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PA28.3-5 | Prostate: BPH, Carcinoma & Prostatitis — SDL Guide (Part 4)

Gleason Grading and ISUP Grade Groups

The Gleason grading system is the most important prognostic tool in prostate pathology. It is based entirely on glandular architecture (not cytological features), assessing the degree of glandular differentiation and infiltration pattern.

Gleason patterns (1–5):

Pattern	Architecture	Differentiation
1	Round, uniform, separate glands, packed but not infiltrating	Well differentiated
2	Loosely packed, slightly variable glands	Well differentiated
3	Discrete, individual infiltrating glands of variable size	Moderately differentiated — most common pattern
4	Fused, cribriform, or poorly formed glands	Poorly differentiated — key threshold
5	No gland formation — solid sheets, cords, single cells, comedonecrosis	Anaplastic

Note: Patterns 1 and 2 are no longer assigned on needle biopsy by modern standards (2014 ISUP revision) — minimum reported is Pattern 3.

Gleason Score: Primary pattern (most prevalent) + Secondary pattern (second most prevalent) = Score (range 6–10 clinically used). E.g., 3+4=7 (most is pattern 3, some is pattern 4).

ISUP Grade Groups (2016 — 5 groups replacing the confusing 6–10 scale):

ISUP Grade Group	Gleason Score	Prognosis
1	3+3=6	Excellent — many managed conservatively
2	3+4=7	Good
3	4+3=7	Intermediate — more pattern 4 = worse
4	4+4=8; 3+5=8; 5+3=8	Poor
5	9–10	Very poor

Gleason Patterns 3, 4, and 5 in Prostate Carcinoma

Clinical significance of the 3 vs 4 threshold:
Gleason pattern 4 is the critical inflection point — its presence (even as the minority pattern in a 3+4=7) significantly worsens prognosis compared to 3+3=6. This is why 3+4 (Grade Group 2) and 4+3 (Grade Group 3) are assigned different ISUP groups despite the same summed score.

Prostate Carcinoma: Staging and Routes of Spread

TNM/AJCC Staging (simplified):

Stage	Definition
T1	Clinically inapparent (not palpable) — T1a: ≤5% of TURP chips; T1b: >5%; T1c: needle biopsy (PSA-detected)
T2	Tumour confined within the prostate capsule
T3	Extracapsular extension (T3a) or seminal vesicle invasion (T3b)
T4	Invades adjacent structures: bladder neck, external sphincter, rectum, levator ani
N1	Regional lymph node metastasis (obturator, internal iliac)
M1	Distant metastasis — most commonly bone

Routes of spread:

1. Direct extension (local spread):
• Extends through the prostatic capsule (extracapsular extension) — most commonly to the neurovascular bundles (posterolateral, explaining nerve-sparing surgery challenges and perineural invasion).
• Seminal vesicle invasion → upstages to T3b, worsens prognosis.
• Bladder base and trigone involvement → urinary symptoms.
• Rectal involvement (less common — Denonvilliers' fascia is a natural barrier).

1. Lymphatic spread: Obturator lymph nodes → internal and external iliac nodes → para-aortic nodes. Lymph node metastasis indicates systemic disease.

3. Haematogenous spread — OSTEOBLASTIC BONE METASTASES:
The most distinctive feature of prostate cancer spread. Metastases to bone are predominantly osteoblastic (sclerotic) — tumour cells secrete endothelin-1 and other factors that stimulate osteoblasts → new bone formation → dense/sclerotic lesions on X-ray and bone scan (contrast with most other carcinoma metastases, which are osteolytic). Sites: vertebral column (lumbar > thoracic), pelvis, proximal femur, ribs, skull. The Batson vertebral venous plexus (valveless, communicates directly with pelvic veins) is the preferred route to the vertebral column. Bone pain (especially back/hip pain in an elderly man) + elevated PSA should immediately raise suspicion.

Routes of Spread in Prostate Cancer

1. Distant haematogenous spread: Lung, liver (less common than bone).

Staging investigations:
• PSA: High PSA (>20 ng/mL) correlates with extracapsular extension or metastasis.
• Multiparametric MRI prostate (mpMRI): Best imaging for local staging — T2, DWI, DCE sequences; detects extracapsular extension, seminal vesicle invasion; PI-RADS score guides biopsy.
• Bone scan (Tc-99m): Detects osteoblastic metastases — indicated when PSA >20, Gleason score ≥8, or T3/T4 disease.
• PSMA PET-CT: Increasingly replacing bone scan — more sensitive for nodal and bone disease; detects recurrence earlier.

PSA Screening, Diagnosis, Treatment, and Prognosis

PSA (Prostate-Specific Antigen):
PSA is a serine protease (encoded by KLK3 gene) secreted by prostatic epithelium — its normal function is to liquefy seminal coagulum. Serum PSA is elevated whenever the epithelial-stromal barrier is disrupted.

Reference ranges (approximate):
• <4 ng/mL — traditionally 'normal' (but ~15% of cancers are PSA <4)
• 4–10 ng/mL — 'grey zone' (25% probability of cancer)
• >10 ng/mL — high suspicion (>50% probability of cancer)
• PSA density (PSA/prostate volume) >0.15 ng/mL/cc favours cancer
• PSA velocity (rise >0.75 ng/mL/year) — suspicious even within grey zone
• Free:total PSA ratio — lower free PSA fraction (<25%) suggests carcinoma (BPH elevates both total and free PSA proportionately)

Screening controversy: Widespread PSA screening reduces cancer-specific mortality (~20% in ERSPC trial) but causes significant overdiagnosis (many indolent tumours that would never cause symptoms are detected and treated) → shared decision-making approach now recommended (USPSTF); most guidelines recommend starting discussion at age 50–55 for average-risk men.

Diagnosis: TRUS-guided needle biopsy (12-core systematic) or MRI-targeted biopsy (for PI-RADS 3–5 lesions). Minimum 10–12 cores from the peripheral zone bilaterally.

Treatment principles:

Stage	Options
Localised (T1-T2, low grade)	Active surveillance; radical prostatectomy; external beam radiotherapy ± brachytherapy
Locally advanced (T3-T4)	Radiotherapy + ADT (androgen deprivation therapy)
Metastatic	Androgen deprivation therapy (ADT) — surgical (bilateral orchidectomy) or medical (LHRH agonists/antagonists: leuprolide, goserelin, degarelix)
Castration-resistant	Enzalutamide/abiraterone (next-gen AR axis inhibitors); docetaxel chemotherapy; PARP inhibitors (if BRCA2 mutation)

Androgen deprivation therapy (ADT) works because prostate cancer cells are androgen-dependent — removing androgens causes apoptosis and tumour regression. Eventually, cancer cells mutate to become castration-resistant (AR amplification, mutations, splice variants like AR-V7) — a clinically important endpoint.

Comparison of BPH, Acute Prostatitis, and Prostatic Carcinoma

Prognosis:
• ISUP Grade Group 1 (Gleason 3+3=6) with PSA <10 and T1c: 10-year cancer-specific survival >95%.
• Metastatic castration-sensitive: median survival ~3–5 years with modern combination therapy.
• Castration-resistant: median survival ~18–36 months depending on treatment era.

> Key prognostic triad: PSA level + Gleason grade + clinical stage — used together to risk-stratify every newly diagnosed prostate cancer patient.