Renal Cell Carcinoma and Renal Angiomyolipoma

Transcription

1 Article Renal Cell Carcinoma and Renal Angiomyolipoma Differential Diagnosis With Real-time Contrast-Enhanced Ultrasonography Zuo-Feng Xu, MD, PhD, Hui-Xiong Xu, MD, PhD, Xiao-Yan Xie, MD, PhD, Guang-Jian Liu, MD, Yan-Ling Zheng, MD, Ming-De Lu, MD, DMSc Abbreviations CECT, contrast-enhanced computed tomography; CEUS, contrast-enhanced ultrasonography; CHI, contrast harmonic imaging; CPS, contrast pulse sequencing; CT, computed tomography; MI, mechanical index; MRI, magnetic resonance imaging; NPV, negative predictive value; PPV, positive predictive value; RAML, renal angiomyolipoma; RCC, renal cell carcinoma; UCA, ultrasonographic contrast agent Received October 8, 2009, from the Department of Medical Ultrasonics, First Affiliated Hospital, Institute of Diagnostic and Interventional Ultrasound, Sun Yat-sen University, Guangzhou, China. Revision requested November 16, Revised manuscript accepted for publication December 14, This work was supported in part by grant B from the Guangdong Health Department and grant of the Public Welfare Research Special Project from the Chinese Ministry of Health. Address correspondence to Hui-Xiong Xu, MD, PhD, Department of Medical Ultrasonics, First Affiliated Hospital, Institute of Diagnostic and Interventional Ultrasound, Sun Yat-sen University, 58 Zhongshan Rd 2, Guangzhou, China. Objective. The purpose of this study was to evaluate the usefulness of contrastenhanced ultrasonography (CEUS) in differentiating renal cell carcinoma (RCC) from renal angiomyolipoma (RAML). Methods. One hundred nineteen patients with 126 renal lesions (33 RAMLs and 93 RCCs) who had undergone CEUS were retrospectively studied. All of the lesions were histopathologically or clinical proved. Contrastenhanced ultrasonography was performed using low acoustic power modes and a sulfur hexafluoride filled microbubble contrast agent. The baseline sonograms and CEUS images were retrospectively analyzed in consensus by 2 radiologists. The tumor echogenicity, enhancement patterns, and degree of enhancement at different phases were evaluated. The diagnostic efficacy of CEUS in differentiating the two diseases was computed and compared. Results. On CEUS, the features of wash-out from hyperenhancement or isoenhancement to hypoenhancement over time (observed in 3.0% of RAMLs and 71.0% of RCCs; P <.001), heterogeneous enhancement (observed in 12.1% of RAMLs and 74.2% of RCCs; P <.001), and an enhanced perilesional rim (observed in 3.0% of RAMLs and 79.6% of RCCs; P <.001) achieved significant difference between RCCs and RAMLs. Early wash-out and heterogeneous enhancement or peritumoral rim enhancement yielded the highest diagnostic capability in differentiating RCC from RAML. The corresponding sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 88.2% (82 of 93), 97.0% (32 of 33), 98.8% (82 of 83), 74.4% (32 of 43), and 90.5% (114 of 126), respectively. Conclusions. The CEUS features of early wash-out, heterogeneous enhancement, and an enhanced peritumoral rim highly suggest RCC, whereas homogeneous enhancement and prolonged enhancement are characteristic manifestations of RAML. Contrast-enhanced ultrasonography is valuable in differentiating RCC from RAML. Key words: contrast-enhanced ultrasonography; differential diagnosis; renal angiomyolipoma; renal cell carcinoma; ultrasonography. Renal cell carcinoma (RCC) and renal angiomyolipoma (RAML) are the frequently encountered solid renal tumors and respectively represent the most common malignant and benign tumors of the kidney. The treatment strategies and prognoses for the two entities are quite different; thus, differential diagnosis between them is important. 1, by the American Institute of Ultrasound in Medicine J Ultrasound Med 2010; 29: /10/$3.50

2 Renal Cell Carcinoma and Renal Angiomyolipoma on CEUS Conventional ultrasonography is noninvasive, convenient, and inexpensive and is the choice of imaging modality in the evaluation of renal diseases. However, on baseline ultrasonography, approximately 30% of RCCs appear as hyper echoic masses, as do RAMLs, and atypical iso echoic or hypoechoic and slightly hyper - echoic RAMLs account for 6% and 29% of all RAMLs, respectively. 3 5 The usefulness of baseline ultrasonography in the clinic is limited because it is hard to differentiate these tumors solely on the basis of their echogenicity. Patients have to be referred for further examinations such as contrast-enhanced computed tomography (CECT) and contrast-enhanced magnetic resonance imaging (MRI) for confirmation. Computed tomography (CT) remains the most appropriate imaging modality for differentiating benign from malignant lesions; the sensitivity and specificity of CT for the differentiation of RCC from other subtypes of renal tumors have been reported as 74% and 100%, and 84% and 91%, respectively. 6 Recently, the development of ultrasonographic contrast agents (UCAs) and contrast-specific imaging techniques has enabled wide use of contrast-enhanced ultrasonography (CEUS) in the liver. The substantially improved ability in depicting both the microcirculation and macrocirculation may also be beneficial in evaluating focal renal lesions. In addition, given the fact that UCAs are relatively harmless with a low incidence of side effects and are not nephrotoxic, CEUS can be used in patients with iodine allergies, impaired renal function, and urinary tract obstruction, which may be contraindications to contrast-enhanced CT or MRI. 7 Although potentially a very useful imaging tool, CEUS is yet not widely used in the evaluation of renal tumors, but it has been proven that CEUS is helpful for differentiating renal pseudo tumors from true renal masses, and CEUS is better than CECT in showing intralesional vascularity and the tumoral pseudocapsule 8 10 In this study, the CEUS features of RCCs and RAMLs were retrospectively evaluated, and the diagnostic efficacy based on the major CEUS features was computed and compared. Materials and Methods Patients Between September 2004 and November 2008, 167 patients with a diagnosis of focal renal lesions on baseline ultrasonography underwent CEUS in our institution. The interval between CEUS and baseline ultrasonographic examinations was no more than 1 week. Among them, 90 patients (93 lesions) with histopathologically proven RCCs (biopsy, n = 3; resection, n = 82) and 29 patients (33 lesions) with histopathologically proven RAMLs (biopsy, n = 8; resection, n = 21) were retrospectively enrolled in the study. The remaining 48 patients were excluded because of the following reasons: (1) no definite final diagnoses (n = 10); and (2) other final diagnoses in 38 patients, including renal metastasis in 7, complex cysts in 10, Bertin columns in 7, renal pelvic carcinoma in 5, renal abscesses in 6, a Wilms tumor in 1, renal adenoma in 1, and a malignant lobus intermedius tumor in 1. The 119 patients included 80 men and 39 women with a mean age ± SD of 42.9 ± 11.9 years (range, years). The diagnoses of 93 RCC lesions were confirmed by means of surgery (n = 89) or ultrasonographically guided biopsy (n = 4), including 72 clear cell carcinomas, 11 papillary carcinomas, 5 mixed cell carcinomas, 4 granular cell carcinomas, and 1 chromophobe cell carcinoma. The diagnoses of 33 RAMLs were confirmed by means of surgery (n = 25) or clinical data (n = 8; history, evidence of an intratumoral fat component on CT or MRI, and unchanged size and echogenicity for at least 2 years of followup). 10 Patients with serious cardiopulmonary diseases, pregnancy, or lactation were excluded from this study. Informed consent was obtained from all patients, and the study was approved by the Ethical Committee of the hospital. Eighty-eight patients with RCC and 25 with RAML had a single nodule in each, and the remaining 6 patients had multiple nodules in each. In patients with multiple nodules, 1 patient with RCC had 2 masses (1 in each kidney), and the other patient with RCC had 3 nodules in her left kidney. Four patients with RAML had 2 nodules in 1 kidney in each. Every nodule visualized on baseline ultrasonography was selected for CEUS; therefore, a total of 126 nodules were observed; 33 lesions were RAMLs (mean diame- 710 J Ultrasound Med 2010; 29:

3 Xu et al ter, 3.7 cm; range, cm), and 93 were RCCs (mean diameter, 4.2 cm; range, cm). Equipment and UCA The ultrasound equipment used in this study included 2 ultrasound machines. One was an Acuson Sequoia 512 scanner (Siemens Medical Solutions, Mountain View, CA) equipped with a 4V1 vector transducer with a frequency range of 1.0 to 4.0 MHz and contrast-specific contrast pulse sequencing (CPS) software, and the other was an Aplio XV machine (Toshiba Medical Systems, Co, Ltd, Tokyo, Japan) equipped with a 375BT convex transducer with a center frequency of 3.75 MHz and the contrast harmonic imaging (CHI) contrast-specific imaging mode. Most patients (n = 97) in this study were scanned with the Sequoia machine, and the remaining 22 were examined with the Aplio machine. The machines were chosen on the basis of availability. The UCA used in this study was SonoVue (Bracco SpA, Milan, Italy), a sulfur hexafluoride (SF6) filled microbubble UCA that is stabilized by phospholipids. A total of 2.4 ml of SonoVue was injected into the antecubital vein in a bolus fashion through a 20-gauge intravenous cannula (Venflon; Becton Dickinson, Helsingborg, Sweden), followed by a flush of 5 ml of a 0.9% sodium chloride solution. In the patients with multiple nodules, repeated injection of 2.4 ml of SonoVue was performed with an interval of greater than 6 minutes. The total dose was no more than 4.8 ml in each patient. Contrast-Enhanced Ultrasonography Baseline ultrasonography of the kidney was initially performed to target the tumor. The imaging settings such as gain, depth, and focal zone were optimized. Generally, a single focal zone was placed at the bottom of the lesion. The transducer was kept in a stable position, and the CPS or CHI function was then initiated. In the contrastenhanced study, low mechanical index (MI) values were used ( for CPS and for CHI). The timer was activated simultaneously at the beginning of SonoVue administration. If the target tumor was small, a dual-display mode was used, in which the tissue and contrast signals were displayed on the same screen. The tumor was observed continuously for at least 3 minutes until clearance of the UCA from the renal parenchyma. The vascular phases of CEUS were classified into cortical (8 15 to seconds after UCA injection), corticomedullary (36 41 to 120 seconds), and late (>120 seconds to the disappearance of bubbles). 7 9,11 Digital cine clips of typical baseline sonograms and whole-process CEUS images were stored in the hard disks incorporated in the scanners for subsequent analysis. Image Analysis The baseline sonograms and CEUS images were retrospectively analyzed in consensus by 2 radiologists who both had at least 4 years of experience in renal CEUS. Both readers were not involved in the ultrasonographic and CEUS scanning and were blinded to any other clinical, pathologic, or imaging findings. The parameters described below were evaluated and recorded: tumor echogenicity (ie, hypoechoic, isoechoic, or hyperechoic) on baseline ultrasonography, the initial enhancement time of the tumor and renal cortex, the enhancement pattern and degree of tumor enhancement, and the dynamic change of the enhancement from the cortical phase to the late phase on CEUS. The contrast enhancement patterns were classified as follows: (1) no enhancement, ie, no appearance of microbubble signals in the lesion; (2) homogeneous enhancement, ie, uniform enhancement; and (3) heterogeneous enhancement, ie, different enhancement extents within the lesion. 12 When a tumor showed heterogeneous enhancement, the area with the highest enhancement was used for determination of the enhancement extent. In comparison with the adjacent renal cortex, the enhancement degree of the tumor was classified as hyperenhancement, isoenhancement, hypoenhancement, and nonenhancement. Perilesional rim enhancement (ie, the so-called pseudocapsule) was recorded, which was defined as an enhanced rim of peritumoral tissue that appeared in the cortical phase and became distinct in the late phase. 13 After the image analysis, the notable enhancement features that were mostly found in RCCs were selected. The value of each feature, as well as the various combinations of them, in differentiating diagnosis between RCCs and RAMLs, was J Ultrasound Med 2010; 29:

4 Renal Cell Carcinoma and Renal Angiomyolipoma on CEUS calculated. The diagnostic performance parameters included sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy. Statistical Analysis The statistical analysis was performed using the SPSS 13.0 software package (SPSS Inc, Chicago, IL). Continuous data are expressed as mean ± SD. A Fisher exact or χ 2 test was used to compare RAMLs and RCCs in terms of the homogeneity of tumor enhancement and enhancement pattern on CEUS. An independent-sample t test was applied to compare the differences in the enhancement time between tumors and the renal cortex. P <.05 was considered to indicate a statistically significant difference. Results Enhancement Timing of Tumors and the Renal Cortex on CEUS The intervals between the start of SonoVue injection and initial enhancement of the 93 RCCs and the adjacent renal cortex were 12.1 ± 3.0 seconds (range, 6 20 seconds) and 12.2 ± 3.2 seconds (range, 6 24 seconds), respectively (P >.05), and those for the 23 RAMLs and the adjacent renal cortex were 12.5 ± 3.3 seconds (range, 7 23 seconds) and 13.2 ± 2.8 seconds (range, 8 19 seconds; P >.05). There was no significant difference between the two groups in the timing of enhancement when compared with that of the renal cortex. The numbers of lesions that showed earlier enhancement, simultaneous enhancement, and later enhancement were 0 (0%), 28 (84.8%), and 5 (15.2%) for RAMLs and 2 (2.2%), 79 (84.9%), and 12 (12.9%) for RCCs (P >.05). Tumor Enhancement Extent and Pattern on CEUS The tumor enhancement degree and pattern are summarized in Tables 1 and 2. During the cortical phase, there was no significant difference in the enhancement degree between RAMLs and RCCs (P <.05). On the other hand, during the corticomedullary and late phases, hypoenhancement was more commonly found in RCCs than RAMLs (both P <.05). The enhancement pattern was also different between the two diseases: sustained hyperenhancement or isoenhancement was observed in most (78.8%) of the RAMLs, whereas wash-out from hyperenhancement or isoenhancement to hypoenhancement was observed in most (71.0%) of the RCCs (P <.001 Figures 1 and 2). The RAMLs usually showed homogeneous enhancement (29 of 33 [87.9%]) rather than heterogeneous enhancement (4 of 33 [12.1%]; Figure 1), whereas most RCCs showed heterogeneous enhancement (69 of 93 [74.2%]) rather than homogeneous enhancement (24 of 93 [25.8%] P <.001; Figure 2). Thin enhanced rims of peritumoral tissue were observed in 74 (79.6%) of the RCC lesions and 1 (3.0%) of the RAML lesions (P <.001; Figure 3). The peritumoral rims appeared simultaneously with the tumor enhancement. They were hyperenhanced or isoenhanced during the cortical phase, whereas in the corticomedullary and late phases, the rims became clearer in comparison with the tumor and the adjacent renal parenchyma (Figure 3). Although the tumor margin was usually well defined both in RAMLs and RCCs on ultrasonography, the boundary of the RCCs was more distinct than that of the RAMLs in the corticomedullary and late phases on CEUS because of the peritumoral rims and early wash-out enhancement pattern. With regard to the relationship between CEUS findings and the subtypes of RCCs, hyperenhancement or isoenhancement in the cortical phase was found in 67 (93.1%) of 72 clear cell carcinomas, whereas 5 (45.5%) of 7 papillary carcinomas showed this pattern (P <.001). Inhomogeneous enhancement was found in 58 (80.6%) of 72 clear cell carcinomas, whereas 5 (45.5%) of 7 papillary carcinomas showed this pattern (P <.05; Table 2). Diagnostic Test Early wash-out, heterogeneous enhancement and peritumoral rim enhancement were the most common findings for RCC. Using early wash-out enhancement and heterogeneous enhancement or peritumoral rim enhancement as the diagnostic standard of CEUS for RCC, the corresponding sensitivity, specificity, PPV, NPV, and accuracy were 88.2% (82 of 93), 97.0% (32 of 33), 98.8% (82 of 83), 74.4% (32 of 43), and 90.5% (114 of 126), respectively. 712 J Ultrasound Med 2010; 29:

5 Xu et al Table 1. Enhancement Degree of RCC and RAML in Terms of Echogenicity on Baseline Ultrasonography Tumor With Different Cortical Phase Corticomedullary Phase Late Phase+ Echogenicity on Hyper- Iso- Hypo- Hyper- Iso- Hypo- Hyper- Iso- Hypo- Ultrasonography n enhanced enhanced enhanced enhanced enhanced enhanced enhanced enhanced enhanced RCC 93 8 (8.6) 74 (79.6) 11 (11.8) 0 (0) a 18 (19.4) a 75 (80.6) a 0 (0) a 16 (17.2) a 77 (82.8) a Hyperechogenicity 25 1 (4.0) b,c 16 (64.0) 8 (32) 0 (0) 8 (32.0) 17 (68.0) 0 (0) 7 (28.0) 18 (72.0) Isoechogenicity 33 4 (12.1) 28 (84.9) 1 (3.0) 0 (0) 4 (12.1) 29 (87.9) 0 (0) 4 (12.1) 29 (87.9) Hypoechogenicity 35 3 (8.6) 30 (85.7) 2 (5.7) 0 (0) 6 (17.1) 29 (82.9) 0 (0) 5 (14.3) 30 (85.7) RAML 33 3 (9.1) 24 (72.7) 6 (18.2) 1 (3.0) a 25 (75.8) 7 (21.2) 3 (9.1) 23 (69.7) 7 (21.2) Hyperechogenicity 25 3 (12.0) 17 (68.0) 5 (20.0) 1 (4.0) 18 (72.0) 6 (24.0) 3 (12.0) 16 (64.0) 6 (24.0) Isoechogenicity 7 0 (0) 6 (85.7) 1 (14.3) 0 (0) 6 (85.7) 1 (14.3) 0 (0) 6 (85.7) 1 (14.3) Hypoechogenicity 1 0 (0) 1 (100) 0 (0) 0 (0) 1 (100) 0 (0) 0 (0) 1 (100) 0 (0) Data are numbers of tumors with percentages in parentheses. a In comparison with RAML, all P <.01. b In comparison with isoechogenicity, P <.01. c In comparison with hypoechogenicity, P <.05. Discussion Since ultrasonography and CT were introduced into clinical practice, better detection and earlier diagnosis for renal cortical tumors have been achieved. Currently, as many as 70% of renal tumors are discovered incidentally, with a median tumor size of less than 5 cm, 14,15 and almost 83% of these asymptomatic tumors were originally found on baseline ultrasonography. 16 Although ultrasonography is helpful for detecting renal lesions, it is unable to show the microvascularity of tumors, and its echogenicity has not been adequate enough for characterization. Forman et al 3 showed that 32% of small RCCs were hyperechoic and thus mimicked RAMLs. Conversely, Jinzaki et al 17 reported that RAMLs containing a small amount of fat often appeared as isoechoic or moderately hyper - echoic on ultrasonography. Therefore, its ability to characterize renal tumors was limited, and further CT examination was required. 18 Evaluation of tumor vascularity is particularly important for their characterization. 10 Contrastenhanced ultrasonography operated at a low MI allows dynamic real-time evaluation of both the macrocirculation and microcirculation of kidneys and tumors; therefore, CEUS may improve the detection and characterization of tumors. Unlike the contrast agents used in CT and MRI, UCAs are blood pool agents, The microbubbles do not diffuse through the vascular endothelium into the interstitium and hence lead to more reliable depiction of tumor vascularity. 19 Most Table 2. Contrast-Enhanced Ultrasonographic Findings of RCC and RAML Late Phase Hyperenhanced Wash-out From or Iso- Hyperenhanced or Sustained Perilesional enhanced in Isoenhanced to Hyperenhanced Sustained Inhomogeneous Rimlike Final Diagnosis n Cortical Phase Hypoenhanced or Isoenhanced Hypoenhanced Enhancement Enhancement RCC (88.2) 66 (71.0) a 16 (17.2) a 11 (1.8) a 69 (74.2) a 74 (79.6) a Clear cell carcinoma (93.1) 55 (76.4) 12 (16.7) 5 (6.9) 58 (80.6) 60 (83.3) Papillary carcinoma 11 5 (45.5) b 3 (27.3) 2 (18.2) 6 (54.5) 5 (45.5 ) c 7 (63.6) Granular cell carcinoma 4 4 (100) 3 (75.0) 1 (25.0) 0 (0) 2 (50.0) 2 (50.0) Mixed cell carcinoma 5 5 (100) 4 (80.0) 1 (20.0) 0 (0) 4 (80.0 ) 4 (80.0) Chromophobe cell carcinoma 1 1 (100) 1 (100) 0 (0) 0 (0) 0 (0) 1 (100) RAML (79.8) 1 (3.0) 26 (78.8) 6 (18.2) 4 (12.1) 1 (3.0) Data are numbers of tumors with percentages in in parentheses. a In comparison with RAML, all P <.01. b In comparison with clear cell carcinoma, P <.001. c In comparison with clear cell carcinoma, P <.05. J Ultrasound Med 2010; 29:

6 Renal Cell Carcinoma and Renal Angiomyolipoma on CEUS Figure 1. Baseline ultrasonography and CEUS in a 58-year-old woman with RAML. Baseline ultrasonography (A) shows a welldefined mass (arrows) with hyperechogenicity relative to adjacent renal parenchyma in the lower pole of the right kidney. In the cortical (B) and late (C) phases of CEUS, the tumor (arrows) shows homogeneous enhancement. The tumor showed a sustained enhancement pattern with isoenhancement in the cortical and late phases. Figure 2. Baseline ultrasonography and CEUS in a 42-year-old woman with RCC. Baseline ultrasonography (A) shows a welldefined mass (arrows) with hyperechogenicity relative to adjacent renal parenchyma in the left kidney. In the cortical (B) and corticomedullary (C) phases of CEUS, the tumor (arrows) shows heterogeneous enhancement. The tumor showed early washout with isoenhancement in the cortical phase followed by hypoenhancement in the corticomedullary phase. A A B B C C 714 J Ultrasound Med 2010; 29:

7 Xu et al importantly, UCAs have no reported clinical side effects on the kidneys in humans to date. 7 Despite the potential advantages, there are few data as yet suggesting the manifestations of CEUS in focal renal lesions. It has been proven that CEUS is helpful for differentiating renal pseudotumors from true renal masses and is better than CECT in showing intralesional vascularity, the tumoral pseudocapsule, 8 10 and tumor vascularity in the septa of cystic renal masses Moreover, using a high-mi contrast-enhanced technique and SH U 508A (Levovist; Schering AG, Berlin, Germany), Tamai et al 10 found tumor blood flow in all 29 patients with renal lesions, whereas CECT failed to show flow in 5 patients, and among clear cell carcinomas, hypervascularity was observed on CEUS in 17 of 18 patients. Using a low-mi contrastenhanced technique and SonoVue, Yang et al 24 found the 76 of 98 renal clear cell carcinomas showed a wash-in and wash-out pattern of enhancement, and 58 of 98 showed pseudocapsule enhancement. Using the CPS technique and SonoVue, Wink et al 25 examined 18 patients with 20 previously identified renal masses by CEUS. They found that inhomogeneous enhancement patterns were observed in carcinomas, and all simple cysts and complex benign cysts showed absence of enhancement inside or in the wall of the lesions and a regular shape. Fan et al 26 reported that the characteristic features of hyperenhancement in the late phase and a heterogeneous enhancement pattern had very high specificity in distinguishing hypervascular RCCs from most RAMLs, and the related specificity reached 100%. Figure 3. A and B, Contrast-enhanced ultrasonography in a 47-year-old man with RCC. In the cortical (A) and late (B) phases of CEUS, the tumor shows heterogeneous enhancement. The peritumoral rim enhancement (arrows) is observed in the cortical phase and becomes distinct in the late phase. C, A gross specimen cross section (hematoxylin-eosin) shows tumoral and necrotic areas surrounded by a thin rimlike pseudocapsule (arrows). D, A histologic section viewed at high power (hematoxylin-eosin, original magnification 100) shows that the pseudocapsule is composed of fibrous tissue (arrows). A B C D J Ultrasound Med 2010; 29:

8 Renal Cell Carcinoma and Renal Angiomyolipoma on CEUS Renal angiomyolipoma is composed of fat, smooth muscle, and abnormal blood vessels. In previous studies, almost all RAMLs were observed to have hyperechogenicity on baseline ultrasonography. 1,16,19 However, in this study, only 88% of RAMLs showed hyperechogenicity. On the other hand, 32% of RCCs also showed hyper - echogenicity on ultrasonography. Therefore, hyperechogenicity on baseline ultrasonography should not be used as a definitive finding for RAML because a substantial overlap was present. As shown in this study, early wash-out of the UCA within the tumor and heterogeneous enhancement or peritumoral rim enhancement were the most valuable CEUS findings for diagnosing RCC, with sensitivity, specificity, PPV, NPV, and accuracy of 88.2%, 97.0%, 98.8%, 74.4%, and 90.5%, respectively. These enhancement characteristics might relate to the pathologic features of RCC, which is characterized by numerous thinwalled blood vessels with rich blood flow, 10,27 and intratumoral necrosis, a pseudocapsule, hemorrhage, and calcification are common. 27 Most RCC nodules showed hypervascular heterogeneous enhancement, which indicated intratumoral necrosis or hemorrhage in the tumors. Peri - tumoral rim enhancement may be a special manifestation for RCC on CEUS. The thin rim enhancement might represent the tumoral pseudocapsule, which results from tumor growth, producing compression, ischemia, and necrosis to adjacent normal parenchyma, with subsequent deposition of fibrous tissue, and is usually associated with a low histologic grade RCC. 28 The presence of a pseudocapsule is considered a useful sign for discriminating RCC and may be a criterion for nephron-sparing surgery. 29 Our results were different from those of Fan et al, 26 which was largely due to the difference in defining the CEUS phases. According to the CEUS guidelines issued in 2008, 7 the CEUS phases of the kidney can be divided into cortical, medullary, and wash-out phases. However, no exact timing was provided. On the basis of the literature 7 9 and our own experience, the kidney enhances quickly and intensely after UCA injection because of the high renal blood flow. Enhancement in the central arteries becomes apparent 10 to 15 seconds after UCA injection. It is followed a few seconds later by enhancement of the renal cortex, whereas pyramids remain hypoechoic. Renal pyramids slowly fill in and become almost isoechoic with the cortex (30 40 seconds after UCA injection). Therefore, we defined the cortical phase as 8 to 15 to 30 to 35 seconds after UCA injection. From 36 to 41 to 120 seconds after UCA injection, the cortex and pyramid were enhanced at the same level; thus, we defined this period as the corticomedullary phase. The microbubbles in the renal parenchyma faded out 120 seconds after UCA injection, and this period was defined as the late phase. There were some limitations in our study. First, the number of RAMLs in the study was smaller than that of RCCs. Further evaluation with a larger number of RAMLs is needed. Second, the kidney enhances quickly and intensely after SonoVue bolus injection because of the abundant renal blood flow. The enhancement level of some renal lesions was very similar to that of the renal cortex. Therefore, the subjective method of imaging analysis (ie, comparing the extent of enhancement of a nodule relative to that of the renal cortex by visual inspection) may have some insufficiency for evaluating the enhancement. Contrast-enhanced ultrasonography of the kidney is also limited by the interference of bowel gas and ribs and can be influenced by the lesion location and patient body configuration, as with conventional ultrasonography. The data analysis in this study was performed by 2 investigators by consensus. In future studies, data analysis should be performed by 2 investigators independently, and the interobserver agreement should be assessed. Two machines were used in this study depending on availability. However, there might have been minor differences between them in the sensitivity to contrast, which should be evaluated in future studies. Finally, only RCCs and RAMLs were included in the diagnostic test; thus, the results are only applicable when there is a need to differentiate between these two entities. In conclusion, CEUS is useful in differentiating RCC from RAML. Heterogeneity of tumor enhancement, earlier wash-out, and an enhanced peritumoral rim are the most valuable CEUS findings for diagnosing RCC, whereas homogeneity of tumor enhancement and sustained enhancement are the characteristic manifestations of RAML. 716 J Ultrasound Med 2010; 29:

9 Xu et al References 1. Siegel CL, Middleton WD, Teefey SA, McClennan BL. Angiomyolipoma and renal cell carcinoma: US differentiation. Radiology 1996; 198: Kim JK, Park SY, Shon JH, Cho KS. Angiomyolipoma with minimal fat: differentiation from renal cell carcinoma at biphasic helical CT. Radiology 2004; 230: Forman HP, Middleton WD, Melson GL, McClennan BL. Hyperechonic renal cell carcinoma: increase in detection at US. Radiology 1993; 188: Jinzaki M, Okhuma K, Tanimoto A, et al. Small solid renal lesions: usefulness of power Doppler US. Radiology 1998; 209: Quaia E, Siracusano S, Bertolotto M, Monduzzi M, Mucelli RP. Characterization of renal tumours with pulse inversion harmonic imaging by intermittent high mechanical index technique: initial results. Eur Radiol 2003; 13: Heidenreich A, Ravery V. Preoperative imaging in renal cell cancer. World J Urol 2004; 22: Claudon M, Cosgrove D, Albrecht T. et al. Guidelines and good clinical practice recommendations for contrast enhanced ultrasound (CEUS): update Ultraschall Med 2008; 29: Setola SV, Catalano O, Sandomenico F, Siani A. Contrastenhanced sonography of the kidney. Abdom Imaging 2007; 32: Nilsson A. Contrast-enhanced ultrasound of kidneys. Eur Radiol 2004; 14(suppl 8):P104 P Tamai H, Takiguchi Y, Oka M, et al. Contrast-enhanced ultrasonography in the diagnosis of solid renal tumors. J Ultrasound Med 2005; 24: Thorelius L. Contrast-enhanced ultrasound for extrahepatic lesions: preliminary experience. Eur J Radiol 2004; 51: Albrecht T, Blomley M, Bolondi L, et al. Guidelines for the use of contrast agents in ultrasound: January Ultraschall Med 2004; 25: Ascenti G, Gaeta M, Magno C, et al. Contrast-enhanced second-harmonic sonography in the detection of pseudocapsule in renal cell carcinoma. AJR Am J Roentgenol 2004; 182: Zhang J, Lefkowitz RA, Ishill NM, et al. Solid renal cortical tumors: differentiation with CT. Radiology 2007; 244: Ascenti G, Zimbaro G, Mazziotti S, Gaeta M, Settineri N, Scribano E. Usefulness of power Doppler and contrastenhanced sonography in the differentiation of hyperechoic renal masses. Abdom Imaging 2001; 26: Quaia E, Calliada F, Bertolotto M, et al. Characterization of focal liver lesions with contrast-specific US modes and a sulfur hexafluoride-filled microbubble contrast agent: diagnostic performance and confidence. Radiology 2004; 232: Quaia E. Microbubble ultrasound contrast agents: an update. Eur Radiol 2007; 17: Park BK, Kim B, Kim SH, Ko K, Lee HM, Choi HY. Assessment of cystic renal masses based on Bosniak classification: comparison of CT and contrast-enhanced US. Eur J Radiol 2007; 61: Ascenti G, Mazziotti S, Zimbaro G, et al. Complex cystic renal masses: characterization with contrast-enhanced US. Radiology 2007; 243: Wang JR, Miao LY, Cui LG, Yang JY, Wang SM, Liu GH. Application of contrast-enhanced ultrasound in the diagnosis of renal cystic lesion [in Chinese]. Zhongguo Yi Xue Ke Xue Yuan Xue Bao 2008; 30: Yang B, Fu NH, Shen DJ, et al. Contrast-enhanced ultrasound in the characteristics of renal tumors. Chin J Ultrasonogr 2007; 16: Wink MH, de la Rosette JJ, Laguna P, Lagerveld BW, Wijkstra H. Ultrasonography of renal masses using contrast pulse sequence imaging: a pilot study. J Endourol 2007; 21: Fan L, Lianfang D, Jinfang X, Yijin S, Ying W. Diagnostic efficacy of contrast-enhanced ultrasonography in solid renal parenchymal lesions with maximum diameters of 5 cm. J Ultrasound Med 2008; 27: Spitz DJ, Gattuso P. Ureter, urinary bladder, and kidney. In: Haber MH, Gattuso P, Spitz DJ, et al (eds). Differential Diagnosis in Surgical Pathology. 1st ed. Philadelphia, PA: WB Saunders Co; 2002: Pickhardt PJ, Lonergan GJ, Davis CJ Jr, Kashitani N, Wagner BJ. From the archives of the AFIP. Infiltrative renal lesions: radiologic-pathologic correlation. Armed Forces Institute of Pathology. Radiographics 2000; 20: Pretorius ES, Siegelman ES, Ramchandani P, Cangiano T, Banner MP. Renal neoplasms amenable to partial nephrectomy: MR imaging. Radiology 1999; 212: Russo P. Renal cell carcinoma: presentation, staging, and surgical treatment. Semin Oncol 2000; 27: Pavlica P, Derchi L, Martorana G, et al. Renal cell carcinoma imaging. Eur Urol 2006; 5(suppl): Jinzaki M, Tanimoto A, Narimatsu Y, et al. Angiomyolipoma: imaging findings in lesions with minimal fat. Radiology 1997; 205: J Ultrasound Med 2010; 29: