medicina

Article
Diagnostic Performance of Contrast-Enhanced
Ultrasound (CEUS) in the Evaluation of Solid
Renal Masses
Thomas Geyer 1, *, Vincent Schwarze 1 , Constantin Marschner 1 , Moritz L. Schnitzer 1 ,
Matthias F. Froelich 2 , Johannes Rübenthaler 1 and Dirk-André Clevert 1
1 Department of Radiology, Ludwig-Maximilians-University Munich, 81377 Munich, Germany;
[email protected] (V.S.); [email protected] (C.M.);
[email protected] (M.L.S.); [email protected] (J.R.);
[email protected] (D.-A.C.)
2 Institute of Clinical Radiology and Nuclear Medicine, University Medical Center Mannheim,
68167 Mannheim, Germany; [email protected]
* Correspondence: [email protected]; Tel.: +49-89-4400-73620




Received: 23 October 2020; Accepted: 17 November 2020; Published: 19 November 2020


Abstract: Background: The present study aims to evaluate the diagnostic performance of
contrast-enhanced ultrasound (CEUS) for discriminating between benign and malignant solid
renal masses. Methods: 18 patients with histopathologically confirmed benign solid renal masses
(11 oncocytomas, seven angiomyolipomas) as well as 96 patients with confirmed renal cell
carcinoma (RCC) who underwent CEUS followed by radical or partial nephrectomy were included
in this single-center study. CEUS examinations were performed by an experienced radiologist
(EFSUMB Level 3) and included the application of a second-generation contrast agent. Results: Renal
angiomyolipomas, oncocytomas, and renal cell carcinomas showed varying sonomorphological
characteristics in CEUS. Angiomyolipomas showed heterogeneous echogenicity (57% hypo-,
43% hyperechoic), while all lesions showed rapid contrast-enhancement with two lesions also showing
venous wash-out (29%). Notably, 9/11 oncocytomas could be detected in conventional ultrasound
(64% hypo-, 9% hyper-, 9% isoechoic) and 2/11 only demarcated upon intravenous application of
contrast agent (18%). All oncocytomas showed hyperenhancement in CEUS, venous wash-out was
registered in 7/11 lesions (64%). Conclusions: In line with the current state of knowledge, no specific
sonomorphological characteristics allowing for accurate distinction between benign and malignant
solid renal masses in CEUS could be detected in our study.

Keywords: CEUS; contrast-enhanced ultrasound; renal cell carcinoma; renal oncocytoma;

renal angiomyolipoma; solid renal mass

1. Introduction
In recent decades, the number of unclear renal lesions incidentally detected on cross-sectional
imaging or ultrasound has grown along with the more widespread use of medical imaging [1–3].
Conventional B-mode ultrasound is the most frequently used imaging modality for the initial
classification of kidney lesions and allows for discriminating between cystic and solid renal lesions.
Complicated renal cysts require dedicated contrast-enhanced computed tomography (CE-CT) or
magnetic resonance imaging (MRI) for definitive characterization and the diagnosis of renal cell
carcinoma (RCC) [4,5].
Recently, the use of contrast-enhanced ultrasound (CEUS) has established itself as a well-tolerated,
highly accurate, and cost-effective imaging modality for diagnosing RCC [6–8]. CEUS represents

Medicina 2020, 56, 624; doi:10.3390/medicina56110624 www.mdpi.com/journal/medicina

Medicina 2020, 56, 624 2 of 8

a valuable alternative for characterizing indeterminate renal lesions especially in patients with
decreased kidney function or allergic predispositions to gadolinium- or iodine-based contrast agents [5].
Unlike contrast-enhanced CT or MRI, ultrasound contrast agents remain confined to the intravascular
system and can be used regardless of the renal or thyroid function [9,10].
In certain cases, however, differentiating benign solid renal masses from RCC remains a challenge.
Renal oncocytoma, a benign parenchymal tumor with an incidence of 4–7% among all primary renal
neoplasms [11], is known for its imaging characteristics similar to RCC in CE-CT [12], MRI [13],
and CEUS [14–16]. Similar difficulties in the distinction between lipid-poor angiomyolipoma and
renal cell carcinoma have been reported by several studies [17–20]. Since treatment recommendations
and further patient management for renal oncocytoma or angiomyolipoma differ significantly from
those for renal cell carcinoma [5], patients could benefit strongly from an adequate radiological
differential diagnosis.
Our study aimed to evaluate the diagnostic performance of CEUS of solid renal masses and
potentially identify imaging features that might allow for distinguishing between benign and malignant
solid renal lesions in the future.

2. Materials and Methods

Our retrospective single-center study was approved by the local institutional ethical committee of
the institutional review board (Ethics Committee, Medical Faculty, Ludwig Maximilian University
of Munich; 17-087; date of approval: 14 March 2017). All contributing authors followed the ethical
guidelines for publication in Medicina. All data used for this study were gathered according to the
principles of the Declaration of Helsinki/Edinburgh in 2002. Before the CEUS examination, oral
and written informed consent of all patients was obtained after potential risks and complications
had been explained in detail. All examinations were performed by one experienced consultant
radiologist (European Federation of Societies for Ultrasound in Medicine and Biology Level 3) using
high-end ultrasound systems with CEUS-specific protocols (GE Healthcare LOGIQ E9, Chicago,
IL, USA, Philips EPIQ7, Seattle, Washington, USA, Siemens Ultrasound Sequoia S20000, S3000,
ACUSON Sequoia, Mountain View, CA, USA). A low mechanical index (<0.2) was used in all patients
to prevent the unintentional destruction of microbubbles. All CEUS examinations included the
intravenous application of 1.0–2.4 mL of a second-generation contrast agent (SonoVue® , Bracco, Milan,
Italy). The application of SonoVue® was followed by 5–10 mL sterile 0.9% sodium chloride solution.
No side-effects upon intravenous administration of SonoVue® were observed.
All examinations included native B-mode to assess tumor size, localization, shape, and echogenicity,
Color Doppler to evaluate tumor vascularization, and CEUS to evaluate the dynamic contrast
enhancement patterns of the lesions compared to the renal parenchyma. To determine enhancement
patterns upon intravenous application of SonoVue® , the lesions were evaluated during the cortical
phase (8–35 s after intravenous injection), the corticomedullary phase (36–120 s after injection), and the
late phase (>120 s after injection to the disappearance of microbubbles). After the injection of SonoVue® ,
cine-loops were created and archived in our institutional picture archiving and communication system
(PACS). Image quality was sufficient in all CEUS examinations. Radiologic reports were created by the
examiner immediately after performing CEUS without knowledge of the histopathological results.
We searched our local database for patients with suspicious renal lesions who underwent CEUS
at our University Hospital. Between 2009 and 2019, 2417 patients with solid renal masses were
examined. In 114 patients, CEUS was followed by either biopsy or radical or partial nephrectomy in
our institutional department of urology and histopathological analysis in our institutional department
of pathology. We included these 114 patients who underwent CEUS and subsequent histopathological
analysis in this study.
Statistical analysis was performed using IBM SPSS Statistics Version 25 (Armonk, NY, USA).
The mean and the standard deviation (SD) were calculated for normally distributed data.
Chi-squared test was performed for qualitative comparison of sonomorphologic features in native
Medicina 2020, 56, 624 3 of 8

B-mode, Color Doppler, and CEUS in benign vs. malignant lesions. Statistical tests were considered
significant for p-values < 0.05.

3. Results
We included 18 patients (16%) with histopathologically confirmed benign lesions: 11 patients
(10%) with oncocytoma and seven patients (6%) with angiomyolipoma. The mean age of this group
at the time of the CEUS examination was 66 years (SD: ± 13 years; range: 32–81 years) with a male
predominance (12 men (11%) and six women (5%), ratio: 2:1). The mean diameter of the confirmed
angiomyolipomas was 2.2 cm (SD: ± 0.8 cm; range: 1.2–3.4 cm). The mean diameter of the confirmed
oncocytomas was 2.3 cm (SD: ± 1.3 cm; range: 1.2–5.5 cm).
Ninety-six patients (84%) with histopathologically confirmed renal cell carcinoma were included
in this study: 47 patients (41%) with clear cell renal cell carcinoma (CCRCC), 42 patients (37%) with
papillary renal cell carcinoma (PRCC), and 7 patients (6%) with chromophobe renal cell carcinoma
(ChRCC). The mean age of these patients at the time of the CEUS examination was 64 years
(SD: ± 12 years; range: 25 to 85 years). We included 79 male (69%) and 17 female (15%) patients
(ratio: 4.6:1). The mean lesion size was 3.3 cm (SD: ± 1.7 cm; range: 0.7–10.0 cm).
Supplementary Table S1 illustrates the varying sonomorphological characteristics of
renal oncocytomas and angiomyolipomas. No significant statistical differences between the
sonomorphological features of benign vs. malignant lesions could be detected (Table 1). In native
B-mode, oncocytomas presented as hypoechoic in seven cases (64%), as hyperechoic in one case (9%),
and as isoechoic in one case (9%). Two lesions could not be detected in native B-mode and Doppler
mode but demarcated upon intravenous application of SonoVue® showing rapid contrast-enhancement
(18%). Only three lesions showed slight hypervascularization in Doppler mode (27%). In all patients
with histopathologically confirmed oncocytoma, early contrast-enhancement upon application of
SonoVue® could be detected (100%) (Figure 1). Seven of those lesions also showed venous wash-out
(64%).

Table 1. Comparison of sonomorphologic characteristics of benign (n = 18) and malignant (n = 96)

renal lesions in absolute numbers and percentages in parentheses.

Benign Malignant p-Value

B-mode
Echogenicity
Hyperechoic 4 (22) 14 (15) 0.41
Hypoechoic 11 (61) 63 (66) 0.71
Isoechoic 1 (6) 14 (15) 0.30
Inhomogeneous 2 (11) 5 (5) 0.34
Color Doppler
Hypervascularization
Yes 4 (22) 12 (13)
0.28
No 14 (78) 84 (88)
CEUS
Arterial hyperenhancement
Yes 18 (100) 96 (100)
1
No 0 (0) 0 (0)
Venous wash-out
Yes 9 (50) 51 (53)
0.81
No 9 (50) 45 (47)
CEUS: contrast-enhanced ultrasound.

In 4/7 patients with confirmed angiomyolipoma, the lesions presented as hypoechoic in

native B-mode (57%) and in 3/7 patients as hyperechoic (43%). Only one lesion showed slight
hypervascularization in Doppler mode (14%). All lesions showed rapid contrast-enhancement (100%)
(Figure 2), whereas only two lesions also showed venous wash-out (29%).
Medicina 2020, 56, 624 4 of 8
Medicina 2020, 56, x FOR PEER REVIEW 4 of 9

(a) (b)

(c)
Figure 1. Renal oncocytoma in the right kidney with a diameter of 1.2 cm. (a) In native B-mode, the
Figure 1. Renal oncocytoma in the right kidney with a diameter of 1.2 cm. (a) In native B-mode, the lesion
lesion presents as slightly hyperechoic (yellow arrow); (b) the lesion shows discrete vascularization
presents in
asDoppler
slightlymode.
hyperechoic
(c) Upon(yellow arrow);
intravenous (b) theoflesion
application shows
SonoVue ®, thediscrete vascularization
lesion shows no signs of in Doppler
mode.Medicina
(c) 2020, 56, x FOR PEER REVIEW
Upon intravenous application of SonoVue ® , the lesion shows no signs of hyperenhancement.
5 of 9
hyperenhancement.

In 4/7 patients with confirmed angiomyolipoma, the lesions presented as hypoechoic in native
B-mode (57%) and in 3/7 patients as hyperechoic (43%). Only one lesion showed slight
hypervascularization in Doppler mode (14%). All lesions showed rapid contrast-enhancement (100%)
(Figure 2), whereas only two lesions also showed venous wash-out (29%).

(a) (b)

(c) (d)
Figure 2. An 81-year-old patient with an unclear lesion in the right kidney incidentally detected in
Figure 2. An 81-year-old patient with an unclear lesion in the right kidney incidentally detected in
contrast-enhanced computed tomography (CT). (a) In native B-mode, an inhomogeneously
contrast-enhanced computed tomography (CT). (a) In native B-mode, an inhomogeneously hyperechoic
hyperechoic lesion with a diameter of 2.5 cm could be registered (right picture, yellow arrow). In the
lesion withcorresponding
a diameter of 2.5 cm could be
contrast-enhanced CTregistered (right
scan (a, left picture,
picture, yellowyellow arrow).
arrow), In the
the lesion corresponding
presents
contrast-enhanced
hypodenseCT with scan
only(a,
lowleft picture, yellow arrow),
contrast-enhancement; the vascularization
(b) no major lesion presents hypodense
could be visualizedwith
in only low
Doppler mode (right
contrast-enhancement; (b) nopicture,
majorred arrow). (c) CEUScould
vascularization showsbea rapid hyperenhancement
visualized in Dopplerofmode the lesion
(right picture,
(right picture, red arrow); (d) no wash-out in the late phase was registered (right picture, red arrow).
red arrow). (c) CEUS shows a rapid hyperenhancement of the lesion (right picture, red arrow);
The patient underwent partial nephrectomy, the results of the histopathological analysis revealed
(d) no wash-out in the
benign renal late phase was registered (right picture, red arrow). The patient underwent
angiomyolipoma.
partial nephrectomy, the results of the histopathological analysis revealed benign renal angiomyolipoma.
The heterogeneous sonomorphological features of the different histological subtypes of RCC are
depicted in Supplementary Table S2. The majority of the CCRCC lesions presented as hypoechoic
(33/47, 70%) compared to six hyperechoic lesions (13%) and five isoechoic lesions (11%). One lesion
was iso-/hypoechoic (2%) and two lesions presented as hyper-/hypoechoic (4%). The PRCC lesions
were hypoechoic in 27/42 cases (64%), hyperechoic in 8/42 cases (19%), and isoechoic in 5/42 cases
(12%). One PRCC lesion could only be detected upon intravenous contrast application (2%) and one
patient with bilateral PRCC presented with a hyperechoic lesion on the left and an isoechoic lesion
on the right side (2%). Notably, 3/7 ChRCC lesions were hypoechoic (43%) compared to 4/7 isoechoic
lesions (57%). Hypervascularization in Doppler Mode was detected in 7/47 CCRCC lesions (15%), in
Medicina 2020, 56, 624 5 of 8

The heterogeneous sonomorphological features of the different histological subtypes of RCC are
depicted in Supplementary Table S2. The majority of the CCRCC lesions presented as hypoechoic
(33/47, 70%) compared to six hyperechoic lesions (13%) and five isoechoic lesions (11%). One lesion
was iso-/hypoechoic (2%) and two lesions presented as hyper-/hypoechoic (4%). The PRCC lesions
were hypoechoic in 27/42 cases (64%), hyperechoic in 8/42 cases (19%), and isoechoic in 5/42 cases (12%).
One PRCC lesion could only be detected upon intravenous contrast application (2%) and one patient
with bilateral PRCC presented with a hyperechoic lesion on the left and an isoechoic lesion on the right
side (2%). Notably, 3/7 ChRCC lesions were hypoechoic (43%) compared to 4/7 isoechoic lesions (57%).
Hypervascularization in Doppler Mode was detected in 7/47 CCRCC lesions (15%), in 2/42 PRCC
lesions (5%), and 3/7 ChRCC lesions (43%). All 96 RCC lesions showed early enhancement upon
application of contrast medium (Figure 3). Venous wash-out could be detected in 18/47 CCRCC lesions
Medicina 2020, 56, x FOR PEER REVIEW 6 of 9
(38%), in 27/42 PRCC lesions (64%), and 6/7 ChRCC lesions (86%).

(a) (b)

(c) (d)

Figure 3.
Figure 3. (a)
(a)Hyperechoic
Hyperechoic renal lesion
renal with
lesion witha diameter
a diameterof 1.6ofcm
1.6visualized in native
cm visualized in B-mode (yellow
native B-mode
arrow); arrow);
(yellow (b) only(b)slight
onlyvascularization was registered
slight vascularization in Doppler
was registered in mode
Doppler(yellow
modearrow).
(yellow(c,d) The
arrow).
lesion did not show hyperenhancement during the early (c, yellow arrow) and late
(c,d) The lesion did not show hyperenhancement during the early (c, yellow arrow) and late phase phase (d, yellow
arrow).
(d, yellowHistopathological results showed
arrow). Histopathological resultsa showed
clear-cella renal cell carcinoma.
clear-cell renal cell carcinoma.

4.
4. Discussion
Discussion
Non-invasive
Non-invasive diagnosis
diagnosis of
of benign
benign solid
solid renal
renal masses
masses remains
remains challenging
challenging since
since lesions
lesions such
such as
as
oncocytoma and lipid-poor angiomyolipoma often show imaging features similar to RCC.
oncocytoma and lipid-poor angiomyolipoma often show imaging features similar to RCC. Our study Our study
aimed
aimedto
tocompare
comparethe
theimaging
imagingcharacteristics
characteristicsof
ofbenign
benignand
andmalignant
malignantsolid
solidrenal
renalmasses
massesininCEUS.
CEUS.
Our findings are consistent with the current state of knowledge. Several previous studies
reported difficulties in the differentiation between RCC and oncocytoma using CEUS. Haendl et al.
[21] described the contrast-enhancement patterns of three oncocytomas: two lesions showed arterial
hypervascularization followed by venous wash-out, whereas one lesion was hypovascular during
the arterial and late phase. Tamai et al. [22] evaluated 29 patients with solid renal lesions using CEUS:
two patients had an oncocytoma showing arterial hypervascularization which made them difficult
Medicina 2020, 56, 624 6 of 8

Our findings are consistent with the current state of knowledge. Several previous studies
reported difficulties in the differentiation between RCC and oncocytoma using CEUS. Haendl et al. [21]
described the contrast-enhancement patterns of three oncocytomas: two lesions showed arterial
hypervascularization followed by venous wash-out, whereas one lesion was hypovascular during the
arterial and late phase. Tamai et al. [22] evaluated 29 patients with solid renal lesions using CEUS:
two patients had an oncocytoma showing arterial hypervascularization which made them difficult to
differentiate from RCC. Gerst et al. [23] prospectively evaluated the imaging characteristics of benign
and malignant renal lesions by CEUS, and all three oncocytomas included in this study presented as
hyperechoic. Two lesions showed rapid contrast-enhancement and venous wash-out, whereas one
oncocytoma showed a continuing hypoenhancement. The oncocytomas evaluated in the present
study also showed various echogenicity (64% hypo-, 9% hyper-, 9% isoechoic) with rapid contrast
enhancement in all lesions and venous wash-out in 7/11 lesions (64%). The imaging characteristics in
our study are thus similar to the findings of these previous studies.
Similar difficulties in the discrimination between angiomyolipoma and RCC have been reported
by previous studies. In the prospective study of Ascenti et al. [24], angiomyolipomas showed a wide
range of characteristics concerning contrast enhancement, and the additional use of a contrast agent
did not lead to higher diagnostic accuracy compared to conventional ultrasound. Other studies,
however, identified imaging characteristics that might help discriminate angiomyolipoma from RCC.
A retrospective study including 33 patients with angiomyolipoma and 93 patients with RCC identified
venous wash-out as a feature highly suggestive of RCC (71%), which allows for differentiation from
angiomyolipoma (3%) [25]. In our study, only 29% of angiomyolipomas showed venous wash-out
compared to 64% of oncocytoma and 53% of RCC. Due to varying results of previous studies and our
small sample size of patients with angiomyolipoma, further studies with larger patient cohorts will be
necessary to evaluate the imaging characteristics of angiomyolipoma in CEUS and potentially detect
reliable features which allow for safe discrimination from RCC.
Since the diagnostic accuracy of contrast-enhanced imaging for differentiation between RCC and
oncocytoma or angiomyolipoma is limited, the common treatment pathway of unclear solid renal masses
frequently includes surgery in the form of radical or partial nephrectomy [5]. Henderson et al. [26]
evaluated the perioperative outcomes of 6042 patients with both malignant and benign renal lesions
who underwent nephrectomy in the UK, and major complications were recorded in 3.9% of all
patients. Therefore, it seems desirable to allow for non-invasive diagnosis of oncocytoma or
angiomyolipoma. The use of biomarkers, such as microRNAs, offers a promising approach for
non-invasive characterization of unclear renal masses [27,28]. Further studies with a focus on the
diagnostic accuracy of these biomarkers are needed in the future.
The use of CEUS for assessing unclear renal lesions brings substantial advantages. CEUS is a safe
imaging modality for patients with decreased renal function, hyperthyroidism, allergic predispositions
to gadolinium- or iodine-based contrast agents, or contradictions for MRI, such as metallic foreign
bodies [5,9,10]. Since CEUS is a non-ionizing imaging technique, its use allows for reducing
exposure to ionizing radiation compared to CT. Furthermore, recent studies have described the
safe application of CEUS, even in pregnant women and children [29,30]. Additionally, CEUS offers a
cost-effective diagnostic approach compared to MRI [8] and could therefore reduce costs associated
with medical imaging.
Several possible limitations of our study should be considered. First, this was a retrospective
single-center study and all patients were examined by only one experienced radiologist. Second,
a small number of patients with oncocytoma (n = 11) and angiomyolipoma (n = 7) were included.
Finally, the sample size of the different histological subtypes of RCC varied with only a small number
of patients with ChRCC (n = 7) compared to CCRCC and PRCC.
In conclusion, our study could not determine a specific sonomorphological feature allowing for
accurate differentiation between benign and malignant solid renal masses by CEUS. Our findings
are in line with several previous studies investigating the diagnostic performance of CEUS in the
Medicina 2020, 56, 624 7 of 8

evaluation of malignant renal lesions and benign lesions such as oncocytoma or angiomyolipoma.
Since the diagnostic workup of benign solid renal lesions often includes surgery associated with
potential complications, further studies with a focus on imaging characteristics in larger patient cohorts,
as well as other potential non-invasive diagnostic procedures such as biomarkers, are required.

Supplementary Materials: The following are available online at http://www.mdpi.com/1010-660X/56/11/624/s1,

Supplementary Table S1: Sonomorphological characteristics of benign renal lesions, Supplementary Table S2:
Sonomorphological characteristics of malignant renal lesions.
Author Contributions: Conceptualization, T.G., J.R. and D.-A.C.; methodology, T.G., J.R. and D.-A.C.;
formal analysis, T.G. and D.-A.C.; investigation, T.G., V.S., C.M., M.L.S., M.F.F., J.R., and D.-A.C.; resources,
T.G., J.R. and D.-A.C.; data curation, T.G.; M.L.S., J.R., D.-A.C.; writing—original draft preparation, T.G., V.S.;
writing—review and editing, T.G., V.S., C.M., M.L.S., M.F.F., J.R., and D.-A.C.; visualization, T.G. and D.-A.C.;
supervision, T.G., V.S., J.R. and D.-A.C.; project administration, T.G., J.R. and D.-A.C. All authors have read and
agreed to the published version of the manuscript.
Funding: This research received no external funding.
Conflicts of Interest: The authors declare no conflict of interest.

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