Prior studies suggested [13] a significant imbalance in the incidence of CCRCC between different genders. The incidence ratio between males and females is around 2:1. This may potentially be attributed to variations in the mutational spectra seen in tumors based on patient gender, such as mutations in X chromosome-encoded genes being more common in tumors derived from male patients, while BAP1 mutations are more commonly observed in tumors in female patients. Fittschen Astrid et al. conducted a retrospective analysis of abdominal ultrasound results of 61,389 patients, [14] revealing that among 270 cases of sporadic AML, females showed a higher occurrence than males (2:1); the peak age of AML onset was between 40 and 60 years old. Furthermore, this study found a significant difference in gender between the CCRCC and AML groups. 62.0% of CCRCC patients were male, while 74.2% of AML patients were female. In addition, gender was also identified as an independent variable in subsequent regression analyses. In this study, statistically significant differences in surgical methods were observed between the CCRCC group and the AML group (all P < 0.05). In the AML group, 61.3% (19/31) of patients underwent partial nephrectomy and no patient underwent radical nephrectomy. In contrast, all patients in the CCRCC group underwent surgical treatment.
Partial nephrectomy was performed in 19 cases of AML, of which 3 cases were epithelioid AML, 7 cases were anadipotic AML, and 9 cases were AML (diameter > 5cm). Therefore, promptly and precisely distinguishing between CCRCC and AML may prevent unnecessary surgical intervention.
Ultrasound technology provides a rapid, secure, reliable, and cost-effective approach to identifying the fundamental features of the lesion, including its location, size, morphology, boundary, echoes, and blood supply. This study revealed significant differences in the US features, such as the echo of the mass and blood flow between the CCRCC group and the AML group (P < 0.05). US of AML showed a hyperechoic mass (83.9%) and inadequate blood flow in the nodule (77.4% of grade 0 and I). In contrast, the US of CCRCC was characterized by hypoechoic (68.4%) and abundant blood flow (53.2% of grade II and III blood flow). Notably, US can differentiate between benign and malignant renal lesions to a certain extent by examining the parameters of nodule echo and nodule blood flow. However, existing research [15] demonstrated that 30%-60% of small renal carcinomas show a hyperechoic lesion on US, which cannot be distinguished from the hyperechoic lesion observed in AML. In addition, many malignant tumors do not possess the distinctive features of high-velocity blood flow. Although blood flow is abundant in malignant tumors, such lesions typically manifest as low-velocity blood flow. The current limitations of conventional color ultrasound include its inability to depict low-velocity blood flow within the tumor and blood flow in deeper or smaller tumors due to the instrument conditions and tumor location.
CEUS can accurately and sensitively assess the state of blood perfusion in the microcirculation and provides real-time and dynamic information on the microvascular perfusion of tissues. The findings improve the ability to detect the lesions and differentiate between benign and malignant lesions [16]. However, the rapid perfusion of renal lesions during conventional CEUS restricts the ability to acquire blood flow signals during the arterial phase, which poses certain limitations on the diagnosis of the disease. H-CEUS is a technique that enhances the temporal resolution of images by increasing the acquisition frame rate. The technique provides a greater temporal and spatial correlation resolution for evaluating vascular enhancement, specifically in microvessels [17]. Xiang Fei et al. [18] verified that H-CEUS enhanced temporal resolution by increasing the frame rate, which was beneficial for accurately depicting the differences in microcirculation in gallbladder polypoid lesions and enhancing the ability to differentiate between cholesterol polypoid lesions and adenoma. F Giangregorio et al. [19] discovered that HiFR-CEUS demonstrated greater vascularization of focal liver lesions (FLL) in the context of liver cirrhosis in the arterial phase compared to C-CEUS. The improved temporal resolution enabled more precise measurement of the perfusion details in the arterial phase.
This study conducted a qualitative and quantitative analysis of the features of H-CEUS in two groups of patients. A comparison of the two groups of H-CEUS revealed statistically significant distinctions in the following parameters: enhancement mode, regression mode, peak intensity, enhancement uniformity, no enhancement, and the presence or absence of a pseudocapsule. H-CEUS in CCRCC was characterized by fast forward enhancement (56/79, 70.9%), slow regression (46/79, 58.2%), heterogeneity (65/79, 82.3%), high enhancement (58/79, 73.4%), accompanied by non-enhanced area (82.3%), and pseudocapsule (84.8%). In contrast, the H-CEUS of AML was characterized by slow forward enhancement (26/31, 83.9%), slow regression (31/31, 100.0%), heterogeneity (21/31, 67.7%), low enhancement (25/31, 80.6%), and often without non-enhanced area and pseudocapsule.
Enhancement mode, regression mode, enhancement uniformity, and peak intensity of the perfusion period parameters showed significant differences between the CCRCC and AML groups, according to the findings of this study. In CCRCC, the H-CEUS enhancement mode was primarily characterized by fast forward enhancement (56/79, 70.9%), slow regression (46/79, 58.2%), heterogeneity (65/79, 82.3%), and high enhancement (58/79, 73.4%). On the other hand, the H-CEUS imaging of AML cases demonstrated a slow forward enhancement (26/31, 83.9%), slow regression (31/31, 100.0%), heterogeneity (21/31, 67.7%), and low enhancement (25/31, 80.6%). The discrepancy in the imaging findings may be attributed to the rich blood supply of CCRCC. Pathologically, CCRCC is characterized by the presence of transparent tumor cells and a dense network of thin-walled capillaries in the stroma. The internal vessel density is elevated, mostly exhibiting a dendritic structure with a larger vessel diameter. The tumor often exhibits cystic cavities, necrosis, and hemorrhage foci. Therefore, H-CEUS showed a fast flow-in with high enhancement of heterogeneity. The large number of arteriovenous fistulas in the tumor promotes the rapid clearance of the contrast agent, showing rapid regression. In contrast, AML lesions have low vascular components, thin lumens, and no elastic layer in the walls, thereby displaying slow perfusion and low enhancement. Additionally, the repeated circulation of microbubbles in the complex microvascular network may contribute to the slow regression of the contrast agent [20-21]. The H-CEUS mode increased the number of image acquisitions, and the frame rate was increased to 50-65 Hz of HFR CEUS, which greatly improves the temporal resolution, and increases the image information and the contrast process, with both CCRCC and AML showing uneven enhancement. Irrespective of tumor malignancy, failure to acquire adequate nutrients for its development will result in ischemic necrosis, leading to the heterogeneity enhancement of tumor.
The H-CEUS results revealed no statistically significant difference was found in terms of the absence of enhancement and the presence of pseudocapsule between CCRCC patients and the AML patients in this study. The majority of the H-CEUS images of CCRCC exhibited no regions of enhancement (82.3%) and pseudocapsules (84.8%). In contrast, only 16.1% of AML images showed areas without enhancement, and only one case (3.2%) displayed a pseudocapsule. The difference in imaging findings may be attributed to CCRCC being a malignant tumor composed of clear or eosinophilic tumor cells with a fine vascular network inside the tumor. Cystic cavities, necrosis, and hemorrhage foci are often seen inside the tumor, which are difficult to visualize with conventional ultrasound. However, CEUS increases the contrast between the tumor tissue and the cystic cavity, necrosis, and hemorrhage foci, clearly displaying small anechoic areas, and showing no enhancement [22]. The pseudocapsule is mostly composed of fibrous tissues and a portion of the normal renal parenchyma. US typically struggles to identify the pseudocapsule due to its similarity in echo to both the tumor and the surrounding normal renal tissue. H-CEUS can clearly show the pseudocapsule, which is surrounds the tumor in a circular shape, and the enhancement time is observed to occur earlier,and the regression time later compared to the renal cortex, showing a circular high enhancement. The findings of this study indicated that the H-CEUS in the CCRCC group exhibited a greater occurrence of areas without enhancement and pseudocapsule, which aligns with prior literature studies [23].
This study further analyzed the TIC parameters of the ROI area of the lesion under the H-CEUS between the CCRCC and AML groups. The results revealed that the TIC parameter AT was lower in the CCRCC group compared to the AML group, whereas the AS was significantly higher in the CCRCC group than in the AML group. The terms AT and AS refer to arrival time and ascent slope in the perfusion period during the contrast process. These terms indicate that CCRCC has a faster forward and a higher slope of increase compared to AML. CCRCC is a highly vascularized malignant tumor characterized by extensive angiogenesis, which may account for this difference [16]. The TIC parameters PI and AUC of CCRCC were also significantly greater than in the AML group. This may be attributable to the fact that CCRCC is a lesion with an abundant blood supply and a significant number of arteriovenous fistulas. During the arterial phase, the contrast agent enters the lesion rapidly via the arteriovenous fistula, leading to a rapid accumulation of a substantial quantity of the contrast agent in the lesion [24]. In addition, although H-CEUS features enhanced the temporal resolution, it does not cause too much damage to the contrast agent, especially the reduction of the absorbtion of the contrast agent during the arterial phase, which shows high enhancement [25]. AML is a benign tumor with fewer blood vessels. Moreover, the tumor contains malformed blood vessels, irregularly thickened vessel walls, and narrow lumens, resulting in slow circulation of the contrast agent within the tumor. This leads to a reduction in the TIC curve PI and AUC [26].
Logistic regression was employed in this investigation to ascertain the independent risk factors associated with CCRCC, including gender, nodule echo, and H-CEUS parameters (pseudocapsule, AS, and AUC). Additional ROC analysis revealed that H-CEUS had a superior AUC in distinguishing between CCRCC and AML compared to the combination of gender and nodular echo. Although no significant difference in diagnostic efficiency was observed between the two, the diagnostic sensitivity and specificity achieved 87.4% and 97.5%, respectively. H-CEUS achieved the best AUC in differentiating CCRCC and AML, with a value of 0.918. H-CEUS is an ultra-wide low focal length-based nonlinear imaging technique that combines the fundamental wave, secondary harmonic, and higher harmonic signals produced by the ultrasound contrast agent to increase the frame rate and more thoroughly observe the microcirculation perfusion process of the rich blood supply lesion, thereby improving the accuracy of the contrast imaging process. In order to differentiate between CCRCC and AML, the AUC and specificity of H-CEUS were found to be superior when compared to those achieved by combing gender and nodule echo characteristics. Therefore, increasing the frame rate of H-CEUS enables a more precise differentiation between CCRCC and AML based on the different microvascular pathological characteristics of the two tumors.
Nevertheless, the limitations of this study should be acknowledged. First, the number of AML cases examined in this study was smaller than that of CCRCC, necessitating a more extensive sample size for further assessment. Secondly, a particular connection between tumor size and the process of CEUS perfusion was hypothesized. However, this study did not categorize the tumor size, tumor grade, and stage separately for the two tumors. Finally, some cases of AML were not pathologically diagnosed, which might introduce bias. In addition, different types of AML have certain differences in angiography methods of CEUS. No subgroup analysis was conducted on AML, which requires a larger sample size in future studies.
In summary, H-CEUS has higher sensitivity and specificity in the differential diagnosis of CCRCC and AML by improving the temporal resolution. This technology enables a more precise ultrasound-based diagnosis for patients with kidney tumors, guiding individualized therapy.