Contrast enhanced ultrasound (CEUS) with parametric imaging and time intensity curve analysis (TIC) for evaluation of the success of prostate arterial embolization (PAE) in cases of prostate hyperplasia

AIM: To evaluate the use of dynamic contrast enhanced ultrasound (CEUS) with parametric color-coded imaging and time intensity curve analysis (TIC) for planning and follow-up after prostate arterial embolization (PAE). MATERIAL/METHOD: Before and after selective iliacal embolization by PAE with a follow up of 6 months 18 male patients (43–78 years, mean 63±3.5 years) with histopathological proven benign prostate hyperplasia were examined by one experienced examiner. A multifrequency high resolution probe (1–6 MHz) was used for transabdominal ultrasound and CEUS with bolus injections of 2.4 ml sulphur-hexafluoride microbubbles. Independent evaluation of color-coded parametric imaging before and after PAE by in PACS stored DICOM loops from arterial phase (10–15 s) up to 1min were performed. Criteria for successful treatment were reduction of early arterial enhancement by changes of time to peak (TTP) and area under the curve (AUC) by measurements in 8 regions of interest (ROI) of 5 mm in diameter at the margin and in the center and changes from hyperenhancement in parametric imaging (perfusion evaluation of arterial enhancement over 15 s) from red and yellow to blue and green by partial infarctions. Reference imaging method was the contrast high resolution 3 tesla magnetic resonance tomography (MRI) using 3D vibe sequences before and after PAE and for the follow up after 3 and 6 months. RESULTS: PAE was technically and clinically successful in all 18 patients with less clinical symptoms and reduction of the gland volume. In all cases color-coded CEUS parametric imaging was able to evaluate partial infarction after embolization with changes from red and yellow to green and blue colors in the embolization areas. Relevant changes could be evaluated for TIC-analysis of CEUS with reduced arterial enhancement in the arterial phase and prolonged enhancement of up to 1 min with significant changes (p = 0.0024). The area under the curve (AUC) decreased from 676±255.04 rU (160 rU–1049 rU) before PAE to 370.43±255.19 rU (45 rU–858 rU) after PAE. Time to peak (TTP) did not change significantly (p = 0.6877); TTP before PAE was 25.82±9.04 s (12.3 s–42.5 s) and after PAE 24.43±9.10 s (12–39 s). Prostate volume decreased significantly (p = 0.0045) from 86.93±34.98 ml (30–139 ml) before PAE to 50.57±26.26 ml (19–117 ml) after PAE. There were no major complications and, in most cases (14/18) a volume reduction of the benign prostate hyperplasia occurred. CONCLUSION: Performed by an experienced examiner CEUS with parametric imaging and TIC-analysis is highly useful to further establish prostatic artery embolization (PAE) as a successful minimal invasive treatment of benign prostatic hyperplasia.

Keywords: Contrast enhanced ultrasound (CEUS); parametric imaging; time intensity curve analysis (TIC); prostate arterial embolization (PAE)

Transurethral prostatectomia (TUR) has been the gold standard for the treatment of benign prostate hyperplasia. In individual cases, embolization of the prostate might be a successful percutaneous treatment option for symptomatic patients with comorbidities or contraindications for surgery. In many cases of benign prostate hyperplasia, angiography shows a hypervascularization of the para-prostate-plexus. To decrease the prostate volume, the prostate arteries can be embolized by super-selective microcatheters [[1], [3], [5]].

The benchmark for prostate imaging is contrast enhanced magnetic resonance tomography imaging (MRI) by a 3-Tesla scanner. This modality achieves parenchymal changes of the prostate at a high resolution and is the benchmark for the evaluation of suspicious malignant tumor lesions. Before intervention usually a contrast enhanced computed angiography (CTA) is performed to visualize the arterial and venous blood flow. CT is not the diagnostic of choice for screening of malignant changes. Both modalities do not allow continuous scanning to assess the perfusion from the early arterial phase to the venous phase. CT perfusion imaging cannot be performed due to the high dose of radiation exposure [[7]]. MRI contrast agent is under suspicion of deposits within the brain and is discussed to be the reason for the systemic nephrogenic fibrosis (NSF) [[7], [9], [11]].

B-mode ultrasound represents an easy and fast method to assess the prostate volume. Using color coded Doppler sonography (CCDS) the hemodynamic changes of the iliacal arteries and the pelvic venous system can be evaluated. High resolution dynamic contrast enhanced ultrasound (CEUS) enables the analysis of the prostate microcirculation [[12], [14]]. Second generation ultrasound contrast agents, e.g. sulphur hexafluoride microbubbles (SonoVue®, BRACCO, Italy), are neither nephro- nor thyreotoxic, which can limit the repeated application of conventional contrast agents e.g. for CT diagnostics. Previous studies proved the importance of CEUS for diagnostic evaluation of the dynamic microvascularization of prostate cancer [[16], [18], [20]].

The goal of this pilot study was to evaluate the use of dynamic contrast enhanced ultrasound (CEUS) with parametric color-coded imaging and time intensity curve analysis (TIC-analysis) in the planning phase and the follow up after prostate arterial embolization (PAE).

Written informed consent was obtained from all patients. The local ethical board permitted the examination and the data collection. Patients with known allergies to contrast-agents (CT, MRI, CEUS), severe pulmonary and cardiac diseases and implanted devices (pacemaker, AICD) were excluded from the study. To rule out prostate cancer, several prostate biopsies including histological work-up, were performed in all patients prior to the study. All patients were examined by a contrast enhanced 3-Tesla MRI (using T1, T2, dynamic vibe 3 D sequences with application of Dotarem® i.v.) (Guerbet, France). In all cases diffusion imaging including ADC maps was achieved for exclusion of tumor like lesions or inflammatory reactions in cases of prostate hyperplasia with adenomas [[17], [19]].

Before and after selective iliacal embolization by PAE with a follow up of 6 months 18 male patients (43–78 years, mean 63 years±6,5) with histopathological proven benign prostate hyperplasia were examined by one experienced examiner.

PAE vascular access was obtained via the common femoral artery by Seldinger technique. The internal iliac arteries were catheterized with a 5 French angiographic catheter. Internal iliac angiograms were performed on anteroposterior and ipsilateral anterior oblique projections to identify the origin of the prostatic arteries. The prostatic arteries were catheterized with micro-catheters. In absence of significant anastomoses between prostate artery and other pelvic arteries embolization was performed with microspheres until complete flow stasis was observed on post-embolization angiograms [[1]].

All ultrasound examinations were performed by one experienced examiner (more than 3000 examinations per year over more than 20 years) using a high resolution multifrequency convex probe (1–6 MHz) and a high-end ultrasound machine (LOGIQ E9/GE/US). Diameter of the prostate was evaluated in three planes and B-mode morphology. Color-coded Doppler sonography (CCDS) and Power Doppler were used for determining microvascularization and hemodynamic evaluation of the iliacal arteries and the paraprostatic plexus. Relevant pathologies of the iliac arteries and iliac veins (e.g. arterial stenosis, deep vein thrombosis, iliac aneurysm) were excluded before catheter embolization. Acute infections and evidence for malignant changes were contraindication for PAE.

Contrast enhanced ultrasound (CEUS) was performed by intravenous bolus injection of 2.4 ml sulphur-hexafluoride microbubbles (SonoVue®, BRACCO, Italy) via a peripheral venous catheter followed by a 10 ml saline solution flush [[16]]. In sweep technology the whole prostate gland was examined by scanning in axial plane. DICOM loops were stored continuously up to 1 min beginning from the early arterial phase after 10 seconds. Until the late phase (3 to 5 minutes) short loops and single images were digitally stored in PACS for independent retrospective reading by two experienced examiners in consensus.

Independent analysis of the dynamic microvascularization of the prostate perfusion was performed using false color parametric imaging integrated into the high-end ultrasound machine using the stored dynamic DICOM loops. Early enhancement was coded in red, intermediate as yellow and prolonged as green nuances. Late and low enhancement was shown in blue pseudo colors. Time intensity curve analyses (TIC) were calculated using ten regions of interest, apical, basal, on the right and left side as well as in the center of the prostate gland. Contrast enhancement over one minute was evaluated by time to peak (TTP) and area under the curve (AUC). A low TTP and high levels characterized hyperenhancement for AUC [[17]]. A successful PAE was defined by a significant reduction of previous hyperenhancement at the margins of the prostate gland with a consequent volume reduction and improvement of clinical symptoms.

Before and after PAE with a follow up to 6 months 18 male patients with histopathological proven benign prostate hyperplasia were examined by one experienced examiner using a multifrequency high resolution probe (1–6 MHz) for transabdominal ultrasound and CEUS with bolus injections of 2.4 ml sulphur-hexafluoride microbubbles. Independent evaluation of color -coded parametric imaging before and after PAE was performed by in PACS stored DICOM loops from arterial phase (10–15 s) up to 1min. Criteria for successful treatment were reduction of early arterial enhancement by changes of TTP and AUC by measurement of 8 regions of interest (ROI) 5 mm in size at the margin and in the center of the prostate gland and changes from hyperenhancement in parametric imaging from red and yellow to blue and green by partial infarctions [[17]].

For calculation of the differences between the center and the margin before and after PAE for each parameter ANOVA for repeated measures with Bonferroni post-test was performed using GraphPad Prism version 5.00 for Mac OS X. Probabilities of less than p = 0.05 were considered significant.

PAE was technically and clinically successful in all 18 cases with a reduction of clinical symptoms and the primary sonographic evaluated reduction of the gland volume. Color-coded perfusion (CEUS) documented changes from red and yellow to green and blue after embolization indicating partial infarctions. This occurred in all cases in the embolized areas. Additionally, relevant changes could be assessed by TIC-analysis with reduced arterial enhancement in the arterial phase and reduced prolonged enhancement of up to 1 min with significant changes (p = 0.0024) in the mean AUC (676±255 rU vs. 370.4±255.2 rU). TTP did not change (p = 0.6877), (25.82±9.04 s vs. 24.4±9.1 s). Prostate volume changed significantly (p = 0.0045) from 86.9±34.9 ml to 50.6±26.3 ml after PAE. The results are summarized in Table 1.

Table 1 Results of US/CEUS measurements before and after PAE

Using a multifrequency probe for transabdominal scanning of the prostate the evaluation of the embolization therapy by contrast enhanced ultrasound was feasible. A bolus injection of up to 2.4 ml of ultrasound contrast agent was sufficient to assess the prostate using the cross- beam technique for 3D volume scanning. During the arterial phase, the dynamic changes between areas with reduced perfusion or partial infarction after PAE and normal perfused areas could be clearly detected in all cases. We did neither observe devascularization nor post-embolic inflammatory necrosis. The pseudo-colors of parametric imaging enabled the detection of differences between normal perfused areas in red and yellow and reduced perfusion in blue and green colors. In green and blue areas of post-embolic infarctions the evaluation of the TIC analysis showed a reduced perfusion by lower levels for area under the curve (AUC). The evaluation of time to peak (TTP) showed only partial differences between the post-embolic and normal perfused areas of the prostate gland.

Figures 1–8 depict representative images of the clinical and ultrasound evaluation PAE using CEUS with parametric TIC-analysis.

Graph: Fig. 1 B mode of an inhomogeneous enlarged prostate gland of a 75 year old male patient with benign prostate hyperplasia and up to 179 ml volume.

Graph: Fig. 2 CEUS of the same case of an inhomogeneous enlarged prostate gland of a 75 year old male patient with benign prostate hyperplasia with early general enhancement of the microbubbles (arrow)after bolus injection of 2.4 ml ultrasound contrast agent.

Graph: Fig. 3 CEUS parametric imaging of the same case of an inhomogeneous enlarged prostate gland of a 75-year-old male patient with benign prostate hyperplasia with early arterial hyper-enhancement of the microbubbles from the left apical part (arrow)after bolus injection of 2.4 ml ultrasound contrast agent.

Graph: Fig. 4 CEUS TIC analysis of the same case of an inhomogeneous enlarged prostate gland of a 75 year old male patient with benign prostate hyperplasia with early arterial and enlarged hyperenhancement of the microbubbles without tumor suspicious wash out after bolus injection of 2.4 ml ultrasound contrast agent. Regions of interest (ROI) at the margin and in the center of the prostate gland.

Graph: Fig. 5 CEUS after PAE of the same case of an inhomogeneous enlarged prostate gland of a 75 year old male patient with benign prostate hyperplasia with now reduced arterial enhancement of the microbubbles of the left part (arrow)after bolus injection of 2.4 ml ultrasound contrast agent.

Graph: Fig. 6 CEUS parametric imaging after PAE of the same case of an inhomogeneous enlarged prostate gland ofa 75 year old male patient with benign prostate hyperplasia with now reduced early arterial hyper-enhancement of the microbubbles from the left apical part (arrow) and in general reduced enhancement after bolus injection of 2.4 ml ultrasound contrast agent.

Graph: Fig. 7 CEUS TIC analysis after PAE of the same case of an inhomogeneous enlarged prostate gland of a 75 year old male patient with benign prostate hyperplasia with reduced arterial and less enlarged enhancement of the microbubbles after bolus injection of 2.4 ml ultrasound contrast agent. Regions of interest (ROI) at the margin and in the center of the prostate gland.

Graph: Fig. 8 Follow up after 6 months with B mode of the less inhomogeneous enlarged prostate gland of the same 75 year old male patient with benign prostate hyperplasia and now only up to 55 ml volume.

Comparison between CEUS perfusion and contrast enhanced MRI after PAE resulted the same areas for devascularization correlating to microinfarctions. Areas of reduced perfusion could be easier detected by CEUS perfusion with parametric imaging, using pseudo-colors like red for hyperemia, blue for devascularization and green for normal perfusion compared to MRI with frequent artifacts by mixed between hyperemia and devascularization after embolization.

For planning of interventional procedures of PAE, the dynamic evaluation of the microvascularization of the prostate gland was very helpful, since in all cases the areas of the highest hypervascularization and the localization for the best embolic treatment effects could be visualized by parametric CEUS perfusion imaging and quantified by TIC-analysis.

There were no major complications and no intolerances against the contrast agents.

In a first study using CEUS for the evaluation of prostate artery embolization in the setting of symptomatic benign prostate hyperplasia a clinical success in 78.5 % of the cases was reported [[20]]. As such, CEUS showed well-defined infarctions in 71.4% [[21]]. Transabdominal and transrectal scanning could not show any differences regarding the evaluation of the post embolization infarctions. In contrast, this study using transabdominal scanning by CEUS showed a strong correlation to the areas of devascularization comparing contrast enhanced MRI and the findings of CEUS.

Usually, CEUS is performed transrectally for the detection and characterization of prostate tumor lesions as part of multimodal imaging with MRI. Image Fusion of CEUS and MRI allows to guide biopsies for histopathological evaluation [[12], [14], [17], [19]]. Considering the EFSUMB guidelines CEUS perfusion could be an important diagnostic tool for the detection of tumor lesions by changes of dynamic microvascularization (Sidhu et al. 2018). In this study, we investigated for the first time the combination of parametric imaging and TIC analysis by transabdominal scanning of benign prostate hyperplasia before PAE. These first results show the high diagnostic value of CEUS for evaluation the treatment success of PAE [[20]] corresponding to the results of other intervention procedure studies using CEUS perfusion for planning and follow up [[22], [24]].

So far, there have been only few case reports and single center studies describing particles and particle sizes suitable for PAE. Factors that seem to be associated with clinical success include young patient age up to 65 years, bilateral embolization and the use of adapted smaller embolization particles [[1], [3], [5]].

Also, by unilateral PAE volume reduction and improvement of clinical symptoms could be achieved. Post-embolization syndrome occurred in up to 4%, including hematuria, urinary tract infections and increase in symptoms with the main complication of miss-embolization of the seminal vesicles [[1], [3], [5]].

Performed by experienced examiners prostatic artery embolization (PAE) can be a successful minimal invasive treatment of benign prostatic hyperplasia. Routinely, contrast enhanced magnetic resonance tomography imaging (MRI) is considered to be the most reliable imaging tool to assess a successful treatment. MRI can detect the morphologic and hemodynamic changes to assess the post embolization effects on the hyperplastic tissue [[1], [3], [5], [20]].

After embolization ischemic necrosis appears to be responsible for the long-term effects of PAE. Extensive and irreversible prostatic ischemia could result in volume reduction of the enlarged adenomatous prostate with reduction of the mass effects on the prostatic part of the urethra. This improved the urine flow dynamics and reduces the symptoms of the urinary tract obstruction [[20]].

Prostatic infarctions were caused by the acute and irreversible occlusion of the prostatic arterial branches after selective embolization. Infarction areas could be detected as well defined, non-enhancing areas in CEUS. After bolus injection of the ultrasound contrast agent in typical cases of post PAE infarction a non-enhancing area can be detected in the arterial phase from 10 s up to 45 s. During the follow up after 24 up to 48 hours a strong correlation between the presence of infarctions with devascularization of these areas in CEUS was observed with the clinical success auf PAE. In addition, a correlation between the extent of the early prostatic infarctions and the degree of prostate shrinkage in the post-interventional follow-up was noted. CEUS can provide early and convincing evidence of the local effect of the embolization. Using color-coded perfusion evaluation in parametric imaging a devascularization could be detected [[17], [19], [21]]. Evaluation by time intensity curve analysis in these cases showed prolonged and reduced contrast medium enhancement with reduced levels for AUC and reduced levels of the peak enhancement. It has been previously described, that the number and size of echogenic foci after PAE correlated with the extent of prostatic infarctions. Multiple and larger echogenic foci could be detected in cases of extensive infarctions [[20]].

The current literature suggests that transabdominal post-inventional scanning using high resolution multifrequency probes have a high diagnostic accuracy to find postinterventional infarction [[17], [19], [21]]. The combination of parametric CEUS imaging and TIC-analysis such as in this pilot study is helpful for an easy to perform post-interventional success evaluation of the dynamic microvascularization of the prostate.

Main limitations of this study are the small number of patients and that parametric CEUS imaging and TIC analysis are only available in high end ultrasound machines and not for all machines as standardized technical procedures. Since bolus injection of ultrasound contrast agents was used, relative perfusion parameters could be evaluated additionally. For the exact volume evaluation of the prostate perfusion real-time 3 -D probes should be used [[14]]. These 4D probe are not often available and cost-intensive. However, transabdominal CEUS perfusion imaging could be a useful imaging tool for the post-inventional follow-up after PAE.

In conclusion, it seems that CEUS with parametric imaging and TIC-analysis can be used to monitor prostatic artery embolization (PAE). It is an advantage that CEUS can be used repeatedly during the follow-up without exposing the patient to further risk after PAE and also for HIFU [[26]].

The authors have no conflict of interest to report.