radiotherapy
Best candidate	Younger, fit, organ-confined	Older, comorbid, or patient choice
Main early complication	Bleeding, anastomotic issues	Acute cystitis/proctitis
Erectile dysfunction	Common (nerve-sparing helps)	Common, delayed onset
Incontinence	More common (stress)	Less common
Bowel symptoms	Rare	Radiation proctitis
PSA after success	Should be undetectable	Falls to a low nadir (not zero)
Secondary malignancy	No	Small long-term risk (bladder/rectal)

Locally advanced / metastatic disease — Androgen Deprivation Therapy (ADT)

Because prostate cancer growth is androgen-dependent, lowering testosterone to castrate levels (<50 ng/dL) is the backbone of advanced-disease treatment.

Methods of castration:

• Surgical: bilateral orchidectomy (subcapsular) — rapid, cheap, definitive; the historical reference standard.
• Medical (LHRH/GnRH analogues): goserelin, leuprolide, triptorelin — cause initial surge then downregulation of pituitary receptors → fall in LH → fall in testosterone.

High-yield: Tumour flare. LHRH agonists cause an initial testosterone surge (flare) in the first 1–2 weeks that can worsen bone pain or precipitate cord compression. Cover with an anti-androgen (e.g. bicalutamide/flutamide) for ~2 weeks before/around starting the agonist. GnRH antagonists (degarelix, oral relugolix) cause no flare and lower testosterone faster.

• Anti-androgens: non-steroidal bicalutamide, flutamide, nilutamide (block androgen receptor).
• CAB (combined androgen blockade): LHRH analogue + anti-androgen.

Newer agents for advanced/castration-resistant disease:

• Abiraterone — inhibits CYP17 (17α-hydroxylase/17,20-lyase), blocking adrenal/intratumoural androgen synthesis; given with prednisolone.
• Enzalutamide, apalutamide, darolutamide — potent second-generation androgen-receptor antagonists.
• Docetaxel — taxane chemotherapy; combined upfront with ADT in high-volume metastatic disease (improves survival).
• Cabazitaxel — second-line chemotherapy.
• Radium-223 (alpha-emitter) — for symptomatic bone metastases, improves survival.
• PARP inhibitors (olaparib) — for BRCA/HRR-mutated castration-resistant cancer.
• PSMA-targeted radioligand (¹⁷⁷Lu-PSMA-617) — for advanced PSMA-positive mCRPC.

Castration-resistant prostate cancer (CRPC)

Defined as disease progressing (rising PSA or radiological progression) despite castrate testosterone levels (<50 ng/dL). It reflects mechanisms such as androgen-receptor amplification/mutation and intratumoural androgen synthesis — hence abiraterone (blocks synthesis) and enzalutamide (blocks receptor) still work. mCRPC = metastatic CRPC.

High-yield: CRPC is NOT "hormone-independent" — it still uses the androgen axis, so AR-targeted drugs (abiraterone/enzalutamide) remain effective. Always confirm testosterone is at castrate level before labelling CRPC.

Flow for newly diagnosed disease (simplified):

Localised low-risk → active surveillance. Localised intermediate/high-risk → radical prostatectomy or radiotherapy + ADT. Node-positive/metastatic → ADT (± docetaxel or abiraterone/enzalutamide upfront). Progression despite castrate testosterone → CRPC → next-line AR agent / chemo / radium-223 / Lu-PSMA.

Complications

• Skeletal: osteoblastic metastases, pathological fracture, spinal cord compression (give high-dose steroids + urgent radiotherapy/decompression), hypocalcaemia (rare, from avid osteoblastic uptake).
• Urinary: bladder outlet/ureteric obstruction → obstructive uropathy and renal failure.
• Treatment-related: ADT side-effects — hot flushes, loss of libido, erectile dysfunction, osteoporosis (use calcium/vitamin D, bisphosphonates/denosumab), metabolic syndrome, anaemia, gynaecomastia; surgery/RT — incontinence and impotence.
• DIC — prostate cancer is a classic cause of chronic disseminated intravascular coagulation.

Key differentials

• Benign prostatic hyperplasia — transition zone, smooth symmetrical enlargement, normal/mildly raised PSA, no induration.
• Chronic prostatitis / granulomatous prostatitis — can raise PSA and harden the gland (BCG-induced granulomatous prostatitis after intravesical BCG).
• High-grade prostatic intraepithelial neoplasia (HGPIN) — premalignant, basal layer retained.
• Prostatic abscess, TB prostatitis.
• Other sclerotic bone lesions — breast metastases (in men, rare), osteoblastic secondaries, Paget's disease (raised ALP, normal PSA).

Feature	Prostate cancer	BPH
Zone	Peripheral	Transition
DRE	Hard, nodular, irregular, loss of median sulcus	Smooth, firm, symmetrical
Onset of LUTS	Late	Early
PSA	Often higher, low free:total	Mild rise, higher free:total
Histology	Loss of basal layer, AMACR+	Basal layer intact

Recently asked / exam angle

• Gleason score basis = architectural/glandular pattern (not nuclear). Score = primary + secondary; 3+4 better than 4+3.
• Zone of origin = peripheral; explains DRE palpability and asymptomatic early disease.
• Osteoblastic (sclerotic) bone metastasis + Batson's plexus spread to vertebrae.
• Investigation of choice for bone secondaries = ⁹⁹ᵐTc bone scan; PSMA-PET for sensitive staging/recurrence.
• LHRH agonist flare prevented by prior anti-androgen; degarelix/relugolix cause no flare.
• Abiraterone mechanism = CYP17 inhibitor; enzalutamide = AR antagonist.
• CRPC definition = progression with castrate testosterone <50 ng/dL.
• Free:total PSA ratio — low ratio favours malignancy.
• IHC: AMACR/racemase positive, p63 & HMWCK (34βE12) negative.
• Differentiating active surveillance vs watchful waiting is a common conceptual MCQ.

Rapid revision

1. 95% of prostate cancers are acinar adenocarcinomas arising in the peripheral zone.

2. Gleason grades architecture 1–5; clinical scores 6–10; ISUP Grade Groups 1–5.
3. 3+4 (GG2) has better prognosis than 4+3 (GG3) — primary pattern dominates.
4. IHC: AMACR positive, p63/HMWCK negative (loss of basal cells); perineural invasion characteristic.
5. PSA is organ-specific, not cancer-specific; cut-off ~4 ng/mL; low free:total ratio → cancer.
6. After radical prostatectomy PSA should be undetectable (<0.2 ng/mL).
7. mpMRI before biopsy, scored by PI-RADS; biopsy is definitive.
8. Bone scan = IOC for skeletal mets (osteoblastic); PSMA-PET most sensitive for staging/recurrence.
9. Metastasis to vertebrae via Batson's valveless venous plexus.
10. LHRH agonists (goserelin/leuprolide) cause flare — pre-treat with anti-androgen; degarelix/relugolix = no flare.
11. Abiraterone = CYP17 inhibitor (+prednisolone); enzalutamide/apalutamide/darolutamide = AR antagonists.
12. CRPC = progression with castrate testosterone (<50 ng/dL); treat with AR agents, docetaxel, radium-223, Lu-PSMA.