Digital rectal examination (DRE)
Annual digital rectal examination is recommended for patients aged over 45 years. The examination is included in the scope of services of the German statutory health insurance funds. Unusual DRE results are the second most common examination findings to entail prostate needle biopsy for the exclusion of a malignant prostate tumour (the most common reason is elevated serum PSA levels). The sensitivity of the rectal digital examination is limited, ranging well below 40%.
The digital rectal examination serves to assess the consistency, shape and size of the prostate, in addition to evaluating the mobility of the rectal mucosa. Findings that give reason to suspect the presence of a tumour (a lump that is not painful to touch) should always be confirmed by a transrectal ultrasound-guided prostate biopsy. However, the DRE is only capable of detecting tumours with a minimum volume of about 0.2 ml. This DRE, as an important pillar of early detection, is not without controversy. Its sensitivity strongly depends on the examiner’s experience and only the peripheral zone of the prostate near the rectum can be palpated. Moreover, more than two-thirds of all prostate carcinomas diagnosed by palpation have already grown into extraprostatic tissue.
Consequently, this examination method alone cannot be regarded as a sufficient diagnostic measure for the early detection of prostate cancer, but it remains an essential part of early prostate cancer detection and diagnosis. In about 30% of the cases where the DRE results are positive, a carcinoma is detected by means of needle biopsy.
PSA (prostate-specific antigen)
The prostate-specific antigen is the most important laboratory parameter in connection with prostate cancer diagnosis. The PSA is not a tumour-specific, but only a prostate-specific protein. Consequently, elevated PSA levels are not necessarily associated with prostate cancer, but may also be indicative of inflammatory processes within the prostatic parenchyma or of BPH. Manipulations of the prostate resulting from the placement of a permanent catheter, digital rectal examination, needle biopsy, TUR procedures or intense sexual activity may also lead to elevated PSA levels. False-negative PSA levels may be caused, for example, by taking 5-alpha reductase inhibitors.
The probability of prostate cancer increases with increasing PSA concentration in the blood. When interpreting the PSA level, however, the age dependency of the serum concentration must also be taken into account, which is why age-specific PSA reference ranges have been introduced.
| Age-specific PSA reference ranges | PSA (ng/ml) |
|---|---|
| 40-49 | 0,0-2,5 |
| 50-59 | 0,0-3,5 |
| 60-69 | 0,0-4,5 |
| 70-79 | 0,0-6,5 |
Because of the high percentage of both false-negative and false-positive results, the reliability of the PSA test is subject to controversy. Prostate cancer can be detected in 22% of all patients with a PSA level of 2.6-4 ng/ml and normal DRE results. On the other hand, studies have demonstrated that the positive predictive value of a PSA level of 4-10 ng/ml only ranges between 12% and 32%, which means that a false-positive result is produced in about 75% of the cases. This leads to a significantly large number of prostate needle biopsies performed unnecessarily.
By contrast, prostate cancer was detected in every second needle biopsy at a PSA level above 10 ng/ml, which is why needle biopsy is recommended predominantly within this reference range. Despite the high PSA level, a tumour that is still limited to the prostate is detected in about 25% of these patients.
Besides the absolute PSA level, the PSA velocity and doubling time can be drawn on to assess the risk of the presence of prostate cancer. A relatively high sensitivity (75%) and specificity (95%) for the presence of prostate cancer has been found at a borderline level of 0.75 ng/ml/year (PSA velocity).
PSA exists in free (fPSA) and bound form (in a complex with chymotrypsin and macroglobulin). The ratio of free PSA / bound PSA is another parameter used in the early detection of prostate cancer. If prostate cancer is present, the percentage of free PSA in the blood is lower than the percentage of PSA bound to proteases. In a prospective, randomised clinical trial, prostate cancer was detected by needle biopsy in 56% of the male patients with a ratio of <10% and in only 8% of those with a ratio of >10%.
Within the above-mentioned reference range of 4-10 ng/ml, unnecessary biopsies are reduced by 20% when taking this ratio into account. Within the reference range of 2.6-4 ng/ml, too, unnecessary biopsies can be reduced by 18% when taking into account the ratio of free PSA / bound PSA.
To what extent a population-wide PSA screening can reduce the PC-related mortality rate was investigated in two large randomised, prospective clinical trials: In the PLCO trial (Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial), 76,693 men in the U.S. were randomly assigned to undergo either a DRE or a PSA test or the currently applied standard on an annual basis.
After a follow-up period of 13 years, no significant difference in the PC-related mortality rate was revealed between the two groups. By contrast, the European ERSPC study (European Randomized Study of Screening for Prostate Cancer), in which 182,160 men aged between 50 and 74 years were randomised (PSA test every 5 years vs. no routine PSA test), revealed a significant reduction in the risk of dying of PC (risk reduced by 21%). To prevent one PC-related death, a total of 1,055 men had to be invited to screening and 37 men had to be treated for prostate cancer. There are 340 cases of overtreatment for seven cases of prevented PC-related deaths, which is equivalent to 48 cases of overtreatment for one case of prevented death.
Because of the partly conflicting results regarding population-wide PSA screening, the U.S. Preventive Task Force spoke out against PSA screening in 2012.
PCA3 (prostate cancer antigen 3)
Besides the above-described long-established prostate screening methods, the past 14 years have seen research into other diagnostic markers to increase the efficiency of prostate cancer detection, thereby being able to perform needle biopsies more selectively. In 1999, it was reported for the first time that the “prostate cancer antigen 3” is only expressed in prostate cancer cells, but not in benign prostate cells or other tissue. A few years later, a method was developed to detect PCA3 in the urine, which was correlated with a high specificity (between 80% and 90%, depending on the cut-off) for the presence of prostate cancer.
In contrast to PSA, the PCA3 directly correlates with the tumour volume and the histological subtype. The PCA3 test is regarded as an additional tool for detecting a tumour predominantly in patients with elevated PSA levels and negative needle biopsy, making it easier for the urologist to decide whether to perform a repeat biopsy or follow-up. A high PCA3 level is associated with a significantly higher probability of detecting a tumour as part of a repeat biopsy.
PSA is better suitable as a screening method than PCA3, but the latter has a significantly higher specificity (90%) and can be used predominantly in patients with still elevated PSA levels after a first negative needle biopsy to decide whether or not a repeat needle biopsy should be performed directly.
Despite these promising results, the PCA3 test cannot replace the measurement of serum PSA levels and should only be used in individual cases.
Transrectal ultrasonography (TRUS)
The third pillar of prostate screening is transrectal ultrasonography (TRUS). As a rule, sonographic changes in the prostate cannot be allocated to a dignity; hypoechogenic lesions in the peripheral zone are most likely to be suspicious.
Overall, only about 50% of all tumours appear to be hypoechogenic in sonography, with the remaining 50% being iso- or hyperechogenic. The sensitivity of sonography alone is well below the sensitivity of a combined PSA test and DRE, which is why TRUS cannot be used as a sole examination method in cancer diagnosis. If a prostate carcinoma is present, transrectal ultrasonography can help identify the clinical stage (capsule infiltration, locally advanced tumour).
Sonography: Horizontal section incl. volume calculation
MRI (magnetic resonance imaging)
As regards new prostate cancer diagnoses, MRI is currently the most reliable imaging method to identify the local stage. However, this examination method is quite time-consuming and expensive and its sensitivity varies greatly in dependence on the examiner’s experience. Its sensitivity for extraprostatic tumour growth to be diagnosed by means of MRI is between 50% and 90%, which reflects the high examiner-dependent variability.
Where an MRI is performed with a 1.5 tesla MRI scanner, an endorectal coil should be used (not necessary with 3 tesla MRI scanners), because this allows for any irregularities or extension beyond the prostatic capsule or a seminal vesicle infiltration to be displayed more even more accurately.
Diffusion MRI with endorectal coil: Suspicious small hypointense lesion on the left at the transition from the central to the peripheral zone in the mid-third of the prostate
TRUS-guided prostate needle biopsy
The only method to obtain a representative prostate sample for the histological and definite detection of prostate cancer is the ultrasound-guided needle biopsy, involving the systematic removal of samples from the apex, the centre and the base of the prostate from both lobes of the prostate. A minimum of 10-12 samples, each of which should be at least 1 cm in length, is recommended. The procedure itself is performed on an outpatient basis; antibiotic treatment (gyrase inhibitor) must be started one day before the procedure and continued for an additional 3 days. A saturation biopsy is performed in cases where no tumour was detected in the first or a second needle biopsy, but the PSA level is still elevated or continues to rise. In this case, 20-30 samples are taken and a prostate carcinoma can ultimately be detected in 30-43% of the patients previously diagnosed as tumour-free.
Complications requiring clarification include bleeding after the procedure and prostatitis; however, these occur in less than 1% of the cases when the procedure is performed by an experienced surgeon.
MRI diagnosis and MRI-guided prostate biopsy
Where the PSA level is elevated and the presence of a prostate carcinoma is therefore suspected after excluding other causes for the pathological level, such as inflammations, the next step to be taken is a prostate biopsy, since only a histological examination allows reliable statements as regards tissue consistency. In some patients, however, the tissue obtained by means of ultrasound-guided biopsy appears to be normal, but the presence of a prostate carcinoma is still suspected. In such cases, a diagnostic MRI examination can provide further insights. MRI is a sensitive method for the morphological visualisation of the prostate and the detection of prostate cancer. Where the diagnostic magnetic resonance imaging (MRI) of the prostate reveals unusual results which should be confirmed by means of a biopsy (removal of samples) to clarify whether it is a malignant disease (prostate cancer) or a benign, inflammatory change of the prostate, a targeted MRI-guided prostate biopsy can be performed, since ultrasound examination methods do not allow for a visualisation or a targeted biopsy of these findings.
University Hospital Tübingen offers two high-quality biopsy techniques:
- Direct MRI-guided prostate biopsy (in the MRI scanner)
- Robot-assisted (Biobot™) biopsy with ultrasound/MRI fusion
MRI-guided prostate biopsy
Where the diagnostic magnetic resonance imaging (MRI) of the prostate reveals unusual results which should be confirmed by means of a biopsy (removal of samples) to clarify whether it is a malignant disease (prostate cancer) or a benign, inflammatory change of the prostate, a targeted MRI-guided prostate biopsy can be performed, since ultrasound examination methods do not allow for a visualisation or a targeted biopsy of these findings. In contrast to saturation biopsy (in which up to 40 samples are taken), this technique requires no anaesthesia and in contrast to conventional ultrasound-guided biopsy, only 2-4 cylindrical samples are removed, which involves far less stress and pain for the patient. This technique is aimed at the targeted, high-precision removal of samples. Owing to years of experience and interdisciplinary collaboration between urology and radiology, the biopsy only takes about 25 minutes (adjustment of the biopsy system to the suspicious finding and targeted sampling). We perform the biopsy at a magnetic field strength of 3 tesla without using an endorectal coil, since we simultaneously have the diagnostic image material at our disposal. Directly before starting the examination, the physician, who has many years of experience in performing biopsies, positions a small sheath in the rectum. The suspicious area is accessed through the rectum by means of the sheath. The position of the sheath is corrected following quick MRI measurements. Once the sheath is positioned correctly in relation to the suspicious area, the biopsy needle is introduced and the needle biopsy is performed, which usually involves no pain. This means that, similarly to the conventional ultrasound-guided biopsy, the prostate biopsy is performed through the rectum, avoiding a long access path via the perineum, which is usually painful and requires local anaesthesia or even general or spinal anaesthesia.
Who can be examined? What needs to be considered before the examination?
As a general rule, MRI examinations or biopsies cannot be performed in patients with cardiac pacemakers. If you have an artificial heart valve, a cochlear implant or an artificial hip joint, the radiologist has to clarify before the examination whether these implants are MRI-compatible. To this end, we need your implant card; please bring it with you on the date of the examination!
MRI examination
The actual examination including biopsy takes about 20-40 minutes.
If you suffer from claustrophobia, you can be given the sedative lorazepam (e.g. Tavor® s.l.) about 30 minutes before the examination. As a side effect of this medicine, you will feel tired and your general reaction time will be reduced significantly, which is why you will not be allowed to drive a car or actively participate in road traffic for the rest of the day and must arrange for someone to pick you up.
At our department, MRI-guided prostate biopsy is performed in collaboration between urology and radiology. Owing to our many years of experience in the field of MRI-guided prostate biopsy, complications associated with a biopsy, such as infections and bleeding, are minimised.
Prostate biopsy is currently not included in the scope of services of statutory health insurance funds.
Benefits of MRI-guided prostate biopsy:
- Avoidance of anaesthesia and any associated risks
- Biopsy is performed in a targeted manner instead of “blind”
- Minimised risk of infection
- Minimised risk of bleeding
- Clear diagnosis for the patient after only one session
Robot-assisted MRI-guided ultrasound biopsy (Biobot)
Robot-assisted navigation systems allow for the targeted biopsy of prostate areas with suspected malignant growth which have previously been diagnosed by means of high-resolution examination techniques (MRI or HistoScanning sonography). To this end, all image data of areas with suspected tumour growth are previously read into the biopsy system, marked and then integrated into the image processing of the high-resolution robot-assisted ultrasound biopsy unit (Biobot®) to plan the puncture during the ongoing ultrasound examination.
This way, this navigation data is made available to the biopsy robot in real time and in anatomical alignment (ultraprecise MRI-assisted navigation). In the first step, the 3D reconstruction of the MRI data record and the reconstruction of lesions with suspected malignant growth take place. For this purpose, the digital data record of a previously performed MRI of the prostate is loaded into the ultrasound scanner. Based on the MRI, anatomical reference points are marked.
This system features a robot-assisted positioning mechanism; navigation takes place through a rectally introduced protective sheath in which the transducer head can move freely without deforming the prostate. The entire system is covered with sterile material. Now the TRUS and MRI data records are fused. The MRI-TRUS image fusion combines the benefits of both techniques: The dynamic guidance of ultrasound is combined with the high diagnostic accuracy of MRI. To minimise the needle deviation resulting from the bevelled tip of the biopsy needle, we use a special needle tip. The successful performance of the biopsy is monitored in the sonographic image on the screen. The samples are taken via a perineal access under completely sterile conditions. The annual number of prostate needle biopsies performed throughout Europe is estimated at 1 million.
Over the last few years, however, the rate of infectious complications following transrectal prostate needle biopsy has increased, caused predominantly by fluoroquinolone-resistance faecal bacteria. The rate of infectious complications rose from 1% in 1996 to 4.1% in 2005. This trend calls for new technical concepts. The maximum of only 2 tiny biopsy puncture sites also reduces the risk of tissue trauma and infections. Moreover, the system precisely records the removal site of every single tissue sample in all three dimensions similarly to a stereotactic biopsy. This makes it possible to accurately locate and classify every single tumour following the biopsy, which is, in turn, the most important prerequisite for the planning of both present and future focal therapeutic concepts.