Dr. med. Dirk Manski



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Prostate Cancer: Screening and Diagnosis


Guidelines and review literature: (EAU Guidelines, Mottet et al, 2015) (S3-Leitlinie Prostatakarzinom der DGU) (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 race), 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 1 ng/ml, further PSA screening is not recommended.


Flowchart for prostate cancer screening based on PSA and digital rectal examination.
flow chart for for prostate cancer screeing with PSA and digital rectal examination

Epidemiology of prostate cancer and screening tests

So far, there are two randomized studies, which examined the 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, risk reduction of 20% (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%.

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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. :

Results of the ERSPC Trial depending on the follow-up (Schroeder u.a., 2014).
Follow-up in years Number needed to screen Number needed to treat
9 1410 48
11 979 35
13 781 27

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.

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 (tumour 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, particularly for distinguishing T2 and T3.

 

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 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].


Prostate cancer risk depending on PSA and DRE: (Cooner et al, 1990) (Ellis et al, 1994) (Hammerer und Huland, 1994).
DRU PSA (ng/ml) Risk for PCA
not suspicious 0–4 4–9 %
not suspicious >4 12–32 %
suspicious 0–4 13–21 %
suspicious >4 42–72 %


Prostate cancer risk within normal PSA values: results from the Prostate Cancer Prevention Trial (Thompson et al, 2004).
PSA (ng/ml) Risk for PCA Risk for Gleason ≥7
<0,5 7 % 0,8 %
0,6–1,0 10 % 1 %
1,1–2,0 17 % 2 %
2,1–3,0 24 % 5 %
3,1–4,0 27 % 7 %

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.
TRUS transrektaler Ultraschall der Prostata mit Prostatakarzinom

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 1.5–3 Tesla scanners. The need for an endorectal coil is no longer necessary for scanners with 3 Tesla and increases patient comfort. The mpMRT uses different examination sequences such as T1-weighting, T2-weightedness, diffusion-weighted imaging (DWI), 1H-MR spectroscopy and dynamic contrast-enhanced MRI (dceMRI), please see table examination sequences of mpMRI of the Prostate.

Examination sequences of mpMRI of the Prostate (Franiel u.a., 2014).
Abbreviation Description Diagnostic information
T1 spin–lattice relaxation time the physiological signal intensity of the prostate in T1 imaging is low.
T2 spin–spin relaxation time the normal peripheral zone has a high homogeneous signal in T2 imaging, the small prostatic capsule presents with lower signal intensity. Prostate cancer foci usually present with a lower signal intensity.
DWI diffusion-weighted imaging imaging correlates with the Brownian motion of water molecules between the cells. In case of prostate cancer, the signal of DWI imaging is lower due to a higher cell density.
1H-MRS proton magnetic resonance spectroscopy provides metabolic information from citrate methylene protons (Cit) and the methyl groups of creatine (Cr)- and choline (Cho)-containing compounds.
dceMRI dynamic contrast-enhanced MRI repeated T1-weighted imaging after the application of contrast media provides information about the blood vessel quantity, blood flow and capillary permeability.

Indications for mpMRI:

The mpMRI is a newly introduced imaging tool with promising clinical results. The current guidelines of the EAU (2016) recommend the mpMRT after negative prostate biopsy and persisting suspicion for prostate cancer. In the case of inconspicuous imaging, a further prostate biopsy is not necessary, while in the case of suspicious lesions, targeted biopsies are possible. mpMRI is also useful to assess the local stage and the pelvic lymph nodes in advanced prostate carcinoma.

mpMRI is not recommended for elevated PSA before prostate biopsy. According to current data, the sensitivity of 85–90% to exclude a significant prostate carcinoma is still too low and prostate biopsy is still recommended even after inconspicuous imaging. The role of the mppMRI of the prostate is also unclear in the context of active surveillance of proven low-risk prostate cancer, but it promises to be a good prognosis parameter to monitor active surveillance.

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.

PI-RADS classification for mpMRI of the prostate (Weinreb et al, 2016).
PI-RADS Score Probability of significant prostate cancer
1 most probably benign
2 probably benign
3 indeterminate (15%)
4 probably malignant (27%), Läsion <1,5 cm
5 highly suspicious of malignancy (88%), Läsion >1,5 cm

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.









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References

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Leitlinienprogramm Onkologie (Deutsche Krebsgesellschaft, Deutsche Krebshilfe, AWMF):
Interdisziplinäre Leitlinie der Qualität S3 zur Früherkennung, Diagnose und Therapie der verschiedenen Stadien des Prostatakarzinoms, Langversion 3.1, 2014 AWMF Registernummer: 034/022OL, http://www.awmf.org/leitlinien/detail/ll/043-022OL.html (Zugriff am: 07.02.2016)


Ellis u.a. 1994 ELLIS, W. J. ; CHETNER, M. P. ; PRESTON, S. D. ; BRAWER, M. K.:
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Roobol, M. J.; Kerkhof, M.; Schröder, F. H.; u.a.m.
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Wein, A. J.; Kavoussi, L. R.; Partin, A. P. & Peters, C. A.
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