Contrast-enhanced ultrasound (CEUS) of cystic renal lesions in comparison to CT and MRI in a multicenter setting

PURPOSE: Contrast-enhanced-ultrasound (CEUS) has been frequently used in assessment of cystic renal lesions. OBJECTIVE: The aim of this study was to investigate the Bosniak classification in CEUS compared to CT and MRI in a multi-center setting. METHODS: Bosniak classification in CEUS examinations of cystic renal lesions were compared to imaging findings in computed-tomography (ceCT) and magnetic-resonance-imaging (ceMRI). Imaging results were correlated to histopathological reports. All examinations were performed by experts (EFSUMB level 3) using up-to-date CEUS examination-protocols. RESULTS: Overall, 173 cystic renal lesions were compared to subgroups CT (n = 87) and MRI (n = 86). Using Bosniak-classification 64/87 renal cysts (73.6%) were rated equal compared to CT with upgrade of four lesions (4.6%) and downgrade of 19 lesions (21.8%) by CT (Intra-class-correlation [ICC] coefficient of 0.824 [p < 0.001]). CEUS compared to MRI, presenting different scoring especially in classes Bosniak IIF (n = 16/31) and Bosniak III (n = 16/28) with an ICC coefficient of 0.651 (p < 0.001). CONCLUSION: CEUS can visualize even finest septal and small nodular wall enhancement, which may result in an upgrade of cystic lesions into a higher Bosniak class compared to CT or MRI. Thus, a modification of the Bosniak classification on CEUS may reduce unnecessary biopsies and surgery.

Keywords: Contrast-enhanced ultrasound; CEUS; Bosniak; renal cyst

• CEUS

• contrast-enhanced ultrasound

• CT

• computed tomography

• MRI

• magnetic resonance imaging

• US

• ultrasound

• PPV

• positive predictive value

• NPV

• negative predictive value

• ICC

• intra-class correlation

• IQR

• interquartile range

Incidentally found cystic renal masses are common in abdominal imaging [[1], [3]]. Focal cystic renal lesions show an age-dependent increasing incidence with more cystic renal lesions found in elderly patients (20% of all fifty years old patients and over 50% in all patients after post mortem autopsy) and a ratio of 2:1 in favour to the female sex [[5]].

Since the introduction in 1986 and its revision in the 90 s the Bosniak classification is the primary tool for morphologic evaluation and treatment planning of cystic renal lesions based on criteria in contrast-enhanced computed tomography (ceCT) [[7]]. Lesions are classified as Bosniak I-IV with an increased likelihood of malignancy in higher Bosniak score. An indication for biopsy or surgical removal is usually associated with Bosniak III-IV lesions respectively. While Bosniak I cysts are simple without complexity and Bosniak IV are easier to detect due to their solid enhancing vascular masses, the differentiation of Bosniak IIF and Bosniak III is difficult and of clinical relevance [[9]]. Bosniak IIF cystic lesions show increased number of septa and minimally thickened or enhancing septa or wall or thick calcifications. Hyperdense cysts >3 cm with no enhancement are also classified as Bosniak IIF in ceCT. Bosniak III cystic lesions are more complex and vary only from multiple contrast-enhancing and thickened septations with septal or mural nodules [[7], [10]]. Malignancy rate in surgically excised Bosniak IIF (25%) and Bosniak III (54%) cystic renal lesions was higher in patients with a history of primary renal malignancy or coexisting Bosniak IV lesion or renal neoplasm [[11]]. During the last decade, magnetic resonance imaging (MRI) became more important in discrimination between benign and malignant cystic renal lesions avoiding radiation exposure, but was demonstrated leading to category migration and management change of complex renal cysts in a significant proportion of cases, likely due to its superior soft tissue and contrast resolution [[12]].

Ultrasound is widely used across all clinical disciplines as a modality of choice in the evaluation of cystic renal lesions. While nonenhanced sonography and colour-coded Duplex sonography (CCDS) are associated with limitations in detection of vascularity in wall and septa, contrast-enhanced ultrasound (CEUS) of the kidney for detection and characterization of renal tumors can be used off-label as a complementary option to visualize these features. CEUS is valuable in patients with pacemaker, chronic renal failure or known allergy to contrast media containing iodine or gadolinium [[5], [13]]. Additionally, US contrast agent can be used without affecting thyroid and renal function. CEUS is associated with a very low incidence of adverse events like an anaphylactic reaction [[14]]. Furthermore, Lamby et al. demonstrated no changes of the mean oxygen partial pressure in the outer medulla which confirms that microbubbles on their did not hinder the co-flow of blood through the renal microvessels [[16]]. In previous studies CEUS demonstrated great potential to improve the Bosniak's classification of cystic lesions compared to CT, based on specific real-time contrast enhancement patterns [[17], [19]]. The purpose of our study was therefore to compare CEUS and both ceCT and ceMRI findings in the evaluation of cystic renal masses using the Bosniak classification system.

This study was approved by the local ethics committee (EA2/205/17). Oral and written informed consent of all patients was obtained before examination. All study data were collected in compliance with the principles expressed in the Declaration of Helsinki 2002. Between 2010 and 2017, 173 regular patients with a cystic renal lesion received CEUS examination of the kidney at one out of three German ultrasound departments. Diagnostic reports of all imaging findings were collected centrally and reviewed retrospectively. Patients had additional ceCT (n = 87) or ceMRI (n = 86) imaging studies for further diagnostic management. The additional imaging studies consist of ceCT and ceMRI scans based on multiphase local imaging protocols using contrast media containing iodine or gadolinium. In some renal lesions histological material could be gathered after surgical removal of the lesion, after biopsy or after fine needle aspiration.

All CEUS examinations were conducted with high-end ultrasound systems with up-to-date CEUS specific local examination protocols available at the time of the examination (Aplio500/Aplio i900, Canon Medical Imaging; Sequoia/S2000/S3000, Siemens Healthineers; HDI 5000/iU22/EPIQ 7/Affiniti, Philips Ultrasound; LOGIQ E9, GE Healthcare and RS80A with Prestige, Samsung Medison Co., Ltd., Seoul, Korea). CEUS examinations were performed and interpreted by one out of three high-experienced radiologists with more than 10 years of experience in CEUS reliant on the local experience, all being EFSUMB level 3 examiner. The Bosniak classes of the CEUS examinations were reported at the time of examination. A second-generation blood pool contrast agent media (SonoVue®, Bracco, Milan, Italy) was used in all examinations and was administered through a peripheral 20–22G needle as a bolus injection followed by a flush of 5 to 10 ml of 0.9% saline solution (0.9% NaCl). Injections of contrast agent were given until satisfactory cine loops could be stored (1.4 to 2.0 ml dose depending on local protocols and US system). After the injection of the contrast agent cine loops were acquired and stored in the picture archiving and radiological information system (PACS) at the site of the examination. A low mechanical index (MI <0.3) was used for all examinations to avoid unintentional microbubble-destruction.

All cystic renal lesions in cross sectional imaging were classified by senior board-certified radiologists from each department with more than five years of experience during clinical routine and blinded to the results of both conventional sonography and CEUS. Lesions were classified as Bosniak I–IV depending on their morphologic appearance and contrast enhancement behaviour. Histopathological results were available in 35 cystic lesions.

Continuous variables were tested for normal distribution using the Kolmogorov-Smirnov-test; variables not following a normal distribution are reported as median and interquartile range (IQR) and were compared using the Mann-Whitney U-Test. Categorical variables were compared using student's t-test or chi2 test, as appropriate. Diagnostic accuracy of CEUS compared to gold standard CT was tested using sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV). Additionally, exact 95% confidence intervals (CI) were calculated for all values. Intra-class-correlation (ICC) was used to compare Bosniak classes in CEUS to both ceCT and ceMRI. Interpretation of ICC inter-rater agreement was defined by Cicchetti [[21]]: Less than 0.40 – poor, 0.40 to 0.59 – fair, 0.60 to 0.74 – good and 0.75 to 1.00 as excellent. All statistical analysis was performed using SPSS software version 24. All tests were two-sided and significance defined by a p-value < 0.05.

Bosniak classification of 173 cystic renal lesions in 173 patients (median age: 66 [IQR: 57–73], 63.3% male patients) were evaluated. Of those, 87 cystic lesions were compared to ceCT and 86 lesions to ceMRI. Distribution of renal cysts' Bosniak classes in initial CEUS examination was: 8 Bosniak I (3.0%), 49 Bosniak II (18.1%), 142 Bosniak IIF (52.6%), 44 Bosniak III (16.3%) und 27 Bosniak IV (10.0%). Bosniak distribution based on CEUS findings are presented in Table 1.

Table 1 Lesion distribution based on contrast-enhanced US findings

Categorical variables are given as absolute/total numbers (n/N) and percentages in brackets.

CEUS scores were equivalent to ceCT in 64/87 (73.6%) with an upgrade of 4 lesions (4.8%) and downgrade of 19 cystic renal lesions (22.9%) by ceCT. (Fig. 1a) Two lesions of Bosniak II were each up- and downgraded by one class and two lesions were downgraded by ceCT from Bosniak IV to III. Representative case of correct scoring in CEUS and ceCT is shown in Fig. 2. More different scorings were found in intermediate complex cysts Bosniak IIF and III: Of 45 Bosniak IIF lesions ceCT rated one lesion as Bosniak I and ten lesions as Bosniak II while three lesions were upgraded into Bosniak III. Five lesions classified as Bosniak III in CEUS were downgraded by ceCT, one as Bosniak II and four as Bosniak IIF. Overall ICC of CEUS and CT was 0.824 (95% -CI: 0.74–0.88; p-value < 0.001). Sensitivity, specificity, PPV and NPV of CEUS compared to gold standard ceCT are presented in Table 2.

Graph: Fig.1 Lesion distribution of CEUS and cross-sectional imaging. Bosniak classification in CEUS compared to a) CT and b) MRI. CEUS showed small number of different scoring (21.8%) using Bosniak classification compared to CT (a), while comparison to MRI (b) demonstrated a higher number of mismatches (55.8%). Abbreviations: CEUS denotes contrast-enhanced ultrasound, CT, computed tomography; MRI, magnetic resonance imaging.

Graph: Fig.2 Representative case of an excellent correlation of a Bosniak II cystic renal lesion in CEUS and CT. a) Contrast-enhanced CT scan: Subcapsular, hyperdense renal cyst (red circle) without any calcifications. They do not show any solid components or contrast enhancement. https://www.thieme-connect.de/media/ultraschall/201603/uim-1947%5f10-1055-s-0042-104646-i3.jpg. b) Intraluminal echo in B-mode ultrasound (right side), CEUS (left side) shows no (septal) contrast enhancement of the cyst, therefore the cyst can be classified as Bosniak type II. Abbreviations: CEUS denotes contrast-enhanced ultrasound, CT, computed tomography.

Table 2 Sensitivity, Specificity, PPV and NPV of CEUS compared to gold standard CT (n = 87)

Abbreviations: PPV denotes positive predictive value; NPV, negative predictive value; CEUS, contrast-enhanced ultrasound; CT, computed tomography.

Equivalent scores in CEUS compared to ceMRI were detected in 48/86 cystic lesions (55.8%) with a wide range of both up- and downgrades. (Fig. 1b) No change was detected in Bosniak class I. Two Bosniak II lesions in CEUS were each upgraded (Bosniak IIF) and downgraded (Bosniak I). More downgrades (5/31 into Bosniak I and 7/31 into Bosniak II) and upgrades (One lesion each into Bosniak III and IV) were classified as Bosniak IIF. 12/28 Bosniak III lesions in CEUS were scored different as followed: 1 as Bosniak I, 4 as Bosniak II and 7 as Bosniak IIF with an upgrade of 4 lesions into Bosniak IV. Bosniak class IV showed a downgrade of 2/14 lesions by ceMRI into Bosniak III. ICC of CEUS compared to ceMRI was 0.651 (95% -CI: 0.51–0.76; p < 0.001). Table 3 presents intra-class-correlation of CEUS to both ceCT and ceMRI.

Table 3 Intra-class-correlation of CEUS vs. CT (n = 87) and CEUS vs. MRI (n = 86)

Abbreviations: CEUS denotes contrast-enhanced ultrasound; CT, computed tomography; MRI, magnetic resonance imaging; ICC, intraclass-correlation.

Comparison to histopathological reports was available in 35 cystic lesions which were occurred by total nephrectomy (n = 17/35, 47%), partial nephrectomy (n = 14/35, 39%) and biopsy as part of minimal-invasive therapy e.g. radiofrequency ablation (n = 4/35, 11%). CEUS showed a sensitivity of 88% (95% -CI: 72–95), specificity of 25% (95% -CI: 5–70), a PPV of 90% (95% -CI: 75–94) and a NPV of 20% (95% -CI: 4–62). One cystic lesion with suspicion of malignancy were histologic confirmed as a renal oncocytoma (classified as Bosniak III) and another one as a multilocular cystic neoplasm (classified as Bosniak IV) in histopathological report. Two cystic lesions (Bosniak II and IIF) showed disease progression and morphologic change after two and five years and both were confirmed as renal cell carcinomas.

This study demonstrates that CEUS shows an excellent correlation to gold standard ceCT and moderate to ceMRI using Bosniak classification and inter-class-correlation in a multicenter setting. Nevertheless, there is a small number of cases in which CEUS scores were different compared to gold standard ceCT mostly resulting in a higher grade (21.8%) by CEUS due to sensitive contrast enhancement detection.

After the introduction and revision of Bosniak's classification a first modification to MRI was described by the same research group in 2004 [[22]]. Our findings agree with the results of single-center studies who compared the accuracy of CEUS with ceCT in a small number of cases. With an equivalent classification of cystic renal lesions in 73.6% compared to ceCT presenting similar results compared to smaller studies by Park et al. 74% and a slightly lower percentage than Clevert et al. 81% [[17], [19]]. Prospective single-center studies presented comparable results with a correct rating in 79% of all cystic renal lesions (n = 46) similar to the classification by ceMRI in that study [[23]]. CEUS showed an upgrade in 19/87 cystic lesion (21.8%) compared to gold standard CT especially in intermediate complex lesions Bosniak IIF (n = 13/45) and Bosniak III (n = 5/10). (Fig. 2) ICC in CEUS and ceCT showed an excellent correlation only in Bosniak IV group while all other groups presented a good (Bosniak I) or moderate correlation (Bosniak II-III). ICC in CEUS and ceMRI was lower in each Bosniak group compared to ceCT which remains the standard imaging tool for Bosniak classification of cystic renal lesions (Table 3). Due to a high spatial resolution US improves the detection of finest septae and nodular wall thickening. Since CEUS is able to detect very small amounts of microbubbles, it has the power to visualize even finest septal enhancement, which is often missed in cross sectional imaging. (Fig. 3)

Graph: Fig.3 Different classification of a cystic renal lesion in CT (Bosniak II) compared to CEUS (Bosniak IIF) due to the sensitive visualization of septal contrast enhancement. A,b) Axial and coronal contrast-enhanced CT scan: a cystic renal lesion of the right kidney without wall thickening or calcifications. Detection of a hairline thin septa without contrast enhancement. This cyst would be classified as Bosniak type II. c) B-mode ultrasound: Detection of more intraluminal septa with nodular thickening due to a high spatial resolution. d) No vascularization of the thin septa using colour-coded Doppler ultrasound. e) Visualization of microvascularization using innovative ultrasound Doppler technique superb micro-vascular imaging (SMI). f) Contrast-enhanced ultrasound of the cyst shows nodular contrast enhancement of the hairline thin septa. Therefore this cyst can be classified as Bosniak type IIF. Abbreviations: CT denotes computed tomography; CEUS, contrast-enhanced ultrasound.

Diagnostic work-up and stratification of these intermediate complex cystic lesions are important to differentiate surgical procedures or follow-up of these lesions [[24]]. While a different rating in Bosniak II and IIF lesions only results in a change of follow-up time interval, surgical removal of Bosniak III lesions is recommended [[25]]. The sensitive detection of microbubbles in CEUS with the visualization of fine septal enhancement and small nodular wall enhancement as a potential to improve the classification of cysts and may result in an upgrade of lesions into a higher Bosniak class [[13], [18], [26]]. Contrast material–specific software allows subtraction of background tissue from the image so that minimal amounts of US contrast enhancement can be visualize which may not be identified at B-Mode US, ceCT or ceMRI [[28]]. (Fig. 4) While number and thickness (>1 mm) of septa and its fine contrast enhancement are major criteria for Bosniak classification [[26]], a high spatial resolution in ultrasound may even visualize more septa and irregular wall thickness. CEUS was superior in detecting the degree of septal wall thickening, septal enhancement, and enhancement of solid components within the lesion compared to CT [[19]]. Recent studies have demonstrated that the accuracy of intravenous ultrasound contrast agent for detection of septal enhancement in complex cystic lesions was superior to CT [[17], [19], [29]].

Graph: Fig.4 CEUS software allows subtraction of background tissue from the image to visualize minimal amounts of septal contrast enhancement. a) B-Mode US using a mid-class ultrasound system: Limited interpretation of the cystic lesion (white arrow) with focal calcification and intraluminal echoes. b) B-mode US using a high-class ultrasound system: Higher resolution but still insufficient interpretation of the renal cyst with intraluminal echo due to focal calcification. c) Visualization of minimal septal contrast enhancement using CEUS. Abbreviations: CEUS denotes contrast-enhanced ultrasound.

Ultrasound and especially CEUS are fast and cost-effective clinical methods of choice for further characterization of unclear cystic renal lesions in CT or MRI [[15], [17], [30]]. Nevertheless, while the amount of contrast agent depends on the US system, an examination of both kidneys and the use of two contrast agent boli can lead to higher costs and longer examination time by the need of a delay up to ten minutes for contrast agent washout prior using a second bolus injection. The most important differential diagnosis of unclear cystic renal lesions is the (cystic) renal cell carcinoma. Larger renal cell carcinoma shows area of necrosis or haemorrhage that can be detected and misinterpreted as cystic lesions in B-mode ultrasound [[5]]. Evaluation of these solid (enhancing) components can be evaluated by the use of contrast media and a dynamic examination. CEUS is an useful method to differentiate between malignant and benign (cystic) renal lesions with a high diagnostic sensitivity according large single-center studies using CEUS with a histopathological validation [[31]]. Although the specificity in our subgroup analysis remains low, there is only a very small number of benign lesions (n = 4/35) in this retrospective cohort. Since the Bosniak classification has worked well using ceCT, it may be appropriate to modify it as opposed to the development of a separate classification for CEUS. If a scoring system for contrast enhancement positive and negative lesions on CEUS is used (regardless of the Bosniak classification), the NPV based on the reference was 100% (0/842 lesions), whereas the PPV was 97% (170/175 lesions) [[28]].

Different advantages and disadvantages of each modality (CT, MRI, CEUS) in visualization and interpretation can result in a mismatch of Bosniak classification. New cross-sectional imaging methods like multiphase dual energy CT with material density iodine datasets can increase readers' confidence for renal lesion detection and characterization [[32]]. Further-more, a meta-analysis of 764 patients by Lassel and colleagues showed that diffusion-weighted MRI and apparent diffusion coefficient (ADC) values can help distinguish between benign and ma-lignanttumors, potentially providing a more efficient radiologist workflow and reducing the number of unnecessarily performed interventions [[33]].

Using CEUS, patient compliance is always required and image interpretation in patients with obesity or bowel gas is still limited due to the physics of ultrasound. Besides operator-depending limitations, CEUS is a good diagnostic alternative for patients with impaired renal function without side-effects and radiation exposure [[15], [34]]. Since the effect of iodinated contrast media in renal insufficiency is well known and recently published studies describes a consistent influence on the kidney perfusion after repeated injections [[35]], we actually do not know the long term effect of gadolinium retention in brain after many injections during follow up [[36]]. CEUS has advantages over contrast-enhanced CT and MRI including unmatched temporal resolution due to continuous real-time imaging [[27]]. Based on a retrospective analysis by Barr et al. including more than 1018 renal masses CEUS can provide increased confidence that Bosniak II and IIF lesions are benign [[28], [37]]. With a high PPV and NPV of CEUS, the evaluation of cystic renal masses could decrease the need for CT, with its associated radiation, or MR imaging, with its higher costs. CEUS was cost-efficient compared to both ceCT and ceMRI in the characterization of unclear liver lesion [[27], [38]]. The use of US and especially CEUS as an additional examination method in a multimodal imaging algorithm has beneficial value in both detection and characterization of small lesions (<10 mm), while CEUS can even visualize thin septae and septal enhancement but has limitations in deeper lesions or due to obesity or bowel gas. While complex cystic renal lesions in polycystic kidneys are often an incidental finding on B-Mode US or cross-sectional imaging, combination of CEUS and ceCT/ceMRI by the use of newer image fusion techniques may increase the diagnostic performance can improve identifiability and characterization of renal tumors in a multimodal approach.

While CEUS needs a high experience for both examination and image interpretation, the need of a nationwide education in CEUS imaging leaded by experts in the field of ultrasound and CEUS is indispensable to guarantee high quality standards.

Main limitation is the small number of histopathological reports since CEUS is compared to either ceCT or ceMRI. Patients with lesions assessed by ceMRI had no additional ceCT for direct comparison. CeMRI is however regarded to be an accurate imaging tool for the assessment of cystic lesions during the last decade and widely used across imaging of cystic renal lesions avoiding radiation exposure. Diagnostic assessment and classification of the renal cysts in ceCT and ceMRI were performed by different local readers. Due to the retrospective nature of this study a more detailed presentation of the reasons for up- and downgrading is difficult. Prospective studies are necessary to evaluate exact reasons for different rating of cystic renal lesions in CEUS compared to other modalities especially gold standard CT.

This study demonstrated that the Bosniak classification in CEUS showed an excellent correlation compared to gold standard imaging ceCT. A major caveat is that applying Bosniak criteria, CEUS upgrades a percentage of lesions compared to ceCT, potential driven by the increased sensitivity of CEUS for septal enhancement. While an upgrade in CEUS might change the workup and management of cystic renal lesions, a modification of the Bosniak classification with special emphasis on septal contrast enhancement pattern in intermediate complex cystic lesions may reduce unnecessary biopsies and surgery by different scoring in CEUS as well as selecting patients for surgery who would otherwise be monitored.

All authors declare no competing interests related to the present article.

None.