It is widely acknowledged that the histopathological variations within renal cell carcinoma significantly impact prognosis and tumor biology. The 5-year survival rate for ccRCC stands at only 55–60%, whereas pRCC and chRCC exhibit significantly higher rates of 80–90% [10]. Consequently, the preoperative classification of renal cell carcinoma holds substantial importance for clinical management. CEUS offers real-time and dynamic insight into microperfusion within lesions, aiding in the differentiation of malignant and benign renal lesions and enhancing the evaluation of complex renal cysts [11]. According to the literature, most ccRCC cases typically present with fast enhancement and high peak intensity, which correlates with invasiveness [12]. However, there is limited literature on the quantitative analysis of CEUS in nccRCC. This study sought to elucidate the CEUS characteristics of 21 nccRCC cases, conducting both qualitative and quantitative analyses to open new avenues for the diagnosis of this disease.

Prior studies [13] have explored CEUS characteristics in nccRCC, emphasizing that nccRCC predominantly exhibits low enhancement in peak intensity and a contrast pattern characterized by slow advancement, rapid washout, and low enhancement. In this study of 21 nccRCC patients, “slow advancement” accounted for 76.19%, low enhancement for 71.43%, and “rapid washout” for 57.14% of cases. Enhanced uniformity was observed in 61.90% of cases, with diffuse enhancement in 66.67%. This angiographic pattern, primarily displaying “slow advancement, rapid washout, and diffuse homogeneous low enhancement”, is consistent with previous research findings [14]. The primary reason behind this “slow advancement, low enhancement” pattern may be attributed to nccRCC’s typically hypovascular nature, with fewer vascular components and greater interstitial content, resulting in slow progression and limited enhancement. The “rapid washout” phenomenon may be linked to the presence of pRCC and chRCC within this nccRCC subgroup, accounting for 61.9%. These tumor types often possess an incomplete capillary network, arteriovenous fistulas, and direct arterial-to-venous blood flow, leading to faster contrast medium clearance than in the surrounding renal cortex. Additionally, nccRCC tumors tend to grow slowly, with rare occurrences of necrosis and cystic degeneration. Consequently, they appear more homogeneous when reaching their peak enhancement. Literature reports [15] suggest that the pseudocapsule results from the deposition, ischemia, or necrosis of fibrous tissue in the adjacent renal tissue during tumor growth, with circular enhancement being a common CEUS manifestation of the pseudocapsule. The contrast-enhanced pseudocapsule sign has demonstrated utility in differentiating benign and malignant renal tumors, with an AUC of 0.777 (95% confidence interval 0.701–0.853), sensitivity of 67.4%, and specificity of 88.0% [16]. However, multivariate Logistic regression analysis showed that the pseudocapsule sign is an independent predictor of RCC [16]. Zhu et al. [17] reported a significant difference in the incidence of CEUS pseudocapsule visualization among RCC patients across various tumor-size subgroups. Notably, the highest pseudocapsule visualization rate was observed in medium-sized tumors (with a diameter of 2–4 cm), reaching 79.3%. Furthermore, there was a statistical difference in the detection rate of CEUS pseudocapsules between ccRCC and nccRCC. Specifically, the detection rate of pseudocapsules in pRCC and chRCC was higher than that in ccRCC, possibly due to the distinct contrast enhancement patterns observed in different subtypes of renal cell carcinoma. pRCC and chRCC are categorized as hypovascular lesions, displaying slow progression and limited enhancement during perfusion in CEUS, followed by rapid fading. Consequently, high-echo rings could be distinctly visualized surrounding the tumor [18, 19]. However, multivariate analysis indicated that the pseudocapsule ring enhancement index is not an independent predictor for distinguishing RCC subtypes [15]. The abovementioned CEUS characteristics primarily rely on subjective qualitative analysis, are susceptible to human factors, and are characterized by subjectivity and low reproducibility.

Vuebox introduces a novel approach for quantitatively evaluating CEUS characteristics. In our study, we employed the quality of fit to assess curve fitting reliability. There were no significant differences in QOF between lesions and the normal renal cortex, and all curves had a GOF > 0.7, indicating reliable and comparable results. Time-related parameters such as RT, TTP, and FT represent the speed and quantity of contrast agent in the flushing stage, reflecting neovascularization within the mass [20]. In our study, RT, TTP, and FT for lesions were lower than those for the normal cortex, although without significant differences (P < 0.05), which might be attributed to the kidney’s single blood supply, with the tumor relying on the renal artery or accessory renal artery, similar to the normal renal cortex, resulting in no significant difference in blood flow perfusion rate. However, the perfusion time parameter mTTI within the lesion was significantly lower than that within the normal renal cortex (P < 0.05), suggesting a shorter overall perfusion time within the lesion, possibly due to the diminished blood supply in nccRCC. PE, WiAUC, WoAUC, and WiWoAUC parameters reflect microcirculation within the tumor. WiAUC, WoAUC, and WiWoAUC represent the time-intensity integral during inflow, outflow, and the combined inflow and outflow phases, respectively, offering a comprehensive and intuitive view of microvessel density within renal tumors and serving as unique quantitative Vuebox indices [21]. Our study results revealed that PE, WiAUC, WoAUC, and WiWoAUC were significantly lower within the lesion than in the normal renal cortex, indicating reduced perfusion, washout, and global blood flow within the lesion. To mitigate potential interference from PE and WiAUC caused by technical or individual variability, we further evaluated relative indicators such as WiPI, WiR, and WoR, ensuring the independence of curve parameters. Our findings showed that WiPI, WiR, and WoR within the lesions were lower than those in the normal renal cortex, with statistically significant differences. This implies reduced speed and quantity of contrast media during perfusion and washout phases within the lesion, leading to low enhancement. These results align with the qualitative analysis findings discussed earlier.

This study qualitatively and quantitatively analyzed the CEUS characteristics of nccRCC, improved the understanding of the disease, and provided a basis for clinical differential diagnosis. Ping Zhao et al. [13] showed that CEUS and contrast-enhanced magnetic resonance imaging (MRI) showed good diagnostic performance in the differential diagnosis of ccRCC and non-ccRCC, with AUC of 0.834 and 0.803 respectively, and there was no significant difference between the two methods (p = 0.54). Rong-xi Liang et al. [9] retrospectively analyzed CEUS and contrast-enhanced CT images of 82 cases with ccRCC, 24 cases with pRCC and 19 cases with ChRCC. The results showed that the enhancement patterns of CEUS and contrast-enhanced CT in the three subtypes of RCC were similar, and all of them could accurately diagnose the lesions of ccRCC, pRCC and ChRCC. Microbubble ultrasound contrast agent is a real blood pool imaging agent, which will not spread to the intercellular space, which greatly improves the sensitivity of blood flow detection at low flow rate and accurately reflects renal tumor perfusion, especially for nccRCC with lack of blood supply. Therefore, CEUS can be used as an alternative for patients with renal insufficiency or hypersensitivity to iodine contrast media that are not suitable for contrast-enhanced MRI or contrast-enhanced CT.

Indeed, the limitations of this study should be acknowledged. Firstly, this is a single-center retrospective study. Secondly, the inclusion of subjects who were pathologically confirmed after surgery may introduce selection bias. Thirdly, the sample size is relatively small, and the study did not differentiate between different subtypes of nccRCC, focusing mainly on the two most common subtypes. Additionally, rare subtypes were underrepresented in the study.