Compliance with ethical standards

This prospective study was approved by the Ethics Committee of the Investigator’s Hospital. The clinical trial registration number is ChiCTR2200055464. Each participant signed a written informed consent form before participating in the study.

Participants

Between December 2021 and February 2022, patients suspected of having a renal mass first detected using conventional US, CT, or MRI were scheduled for SonoVue CEUS. The inclusion criteria were as follows: (i) participants aged between 18 and 85 years, (ii) participants who planned to undergo mass resection, (iii) participants who were to undergo SonoVue CEUS for their renal masses, and (iv) participants who voluntarily participated in the study and signed informed consent for Sonazoid CEUS. The exclusion criteria were as follows: (i) patients who had a change in their treatment strategy and underwent conservative treatment; (ii) contrast-enhanced ultrasound images that did not meet our expectations because of excessive movement or the inability to breathe peacefully by the participant during the CEUS procedure; and (iii) patients who went to another hospital for surgery and were lost to follow-up. The demographic and clinical data of the participants (sex, age, height, weight, and body mass index) were recorded. All enrolled participants underwent surgical resection. The histopathological results were used as the gold standard.

Conventional US and Contrast-enhanced US examination

The conventional US and CEUS were performed by two radiologists (Y.G. and H. Z). Both radiologists were well versed in CEUS; Y.G. has more than 10 years of experience and H. Z has more than 2 years of experience in the procedure. The radiologists used the Logiq E9 system (GE Healthcare, Milwaukee, WI, USA) with a C1-6 (frequency, 1-6 MHz) broadband convex array probe equipped with amplitude modulation in contrast imaging mode.

Initial grayscale imaging and color Doppler flow imaging (CDFI) scanning were performed to determine the location, size, shape, margin, internal echogenicity, and vascularity of the masses. Optimal scanning containing both the mass and normal adjacent renal parenchyma was selected and switched to the CEUS imaging mode using amplitude-modulation technology.

Second-generation contrast agents SonoVue (Bracco SpA, Milan, Italy) and Sonazoid (GE Healthcare, Milwaukee, WI, USA) were used in this study. The mechanical index was 0.10–0.15 for SonoVue and 0.20–0.23 for Sonazoid. First, SonoVue CEUS was performed. Five milliliters of saline were injected into a bottle of the SonoVue freeze-dried powder to fully oscillate before injection, and the participants received an intravenous bolus in the antecubital vein at a dose of 1.2 mL contrast agent, followed by 5 mL of saline flush. The timer and video recorder were started directly after the injection. All participants were required to breathe calmly during the CEUS. The first 2 min was recorded continuously, and then the subsequent scans at 3,4, 5 min were intermittent acquisitions.

Sonazoid CEUS was performed on the following day. Sonazoid was used at the recommended dose of 0.6 mL and injected into the antecubital vein by the same method as SonoVue; similarly, the vascular phase was scanned and recorded in the same way as SonoVue, and then scanned continuously for 30 s at 7 min in the post vascular phase and recorded. Finally, the findings of SonoVue CEUS and Sonazoid CEUS in all participants were compared and analyzed.

Image analysis

Both CEUS examinations were analyzed independently by the two radiologists. The radiologists were blinded to the CT or MRI findings, clinical histories, and final histological results.

The research indicators of conventional US were as follows: size (<4 cm or >4 cm), shape (round/oval or irregular), margin (well defined or poorly defined), echogenicity (hyper, iso, or hypo) compared to normal adjacent renal parenchyma renal cortex, and color flow signals (rich or poor vascular) on Color Doppler Flow Imaging (CDFI). Round/oval was defined as that the shape of renal mass is spherical without nodular prominence. If it met any of the following two criteria, we determined the shape of the mass to be irregular: (i). renal mass with locally raised protrusion and smooth margin; (ii) renal mass with sharply and unsmooth nodular margin. Well defined of margin were defined as that the margin between tumor and renal parenchyma is clear; poorly defined of margin were defined as that the margin between tumor and renal parenchyma is unclear [ ]. Rich vascularity was defined as a large number of strip, ring, or “holding ball” color flow signals in the edge and interior of the renal mass, while poor vascularity was defined as no color flow or slight and star-like color flow signal in the renal mass [ ].

The research indicators for CEUS were wash-in, wash-out, pseudocapsule sign, wash-in patterns, degree of peak enhancement, and homogeneity of enhancement. The normal renal cortex adjacent to the mass was used as a control for the comparison of the degree of enhancement. The indicators were defined as follows: wash-in and wash-out were classified as fast/similar or slow, the pseudocapsule sign was defined as perilesional rim enhancement, and the wash-in patterns on CEUS was classified as either centripetal or global. Centripetal was defined as vascular filling from the periphery to the center, and global was defined as diffuse filling of vessels; the degree of mass peak enhancement was classified as hyper-, iso-, or hypo-enhancement [ ]; and the homogeneity at the time of peak enhancement was classified as homogeneous or heterogeneous. Homogeneity was defined as complete enhancement in areas of the mass without any defects, and heterogeneity was defined as a mass with unenhanced areas, regardless of the various enhancement degrees [ ].

Statistical analysis

All statistical analyses were performed using IBM SPSS Statistics for Windows, version 22.0. Continuous variables are expressed as mean values ± the standard deviation, and categorical variables are expressed as frequencies (percentages). Differences between SonoVue and Sonazoid CEUS for each enhancement feature were analyzed using McNemar’s test. Differences in enhancement features using conventional US among the four groups were analyzed using Fisher’s exact test (bilateral). The sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV) were calculated to assess the performance of SonoVue CEUS and Sonazoid CEUS for the diagnosis of ccRCC. Statistical significance was set at p < .05.

Participants and renal mass information

A total of 65 participants met the inclusion criteria. Among them, eight were excluded because the treatment strategy changed in six participants who underwent conservative treatment and two went to another hospital for surgery and were lost to follow-up. Accordingly, 57 observations in 57 participants (39 men, 18 women; mean age ± standard deviation, 55.1 y ± 1.8) were included in our study ( Fig. 1 ). The clinicopathological characteristics of the participants and target observations are described in Table 1 .

Flowchart of the study population. CEUS, contrast-enhanced ultrasonography; CT, computed tomography; MRI, magnetic resonance imaging; ccRCC, clear cell renal cell carcinoma; pRCC, papillary renal cell carcinoma.

The mean size of the observed masses was 5.8 ± 0.5 cm. Of these masses, 63.2% (36 of 57) were confirmed as ccRCC, 8.8% (5 of 57) as papillary renal cell carcinoma (pRCC), 15.8% (9 of 57) as non-ccRCC and non-pRCC malignancies, and 12.2% (7 of 57) as benign masses. Non-ccRCC and non-pRCC malignant masses included two chromophobe renal cell carcinoma (chRCCs), one squamous cell carcinoma (SCC), one mucinous tubular and spindle cell carcinoma (MTSCC), one Xp11.2 translocation/TFE3 gene fusions renal cell carcinoma (Xp11.2/TFE3 RCC), one metastatic lung adenocarcinoma (LUAD), 2 urothelial carcinomas, and one Wilms tumor. Benign masses included five angiomyolipoma (AML), one oncocytoma, and one mixed epithelial and stromal tumor of the kidney (MESTK).

Comparison of enhancement features of renal masses with SonoVue and Sonazoid

All CEUS imaging characteristics of wash-in, wash-out, pseudocapsule sign, wash-in patterns, degree of peak enhancement, and homogeneity of enhancement between SonoVue and Sonazoid in the four groups (ccRCC, pRCC, non-ccRCC and non-pRCC malignancies, and benign masses) are shown in Table 3 , Figures 2 and 3 . None of the enhancement features of the renal masses showed significant differences with the use of SonoVue or Sonazoid in the four groups ( p > .05).

Images in a 50-year-old man with a 7.0-cm diameter mass that is pathologically confirmed as SCC. (a) Conventional ultrasound demonstrate an iso-echogenic mass located in the upper pole of the left kidney (arrows). (b) CDFI show a lack of intratumoral vessel signals in the mass (arrows). (c) SonoVue CEUS imaging: the mass show a non-enhancing area with a pseudocapsule (arrows). (d) Sonazoid CEUS imaging: the mass show heterogeneous hypo-enhancement with pseudocapsule (arrows).

Images in a 74-year-old man with a 5.3-cm diameter mass that is pathologically confirmed as ccRCC. (a) Conventional ultrasound demonstrate an iso-echogenic mass located in the upper pole of the right kidney (arrows). (b) CDFI show a few pointy vascularity signals around the mass periphery (arrows). (c) SonoVue CEUS imaging: the mass show heterogeneous hyperenhancement with pseudocapsule (arrows). (d) Sonazoid CEUS imaging: the mass show heterogeneous iso-enhancement with pseudocapsule (arrows).

Comparison of conventional US and Sonazoid CEUS features among the four groups of renal masses

Conventional ultrasound and Sonazoid CEUS features of the four groups of renal masses are shown in Tables 2 and 4 . There were no significant differences in the size, shape, margin, or wash-in patterns ( p > .05). In conventional ultrasound, regarding echogenicity, the frequency of hyper-echogenicity in benign masses (7/7, 100%) was higher than that in ccRCC (6/36, 16.7%) and pRCC (1/5, 20%) ( p all <.05), and a higher percentage of hyper-echogenicity was detected in the non-ccRCC and non-pRCC malignancy groups (5/9, 55.6%) than in the ccRCC group (6/36, 16.7%) ( p all <.05). Regarding CDFI, poor vascularity was observed in all pRCC samples (5/5, 100%), whereas the main CDFI feature in ccRCC was rich vascularity (25/36, 69.4%) ( p < .05). There was no significant difference in the CDFI between the other groups ( p > .05). For the wash-in pattern, the frequencies of fast/similar in ccRCC (29/36, 80.6%) were higher than those in pRCC (1/5, 20%) and the non-ccRCC and non-pRCC malignancy groups (4/9, 44.4%) ( p all <.05). For the wash-out pattern, the frequencies of fast/similar in the ccRCC (31/36, 86.1%), non-ccRCC and non-pRCC malignancy groups (9/9, 100%) were higher than those in the benign group (3/7, 42.9%) ( p all <.05); the frequencies of fast/ similar in the pRCC (5/5, 100%) were higher than those in the ccRCC (31/36, 86.1%), benign group (3/7, 42.9%), and equal to non-ccRCC and non-pRCC malignancy groups (9/9, 100%) ( p all >0.05). A higher percentage of pseudocapsules was detected in the ccRCC (30/36, 83.3%) and pRCC (5/5, 100%) groups than in benign RCC group (2/7, 28.6%) ( p all <.05) ( Figs. 4 and 5 ). A higher percentage of pseudocapsules was detected in the ccRCC group (30/36, 83.3%) than in the non-ccRCC and non-pRCC (4/9, 44.4%) and benign RCC (2/7, 28.6%) groups ( p all <.05). Regarding the degree of peak enhancement, the frequency of hypo-enhancement in the ccRCC group (3/36, 8.3%) was lower than those in the pRCC (4/5, 80%), non-ccRCC and non-pRCC (6/9, 66.7%) groups (all p < .05) ( Fig. 4 ). The frequency of homogeneous enhancement in pRCC (4/5, 80%) was higher than that in ccRCC (2/36, 5.6%), non-ccRCC and non-pRCC malignancies (1/9, 11.1%) (all p < .05). A higher percentage of heterogeneity was detected in the ccRCC group (34/36, 94.4%) than in the benign (4/7, 57.1%) and pRCC (1/5, 20%) groups (all p < .05).

Table 2

The conventional ultrasound features of renal masses

	Size (cm)		Shape		Margin		Echogenicity			CDFI
Pathology	<4	≥4	Round/Oval	Irregular	Well defined	Poorly defined	Hyper-	Iso-	Hypo-	Rich vascular	Poor vascular
Malignant (n = 50)
ccRCC (n = 36)	13 (36.1)	23 (63.9)	22 (61.1)	14 (38.9)	27 (75)	9 (25)	6 (16.7)	14 (38.9)	16 (44.4)	25 (69.4)	11 (30.6)
pRCC (n = 5)	2 (40)	3 (60)	4 (80)	1 (20)	4 (80)	1 (20)	1 (20)	1(20)	3 (60)	0 (0)	5 (100)
Non-ccRCC and non-pRCC malignancy
chRCC (n = 2)	1 (50)	1 (50)	2 (100)	0 (0)	2 (100)	0 (0)	2 (100)	0 (0)	0 (0)	1 (100)	1 (100)
SCC (n = 1)	0 (0)	1 (100)	1 (100)	0 (0)	1 (100)	0 (0)	0 (0)	1 (100)	0 (0)	0 (0)	1 (100)
MTSCC (n = 1)	0 (0)	1 (100)	1 (100)	0 (0)	1 (100)	0 (0)	0 (0)	0 (0)	1 (100)	1 (100)	0 (0)
Xp11.2/TFE3 RCC (n = 1)	0 (0)	1 (100)	0 (0)	1 (100)	0 (0)	1 (100)	0 (0)	1 (100)	0 (0)	1 (100)	0 (0)
Metastatic LUAD (n = 1)	1 (100)	0 (0)	0 (0)	1 (100)	0 (0)	1 (100)	0 (0)	0 (0)	1 (100)	0 (0)	1 (100)
Urothelial carcinoma(n=2)	0 (0)	2 (100)	0 (0)	2 (100)	0 (0)	2 (100)	2 (100)	0 (0)	0 (0)	1 (50)	1 (50)
Wilms tumor (n = 1)	0 (0)	1 (100)	0 (0)	1 (100)	0 (0)	1 (100)	1 (100)	0 (0)	0 (0)	1 (100)	0 (0)
Benign (n = 7)
AML (n = 5)	3 (60)	2 (40)	3 (60)	2 (40)	3 (60)	2 (40)	5 (100)	0 (0)	0 (0)	0 (0)	5 (100)
Oncocytoma (n = 1)	1 (100)	0 (0)	1 (100)	0 (0)	1 (100)	0 (0)	1 (100)	0 (0)	0 (0)	1 (100)	0 (0)
MESTK (n = 1)	0 (0)	1 (100)	0 (0)	1 (100)	0 (0)	1 (100)	1 (100)	0 (0)	0 (0)	1 (100)	0 (0)

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