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Prostate Cancer: Screening and Diagnosis

• Prostate cancer (1/14): Definition and epidemiology
• Prostate cancer (2/14): Etiology
• Prostate cancer (3/14): Pathology
• Prostate cancer (4/14): Signs and symptoms
• Prostate cancer (5/14): Screening
• Prostate cancer (6/14): Staging
• Prostate cancer (7/14): Treatment options
• Prostate cancer (8/14): Active surveillance
• Prostate cancer (9/14): Prostatectomy
• Prostate cancer (10/14): Radiation therapy
• Prostate cancer (11/14): Brachytherapy
• Prostate cancer (12/14): TURP and experimental treatment options
• Prostate cancer (13/14): Hormonal therapy of advanced prostate cancer
• Prostate cancer (14/14): Treatment of castration-resistant prostate cancer

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

Recommendations for Prostate Cancer Screening

Prostate cancer screening includes measurement of the prostate-specific antigen concentration (PSA) and digital rectal examination (DRE) in asymptomatic men. If either examination is repeatedly suspicious, a needle biopsy of the prostate is recommended. Prostate cancer screening is controversial due to limited evidence to reduce overall mortality, see quote the German Guideline for prostate cancer (S3 Guideline, 2015):

The proportion of prostate carcinomas detected in screening groups is significantly higher compared to observational groups. The screening also reveals numerous carcinomas that do not require treatment. The prostate cancer-specific mortality is either reduced or not significantly affected by the screening. An influence on the overall survival time has not been demonstrated.

Age recommendations for PSA screening:

In general, PSA screening is recommended with the age of 45 years [see figure flowchart prostate cancer screening]. In high-risk patients for prostate cancer (first-degree relatives with prostate cancer, black men), PSA screening may be started with the age of 40. The screening test should be performed annually. With low PSA concentrations and inconspicuous DRE, the screening intervals can be extended depending on PSA levels: 1–2~ng/ml every 2 years and below 1 ng/ml every 4 years. For men over 70 years and a PSA value below 1 ng/ml, further PSA screening is not recommended.

Flowchart for prostate cancer screening based on PSA and digital rectal examination.

Evidence of Prostate Cancer Screening

So far, there are two randomized studies, which examined the reduction of mortality by prostate cancer screening.

PLCO trial:

Randomized study, 76.693 men, screening with DRE and PSA vs. "Standard care" (Andriole et al., 2009). Follow-up 7 years. Number of diagnosed prostate cancer: 2820 vs. 2322. 50 vs. 44 deaths (not significant). The study is criticized for methodological errors because 90% of patients in the observational group received a PSA test (Shoag et al., NEJM 2016).

ERSPC trial:

Randomized study, 72,952 men screening with DRE and PSA vs. 89 435 men with "standard care" (Schröder et al., 2009). Cumulative incidence of prostate cancer after 9 years of follow: 8.2% vs. 4.8%, in absolute numbers 5990 vs. 4307. Relative risk of death from prostate cancer in the screening group was 0.8 (214 vs. 326 deaths due to prostate cancer). If men were excluded due to non-compliance, the relative risk of prostate cancer death in the screening group was 0.7, risk reduction of 30% (Roobol et al., 2009). The relative risk of bone metastases or PSA >100 ng/ml in the screening group was 0,59, risk reduktion of 41%.

According to the primary results of the ERSPC trial, 1410 men must participate in the screening program (number needed to screen) to prevent one death due to prostate cancer. Furthermore, 48 men must be treated for prostate cancer (number needed to treat) to prevent one death due to prostate cancer. With prolonged follow-up, the number needed to screen and to treat is further reduced. :

Arguments against PSA screening:

Opponents of PSA screening fear an overtreatment of clinically insignificant prostate cancer and refer to epidemiology data and above mentioned trials. Although the ERSPC trial showed a reduction in mortality up to 30% with PSA screening, the reduction is judged to be too low to generally recommend PSA screening.

Risk-adapted PSA screening:

In order to avoid over-diagnosis and over-treatment, a risk calculatur was introduced based on the data of the ERSPC trial. With the help of age, LUTS, ethnicity, family history, DRE, prostate volume and PSA, the risk of a cancer positive prostate needle biopsy can be estimated. The risk calculator is published in the internet: www.prostatecancer-riskcalculator.com.

Diagnosis of Prostate Cancer

Digital rectal examination (DRE)

DRE for screening

Sensitivity of DRE (probability of suspicious DRE if prostate cancer is present) for localized prostate cancer is low. The specificity of DRE (probability of prostate cancer in suspicious DRE) is also low. Specificity can be improved by consideration of the PSA concentration: specificity for suspicious DRE in white men is 5% (0–1 ng/ml), 14% (1.1 to 2.5 ng/ml) and 29% (2.6 to 4 ng/ml). For black men, the specificity of suspicious DRE is almost twice as high for the same PSA concentration.

DRE and assessment of local tumor stage:

T1 (not palpable), T2 (palpable tumor, organ confined), T3a (tumor extends through the prostatic capsule), T3b (seminal vesicle invasion), T4 (infiltration of neighboring organs such as the rectum or pelvic wall). The accuracy of the DRE for the local tumor stage is low, imaging of the pelvic organs is recommended for locally advanced prostate carcinoma.

Prostate specific antigen (PSA)

PSA is important for screening, to predict prognosis for biopsy proven prostate cancer and for follow-up after curative therapy or in metastatic disease. See section laboratory values/PSA.

PSA and screening for prostate cancer:

One gramm of benign prostatic hyperplasia increases the PSA concentration by 0.3 ng/ml, while one gramm of prostate cancer leads to an increase of PSA by 3.5 ng/ml. Due to the significant differences in quantities of tissue for BPH (many gramms) or prostate cancer (few grams), static normal values are unable to differentiate between prostate cancer or BPH.

Reference values of PSA

It is not wise to initiate prostate biopsy for a fixed reference value (e.g., 4 ng/ml). The prediction accuracy of the PSA would be to low, too many prostate biopsies would yield benign hyperplasia as a result and some prostate cancer might be overlooked. The prediction accuracy of PSA can be improved by the combined consideration of age-related reference values, the yearly increase (PSA velocity) and the concentration of free PSA (fPSA). Suspekt for carcinoma are PSA levels above 2.5 ng/ml, a PSA velocity above 0.75 ng/ml/year and fPSA values below 20% [EAU Guidelines]. An elevated PSA level should be controlled for confounding factors and repeated.

In addition, the PSA concentration must be interpreted in relation to other clinical variables (DRE, age, family history, imaging). This reduces unnecessary prostate biopsies and improves the detection of prostate carcinoma [Table PSA, DRE and prostate carcinoma risk]. There is also a risk for prostate carcinoma within the normal range of the PSA concentration, even there the risk is dependent on the level of the PSA concentration [Table Normal PSA values and prostate carcinoma risk].

Transrectal ultrasound of the prostate (TRUS)

Transrectal ultrasound probes use 4 to 10 MHz transducers with transverse and sagittal image construction. Prostate cancer foci present as hypoechoic areas, but are often not seen (isoechoic) [fig. advanced prostate cancer in TRUS]. Prostate cancers, which are visible in TRUS as hypoechoic areas, have a larger tumor volume, a higher Gleason score and a worse prognosis than non-visible carcinomas (Amiel and Slavin, 2006). However, transrectal sonography is not reliable enough to be used to screen localized prostate carcinoma. Modern ultrasound methods have been developed to improve the visibility of prostate cancer (elastography or histoscanning), but did not prove to be reliable enough in controlled trials, please see section experimental prostate cancer diagnosis.

TRUS with locally advanced prostate cancer within the right lobe (pT3a). Left image transversal plane and right image sagittal plane.

Multiparametric MRI of the prostate

Multiparametric MRI (mpMRI) is used to localize intraprostatic tumor growth and to assess the local tumor stage. Prerequisite for a high quality mpMRT is the use of 1.5 or 3 Tesla scanners. The mpMRT uses different examination sequences such as T1- and T2-weighting, diffusion-weighted imaging (DWI), ¹H-MR spectroscopy and dynamic contrast-enhanced MRI (dceMRI), please see table examination sequences of mpMRI of the Prostate.

Indications for mpMRI:

Performing mpMRI prior to a prostate biopsy offers several advantages: suspicious areas on imaging can be targeted for biopsy and patients with completely unremarkable imaging can omit prostate biopsy (depending on the PSA). In the current EAU guidelines (as of 2020), mpMRI is recommended prior to the first prostate biopsy; the German S3 guideline is more cautious and suggests mpMRI as an option. According to current data, the sensitivity is 85–90% to exclude significant prostate carcinoma. If clinical suspicion is high and imaging is unremarkable, a prostate biopsy should still be recommended.

All current guidelines recommend mpMRI after negative prostate biopsy and persistent suspicion of prostate cancer. If imaging is unremarkable, further prostate biopsy may initially be omitted; targeted biopsy is possible for suspicious lesions.

Local advanced prostate carcinoma is also an indication for mpMRI, and the pelvic lymph nodes should also be assessed.

mpMRI during active surveillance is a good follow-up parameter. Current guidelines recommend mpMRI starting active surveillance if not done yet and before any further follow-up biopsy.

PI-RADS Classification:

In 2012, the European Society of Urogenital Radiology (ESUR) published a guideline, which was updated in 2014, to improve and standardize the technique and interpretation of mpMRI [table PI-RADS classification for mpMRI]. PI-RADS stands for Prostate Imaging Reporting and Data System. The higher the PI-RADS score of a lesion, the more likely is the presence of a significant prostate carcinoma.

The reporting of the lesion localization is also standardized: the prostate is divided along the urethra in the right and left, the prostate is divided into the anterior/posterior and the apex/middle/base. The lesions are additionally assigned to the individual zones: peripheral zone, transition zone, central zone or anterior fibromuscular stroma.

Prostate needle biopsy

Indications for prostate needle biopsy:

Indications for a prostate needle biopsy are a suspicious DRE and/or an elevated/rising PSA concentration. The prediction accuracy of PSA can be improved by the combined consideration of age-related reference values, the yearly increase (PSA velocity) and the concentration of free PSA (fPSA), see above. If in doubt, a multiparametric MRI of the prostate can help in the decision for or against a prostate biopsy. At a certain age, localized prostate carcinoma has not a significant influence on the life expectancy, so prostate biopsy should be indicated in relation to life expectancy, PSA concentration and symptoms.

Negative prostate biopsy and elevated PSA:

In the case of persisting clinical suspicion for prostate carcinoma, the prostate biopsy should be repeated, possibly with an increased number of biopsy cores and after performing a mpMRI to enable targeted biopsy. The second biopsy can be delayed for at least 6 months without any worries about tumor progression. The results of the European Screening Study show that especially small tumors are missed by the first biopsy.

Technique of prostate biopsy:

Transrectal prostate biopsy guided with ultrasound imaging is standard of care, alternatively the biopsy is done transperineal. At least 10 biopsy cores are taken from different locations of the prostate, see section surgical technique of prostate biopsy.

Pathological interpretation of prostate biopsy:

See section prostate cancer/pathology for interpretation.

References

DeMarzo u.a. 2003 DEMARZO, A. M. ; NELSON, W. G. ; ISAACS, W. B. ; EPSTEIN, J. I.: Pathological and molecular aspects of prostate cancer.
In: Lancet
361 (2003), Nr. 9361, S. 955–64N. Mottet (Chair), J. Bellmunt, E. Briers (Patient Representative), R.C.N. van den Bergh (Guidelines Associate), M. Bolla, N.J. van Casteren (Guidelines Associate), P. Cornford, S. Culine, S. Joniau, T. Lam, M.D. Mason, V. Matveev, H. van der Poel, T.H. van der Kwast, O. Rouvière, T. Wiegel Guidelines on Prostate Cancer of the European Association of Urology (EAU), https://uroweb.org/guideline/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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Pound u.a. 1999 POUND, C. R. ; PARTIN, A. W. ; EISENBERGER, M. A. ; CHAN, D. W. ; PEARSON, J. D. ; WALSH, P. C.: Natural history of progression after PSA elevation following radical prostatectomy.
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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).
Eur. Urol. 2009, 56, 584-591.

Wein, A. J.; Kavoussi, L. R.; Partin, A. P. & Peters, C. A. Campbell-Walsh Urology
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