Working up prostate cancer runs in sequence: screen asymptomatic men, pursue diagnosis with PSA and imaging, confirm with biopsy, then grade and stage the tumour and evaluate for inherited risk. The sections below follow that order.
Screening
Screening tests asymptomatic men to detect prostate cancer earlier; three landmark randomized trials (ERSPC and Göteborg positive, PLCO negative) and successive guideline revisions define when and how to screen. The primary outcome in every screening trial is cancer-specific mortality.
Evidence — Key Trials
Of seven randomized trials, the three most informative (per CUA/AUA) are PLCO (no net benefit), ERSPC (net benefit), and Göteborg (net benefit).
- PLCO (Andriole 2009; Pinsky 2019) — n=76,685 US men aged 55–74; annual PSA ×6 + DRE ×4 vs usual care (biopsy if PSA >4 or suspicious DRE). No difference in cancer-specific mortality (RR 0.93) and slightly increased incidence (RR 1.05). Heavily criticized for high contamination (~77%), extensive pre-screening, poor biopsy adherence, and being underpowered.
- ERSPC (Schröder 2009; Hugosson 2019) — n=162,243 men aged 55–69 across 8 countries; PSA every 4 years vs usual care. Cancer-specific mortality RR 0.80; number needed to invite (NNI) 570, number needed to diagnose (NND) 18 (in those actually screened, ~37% reduction, number needed to screen ~98, NND ~5); incidence RR 1.41; contamination ~20–25%. A subgroup of men who discontinued screening at 70–74 (de Vos 2024) had a cumulative cancer-specific mortality by age 85 of only 0.54%.
- Göteborg (Hugosson 2010/2018) — n=20,000 men aged 50–64; PSA every 2 years (thresholds lowered over time to 2.5 ng/mL). Cancer-specific mortality RR 0.65; NNI 231, NND 10; incidence RR 1.51; 41% fewer advanced cases at diagnosis.
- CAP (Martin 2018/2024) — n=415,357 UK men aged 50–69; a single PSA invitation vs usual care (cancers offered the ProtecT trial). Cancer-specific mortality RR 0.92 at 15 years (absolute difference 0.09%; 0.69% vs 0.78%) with no overall-survival difference; increased low-risk detection.
Number needed to invite to screening (for context): colorectal FOBT 900, flexible sigmoidoscopy 450; mammography 1904 (age 39–49), 1339 (50–59), 377 (60–69); prostate — ERSPC 570, Göteborg 231, CAP 1111.
USPSTF Recommendations
Grade I (insufficient evidence) in 1996, 2002, and 2008 (<75); grade D (against) for ≥75 in 2008 and for all men in 2012. Current (2018): grade C (selectively offer after shared decision-making) for men 55–69, and grade D (against) for men ≥70.
When to Start Screening
| Guideline | Not recommended | Offer if increased risk | Routine start |
|---|---|---|---|
| CUA 2022 | Age <45 | 45–50 if increased risk (e.g. first-/second-degree family history) | ≥50 |
| AUA 2023 | Age <40 | 40–45 if Black ancestry, germline mutation (BRCA, Lynch), or strong family history | 45–50 (baseline PSA) |
| NCCN 2024 | Age <40 | 40–45 if risk factors (as AUA) | 45–75 |
The 2023 AUA earlier-start change is supported by the prognostic value of a baseline midlife PSA; the positive trials (Göteborg-1, ERSPC) began at 50 and 55, and there is no randomized evidence supporting routine screening before 45. A "strong" family history = ≥1 brother/father or ≥2 male relatives diagnosed <60, who died of prostate cancer, or who had metastatic disease; or ≥2 HBOC/Lynch-spectrum cancers (genotype these patients).
Frequency and Discontinuing Screening
- CUA 2022: PSA <1 ng/mL every 4 years, 1–3 every 2 years, >3 more frequent/adjunctive testing. Discontinue if age >70, age >60 with PSA <1, or life expectancy <10 years.
- AUA 2023: screen every 2–4 years for ages 50–69 (PSA 1–3 → every 1–4 years; PSA <1 → prolong). At age 60 with PSA <1, or age ≥75 with PSA <3, reasonable to lengthen the interval or stop (shared decision-making); screen more frequently if higher-risk; continue (every 2–4 years) only with life expectancy ≥10 years.
- NCCN 2024: PSA <1 every 2–4 years, 1–3 every 1–2 years (high-risk ≤3 every 1–2 years). Discontinue if life expectancy <10 years or age >75 (beyond 75 only in very healthy men).
- Use life-expectancy calculators (e.g. SSA, MSKCC, Cambridge Prognostic Groups), which are more reliable than clinician judgment.
Diagnosis
Prostate cancer is the only genitourinary malignancy diagnosed by screening. Localized disease is usually asymptomatic, so evaluation centers on PSA, increasingly multiparametric MRI, and ultimately biopsy when clinically significant cancer is suspected and the diagnosis will change management.
Clinical Presentation
At diagnosis, ~80% present with localized, ~12% regional, and ~5% metastatic disease (the metastatic proportion has fallen with PSA screening). Regional symptoms (advanced disease): lower-urinary-tract symptoms, hematuria, hematospermia, obstruction/renal failure, reduced ejaculate volume. Metastatic symptoms: bone pain, lethargy, anemia, weight loss, pathologic fractures, lower-extremity edema; rarely malignant retroperitoneal fibrosis, paraneoplastic syndromes, DIC, or paralysis.
History and Physical Exam
- History — symptoms, risk factors, eligibility/competing risk (will the patient benefit, given age/comorbidity?), and patient preference. A strong family history (≥1 brother/father or ≥2 male relatives diagnosed <60, who died of, or who had metastatic prostate cancer; or ≥2 HBOC/Lynch-spectrum cancers) should prompt genotyping (see the Epidemiology tab).
- Digital rectal exam (DRE) — a palpable tumor reflects local extent (cT stage) but DRE has poor sensitivity/reproducibility (useful to detect, not to stage); an abnormal DRE raises the risk of high-grade (Gleason 8–10) cancer. Per 2023 AUA, PSA is the primary screening test and DRE should not be used alone, but if PSA ≥2 ng/mL, strongly consider a supplementary DRE.
PSA
PSA liquefies semen, has a half-life of 2–3 days, becomes detectable at puberty, and circulates free (20–30%) or bound (70–80%) (to α1-antichymotrypsin, α2-macroglobulin, α1-protease inhibitor). It is the single test with the highest positive predictive value, though 70–80% of men with an elevated PSA do not have cancer — repeat a newly elevated value (25–40% normalize). PSA inversely correlates with organ-confined disease:
| PSA | Organ-confined (pT2) | Nodal involvement | |
|---|---|---|---|
| <4 ng/mL | 80% | PSA >20 | 20% |
| 4–10 | 66% | PSA >50 | 75% |
| >10 | <50% |
- Causes of elevation: prostate disease (BPH, prostatitis, cancer) and manipulation — biopsy and TURP cause large rises (median +6–8 and +6–13 ng/mL, returning to baseline in 2–3 weeks); cystoscopy, catheterization, DRE, and TRUS cause minimal change; long bike rides and ejaculation raise it ~10%.
- Clinical factors: PSA rises with age and prostate volume (~4%/mL), is higher in African-American men, and falls with increasing BMI.
- Derivatives (improve specificity): PSA density (≥0.15 supports biopsy in PSA 4–10 with normal DRE); PSA velocity (>0.75 ng/mL/yr; do not use as a sole biopsy trigger); % free PSA (low %fPSA → higher risk; Catalona 1998 — AUC 0.72 vs 0.53 for total PSA; ≤25% gives 95% sensitivity/20% specificity; FDA-approved for PSA 4–10 with negative DRE); and complexed PSA. 5-ARIs halve total PSA by 12 months (double the measured value to interpret; %fPSA is unchanged).
Blood, Urine and Tissue-Based Markers
Beyond PSA, a range of blood, urine, and tissue biomarkers refine the decision to biopsy (especially with a mildly elevated PSA or a prior negative biopsy) and help estimate the risk of aggressive disease.
PSA Biology
PSA is a 33-kD serine protease of the kallikrein family that liquefies semen, produced mainly by prostatic luminal epithelial cells (synthesized as preproPSA → proPSA → active PSA after hK2 cleavage). Its expression is androgen-driven (detectable at puberty) — so in hypogonadal men a low PSA may not reflect true prostate disease. It is also found in female ejaculate, breast milk, and amniotic fluid, with ectopic expression in some non-prostatic tumors. Half-life is 2–3 days; it circulates bound/complexed (70–80%) and free (20–30%).
- Bound forms: α1-antichymotrypsin (binds most PSA irreversibly; detectable), α2-macroglobulin (binds 5–10%; undetectable by most assays), α1-protease inhibitor (1–2%; detectable).
- Free forms (inactive isoforms): intact PSA, BPSA (transition-zone, high in BPH), and proPSA (−2/−4/−7; high in prostate cancer).
Landmark studies: Stamey 1987 established PSA as a marker of disease progression/treatment response; Catalona 1991 established its screening role (no "normal" value — cancer occurs at low PSA, and risk is a continuum); Catalona 1994 showed detection is highest with PSA and DRE together (PSA alone > DRE alone).
Adjunctive Biomarkers
- Blood: Prostate Health Index (PHI) = fPSA + tPSA + −2proPSA (FDA-approved for age ≥50, PSA 4–10, negative DRE); 4Kscore = fPSA + tPSA + intact PSA + hK2 (for elevated PSA considering biopsy).
- Urine: PCA3 — a prostate-specific long non-coding RNA (9q21–22); a post-DRE urine test reported as the PCA3:PSA mRNA ratio ×1000 (common cutoffs 10/25/35; FDA-approved after a negative biopsy and for initial screening). TMPRSS2:ERG — ~100% specific but only ~50% sensitive; best used in a urine multiplex with PCA3. Also ExoDx, MiPS, SelectMDx.
- Tissue: epigenetic changes — hypermethylation silences genes (GSTP1, APC, RARβ2, RASSF1A) and hypomethylation activates oncogenes (ConfirmMDx assays methylation in negative-biopsy tissue; NPV 0.90, sensitivity 0.68). Gene-expression panels: Prolaris (31 cell-cycle genes; progression/death risk), Oncotype DX (adverse pathology at prostatectomy), and Decipher (metastasis risk in high-risk and biochemical-recurrence disease).
Imaging
- TRUS does not improve staging over DRE, tends to understage, and poorly detects transition-zone lesions.
- Multiparametric MRI (mpMRI) — key sequences: T2WI (zonal anatomy and transition-zone lesions; cancer is low-intensity, with a benign DDx of hemorrhage, atrophy, prostatitis, post-treatment change, scars, and BPH stromal hyperplasia); DWI/ADC (best for peripheral-zone lesions; cancer restricts diffusion — low ADC, and lower ADC = higher grade); T1WI (hemorrhage); DCE (vascularity — focal early enhancement suggests malignancy). Biparametric MRI (T2 + DWI, no contrast/coil) has equivalent sensitivity/specificity to mpMRI (Woo 2018). Post-biopsy MRI should wait 6–8 weeks (hemorrhage mimics cancer).
- PI-RADS scores each lesion 1–5 for the likelihood of clinically significant cancer (defined as Gleason ≥7, volume ≥0.5 cc, and/or EPE):
| PI-RADS | Detection (any cancer) | PPV for GG≥2 |
|---|---|---|
| 1–2 | 15% | 7% |
| 3 | 25% | 12–15% |
| 4 | 58% | 39–48% |
| 5 | 85% | 72% |
PI-RADS ≥4 → biopsy should be considered; ≤3 → depends on other factors.
- MRI-and-biopsy evidence (condensed): PROMIS (Ahmed 2017) — mpMRI as a triage test had sensitivity 88%, NPV 76%, specificity 45%, and could avoid ~25% of biopsies. PRECISION (Kasivisvanathan 2018) — MRI ± targeted biopsy was non-inferior and superior to standard TRUS for significant cancer (38% vs 26%) with less insignificant cancer. STHLM3-MRI (Eklund 2021) and GÖTEBORG-2 (Hugosson 2022/2024) — in screening, MRI with targeted-only biopsy detects significant cancer non-inferiorly while markedly reducing insignificant-cancer detection. MRI-FIRST (Rouvière 2019) and Ahdoot 2020 — combining targeted and systematic biopsy maximizes detection (don't omit systematic). About 10% (up to 20%) of negative MRIs still harbor significant cancer; predictors include PSA density >0.15, prior negative biopsy, abnormal DRE, and family history.
- PSMA-PET — PSMA (glutamate carboxypeptidase II) is overexpressed in >90% of prostate cancers (more with higher grade and castration resistance). Tracers: 18F-DCFPyL (Pylarify) and 68Ga-PSMA-11. Physiologic uptake (lacrimal/salivary glands, kidneys; celiac/stellate ganglia can mimic nodes); false negatives with small-volume disease, neuroendocrine differentiation, or prolonged ADT. proPSMA (Hofman 2020) — in high-risk disease, PSMA-PET-CT beat conventional imaging for nodal/distant metastasis (accuracy 92% vs 65%; sensitivity 85% vs 38%) and changed management more often with less radiation. Roles: primary staging of high-risk disease, staging biochemical recurrence (most common indication), and selecting patients for PSMA radioligand therapy; FDA-approved to detect metastases not seen on conventional imaging and to evaluate biochemical recurrence. It is far more sensitive than conventional imaging at low PSA (<0.5–2.0 ng/mL).
- Metastatic staging: CT/MRI for regional nodes; radionuclide bone scan is the most common test for skeletal metastases (PSMA-PET is more sensitive at low PSA).
Transrectal Ultrasound (TRUS)
Transrectal ultrasound (TRUS) is the workhorse for prostate volume measurement and biopsy/brachytherapy guidance; it is insensitive and non-specific for cancer detection itself.
Uses and Technique
Uses (5): assess prostate volume, locate focal abnormalities, assess for an obstructive cause of infertility (dilated seminal vesicles from ejaculatory-duct obstruction), guide biopsy, and guide brachytherapy seed placement.
Increasing probe frequency increases resolution but decreases penetration; the common 7-MHz transducer images the peripheral zone (where most cancers arise) well. On axial view the right prostate appears on the left of the screen (like CT). Zonal anatomy: anterior fibromuscular stroma, transition zone, central zone, peripheral zone, periurethral zone — the PZ and CZ cannot be distinguished on TRUS (collectively "PZ", the isoechoic reference); the TZ is hyperechoic, and corpora amylacea mark the PZ–TZ plane.
Lesions and Post-Treatment Appearance
- Cancer echogenicity: hypoechoic 60%, isoechoic 39%, hyperechoic 1%; a hypoechoic lesion contains cancer ~20% of the time (biopsy it, but it's neither pathognomonic nor grade-correlated). DDx of a hypoechoic lesion (6): prostate cancer, granulomatous prostatitis, prostatic infarct, lymphoma, BPH nodules, normal urethra.
- Post-treatment volume change: external-beam radiation decreases volume by 6 months; brachytherapy reduces it ~37% at 1 year and >50% at 8 years; 5-ARIs ~21% at 6 months; ADT ~30%. Irradiated prostates appear diffusely hypoechoic.
Prostatic Cysts
Anechoic; classified congenital vs acquired. Congenital cysts arise from Müllerian (prostatic utricle, Müllerian-duct cysts) or Wolffian (ejaculatory-duct, seminal-vesicle cysts) structures. An enlarged prostatic utricle (midline, at the verumontanum) is associated with genital anomalies (hypospadias most common, ambiguous genitalia, undescended testes, urethral polyps). Müllerian-duct and SV cysts should prompt renal ultrasound for unilateral renal agenesis. Zinner syndrome = ipsilateral SV cyst + ejaculatory-duct obstruction + unilateral renal agenesis.
Estimating Volume
Most formulas assume an ideal shape — ellipsoid (π/6 × transverse × AP × longitudinal), sphere, or prolate spheroid — and correlate well with specimen weight (1 cc ≈ 1 g). Planimetry (summing areas across cross-sections) is the most accurate ultrasound method.
Proceeding to Biopsy
Biopsy is offered when clinically significant cancer is suspected and the diagnosis will influence management. The PSA threshold is controversial (the PCPT showed ~15% cancer detection even with PSA <4, including Gleason ≥7) — for BRCA carriers, the referral threshold is 3 ng/mL. Validated risk calculators (ERSPC, PCPT, PBCG) and adjunctive blood/urine markers (detailed in the Blood, Urine and Tissue-Based Markers section earlier in this tab) refine the decision, especially for PSA 2.5–10 with a prior negative biopsy. With PSA >50 ng/mL (and no benign explanation), biopsy may be omitted when it poses significant risk and treatment is urgent (e.g. impending cord compression).
- Technique: a systematic biopsy samples ≥12 cores; for an MRI-visible lesion, perform targeted plus systematic biopsy; with a negative MRI but elevated risk, proceed with systematic biopsy (negative-MRI NPV ~91% for GG2+).
- Repeat biopsy by prior finding: focal HGPIN — no immediate repeat (~20–30% subsequent cancer, same as after a benign biopsy); multifocal HGPIN — risk-based (~30% GG2+); ASAP — additional testing (30–50% cancer, 10–20% GG2+); atypical intraductal proliferation — additional testing; negative biopsy — reassess risk with a calculator that incorporates the prior negative biopsy and obtain MRI before re-biopsy (don't repeat on PSA alone).
Prostate Biopsy
Prostate biopsy confirms the diagnosis when clinically significant cancer is suspected. The transrectal and transperineal routes have similar cancer-detection rates, but differ in infectious risk and access to anterior/apical tumors.
Indications and Contraindications
Indications: detection (raised PSA without UTI/retention/acute prostatitis, or an abnormal DRE), restaging (rising PSA after non-surgical treatment), active-surveillance protocols, and suspicious-but-not-diagnostic histology. Contraindications: significant coagulopathy, severe immunosuppression, acute prostatitis.
Approach
| Transrectal | Transperineal | |
|---|---|---|
| Trajectory | Through the rectum | Through perineal skin (avoids rectum) |
| Advantages | Patient comfort/preference; familiarity | Fewer infections; better anterior/apical detection; feasible without a rectum |
| Drawbacks | Higher infection risk | May need more anesthesia (but can be done under local) |
Preparation
- Anticoagulation: low-dose aspirin can be continued; warfarin and clopidogrel are stopped 7–10 days before; NOACs (apixaban, dabigatran, rivaroxaban) 2–5 days before; biopsy when INR <1.5, with heparin bridging for high thromboembolic risk.
- Antibiotic prophylaxis — transrectal: recommended for all patients (2019 AUA: a fluoroquinolone, or a cephalosporin + aminoglycoside; rectal-swab-targeted prophylaxis has utility where fluoroquinolone resistance is a concern). A Cochrane review (Zani 2011) found prophylaxis reduces bacteriuria, UTI, bacteremia, fever, and hospitalization. Transperineal: the NORAPP trial (2022) found antibiotics do not significantly reduce infection. A cleansing enema improves the acoustic window (infection benefit debatable).
Cores and Technique
- Transrectal: the extended 12-core systematic biopsy (apical and far-lateral cores) is standard — increasing from 6 to 12 cores improved detection, but going to 18–21 (saturation) is reserved for repeat biopsy. Transperineal: ~20 cores (5 sites per side). ≥2 cores per MRI target (incremental value diminishes beyond 3); the transition zone and seminal vesicles are not routinely sampled (isolated TZ tumors occur <5%); submit sextant cores in separate containers.
- Technique (condensed): a biplanar probe (side- or end-fire — equivalent detection), an 18-gauge biopsy device, and a periprostatic nerve block (1% lidocaine, max 3 mg/kg, or 7 mg/kg with epinephrine; ~5 mL per side at the base/neurovascular bundle). Transrectal is usually done in the left-lateral decubitus position; transperineal in lithotomy (often with a pudendal block — the pudendal nerve lies ~2 cm lateral to the anal verge and ~3 cm deep). After a DRE, scan base-to-apex, measure volume, perform the nerve block, and biopsy per template. Targeted biopsy of an MRI lesion uses software-based or cognitive fusion (comparable in expert hands).
Complications
- Bleeding: hematuria ~50% (intervention <1%), hematospermia ~50% (persists >4 weeks in ~30%), rectal bleeding ~30% (intervention ~2.5%; avoided by the transperineal route).
- Infection (prostatitis/fever/epididymitis): transrectal ~5–7% (> transperineal); hospitalization for infection ~1–3%. An Ontario cohort showed 30-day admission rising from 1% (1996) to 4% (2005), mostly infectious, with 30-day mortality 0.09%. Risk factors (6): non-White race, more comorbidities, diabetes, prostate enlargement, foreign travel, recent antibiotic use.
- Other: transient LUTS 6–25%, urinary retention <1%, transient erectile dysfunction <1%, and false negatives (initial detection ~22% for PSA 4–10, then 10% / 5% / 4% on second/third/fourth biopsy).
Pathology
Most prostate cancers are peripheral-zone adenocarcinomas, graded by the Gleason system (now reported as Grade Groups 1–5) and staged by the AJCC 8th-edition TNM system. Precursor and atypical biopsy findings (HGPIN, ASAP) drive repeat-biopsy decisions, and the radical-prostatectomy specimen yields the strongest prognostic factors.
Precursor and Atypical Lesions
- Adenosis — characteristically in the transition zone; not associated with increased risk of harboring or developing adenocarcinoma.
- Prostatic intraepithelial neoplasia (PIN): low-grade PIN should not be reported (not reproducibly distinguishable from benign tissue). High-grade PIN (HGPIN) is a precursor to many peripheral intermediate/high-grade cancers (though not necessary for cancer); ~20% harbor the TMPRSS2:ERG fusion; PSA is not elevated. Cancer on subsequent biopsy within a year is ~26.4% — not significantly higher than the 10–25% after a benign biopsy. Management by number of cores: 1 core → repeat biopsy at 3 years; ≥2 cores → repeat within 1 year.
- Atypia / atypical small acinar proliferation (ASAP) — suggestive but not diagnostic of cancer (~5% of biopsies). Cancer risk is ~40–50% (much higher than HGPIN). Seek expert review first; all patients should have a repeat biopsy, typically within 6 months, regardless of PSA.
Adenocarcinoma
- Location: ~85% arise in the peripheral zone; most cT1c tumors are posterior/posterolateral; multifocal in >85%.
- Spread: because the prostate lacks a discrete capsule, extraprostatic extension (EPE) is the preferred term; it occurs preferentially posteriorly/posterolaterally. Transition-zone tumors need larger volumes than peripheral-zone tumors for comparable EPE/metastasis. Most frequent metastatic sites (descending): lymph nodes > bone > lung > bladder > liver > adrenal.
- Histology: malignant glands lack basal cells (basal cells label with high-molecular-weight cytokeratin and TP63).
Gleason Grading and Grade Groups
| Gleason pattern | Description |
|---|---|
| 1 | Circumscribed nodule of closely packed, uniform, medium-sized acini |
| 2 | Like pattern 1 but with minimal edge infiltration; more loosely arranged |
| 3 | Discrete, smaller, infiltrative glands with marked size/shape variation |
| 4 | Fused microacinar, ill-defined, or cribriform glands; hypernephromatoid |
| 5 | No glandular differentiation (sheets/cords/single cells); comedocarcinoma with necrosis |
On biopsy the Gleason score is the most common pattern + the highest grade (ISUP 2005; the high grade is included because biopsy underestimates burden). Gleason 2–4 should not be assigned on needle biopsy. The 2014 ISUP Grade Group system:
| Grade Group | Gleason | Description |
|---|---|---|
| 1 | ≤6 | Only well-formed glands |
| 2 | 3+4=7 | Predominantly well-formed + lesser poorly-formed/fused/cribriform |
| 3 | 4+3=7 | Predominantly poorly-formed/fused/cribriform + lesser well-formed |
| 4 | 8 (4+4, 3+5, 5+3) | Only poorly-formed/fused/cribriform glands (or combinations lacking glands) |
| 5 | 9–10 | Lacks gland formation (± necrosis) |
Advantages: reassures Grade Group 1 patients (lowest possible grade), separates Gleason 3+4 from 4+3 (prognostically distinct), and unifies biopsy and prostatectomy reporting.
Specimen Assessment
Biopsy — grade and tumor extent generally predict adverse RP findings, but favorable biopsy findings don't guarantee favorable RP findings (sampling error). Upgrading from biopsy to RP is associated with increased cancer extent, increased PSA, fewer cores sampled, and a smaller prostate. Intraductal carcinoma (high-grade, poor prognosis — treat definitively) and perineural invasion (~75% EPE; prognostic for external-beam radiotherapy, less so brachytherapy) are notable.
Radical prostatectomy — prognostic factors (7): lymph-node involvement (15-yr BCR-free/metastasis-free/cancer-specific survival 7.1%/41.5%/57.5%), grade group, tertiary high-grade pattern, vascular invasion, extent of EPE (focal vs non-focal), seminal-vesicle invasion (5-yr progression ~65%), and positive margins (~15% after RALP; only ~50% progress; margin length usually doesn't affect risk, but extent and grade at the margin are prognostic for adjuvant-radiation decisions). 5-year biochemical-relapse-free survival by grade group: GG1 97%, GG2 88%, GG3 70%, GG4 64%, GG5 34%. Non-prognostic at RP: tumor volume and perineural invasion (common; do not include in the report).
Treatment effect: endocrine therapy causes atrophy/squamous metaplasia and artifactually higher grade; neither hormonal nor radiation-treated cancers should be assigned a Gleason score.
Other Histologic Subtypes
- Neuroendocrine / small cell (<0.5–1%) — suspect with brain metastasis, pelvic masses, visceral involvement, or osteolytic metastasis with hypercalcemia (PTHrP). PSA is low/undetectable; chromogranin A and urine serotonin metabolites may be present; not Gleason-graded. Hormone-unresponsive — treat with chemotherapy (cisplatin/etoposide or docetaxel/carboplatin) + radiation; survival generally <12 months.
- Prostatic duct adenocarcinoma (0.4–0.8%) — periurethral, exophytic; hematuria/obstruction; low PSA (often normal PSA and DRE); aggressive (regarded as Grade Group 4).
- Pure squamous carcinoma (rare, aggressive); mucinous (not more aggressive; treated by prostatectomy); urothelial carcinoma of the prostate (see that tab); sarcomas (0.1–0.2%); leukemia/lymphoma.
Staging
TNM Staging (AJCC 8th Edition)
Clinical stage uses DRE, PSA, biopsy, and imaging (MRI is recognized for cT categorization); pathologic stage follows prostatectomy.
| T stage | Definition |
|---|---|
| cT1a / cT1b | Incidental finding in ≤5% / >5% of resected tissue |
| cT1c | Identified by needle biopsy (e.g. for elevated PSA) |
| cT2a / cT2b / cT2c | ≤½ of one lobe / >½ of one lobe / both lobes |
| pT2 | Organ-confined (subdivision has no prognostic significance) |
| cT3a / pT3a | Extraprostatic extension (pT3a also includes microscopic bladder-neck invasion) |
| cT3b / pT3b | Seminal vesicle invasion (pT3b = muscle wall of the SV) |
| T4 | Invades external sphincter, rectum, bladder, levators, or pelvic wall |
pT1 does not exist — cT1a–c convert to pT2 (organ-confined) or pT3 (EPE) after prostatectomy. Microscopic bladder-neck invasion (pT3a) has not been associated with independent increased recurrence risk. N: N0 / N1 (regional node metastasis). M: M1a (non-regional nodes) / M1b (bone) / M1c (other distant sites — liver, lung, brain).
Evaluation
Germline mutations are inherited; somatic mutations are acquired. Indications (AUA 2022 / NCCN): Ashkenazi Jewish ancestry, a known familial cancer-risk mutation, a strong personal/family history of related cancers (breast, colorectal, ovarian, pancreatic, upper-tract urothelial), a strong family history of prostate cancer, adverse tumor features (high-risk disease, or intermediate-risk with intraductal/cribriform morphology), and metastatic or high-/very-high-risk localized disease. Multiplex tests (STHLM-3 — clinical variables + blood biomarkers + polygenic risk score; AUC 0.74 vs 0.56 for PSA, reducing biopsies ~32%) and polygenic risk scores (SNP-based) are emerging but cannot yet distinguish aggressive from indolent disease.
Self-Test
1. Describe the three key prostate-cancer screening trials. PLCO (no net benefit), ERSPC (net benefit, CSM RR 0.80), and Göteborg (net benefit, CSM RR 0.65).
2. List three limitations of the PLCO trial. High contamination (~77%), extensive pre-screening of the control arm, poor adherence to diagnostic biopsy, and underpowering.
3. What was the primary outcome in PLCO, ERSPC, and Göteborg? Cancer-specific mortality.
4. What is the function and half-life of PSA? It liquefies semen; half-life 2–3 days.
5. How does PSA circulate in blood? Free (20–30%) and bound (70–80%) — bound to α1-antichymotrypsin, α2-macroglobulin, and α1-protease inhibitor.
6. When does serum PSA become detectable? At puberty.
7. Optimal MRI sequence for hemorrhage, transition zone, vascularity, and peripheral zone? Hemorrhage — T1WI; transition zone — T2WI; vascularity — DCE; peripheral zone — DWI/ADC.
8. Describe the PROMIS and PRECISION trials. PROMIS — mpMRI as a triage test before biopsy (sensitivity 88%, NPV 76%) could avoid ~25% of biopsies. PRECISION — MRI ± targeted biopsy was non-inferior and superior to standard TRUS biopsy for significant cancer (38% vs 26%) with less insignificant cancer.
9. Differential for a low-T2-signal lesion? Cancer, hemorrhage, atrophy, prostatitis, post-treatment change, scars, and BPH stromal hyperplasia (mnemonic CHAPPSS).
10. Components of the Prostate Health Index and the 4Kscore? PHI = fPSA, tPSA, −2proPSA. 4K = fPSA, tPSA, intact PSA, hK2.
11. What does the PCA3 ratio represent? Urine PCA3 mRNA to urine PSA mRNA (×1000).
12. DNA hypo- vs hypermethylation — which silences and which activates? Hypermethylation silences; hypomethylation activates.
13. List the uses of TRUS. Assess prostate volume, locate focal abnormalities, assess for an obstructive cause of infertility, guide biopsy, and guide brachytherapy seed placement.
14. What proportion of cancers are hypo-, iso-, and hyperechoic on TRUS? Hypoechoic 60%, isoechoic 39%, hyperechoic 1%.
15. Differential for a hypoechoic TRUS lesion? Prostate cancer, granulomatous prostatitis, prostatic infarct, lymphoma, BPH nodules, normal urethra.
16. List the complications of TRUS biopsy. Hematuria, hematospermia, rectal bleeding, infection, urinary retention, and false-negative results.
17. Advantages and disadvantages of transperineal biopsy? Advantages — reduced infection and better identification of apical/anterior tumors. Disadvantage — may require more anesthesia.
18. Next step for atypia, HGPIN, and adenosis on biopsy? Atypia/ASAP — repeat biopsy within 6 months; HGPIN — repeat at 3 years if 1 core, within 1 year if ≥2 cores; adenosis — benign, repeat only as clinically indicated (PSA, DRE).
19. Significance of perineural invasion on biopsy vs prostatectomy? Biopsy — associated with increased risk of EPE; prostatectomy — non-prognostic (common, omit from report).
20. Describe the TNM staging of prostate cancer. cT1 (incidental/biopsy-detected), cT2 (palpable, confined), cT3a (EPE), cT3b (seminal vesicle), T4 (adjacent organs); N1 regional nodes; M1a non-regional nodes, M1b bone, M1c other sites.