Renal Masses With Equivocal Enhancement at CT: Characterization With Contrast- Enhanced Ultrasound

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1 Genitourinary Imaging Original Research Bertolotto et al. Use of Contrast-Enhanced Ultrasound to Characterize Renal Masses Genitourinary Imaging Original Research Michele Bertolotto 1 Calogero Cicero 2 Rosaria Perrone 1 Ferruccio Degrassi 1 Francesca Cacciato 1 Maria A. Cova 1 Bertolotto M, Cicero C, Perrone R, Degrassi F, Cacciato F, Cova MA Keywords: characterization, contrast-enhanced ultrasound, equivocal enhancement, renal CT, renal masses DOI: /AJR Received June 19, 2014; accepted after revision August 22, Based on presentations at the Radiological Society of North America 2009 annual meeting, Chicago, IL, and the European Congress of Radiology 2010 annual meeting, Vienna, Austria. 1 Department of Radiology, University of Trieste, Strada di Fiume 447, Trieste 34149, Italy. Address correspondence to M. Bertolotto (bertolot@units.it). 2 Department of Radiology, Ospedale San Bassiano, Bassano del Grappa, Italy. WEB This is a web exclusive article. AJR 2015; 205:W557 W X/15/2045 W557 American Roentgen Ray Society Renal Masses With Equivocal Enhancement at CT: Characterization With Contrast- Enhanced Ultrasound OBJECTIVE. The purpose of this article is to retrospectively investigate in two radiology centers the role of contrast-enhanced ultrasound in the characterization of renal masses with equivocal enhancement at CT (i.e., with a density increase of HU between unenhanced and contrast-enhanced scans) not characterized with conventional ultrasound modes. MATERIALS AND METHODS. Forty-seven renal lesions (range, cm; average, 2.6 cm) with equivocal enhancement at CT underwent contrast-enhanced ultrasound using sulfur hexafluoride filled microbubbles. Examinations were digitally recorded for retrospective blinded evaluation by two radiologists with 20 and 10 years experience in urologic imaging. Histologic results were available for 30 of 47 (64%) lesions (25 primary malignant tumors, two metastases, and three primary benign lesions). Two lesions increased in size and complexity during the follow-up and were considered malignant. One Bosniak category III and 14 category IIF cysts were stable after a follow-up of at least 3 years and were considered benign. ROC curve analysis was used to assess the capability of contrast-enhanced ultrasound to differentiate benign from malignant lesions. RESULTS. Twelve likely complex cystic lesions at gray-scale ultrasound were cystic also on contrast-enhanced ultrasound and reference procedures. Eleven of 34 lesions that appeared solid at gray-scale ultrasound were cystic on contrast-enhanced ultrasound and reference procedures. One lesion considered likely solid by one radiologist and possibly cystic by the other was a solid tumor at contrast-enhanced ultrasound and histologic analysis. The diagnostic performance of contrast-enhanced ultrasound to characterize the lesions as benign or malignant was high for both readers (AUC, and 0.966, respectively). CONCLUSION. Contrast-enhanced ultrasound is effective for characterizing renal lesions presenting with equivocal enhancement at CT. O n CT studies, the most important criterion for differentiating renal lesions is the determination of their enhancement [1]. Many tumors enhance considerably, whereas hypovascular tumors enhance to a lesser degree, and benign cystic renal masses do not measurably enhance. When there is a question of whether a mass enhances, Hounsfield unit measurements should be obtained with comparison between the unenhanced and contrast-enhanced images [1]. With nonhelical CT scanners, a difference of 10 HU was considered as evidence of enhancement [2]. With helical and MDCT scanners, many authors suggest increasing the threshold from 10 HU to HU [3 7] because, after contrast material administration, a simple cyst may show pseudoenhancement, an artifactual increase in the attenuation of 10 HU or more, which is postulated to result from an inadequate correction for beam hardening in the image reconstruction algorithm used in modern scanners [3, 7 11]. Pseudoenhancement of cysts may lead to their misinterpretation as a renal neoplasms. Indeed, there are indeterminate renal masses that enhance by HU and need further evaluation for definitive characterization [1]. These lesions are either cysts displaying pseudoenhancement or hypovascular tumors. Gray-scale sonography can be used as a problem-solving modality to characterize renal lesions with equivocal enhancement at CT [1, 12] because simple or minimally complicated cysts show anechoic content and thin walls. Cysts containing blood or debris, however, usually have echogenic or mixed sonographic appearance, and MRI is usually regarded as the modality of choice for char- W557

2 Bertolotto et al. acterization [1]. In our clinical experience, color Doppler examination does not add significantly to lesion characterization in these patients because both cysts and hypovascular tumors usually do not display color signals. According to the guidelines and recommendations of the European Federation of Societies for Ultrasound in Medicine and Biology, contrast-enhanced ultrasound is an emerging problem-solving modality in renal abnormalities [13]. Contrast-enhanced ultrasound is particularly indicated for differential diagnosis between solid lesions and cysts presenting with equivocal appearance at conventional sonography, for characterization of complex cystic masses, and for the follow-up of nonsurgical renal lesions. Investigations have shown that contrast-enhanced ultrasound is more sensitive than CT in detecting blood flow in hypovascular lesions [14] and in detecting enhancement of the cystic wall, septa, and solid components in complex cystic lesions [15]. Preliminary investigations show that contrast-enhanced ultrasound can be used to differentiate between lesions with equivocal enhancement at CT [14], but validation with systematic studies is lacking. The aim of this study is to investigate a consecutive series of patients and to determine whether indeterminate renal masses with equivocal enhancement on CT can be effectively characterized as cystic or solid and as benign or malignant at contrast-enhanced ultrasound. Materials and Methods This retrospective study was approved by the University of Trieste and Ospedale San Bassiano institutional review boards, and all data were processed without patient-identifying information. Hence, the requirement for informed consent was waived. A computer search in the database at our institutions was done for the clinical and radiologic records of the patients who underwent contrast-enhanced ultrasound of the kidney between October 2003 and August Only patients with images and digital clips from CT, conventional sonographic modes, and contrast-enhanced ultrasound available for retrospective review were considered. With regard to CT, only investigations with both unenhanced and contrast-enhanced images in the nephrographic phase were collected ( seconds after the injection of contrast material) [16, 17], whereas cases lacking unenhanced scans were excluded. Patients with renal lesions having an attenuation difference of HU between the unenhanced and the contrast-enhanced images and echogenic or mixed appearance at gray-scale sonography were eventually selected, whereas lesions presenting as simple cysts or minimally complicated cysts were characterized as benign on conventional sonographic modes and were excluded from this series. This process yielded a total of 47 patients for whom contrast-enhanced ultrasound was performed to characterize indeterminate renal masses with equivocal enhancement on CT (38 men and nine women; age range, years; mean [± SD] age, 65 ± 13 years; median age, 66 years). Forty-three patients had one indeterminate lesion (19 in the right and 24 in the left kidney), one patient had two indeterminate lesions in the left kidney, and two patients had multiple lesions with equivocal enhancement in both kidneys. The remaining patient had one lesion in the left kidney with equivocal enhancement and one obviously enhancing solid renal tumor. Two patients had previously undergone surgery for renal cancer, one with lung cancer and one with colon cancer. Imaging was performed using different CT scanners. After a preliminary gray-scale and color Doppler study, lesion vascularity was investigated with contrast-enhanced ultrasound using a variety of sonographic equipment and contrastspecific modes (Table 1). The power of the ultrasound beam was set to obtain minimum microbubble destruction. A 1.2- to 2.4-mL bolus of sulfur hexafluoride filled microbubbles (SonoVue, Bracco) was injected to evaluate each kidney by using a 20-gauge cannula, followed by a 10-mL normal saline flush. The transducer was moved during the contrast circulation to explore all lesion aspects, and real-time video clips were recorded and stored. Image Analysis In patients with more than one renal lesion presenting with equivocal enhancement on CT, the largest was considered for the purpose of this study. CT images were reviewed retrospectively in random order by a radiologist with 17 years experience in renal CT who was aware of the presence and site of a renal lesion presenting with equivocal enhancement but was blinded to the findings of the reference procedures. The radiologist involved in examination of CT scans was asked to assess lesion size and density on the unenhanced and contrast-enhanced scan during the nephrographic phase ( seconds after the injection of contrast material). In cases of homogeneous density, a single ROI encompassing the entire lesion was used, whereas in cases of inhomogeneous density, multiple ROI measurements were obtained throughout the lesion [12], and the largest density difference was used between the unenhanced and the contrast-enhanced nephrographic scan. Sonographic images and cine clips obtained during microbubble contrast agent administration were reviewed in random order by two independent on-site radiologists (with 20 and 10 years experience in urologic imaging, respectively) who were blinded to the appearance of the lesion at CT and to the findings of the reference procedures. Identifying information was masked. Two separate evaluation sessions with a 2-week interval were scheduled. During the first session, the reviewers evaluated conventional sonographic modes; during the second session, they evaluated the conventional modes and contrast-enhanced ultrasound. The reviewers were asked to characterize the lesions as solid or cystic, to classify those with cystic appearance at contrast-enhanced ultrasound according to the Bosniak criteria, as described in previous investigations [15, 18, 19], and to evaluate whether lesions were benign or malignant according to contrast-enhanced ultrasound characteristics. On conventional ultrasound modes, no attempt was made to classify the cystic lesions according to the Bosniak criteria or to characterize the lesions as benign or malignant. For the purpose of this study, criteria used to characterize a renal lesion as solid on conventional sonographic modes was echogenic content with no or minimal anechoic component. A lesion was characterized as possibly cystic at gray-scale TABLE 1: Sonographic Equipment and Contrast-Specific Modes Used for Contrast-Enhanced Ultrasound Equipment, Manufacturer Scanning Mode Transducer IU22, Philips Healthcare Sequoia, Acuson (now Siemens Healthcare) HDI5000, ATL (now Philips Healthcare) Pulse inversion harmonic imaging Cadence contrast pulse sequencing Pulse inversion harmonic imaging Convex array (model C5 1) Convex array (model 4C1) Convex array (model C5 2 HDI) EsaTune, Esaote Contrast-tuned imaging Convex array (model CA430E) Mechanical Index No. of Patients W558

3 Use of Contrast-Enhanced Ultrasound to Characterize Renal Masses sonography in the presence of anechoic or markedly hypoechoic areas filling more than half of its volume, mobile echoes, or mixed echogenicity with increased through-transmission. On contrast-enhanced ultrasound, a lesion was considered solid if more than half the volume was enhancing solid tissue [20] and as cystic if it was composed predominantly of nonenhancing spaces [12]. The sonographers were asked to score their diagnostic confidence to characterize the lesion as cystic or solid according to a 4-point scale: 0, the lesion cannot be characterized; 1, poor diagnostic confidence; 2, fair diagnostic confidence; and 3, the lesion can be definitely characterized. For the purpose of this study, Bosniak category IIF cysts were considered probably benign, category III cysts were considered indeterminate, solid tumors were considered probably malignant, and category IV cysts were considered definitely malignant. Reference Standard Histologic confirmation was available for 30 of 47 (64%) patients; 28 patients underwent surgery, whereas in two patients with advanced lung and colon cancer, renal metastasis was suspected on clinical grounds and was confirmed by biopsy. Among the 28 excised lesions, 25 were malignant and three were benign. There were 23 papillary, one oncocytic papillary, and one unclassified renal cell carcinomas. One benign lesion was an oncocytoma, and two were multilocular cystic nephromas. One patient had a category III cyst that was stable after a follow-up of 5 years and was considered benign. Two poor surgical candidates had a category IV cyst and a solid tumor, respectively. Tumor progression was found during the follow-up, and lesions were considered malignant. The remaining 14 patients had category IIF cysts that were stable after a follow-up of at least 3 years and were considered benign (Table 2). TABLE 2: Final Diagnosis of 47 Renal Lesions With Equivocal Enhancement at CT Reference Standard No. of Lesions Mean (SD) Diameter (cm) Final Diagnosis Surgery (1.9) Primary malignancy Surgery (0.9) Primary benign lesion Biopsy (1.1) Secondary malignancy Follow-up (1 2 years) (1.3) Malignant a Follow-up (> 3 years) (1.2) Benign a Diagnosis of malignancy was based on evidence of disease progression. TABLE 3: Bosniak Category Assigned by the Two Radiologists to 23 Cystic Lesions With Equivocal Enhancement at CT Radiologist 2, Bosniak Category Statistical Analysis ROC curve analysis was used to assess the overall confidence in the diagnosis of solid and cystic lesions on conventional modes and on contrastenhanced ultrasound and of benign and malignant lesions on contrast-enhanced ultrasound. The AUC was calculated using commercially available software (MedCalc for Windows, version , MedCalc Software) and was compared using the method described by Hanley and McNeil [21]. A p value of less than 0.05 was considered to indicate a statistically significant difference. Interreader agreement was assessed using kappa and weighted kappa statistics for lesion characterization as solid or cystic and for assessment of the Bosniak score of the cystic masses, respectively. Agreement was graded as poor (κ < 0.20), moderate (κ 0.20 and κ < 0.40), fair (κ 0.40 and κ < 0.60), good (κ 0.60 and κ < 0.80), and very good (κ = 0.8 1). The diagnostic confidence in categorizing the lesions as cystic or solid on gray-scale sonography and contrast-enhanced ultrasound was compared using the Wilcoxon test for paired samples. Results On CT, the reference lesions ranged in diameter from 0.8 to 7.7 cm (mean, 2.6 cm; median, 2.3 cm). The density difference between the unenhanced and contrast-enhanced nephrographic scans was HU (mean, 13.7 HU; median, 13.0 HU; SD, 3.0 HU). No lesion displayed color signals at color Doppler examination. Interreader agreement in categorization of the renal lesions as cystic or solid was very good for gray-scale sonography (κ = 0.946), and complete concordance between the two readers was found for contrast-enhanced ultrasound (κ = 1). The average diagnostic confidence in categorizing the lesions as cystic or solid was statistically significantly higher for contrast-enhanced ultrasound (2.62 for both reviewers vs 1.83 and 1.87 for reviewer 1 and reviewer 2, respectively, for gray-scale sonography; p < 0.001). On gray-scale sonography, both readers categorized 12 lesions as likely cystic. All were cystic on contrast-enhanced ultrasound and at surgery or the reference procedure (Fig. 1). Both readers categorized 34 lesions as likely solid on gray-scale sonography. Twenty-three were solid (Fig. 2), whereas 11 of them (32.4%) were cystic on Radiologist 1, Bosniak Category IIF III IV IIF III IV Note Data are number of lesions. contrast-enhanced ultrasound and on the reference procedure (Fig. 3). One lesion was considered likely solid on gray-scale sonography by the first reviewer and possibly cystic by the other because of inhomogeneous content, with some anechoic portions and markedly increased through-transmission (Fig. 4). It was a solid tumor at contrast-enhanced ultrasound and a papillary tumor at histologic analysis. ROC curve analysis was used to assess the overall confidence of diagnosis of lesions as benign or malignant on contrastenhanced ultrasound. Sensitivity and specificity were high for both readers (96.7% and 94.1%, respectively, for radiologist 1; 93.3% and 94.1%, respectively, for radiologist 2). The AUC values were and for radiologist 1 and radiologist 2, respectively, with no statistically significant differences between them. There were differences in the classification of the 23 cystic renal masses according to the Bosniak criteria (Table 3). The same score was assigned by both sonographers to 17 of 23 (74%) cysts; four of 23 (17%) cysts were scored as category IIF by the first reviewer and as category III by the second reviewer; and two cysts were scored as categories III and IV by the first reviewer and as categories IIF and III by the second reviewer, respectively. Despite differences in classification of cystic renal masses, good interobserver agreement was found for classification of cystic lesions as well (weighted κ = 0.70). W559

4 Bertolotto et al. Discussion Characterization of indeterminate renal masses is a common clinical problem [22]. Lesions are often identified incidentally on sonography or on a CT or MRI scan performed for another purpose. Often, no unenhanced images are available for these patients, or only unenhanced images have been obtained, such as in the setting of renal colic. In this instance, many renal masses cannot be characterized, because characterization requires a CT or MRI examination performed before and after administration of IV contrast material [17]. Sonography allows characterization of many incidentally detected renal lesions as simple or minimally complicated cysts that do not require additional follow-up. Lesions displaying intralesional flows at color Doppler examination are characterized as presumably malignant tumors, but those lacking vascularization remain indeterminate and must be investigated with dedicated contrast-enhanced studies [17]. Among indeterminate renal masses at CT, those with equivocal evidence of enhancement are an uncommon subgroup. As a result of a faint increase in density (10 20 HU) between the unenhanced and the nephrographic phase, these lesions remain indeterminate despite the availability of both of the two scans [17, 23]. They are either hypovascular tumors or cysts displaying pseudoenhancement, which are more often small (< 2 cm) [3, 10], but occasionally larger. In our series, the largest lesion displaying equivocal enhancement was a category IV papillary cystic tumor with a diameter of 7.7 cm. Two solid papillary tumors of 5.1 and 4.5 cm enhanced by 12 HU. If the renal mass with equivocal enhancement at CT is a simple or minimally complicated cyst, sonography is sufficient, but in cases of mixed or echogenic content, diagnosis cannot be reached, and contrastenhanced MRI is considered the modality of choice to attempt characterization [1, 17]. MRI, however, is expensive, and cannot be used for patients with a pacemaker, uncooperative patients, and patients with severe renal failure. Moreover, unequivocal enhancement may be difficult to show in small hypovascular lesions for which image subtraction cannot be performed effectively. Contrast-enhanced ultrasound is an emerging technique for the investigation of renal masses [24 26]. The main clinically recognized indication in the kidney is the characterization of renal complex cysts. Several investigations have shown that contrastenhanced ultrasound has at least the same diagnostic accuracy as contrast-enhanced CT for renal cyst classification according to the Bosniak criteria and is more sensitive than CT to detect the microvascularization of the wall and septa of cystic masses, with the advantage of the absence of radiation [15, 18, 19]. This fact also favors the use of contrast-enhanced ultrasound in the follow-up of cystic lesions managed conservatively [13]. Other emerging renal applications for contrast-enhanced ultrasound are detection of renal parenchymal ischemia [27], differential diagnosis between solid tumors and pseudotumors, and early detection of residual tumor after renal tumor ablation [28]. In a recent retrospective investigation [22], contrast-enhanced ultrasound gave valuable information for the characterization of indeterminate renal masses. In that series, the initial imaging studies were unenhanced CT, contrast-enhanced CT, MRI, or unenhanced sonography. Contrast-enhanced ultrasound had a sensitivity of 100% and specificity of 95% in lesion characterization [22]. There is controversy about the usefulness of contrast-enhanced ultrasound in the differentiation between benign and malignant solid renal masses, because the perfusion pattern of the renal tumors is variable. According to the guidelines of the European Federation of Societies for Ultrasound in Medicine and Biology, contrast-enhanced ultrasound is not able to differentiate between malignant and benign solid masses with an adequate diagnostic accuracy [13]. Contrast-enhanced ultrasound has the distinct advantage over CT and color Doppler sonography of being more sensitive in detecting blood flow in hypovascular lesions. It is able to identify intralesional flows in virtually all solid lesions and is, therefore, able to differentiate solid hypovascular tumors from atypical cystic masses [14, 22 24]. In our series of lesions, which were either hypovascular tumors or complex cysts, gray-scale sonography was not able to differentiate between cystic and solid masses. Contrastenhanced ultrasound, on the other hand, showed an absolute sensitivity and specificity for this differentiation, thanks to its ability to show unequivocal enhancement within the lesions, even when they were not characterized on CT. Moreover, contrast-enhanced ultrasound was able to score the cystic masses according to the Bosniak criteria in this population of hypovascular lesions as well. A limitation of the current study is its retrospective design. This can introduce caseselection bias because some cases may have not been recorded for inclusion. As occurs for all the ultrasound modes, the diagnostic performance of contrast-enhanced ultrasound is dependent on the operator s skill. In our opinion, however, evaluation of renal lesion vascularity on contrast-enhanced ultrasound is not technically difficult, because it is substantiated by a very good interreader agreement obtained in this and in other studies on different renal abnormalities [15, 18, 27, 29]. The major limitation of this study is that the diagnosis of benign or malignant tumor has been confirmed histologically in only 30 of 47 (64%) cases. One of the patients who did not undergo surgery had a category III cyst that was considered benign because it remained stable after a follow-up of 5 years, whereas two other patients who did not undergo surgery had evidence of disease progression during the follow-up, and their lesions were considered malignant. The remaining nonexcised lesions were category IIF cysts, for which follow-up, instead of surgery, is recommended. These cysts had a follow-up for at least 3 years, which is commonly considered adequate [15, 18, 30 32]. However, the time needed to follow up a presumably benign cyst according to the Bosniak criteria is still debated. Gabr et al. [33] and Bosniak [34] recommend a 3- to 5-year period of follow-up to ensure benign behavior. As a consequence, the number of benign lesions might have been overestimated in our study. In conclusion, the challenge of characterizing renal masses with equivocal enhancement at CT can be faced with sonographic modes. Gray-scale sonography is sufficient to diagnose these lesions as simple or minimally complicated cysts. In cases of mixed or echogenic content, contrast-enhanced ultrasound can be performed immediately after the conventional gray-scale and Doppler investigations and allows classification of the lesions with a high degree of accuracy. References 1. Israel GM, Bosniak MA. How I do it: evaluating renal masses. Radiology 2005; 236: Bosniak MA. The current radiological approach to renal cysts. Radiology 1986; 158: Birnbaum BA, Maki DD, Chakraborty DP, Jacobs JE, Babb JS. Renal cyst pseudoenhancement: evaluation with an anthropomorphic body CT phantom. Radiology 2002; 225:83 90 W560

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6 Bertolotto et al. A C D Fig year-old woman with surgically proven multiloculated cystic nephroma discovered in left kidney showing equivocal enhancement on CT. A and B, Axial unenhanced (A) and contrast-enhanced (B) CT scans show 3-cm mass (arrow) in middle portion of left kidney. Lesion density is slightly inhomogeneous on both unenhanced and contrast-enhanced scans, but no definite enhancement is appreciable. Attenuation measurements are 15 and 30 HU for unenhanced and contrast-enhanced scan, respectively. C and D, Gray-scale (C) and contrast-enhanced (D) sonography show lesion (arrows) with multiple enhancing septa with irregularities, suggesting indeterminate cystic mass (Bosniak category III). B W562

7 Use of Contrast-Enhanced Ultrasound to Characterize Renal Masses A C Fig year-old man with surgically proven papillary renal cell carcinoma discovered in right kidney showing equivocal enhancement on CT. A and B, Axial unenhanced (A) and contrast-enhanced (B) CT scans show 2.5-cm mass (arrow) in middle portion of right kidney, which is recognizable only after contrast agent administration. Attenuation measurements are 32 and 50 HU for unenhanced and contrast-enhanced scan, respectively. C, Gray-scale sonography shows hyperechogenic solidlike mass (arrow). D, Contrast-enhanced sonography shows solid hypovascular tumor (arrow). B D W563

8 Bertolotto et al. A C D Fig year-old man with surgically proven papillary renal cell carcinoma discovered in right kidney showing equivocal enhancement on CT. A and B, Axial unenhanced (A) and contrast-enhanced (B) CT scans show 7.5-cm mass (arrow) in middle portion of right kidney with slightly inhomogeneous density both before and after contrast agent administration. Attenuation measurements are 51 and 61 HU for unenhanced and contrast-enhanced scan, respectively, in densest regions. C, Gray-scale sonography shows inhomogeneously hypoechoic mass (arrows) with solidlike appearance. D, Contrast-enhanced sonography shows cystic mass (arrows) containing enhancing wall nodules (arrowheads) consistent with Bosniak category IV lesion. B W564

9 Use of Contrast-Enhanced Ultrasound to Characterize Renal Masses A C D Fig year-old man with surgically proven papillary renal cell carcinoma discovered in right kidney showing equivocal enhancement on CT. A and B, Axial unenhanced (A) and contrast-enhanced (B) CT scans show 2.5-cm mass (arrow) in middle portion of right kidney. Attenuation measurements are 49 and 67 HU for unenhanced and contrast-enhanced scan, respectively. C, Gray-scale sonography shows inhomogeneously echogenic lesion (arrow) with anechoic area (arrowheads) and increased through-transmission. Lesion was considered likely solid by one sonographer and possibly cystic by other sonographer. D, Contrast-enhanced sonography shows solid hypovascular tumor (arrow). B W565