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Prostate Cancer: Screening and Diagnosis

Guidelines and review literature: EAU Guidelines Prostate Cancer, (S3-Leitlinie Prostatakarzinom) (Walsh-Campbell Urology 11th Edition).

Prostate Cancer Screening

Recommendations for prostate cancer screening

Prostate cancer screening is based primarily on measurement of prostate-specific antigen (PSA). Digital rectal examination (DRE) complements risk assessment but is not suitable as a stand-alone screening test. Persistently suspicious findings require further diagnostic evaluation. PSA screening detects more prostate cancers than observation alone, including cancers that would never become clinically relevant. It reduces prostate cancer-specific mortality; a benefit for overall mortality has not been demonstrated. Before screening, men should receive balanced counseling about potential benefits and harms, including false-positive and false-negative results, overdiagnosis, overtreatment, and the possible consequences of further investigations.

PSA screening should generally begin at 45 years of age. In men at increased risk, screening should begin at 40 years of age. Increased risk includes a family history of prostate cancer in first-degree relatives, a pathogenic BRCA2 variant, and African ancestry.

PSA >2 ng/mL: annual PSA testing.
PSA 1–2 ng/mL: PSA testing every two years.
PSA <1 ng/mL: PSA testing every four years.
Men older than 70 years with a PSA value <1 ng/mL do not require further PSA screening.

Flowchart for prostate cancer screening based on PSA and digital rectal examination. (*) Current international guidelines recommend multiparametric MRI before the first prostate biopsy.

Evidence for prostate cancer screening

Two large randomized trials have examined whether prostate cancer screening reduces prostate cancer mortality.

PLCO trial

The PLCO trial randomized 76,693 men to PSA testing and DRE or usual care. After seven years, 2,820 versus 2,322 prostate cancers and 50 versus 44 prostate cancer deaths were recorded; the mortality difference was not statistically significant. Interpretation is limited by substantial PSA testing in the control group: approximately 90% of control participants received PSA testing.

ERSPC trial

In the ERSPC trial, 72,952 men underwent PSA-based screening and 89,435 men received usual care. After nine years, the cumulative incidence of prostate cancer was 8.2% versus 4.8% (5,990 versus 4,307 cancers). The relative risk of prostate cancer death in the screening group was 0.80 (214 versus 326 deaths). After adjustment for nonattendance, the relative risk was 0.70. The incidence of metastatic disease or PSA values >100 ng/mL was reduced by 41%.

ERSPC trial: number needed to screen and number needed to treat to prevent one prostate cancer death.
Follow-up	Number needed to screen	Number needed to treat
9 years	1,410	48
11 years	979	35
13 years	781	27

Arguments against PSA screening

Opponents of PSA screening emphasize overdiagnosis and overtreatment of clinically insignificant prostate cancer. Although PSA screening reduces prostate cancer mortality, its absolute benefit must be balanced against the harms of unnecessary biopsies, diagnosis, and treatment. Risk-adapted screening is intended to improve this balance.

Risk-adapted PSA screening

Risk calculators derived from ERSPC data estimate the likelihood of a cancer-positive prostate biopsy using age, lower urinary tract symptoms, ethnicity, family history, DRE, prostate volume, and PSA. An example is available at www.prostatecancer-riskcalculator.com.

Diagnosis of Prostate Cancer

Digital rectal examination

DRE for screening

The sensitivity of DRE for localized prostate cancer is low, and the positive predictive value of a suspicious DRE is also low. Its predictive value increases with PSA concentration. In men without an elevated risk profile, the probability of prostate cancer after a suspicious DRE is approximately 5% with PSA 0–1 ng/mL, 14% with PSA 1.1–2.5 ng/mL, and 29% with PSA 2.6–4 ng/mL.

DRE and local tumor stage

DRE may suggest T1 disease (not palpable), T2 disease (palpable and organ-confined), T3a disease (extraprostatic extension), T3b disease (seminal-vesicle invasion), or T4 disease (infiltration of adjacent structures such as rectum or pelvic wall). Its accuracy for local staging is limited; MRI is preferred when assessment of local tumor extension is clinically relevant.

Prostate-specific antigen

PSA is used for screening, risk assessment before biopsy, prognostic assessment in biopsy-proven prostate cancer, and follow-up after curative or systemic treatment.

PSA and prostate cancer screening

One gram of benign prostatic hyperplasia increases PSA by approximately 0.3 ng/mL, whereas one gram of prostate cancer increases PSA by approximately 3.5 ng/mL. Because benign hyperplasia commonly has a much larger tissue volume, a single fixed PSA threshold cannot reliably distinguish benign disease from prostate cancer.

A fixed biopsy threshold such as PSA 4 ng/mL is inappropriate. PSA should be interpreted together with age, DRE, family history, prostate volume, PSA density, PSA kinetics, free PSA, and imaging. Findings suspicious for prostate cancer include PSA >2.5 ng/mL, PSA density >0.15 ng/mL/mL, PSA velocity >0.75 ng/mL per year, and free PSA <20%. An isolated asymptomatic PSA elevation should be checked for confounders and repeated before biopsy is planned.

Transrectal ultrasound of the prostate

Transrectal ultrasound (TRUS) uses 4–10 MHz probes and provides transverse and sagittal imaging. Prostate cancer may appear as a hypoechoic lesion, but many cancers are isoechoic or hyperechoic and therefore not visible. Hypoechoic cancers tend to have a larger tumor volume, a higher Gleason score, and a less favorable prognosis. TRUS is not sufficiently reliable for screening of localized prostate cancer. Elastography and histoscanning have not shown sufficient reliability in controlled trials.

Transrectal ultrasound showing locally advanced prostate cancer in the right lobe — TRUS with locally advanced prostate cancer in the right lobe (pT3a). The left image is transverse and the right image sagittal. The tumor is visible as a markedly hypoechoic area.

TRUS image showing extraprostatic extension of a left-sided prostate cancer — TRUS with locally advanced prostate cancer: extraprostatic tumor growth arising from the left lobe is visible.

Second TRUS image showing extraprostatic extension of a left-sided prostate cancer — TRUS with locally advanced prostate cancer: extraprostatic tumor growth arising from the left lobe is visible.

Multiparametric MRI of the prostate

Multiparametric MRI (mpMRI) is used to localize intraprostatic tumor growth and to assess local tumor stage. High-quality mpMRI requires a 1.5- or 3-Tesla MRI scanner. The examination includes T1- and T2-weighted imaging, diffusion-weighted imaging (DWI), apparent diffusion coefficient (ADC) mapping, and dynamic contrast-enhanced MRI (DCE-MRI). Proton MR spectroscopy is no longer routinely required.

Relevant sequences of multiparametric prostate MRI.
Sequence	Diagnostic information
T1-weighted imaging	Low physiological prostate signal; useful for detecting hemorrhage and assessing pelvic anatomy.
T2-weighted imaging	Normal peripheral zone is hyperintense; prostate cancer usually has lower signal intensity.
DWI and ADC map	Restricted diffusion reflects high cellular density and is a key feature of clinically significant cancer.
DCE-MRI	Early focal enhancement may support detection of clinically significant cancer.

Indications for mpMRI

mpMRI before the first prostate biopsy permits targeted biopsy of suspicious lesions and may allow biopsy to be avoided in selected men with an unremarkable MRI and low clinical risk. The negative predictive value for clinically significant prostate cancer is approximately 85–90%. A systematic biopsy should nevertheless be considered when clinical suspicion remains high despite a negative MRI.

After a negative biopsy with persistent suspicion of prostate cancer, mpMRI should be performed before repeat biopsy. In patients with PI-RADS ≥3 lesions, targeted biopsy is indicated and is usually combined with systematic biopsy. If MRI is PI-RADS 1–2, repeat biopsy may be omitted depending on PSA density, PSA kinetics, family history, and overall clinical risk.

mpMRI is also indicated if assessment of local tumor extension is relevant and is recommended at the beginning of active surveillance and before subsequent surveillance biopsies.

PI-RADS classification

PI-RADS (Prostate Imaging Reporting and Data System) standardizes acquisition, interpretation, and reporting of prostate MRI. The higher the score, the greater the likelihood of clinically significant prostate cancer.

PI-RADS v2 classification.
PI-RADS score	Likelihood of clinically significant prostate cancer
1	Very low; clinically significant cancer is highly unlikely.
2	Low; clinically significant cancer is unlikely.
3	Equivocal; approximately 15–25% likelihood.
4	High; approximately 40–60% likelihood.
5	Very high; approximately 70–90% likelihood, usually with a lesion ≥1.5 cm or extraprostatic extension.

Lesion localization is reported according to side, anterior/posterior location, apex/mid-gland/base, and prostate zone (peripheral, transition, central, or anterior fibromuscular stroma).

Prostate biopsy

Indications for prostate biopsy

A suspicious DRE and/or a persistently elevated or rising PSA concentration are indications for prostate biopsy. PSA should first be interpreted with age, PSA density, PSA kinetics, free PSA, family history, DRE, and MRI findings. In men with a clearly limited life expectancy of less than ten years, biopsy is generally indicated only for symptomatic disease or suspicion of advanced cancer.

Negative prostate biopsy with persistent PSA elevation

In men with persistent clinical suspicion after a negative biopsy, mpMRI should be performed before repeat biopsy. A PI-RADS ≥3 lesion should undergo targeted biopsy, usually combined with systematic sampling. With PI-RADS 1–2, a repeat biopsy can be omitted in selected low-risk men. Small tumors may be missed by the initial biopsy.

Technique of prostate biopsy

The transperineal approach is preferred because it substantially reduces infectious complications. If a transrectal biopsy is performed, local antimicrobial resistance patterns, antibiotic prophylaxis, and rectal preparation should be considered. Systematic biopsy generally includes at least ten cores from the peripheral zone. MRI-targeted fusion biopsy should be added when a suspicious MRI lesion is present.

Pathological interpretation of prostate biopsy

For pathological interpretation, including Gleason grading, ISUP grade groups, tumor extent, and reporting of adverse histological findings, see Prostate cancer: Pathology.

prostate cancer symptoms

Index

prostate cancer staging

Index: 1–9 A B C D E F G H I J K L M N O P Q R S T U V W X Y Z

References

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G. L. Andriole, R. L. Grubb, S. S. B. et. al., and the PLCO Project Team. Mortality results from a randomized prostate-cancer screening trial.
N Engl J Med, Mar 2009. Cooner u.a. 1990 COONER, W. H. ; MOSLEY, B. R. ; RUTHERFORD, Jr. ; BEARD, J. H. ; POND, H. S. ; TERRY, W. J. ; IGEL, T. C. ; KIDD, D. D.: Prostate cancer detection in a clinical urological practice by ultrasonography, digital rectal examination and prostate-specific antigen.
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DeMarzo u.a. 2003 DEMARZO, A. M. ; NELSON, W. G. ; ISAACS, W. B. ; EPSTEIN, J. I.: Pathological and molecular aspects of prostate cancer.
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Ellis u.a. 1994 ELLIS, W. J. ; CHETNER, M. P. ; PRESTON, S. D. ; BRAWER, M. K.: Diagnosis of prostatic carcinoma: the yield of serum prostate specific antigen, digital rectal examination and transrectal ultrasonography.
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Roobol, M. J.; Kerkhof, M.; Schröder, F. H.; u.a.m. Prostate cancer mortality reduction by prostate-specific antigen-based screening adjusted for nonattendance and contamination in the European Randomised Study of Screening for Prostate Cancer (ERSPC).
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Wein, A. J.; Kavoussi, L. R.; Partin, A. P. & Peters, C. A. Campbell-Walsh Urology
. Elsevier, 2015. ISBN 978-1455775675.

Deutsche Version: Früherkennung des Prostatakarzinoms

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