Imaging of Prostate Cancer
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Background: Prostate cancer is the most common type of solid tumor in men and the second most common cause of cancer-related death in males in Germany. The conventional strategy for its primary detection, i.e., systematic ultrasound-guided prostate biopsy in men who have elevated PSA levels and/or positive findings on digital rectal examination, fails to reveal all cases. The same is true of the use of conventional computed tomography (CT), magnetic resonance imaging (MRI), and skeletal scintigraphy for the early detection of recurrences and distant metastases.
Methods: This review is based on pertinent publications retrieved by a selective search, including the German clinical practice guideline on prostate cancer and systematic review articles.
Results: Prospective multicenter trials have shown that the detection of clinically significant prostate cancer is markedly improved with multiparametric MRI (mpMRI) and MR/TRUS fusion biopsy (TRUS = transrectal ultrasonography), compared to conventional systematic biopsy. A recent Cochrane review showed that the rate of overdiagnosis of low-risk prostate cancer was reduced with mpMRI and MR/TRUS fusion biopsy compared with conventional systematic biopsy (95/1000 vs. 139/1000), and that clinically significant prostate cancer was more reliably detected (sensitivity 72% vs. 63%), albeit with slightly lower specificity (96% vs. 100%). Prostate-specific membrane antigen (PSMA) hybrid imaging improves the detection of lymphogenic and bony metastases in patients with high-risk prostate cancer. PSMA hybrid imaging is most commonly used to detect biochemical recurrences. A meta-analysis showed that the detection rate depends on the PSA concentration: 74.1% overall, 33.7% with PSA <0.2 ng/mL, and 91.7% with PSA ≥= 2.0 ng/mL.
Conclusion: The appropriate use of mpMRI and MR/TRUS fusion biopsy improves the initial detection of prostate cancer as well as the assessment of the prognosis. PSMA hybrid imaging is useful for the staging of high-risk patients and for the detection of recurrences. These methods are now recommended in the German clinical practice guideline on prostate cancer as well as in guidelines from other countries.
Prostate cancer is the most common type of solid tumor in men and the second most common cause of cancer-related death in men in Germany (1). Mortality varies by a factor of 10 depending on the pathological risk category (2), but the initial detection has been subject to limitations thus far. In recent years, early detection and primary diagnosis, as well as the detection of distant metastases and recurrences have been notably improved by means of modern imaging techniques.
Developments in diagnosing prostate cancer
For decades, the standard for diagnosing prostate cancer was ultrasound-guided transrectal (TRUS) prostate biopsy with up to 12 cores, which was undertaken because of a raised PSA (prostate specific antigen) value and/or abnormal findings on digital-rectal examination. On the basis of a Gleason score deduced from these 12 biopsy punches taken from the prostate and the PSA value, the tumor was classified as low-risk, intermediate-risk, and high-risk prostate cancer (3) and the indication was decided for further treatment (active surveillance versus active therapy). This diagnostic approach is, however, unsatisfactory in view of the known biological heterogeneity and multifocality of prostate cancer. The low specificity of the PSA serum measurement (4) and the limitations of the systematic biopsy can lead to overdiagnosis with an overestimate of the clinical prognosis or over treatment, respectively. On the other hand, a pathological upgrading of the initial Gleason score has been observed in 28.6% of the final prostatectomy specimens (5). More than 40% of mostly small carcinomas in apical or ventral position in the prostate can remain undetected (6). Transrectal ultrasound examination combined with contrast enhanced sonography, ultrasound elastography, or computer guided sonography (histoscanning) have not found their way into routine clinical practice and are therefore not recommended for the primary diagnosis of prostate cancer (7).
Multiparametric MRI in the detection of localized prostate cancer
Multiparametric MRI scanning (mpMRI) is currently the most precise imaging method for the detection of suspected prostate cancer, for T staging (8), and for monitoring purposes in active surveillance (9). The method is based on high-resolution images with three different contrasts, or MRI sequences (hence “multiparametric”) and can be routinely undertaken with modern 1.5T and 3.0T MR scanners (10):
- T2 weighted imaging (T2w) for displaying the prostate anatomy
- Diffusion weighted imaging (DWI) as a biomarker of regionally altered cell density, and
- Dynamic contrast enhanced (DCE) MRI as a biomarker of regionally altered vascular density (microvascularization).
In carcinomas with a high cell density, the Brownian molecular motion of the interstitial tissue fluid is restricted compared with normal glandular tissue, which can be visualized and additionally quantified by using DWI (apparent diffusion coefficient, ADC). As a result of neovascularization, cancers are characterized by increased vascular density and permeability, which manifests on DCE as early arterial and increased contrast medium accumulation. Of note, this means microstructural tissue characteristics can be visualized whose dimension is below the actual anatomical resolution limit of MRI ([μm] versus [mm]). In the glandular [gland-rich] peripheral zone, cancers are contrasted on mpMRI in a characteristic manner because of their changed cell density and neovascularization (Figure 1). In the transitional zone, which has undergone nodular changes subsequent to benign prostatic hyperplasia (BPH), it is, however, more difficult to detect cancers, as BHP nodules consist in variable ways of heterogenous glandular and stromal parts, and the stromal components also have restricted fluid diffusion and an increased vascular density.
Several prospective randomized multicenter trials and meta-analyses have shown that mpMRI is superior to systematic prostate biopsy. A recently published meta-analysis of 10 studies (2489 patients) showed for the detection of clinically significant prostate cancer by means of mpMRI a pooled sensitivity of 94% [95% confidence interval: 0.83; 0.98] and a specificity of 54% [0.42; 0.65] (11). Between 0 and 30.8% of clinically significant prostate cancers remained undetected. The negative predictive value of mpMRI is comparatively high, at 90%. What is less satisfactory is the low specificity with a positive predictive value of only 27–43% (12, 13, 14). Also, after a negative mpMRI result, a residual uncertainty of 7–12% remains for the presence of clinically significant prostate cancer (Gleason score group ≥= 2). Improved primary detection can be achieved, for example, by combining the mpMRI result with clinical risk models, such as the European Randomised Study of Screening for Prostate Cancer (ERSPC) (15). The results of important studies of widening the use of mpMRI to include younger age groups—for example, on the basis of PSA and multiple kallikrein panels, as in the ProScreen study (16)—will define in greater detail the role of mpMRI. Biparametric MRI (Tw2 and DWI) is available as a more efficient alternative and does not use contrast medium. A recently published study of population based screening found that including biparametric MRI reduced the need for biopsy by 48%. If a biopsy was needed, the rate of benign findings was reduced by 73% and the rate of clinically insignificant prostate cancers by 62%. The detection rate for clinically significant prostate cancer was not reduced—it was even slightly raised, by 3% (17).
MR/TRUS fusion biopsy
Targeted tissue sampling from suspected cancerous findings of mpMRI improves the precision and reliability of the initial pathological diagnosis, Three methods have been developed for MRI guided prostate biopsy: (1) cognitive fusion biopsy—that is, conventional TRUS biopsy compared with the available MR images, (2) direct MRI guided biopsy in the MR tomograph, and (3) MR/TRUS fusion biopsy—that is, a conventional TRUS guided biopsy, during which the ultrasound images are fused with previously obtained MR images including the marked lesions. For reasons of practicality and precision, MR/TRUS fusion biopsy has become the preferred approach (Figure 2).
Studies from 2010 onwards have confirmed the clear superiority of the combined systematic plus MRI guided fusion biopsy of the prostate in the detection of clinically significant—and thus in need of treatment—prostate cancers (18, 19). The use of fusion biopsy has raised the detection rate of clinically significant prostate cancer from about 50% (systematic 12-tims/fold biopsy) to more than 90% (20). The prospective randomized trials PROMIS (6) and PRECISION (18) as well as the Cochrane review (12) confirmed that undertaking mpMRI before the biopsy improves the detection of clinically significant prostate cancer compared with systematic biopsy. In a recent Cochrane review, the combination of MRI and MRI guided biopsy was found to be superior to the standard 12-times biopsy. Overdiagnosis of low-risk prostate cancer was reduced (139 versus 95 in every 1000 men), and clinically significant prostate cancer was detected more reliably (sensitivity 72% versus 63%; specificity 96% versus 100%) (12). By reliably excluding tumors requiring active treatment, defining the indication and undertaking active surveillance were improved by including MRI in combination with regular clinical controls including PSA measurement and re-biopsies (9). In centers of excellent, MRI/TRUS fusion biopsy has by now become the standard approach.
Improving and ensuring diagnostic quality
A reliably high investigative quality of mpMRI is required for scientific studies as well as for patient care. The European Society of Urogenital Imaging (ESUR) and the American College of Radiology (ACR) developed guidelines and quality standards for conducting the investigation and diagnosis, which are continually being revised and updated. (Prostate Imaging Reporting and Data System, PI-RADS, currently: Version V2.1) (21, 22, 23). For the peripheral and transitional zones, different radiological assessment criteria are applied. In the peripheral zone, the primary decision aid is assessed to be changes in cell density (DWI) and in unclear cases changes in the vascular density (DCE). In the transitional zone, the assessment follows primarily morphological criteria (T2w), and in unclear situations, cell density (DWI) is jointly used to reach a decision. The probability of the presence of a clinically significant prostate cancer is classified by using a 5-point Likert scale; findings that are probably benign are described as PI-RADS 1 and 2 and findings that are probably malignant as PI-RADS 4 and 5. PI-RADS3 describes unclear findings. In such cases it is useful to consult the PSA serum measurement (PSA density) relative to the prostate volume for an individual risk assessment (24).
However, the interpretation of the mpMRI can be subject to substantial variation, in spite of PI-RADS (25). Reproducibility therefore needs to be improved, especially outside centers of excellence. In Germany, the AG Uroradiologie und Urogenitaldiagnostik—Deutsche Röntgengesellschaft (DRG, the German Radiological Society’s uroradiology and genitourinary diagnostics working group) and the Berufsverband der Deutschen Radiologen e.V. (DBR, the Professional Association of German Radiologists) are offering a “special certification mpMRI prostate” or a “Certificate mpMRI prostatography.” Corresponding recommendations for how to conduct mpMRI have been published just recently (23). After a structured examination procedure, the respective radiology hospitals/practices receive certification that they conduct mpMRI in accordance with the currently valid international standards (26, 27).
The role of artificial intelligence
Prostate mpMRI using artificial intelligence (AI) is currently a highly active research area, from which many innovative impulses are to be expected in the near future (28, 29). In the meantime, deep learning systems have become capable of analyzing mpMRI investigations in a fully automated manner and to assign a tumor probability to every image voxel (Figure 3). The equivalence of such deep learning analyses with radiological evaluation according to PI-RADS has already been shown retrospectively, even though, in contrast to radiologists, no satisfactory agreement has been reached with regard to the definition of the lesion segmentation (3). With further basic research in increasingly more realistic quasi-clinical scenarios it is to be expected that AI algorithms as diagnostic decision support tools will become more widely used. In the context of a project funded by the Federal Ministry for Economic Affairs and Energy (Clinic 5.1), the foundations for the development of AI systems to support doctors’ decisions in the clinical diagnosis and treatment of prostate cancer are currently being created (31).
Multiparametric MRI in the current S3 guideline
In May 2021 the new S3 guideline for prostate cancer Version 6.0 was published (7). According to the guideline, mpMRI basically needs to be consistent with current quality standards (recommendation 5.13). It should be undertaken in the primary diagnostic evaluation before the first biopsy (5.16a). If mpMRI was not undertaken beforehand, it should be done after a negative systematic biopsy if cancer continues to be suspected (5.17a) and before an indication is made in favor of active surveillance (5.18a). Suspect findings (PI-RADS) should undergo targeted biopsy, in the context of the primary diagnosis (5.14a) as well as in patients considering active surveillance (5.18b). The initial biopsy in the context of primary diagnostic evaluation should include a systematic biopsy in addition to mpMRI guided biopsy (5.14b). In case of a normal mpMRI—that is, without a finding of a suspect focus (PI-RADS 1–2), patients should nevertheless be offered a systematic biopsy in addition to PSA monitoring (5.16b). Patients considering focal therapy should undergo mpMRI, mpMRI fusion biopsy, and systematic biopsy (6.39a). If an MRI biopsy is not possible, a template biopsy can be carried out as an alternative (6.39b). The recommendations are consistent with those of the European Association of Urology (32) and the latest NICE guidelines (National Institute for Health and Care Excellence, London) (33).
The role of PSMA-PET/CT in the diagnostic assessment of metastatic prostate cancer and recurrence
In case of a biochemical recurrence (PSA rise) after primary treatment, the detection of the precise localization of the recurrence (local, regional, or distant) has a crucial influence on subsequent therapeutic planning. For example, the detection of local lymph node metastases after primary radical prostatectomy (RPE) or initial radiotherapy is decisive factor for planning salvage radiotherapy and the radiation schedule (Figure 4) or salvage RPE. In recent years, prostate specific membrane antigen (PSMA) has become the particular focus as the target structure of detection/diagnosis but also of therapy (theranostics). Molecular PET hybrid imaging (PET/CT and PET/MRI) uses a small molecule as a radiopharmaceutical, which selectively binds to PSMA and thereby enables detection/diagnostic evaluation with high specificity and sensitivity.
The introduction of PSMA-PET/CT since 2011 has resulted in fundamental improvements in the detection of early lymphogenic and bone metastases compared with the limited conventional CT, MRI, and bone scintigraphy. PSMA-PET hybrid imaging is currently most commonly used in the setting of a biochemical recurrence after primary therapy of prostate cancer (for review articles 34, 35). A review article including 43 studies and 5832 patients found an overall detection rate of 74.1% [69.2%; 78.5%], which depended on the PSA concentration (from 33.7 % in PSA < 0.2 ng/mL to 91.7 % in PSA ≥= 2.0 ng/mL) (35). Early studies already showed the sensitivity of PSMA-PET/CT in detecting metastatic spread when PSA concentrations were low (36). The reliability of PSMA-PET/CT was confirmed in large case series (37). Visschere et al (34) included 98 studies in a systematic review with a focus on early biochemical recurrence. Detection rates were between 11.3% and 58.3% for PSA concentrations <0.2 ng/mL and between 11.0% and 65.0% for PSA values <0.5 ng/mL.
For the primary detection of spread in patients with high risk prostate cancer, accurate staging is of substantial relevance for deciding on treatment—from local therapy to a multimodal therapeutic approach using a combination of surgery, radiotherapy, and systemic therapy. Prostate cancers with a Gleason score of ≥=8, a PSA value ≥=20 ng/mL (2), or patients with morphological local advanced cancer on MRI are considered high risk. In such patients, a recent randomized multicenter trial showed the superiority of PSMA-PET/CT compared with conventional imaging (abdominal CT and skeletal scintigraphy) (38). The precision of PSMA-PET/CT in the initial detection of metastases was 91–95%—clearly superior to that of conventional imaging (59–74%). Compared with PSMA-PET/CT conventional imaging was found to have lower sensitivity (38% [24–52] vs 85% [74–96]) and specificity (91% [85–97] vs 98% [95–100]). Molecular hybrid imaging has recently undergone important further development, with the development of F-18 based PSMA ligands (39). Using fluorine-18 rather than gallium-68 as a marker makes radiopharmaceutical production easier and activity higher. F-18 based ligands can also be delivered to PET/CT centers without their own radiopharmacy. Further diagnostic, therapeutic, and theragnostic developments are to be expected.
PSMA-PET/CT is currently not available nationwide but can be accessed in different ways regionally through certain insurance schemes and Ambulante Spezialärztliche Versorgung (ASV, outpatient specialist care).
PSMA-PET hybrid imaging in the current S3 guideline
This method has greater precision in detecting metastatic prostate cancer than the combination of computed tomography and bone scintigraphy (5.25a). In primary high risk prostate cancer (Gleason score ≥=8 or T category ≥=T3 or PSA ≥=20 ng/mL) it can be used to detect tumor spread (5.25b). In the context of diagnosing recurrence, it can be used after primary curative therapy to assess the tumor volume, if the finding is of therapeutic consequence (5.29a)—a negative PSMA-PET result should, however, not delay early salvage therapy (5.29b).
In the advanced stages of castration resistant prostate cancer, systemic therapies take priority, whose selection depends on determining the metastatic burden with precision. Molecular PET hybrid imaging is of increasing importance in this setting too. Additionally, after all guideline conform therapeutic options have been exhausted, radiopharmaceuticals marked with lutetium-177 as a β-emitter open up the possibility of systemic radionuclide based Lu-177-PSMA therapy (40). According to the interdisciplinary S3 guideline, patients with castration resistant progressive disease who are in good general condition can— after the recommended therapeutic options have been exhausted—be offered a therapeutic attempt using lutetium-177 PSMA on the basis of the recommendation of an oncologic multidisciplinary team session (7.51).
Modern imaging techniques have substantially improved the detection/diagnostic evaluation of prostate cancer and therefore patient care in recent years. mpMRI and MR/TRUS fusion biopsy improve the initial detection and prognosis classification, and PSMA hybrid imaging improve staging in high risk patients as well as the detection of cancer recurrence. The methods have been implemented in the recent S3 guideline and are increasingly available in private practices. However, the costs are not as a rule reimbursed by the statutory health insurers. Randomized controlled trials investigating the endpoint mortality do not yet exist as survival times are very long especially for patients diagnosed at an early stage and at low or intermediate risk. For this reason, it is not yet possible at this time to evaluate this long term endpoint for these relatively new [“young”] diagnostic approaches. Furthermore, a wide spectrum of therapeutic options is available for prostate cancer, which needs to be borne in mind when drawing conclusions about the impact of the imaging techniques described in this article on patients’ overall survival. Further methodological developments are to be expected from the integration of imaging based, clinical, and molecular biology based parameters in association with AI.
Conflict of interest statement
Prof. Schlemmer receives research funding from the Federal Ministry for Economic Affairs and from the German Aerospace Center. He ran a cooperation with Bayer AG and Guerbet GmbH. He received consultancy fees from the German Radiological Society (BDR). He received lecture honoraria at several specialist conferences and was reimbursed travel expenses from Siemens Healthineers und Bayer Vital GmbH/Bayer Health AG. He sits on the board of trustees of the Roland Ernst Foundation and acted as a consultant to Curagita until 12/2018. He is president of the European Society of Oncology Imaging and has been a member of the guideline group of the guideline program “Prostate cancer” since December 2016, as well as a member of the guideline committee of the American Society of Clinical Oncology. He maintains a scientific collaboration with Siemens. He received study support from German Cancer Aid and Profound Medical.
Prof. Krause received financial funding and financial contributions for lectures from AAA/Novartis. He is a member of the advisory board of ITM solution GmbH and president of the German Society for Nuclear Medicine.
Prof. Bonekamp received lecture honoraria at various specialist conferences and was reimbursed travel expenses and occasionally received honoraria from Bayer Vital GmbH/Bayer Health AG. In the Profound Phase 2 Study, he received from Profound Medical the equipment in the context of MR thermometry-monitored transurethreal prostate ablation study.
PD Schwarzenböck was reimbursed travel expenses from the European Association of Nuclear Medicine.
Prof. Hohenfelder received research grants from the Federal Ministry for Economic Affairs and the German Aerospace Center in the context of the consortium project Clinic 5.1.
Dr Schütz declares that no conflict of interest exists.
Manuscript received on 6 April 2021, revised version accepted on 26 July 2021.
Translated from the original German by Birte Twisselmann, PhD.
Prof. Dr. med. Dipl.-Phys. Heinz-Peter Schlemmer
Radiologie, DKFZ Heidelberg
Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
Cite this as:
Schlemmer HP, Krause BJ, Schütz V, Bonekamp D, Schwarzenböck S, Hohenfellner M: Imaging of prostate cancer. Dtsch Arztebl Int 2021; 118: 713–9. DOI: 10.3238/arztebl.m2021.0309
Department of Urology, University of Heidelberg Medical Center: Prof. Dr. med. Markus Hohenfellner,
Dr. med. Viktoria Schütz
Department of Nuclear Medicine, University of Rostock: PD Dr. med. Sarah M. Schwarzenböck, Prof. Dr. med. Bernd Joachim Krause
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