Carcinoma of Prostate

Overview

2nd commonest cancer in men (after lung). >50yr, prevalence rises steeply with age — >50% of 80yr-olds have latent carcinoma. 4 clinical categories:

1. Latent — incidental autopsy finding (25-35% of autopsies)
2. Incidental — found in 15-20% of BPH prostatectomies
3. Occult — no local symptoms, metastases found on workup
4. Clinical — detected by DRE/investigation, biopsy-confirmed

Etiology

1. Endocrine — androgens essential for prostate epithelium. Evidence: orchiectomy arrests metastatic disease; oestrogen → regression; RARE in eunuchs/Klinefelter’s; arises during high-androgen life phase
2. Racial/geographic — low Japanese/Chinese, high Americans, African Americans MARKEDLY higher (androgen receptor gene variation)
3. Environmental — high dietary fat, PAH exposure ↑risk; flavonoids/antioxidants/selenium protective
4. Nodular hyperplasia — NOT a true precursor despite superficial plausibility (different zones — see BPH). ~15-20% concurrent = shared ageing risk, not causation
5. Heredity — familial clustering, 2x risk in 1st-degree relatives, BRCA2 = 20x risk

Histogenesis

Multistep from PROSTATIC INTRAEPITHELIAL NEOPLASIA (PIN) — atypical luminal cells over diminished basal layer, low→high grade. High-grade PIN → invasive adenocarcinoma.

Molecular:

• Epigenetic — GSTP1 gene promoter hypermethylation → loss of carcinogen-detoxifying function
• Somatic mutation — ETS transcription factor gene rearranged near TMPRSS2 promoter → TMPRSS2-ETS fusion gene (characteristic)

Morphology

Gross: size variable (enlarged/normal/smaller — unlike BPH, size unreliable). 95% PERIPHERAL ZONE, esp. posterior lobe (mirror image of BPH’s periurethral origin). Firm, fibrous, homogeneous with irregular yellowish areas.

Micro — 4 types, ADENOCARCINOMA = 96% (others: transitional cell, squamous, undifferentiated = rare).

Adenocarcinoma features:

1. Architectural disturbance — loss of convoluted pattern; BACK-TO-BACK acini, no stroma, or haphazard
2. Stroma — normal fibromuscular sling lost/reduced; tumour infiltrates/replaces stroma
3. Gland pattern by grade: well-diff = small/medium glands, single cuboidal/low columnar layer; mod-diff = cribriform/fenestrated; poor-diff = solid/trabecular, little/no glands
4. Tumour cells — OUTER BASAL LAYER LOST (key diagnostic clue). Clear/dark/eosinophilic cytoplasm variants. Nuclear atypia generally SLIGHT despite malignancy — deceptively bland cytology
5. Invasion — PERINEURAL invasion = early/frequent/important diagnostic feature. Lymphatic/vascular harder to detect.

Spread

Direct — through capsule, late: bladder neck, seminal vesicles, trigone, ureteral openings.

Metastases:

• Lymphatic — periprostatic network → sacral/iliac/para-aortic nodes. OBTURATOR node = earliest site
• Haematogenous — OSTEOBLASTIC (not lytic!) bone mets, esp. PELVIS+LUMBAR SPINE — distinctive among metastatic cancers (most are lytic). Also lungs, kidneys, breast, brain. Via retrograde prostatic venous plexus or systemic circulation.

Clinical features/diagnosis

Symptomatic: urinary obstruction, dysuria, frequency, retention, haematuria. 10% present with BACK PAIN (skeletal mets). By symptom onset: DRE = hard, nodular, FIXED gland.

Tumour markers:

• PAP — ↑ once beyond capsule/metastasised; also in normal tissue (less specific)
• PSA — normal 0-4ng/ml, 4-10=suspicious (~10% risk), >10=DIAGNOSTIC. Distinguishes from urothelial/colonic Ca, lymphoma, prostatitis. IHC confirms met origin. COUNTERINTUITIVE: PSA HIGHER in LOW-grade than high-grade tumours.

Diagnosis: TRIPLE APPROACH — DRE + serum PSA + TRUS-guided core biopsy.

Grading/staging

GLEASON grading (replaced old WHO grade I-III) — based on glandular differentiation/distribution + growth pattern vs stroma. Primary+secondary pattern scored 1-5 each, summed = Gleason score /10.

TNM staging = international standard, incorporates PSA+DRE+extent.

Treatment: surgery, radiotherapy, hormonal therapy. Hormonal — exploits androgen dependence: bilateral orchiectomy ± oestrogen. Surgical: TUR, radical prostatectomy, TULIP.

Clinical relevance

Osteoblastic (not lytic) bone mets = one of most specific high-yield facts distinguishing prostate Ca from most other metastatic cancers — sclerotic lesions in older man with bone pain should specifically raise prostate Ca. PSA paradox (higher in LOW-grade) = counterintuitive, frequently tested — well-differentiated cells retain more normal secretory apparatus (more PSA/cell) than poorly-differentiated dedifferentiated cells. Basal layer loss = single most reliable histologic malignant-vs-benign feature — atypia otherwise remarkably subtle, why IHC basal markers used in equivocal cases. Zone-specific origin (peripheral=cancer, periurethral=BPH) explains key clinical asymmetry — BPH causes early obstructive symptoms (periurethral location), cancer can grow substantially in peripheral zone before ANY urinary symptoms — exactly why DRE+PSA screening exists.

Overview

Prostate cancer is the second most common cancer in men (after lung cancer). A disease of men over 50, with prevalence rising steeply with age — >50% of men aged 80 have asymptomatic (latent) carcinoma. Because it is so often small and clinically silent, prostate carcinoma is classified into four clinical categories rather than treated as a single presentation:

1. Latent carcinoma — unexpected small focus found at autopsy in men dying of other causes (25–35% of autopsies).
2. Incidental carcinoma — found in 15–20% of prostatectomies performed for BPH.
3. Occult carcinoma — no local prostatic symptoms, but metastases discovered on examination/investigation.
4. Clinical carcinoma — detected by rectal examination/investigation and confirmed on biopsy.

Etiology

Cause remains unclear, but several factors are implicated:

1. Endocrine factors — androgens are essential for prostatic epithelial development/maintenance, though the exact mechanism linking androgen to malignant transformation is unclear. Indirect evidence for an androgen role: orchiectomy arrests metastatic disease; oestrogen administration causes regression; cancer is extremely rare in eunuchs and Klinefelter syndrome; cancer arises during the high-androgen phase of life (though it may stay latent until androgen decline with age).
2. Racial/geographic factors — low in Japanese/Chinese populations, high in Americans; African Americans have a markedly higher incidence than whites, possibly related to androgen receptor gene variation.
3. Environmental factors — high dietary fat, polycyclic aromatic hydrocarbon exposure raise risk; flavonoids, antioxidants, selenium may be protective.
4. Nodular hyperplasia — despite superficial plausibility, BPH is not considered a true precursor (see Benign Prostatic Hyperplasia for the zone-specific explanation); concurrent occurrence in ~15–20% of hyperplastic prostates reflects shared ageing risk, not causation.
5. Heredity — familial clustering, 2× risk in first-degree relatives; BRCA2 carriers have a 20× increased risk.

Histogenesis

A genuine multistep process, arising from the premalignant lesion prostatic intraepithelial neoplasia (PIN) — multiple foci of cytologically atypical luminal cells overlying a diminished basal cell layer in prostatic ducts, graded low- to high-grade; high-grade PIN progresses to invasive adenocarcinoma.

Molecular changes:

• Epigenetic: hypermethylation of the GSTP1 (glutathione S-transferase) gene promoter → loss of function of a carcinogen-detoxifying enzyme.
• Somatic mutation: gene rearrangement placing the ETS family transcription factor gene near the TMPRSS2 promoter, producing the TMPRSS2-ETS fusion gene characteristic of prostate cancer.

Morphology

Gross: prostate may be enlarged, normal, or even smaller than normal (unlike BPH, size is not a reliable indicator). 95% arise in the peripheral zone, especially the posterior lobe — the anatomic mirror image of BPH’s periurethral origin. Firm, fibrous; cut surface homogeneous with irregular yellowish areas.

Micro — four histologic types, with adenocarcinoma accounting for 96% (the other three — transitional cell, squamous cell, undifferentiated — are rare and resemble their counterparts elsewhere in the body). Key features of adenocarcinoma:

1. Architectural disturbance — loss of the normal convoluted intra-acinar papillary pattern; acini are closely packed back-to-back without intervening stroma, or haphazardly distributed.
2. Stroma — the normal fibromuscular sling around acini is lost or reduced; tumour cells may directly infiltrate/replace stroma.
3. Gland pattern by grade — well-differentiated: small/medium glands, single layer of cuboidal/low columnar cells; moderately-differentiated: cribriform/fenestrated pattern; poorly-differentiated: little/no glandular arrangement, solid/trabecular pattern instead.
4. Tumour cells — the outer basal layer (present in normal/benign acini) is lost — itself a key diagnostic clue; cells may be clear (foamy cytoplasm), dark (basophilic), or eosinophilic (granular); nuclear atypia is generally only slight, despite malignancy — prostatic adenocarcinoma is notorious for looking deceptively bland cytologically.
5. Invasion — perineural invasion (into intraprostatic perineural spaces) is an early, frequent, and important diagnostic feature; lymphatic/vascular invasion occurs but is harder to detect.

Spread

Direct: through the capsule and beyond; late-stage extension into bladder neck, seminal vesicles, trigone, ureteral openings.

Metastases: both lymphatic and haematogenous.

• Lymphatic — via the rich periprostatic network to sacral, iliac, para-aortic nodes; the obturator node is the earliest site.
• Haematogenous — classically produces osteoblastic (bone-forming, not lytic) osseous metastases, especially pelvis and lumbar spine — a distinctive feature among metastatic cancers, most of which are osteolytic; also lungs, kidneys, breast, brain. Spread may occur via retrograde flow through the prostatic venous plexus or systemic circulation.

Clinical Features and Diagnosis

Symptomatic disease: urinary obstruction, dysuria, frequency, retention, haematuria; 10% present with back pain from skeletal metastases. By symptom onset, the tumour is usually palpable on digital rectal examination (DRE) as a hard, nodular, fixed gland.

Tumour markers:

• Prostatic acid phosphatase (PAP) — elevated once disease extends beyond the capsule or metastasises; also present in normal prostatic tissue (less specific).
• Prostate-specific antigen (PSA) — normal 0–4 ng/ml; 4–10 ng/ml is suspicious (~10% cancer risk); >10 ng/ml is diagnostic. Useful for distinguishing prostatic cancer from urothelial/colonic carcinoma, lymphoma, prostatitis, and (via immunohistochemistry) for confirming a metastasis’s prostatic origin. Notably, PSA tends to be higher in low-grade than high-grade tumours — a counterintuitive point worth remembering explicitly.

Diagnostic approach: the standard triple approach — DRE, serum PSA, and TRUS-guided core needle biopsy.

Grading and Staging

Gleason grading (now standard, replacing the older WHO/Mostofi grade I–III system) — based on glandular differentiation/distribution and growth pattern relative to stroma, scored 1–5 for both the primary (predominant) and secondary (next most common) pattern; the two scores sum to a Gleason score out of 10.

TNM staging — the international standard, incorporating PSA level and DRE findings alongside tumour/node/metastasis extent.

Treatment: surgery, radiotherapy, hormonal therapy. Hormonal treatment exploits the tumour’s androgen dependence — bilateral orchiectomy ± oestrogen administration deprives tumour cells of testosterone’s growth-promoting effect. Surgical options: TUR, radical prostatectomy, TULIP (transurethral ultrasound-guided laser-induced prostatectomy).

Clinical Relevance

• Osteoblastic (rather than osteolytic) bone metastasis is one of the most specific, high-yield facts distinguishing prostate cancer from most other metastatic malignancies — recognising sclerotic rather than lytic lesions on imaging in an older man with bone pain should specifically raise prostate cancer in the differential.
• The paradox of PSA being higher in low-grade than high-grade tumours is a genuinely counterintuitive, frequently tested fact — it reflects that well-differentiated tumour cells retain more of the normal glandular secretory apparatus (and thus produce more PSA per cell) than poorly-differentiated cells, which lose that specialised function as they dedifferentiate.
• The loss of the basal cell layer is the single most reliable histologic feature separating malignant from benign prostatic glands, since architectural and cytologic atypia in prostate cancer can otherwise be remarkably subtle — this is why immunohistochemical basal cell markers are used diagnostically in equivocal cases.
• The zone-specific origin (peripheral zone for cancer, periurethral zone for BPH) directly explains a key clinical asymmetry: BPH causes obstructive urinary symptoms early because of its periurethral location, while prostate cancer can grow substantially in the peripheral zone before causing any urinary symptoms at all — which is exactly why DRE and PSA screening exist as tools to detect disease before symptoms would otherwise prompt evaluation.

• PIN-to-adenocarcinoma histogenesis with the GSTP1/TMPRSS2-ETS molecular changes
• Lymphatic (obturator-node-first) vs haematogenous (osteoblastic) spread routes compared
• PSA reference ranges mapped to diagnostic significance

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