Abstract
Background
Renal pseudotumors appear as benign cortical hypertrophies and are typically assessed by contrast-enhanced computed tomography or magnetic resonance imaging to rule out malignancy.
Purpose
To investigate whether contrast-enhanced ultrasound (CEUS) can rule out renal neoplasm and thus potentially reduce cross-sectional imaging and further follow-up in these patients.
Material and Methods
Thirty-two patients with presumption of developmental renal pseudotumor on CEUS between June 2011 and July 2019 were retrospectively analyzed. All patients were examined with a standardized renal US protocol including B-mode, color-coded duplex sonography (CCDS), and CEUS by an experienced radiologist (EFSUMB level 3). Images were retrospectively interpreted in consensus by two highly experienced radiologists. Histopathological reports, cross-sectional imaging findings, and clinical course (treatment response, long-term imaging follow-up) were defined as standard of reference.
Results
CEUS correctly identified 8/9 neoplastic lesions and missed one oncocytoma within the 32 included patients. Irregular vessel structure (88.9% vs. 13.0%, P = 0.007) and hyperenhancement (66.6% vs. 17.4%, P = 0.031) on CEUS were more common in neoplasm compared to developmental pseudotumors reaching statistical significance. Compared with the standard of reference, CEUS had 89% sensitivity (95% confidence interval [CI] 57–98), 96% specificity (95% CI 80–99), a positive predictive value of 89% (95% CI 57–98), and a negative predictive value of 96% (95% CI 79–99) for ruling out renal malignancy in developmental pseudotumors.
Conclusion
CEUS is a safe and fast method to rule out neoplasm in the diagnostic work-up of renal pseudotumors. In conjunction with B-mode and CCDS, CEUS has the potential to reduce further (invasive) diagnostic procedures.
Introduction
Cancer of the kidney is the ninth most common cancer in men and the 14th most common cancer in women (1). Depending on tumor size, renal cell carcinoma (RCC) is detected by ultrasound (US) with a sensitivity of 82%–83% and a specificity of 98%–99% (2). Although the diagnostic performance seems to be good, the specific subgroup of renal pseudotumors poses a challenge to the examiner in differentiation of benign and malignant lesions due to their partly displacing phenomenology, despite their benignity. In a meta-analysis with histological confirmation, Wang et al. (3) found a sensitivity of 88% and specificity of 80% for differentiation of benign and malignant renal lesions using contrast-enhanced ultrasound (CEUS) (3). This draws attention to the question of whether CEUS helps to distinguish developmental pseudotumors and malignant renal lesions dependably. Reliable differentiation of renal pseudotumors from malignant renal lesions is clinically relevant because these rare lesions can imitate neoplasms of the kidney.
Four types of renal pseudotumors are categorially distinguished: developmental (e.g. dromedary hump); infectious (e.g. abscess); granulomatous (e.g. sarcoidosis); and vascular (e.g. renal pelvic hematoma) pseudotumors (4). Among developmental renal pseudotumors, the hypertrophied column of Bertin is a frequent variant (5). Columns (also known as “septa”) of Bertin manifest as cortical renal tissue pushing into the pelvis between the medullary pyramids (6). Prominent columns of Bertin are normally examined with contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) to exclude renal malignancy (4). Other variants of developmental renal pseudotumors are dromedary or splenic humps. They present as focal cortical bulges of the left kidney from the surface facing the spleen (4). A further variation is persistent renal lobulation. This kind of developmental renal pseudotumor results from failure of retraction of fetal renal lobulation and is characterized by a cortical bulge between two medullary pyramids (4).
The current European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) guidelines for the clinical use of CEUS in non-hepatic applications by Sidhu et al. (7) provides specific recommendations for off-label use in focal renal lesions. The most important feature of renal pseudotumors in CEUS is a consistent enhancement pattern in all vascular phases compared to surrounding parenchyma, while malignant renal lesions show different degree or distribution of enhancement in at least one vascular phase (7). Another criterion to distinguish a renal pseudotumor from malignancy is vascular architecture. A pseudotumor shows normal “branching from the hilum to the periphery without disruption of vessels or aberrant vessels” in the early arterial phase (7). Since a small number (5%) of solid renal masses show isoenhancement in all vascular phases on CEUS, this criterion is important to detect these less common cases (8). Furthermore, a visible medullary pyramid in the suspicious lesion was described as a criterion for renal pseudotumors (9,10).
Renal pseudotumors are reliably diagnosed with contrast-enhanced MRI or CT. In terms of costs and risks of contrast agent administration, reliable diagnostic confirmation of pseudotumors with CEUS would be desirable. Thus, the aim of the present study was to investigate if CEUS can reliably confirm renal pseudotumors and rule out malignancy.
Material and Methods
Study cohort
This retrospective study was approved by the local institutional ethics committee. Oral and written informed consent of all patients was obtained before the examination. All study data were collected in compliance with the principles expressed in the 2002 Declaration of Helsinki.
Inclusion criteria were: (i) a presumption of a pseudotumor in prior B-mode US or a referral with suspicious ultrasound finding in external ultrasound examination; (ii) an imaging follow-up with MRI, CT, or CEUS as reference standard or surgery with histological confirmation; and (iii) sufficient image quality for analysis.
Assessment of pre-existing co-morbidities and history of cancer was performed by a structured review of the radiology information system (RIS) and general documentation system.
Between June 2011 and January 2019, 32 patients underwent an ultrasound examination of the kidney (n = 31) or renal transplant (n = 1) using B-mode, CCDS, and CEUS. Patients with missing follow-up data and/or insufficient image quality were excluded. Patients were referred for further evaluation by CEUS examination of inconclusive B-mode US findings from an external institution (n = 13) or from our department (n = 19).
CEUS examination protocol
Gray-scale B-mode US of the kidney was performed for lesion detection and for assessment of kidney size, echogenicity, and homogeneity using high-end ultrasound systems with 1–6 MHz convex array transducers (Aplio 500/Aplio i900, Canon Medical Systems Corporation, Tochigi, Japan; Acuson Sequoia/S3000, Siemens Healthineers, Mountain View, CA, USA). Color-coded duplex sonography (CCDS), Power Doppler imaging (PDI), and microflow imaging (superb microvascular imaging [SMI]) after 2015 were employed to determine vessel structure in the target area. The kidney was examined in modified longitudinal and transverse planes and, if necessary, in deep inspiration and with optimized scanning positions.
CEUS examinations were performed during clinical routine using high-end US systems with up-to-date CEUS-specific protocols available at the time of the examination. The examinations were performed at 1–6 MHz using a convex array transducer. Ultrasound B-mode images were optimized using spatial compounding and frequency-based compounding, in case of Canon systems also optimized by ApliPure™ level 5, differential Tissue Harmonic Imaging (dTHI©), and Precision Imaging© with level 4 speckle reduction (SR). CEUS was performed at 1–5 MHz with 10 fps. A very low mechanical index (MI; 0.06–0.07) was used to avoid early microbubble destruction. A bolus of 1.2–1.6 mL of US contrast agent (SonoVue®, Bracco Imaging, Milan, Italy) was repeatedly injected up to three times until satisfactory cine loops were acquired. It should be noted that a single bolus injection of contrast agent is often normally used in clinical routine, a full package size has no economic issue due to both internal and manufacturer’s hygiene guideline which requires a single use of a vial per patient. Baseline B-mode US, CCDS, and CEUS (for qualitative assessment of contrast-enhancement pattern) were performed by a single highly experienced radiologist with >10 years of experience in CEUS (EFSUMB level 3).
Image interpretation
All B-mode US images, CCDS, and CEUS loops were retrospectively evaluated in consensus by two experienced radiologists (M.H.L., T.F.), one of them an EFSUMB level 3 examiner. B-mode US features were homogeneity, echogenicity, lesion shape, maximum lesion size, and lesion-to-regular-cortex ratio. CCDS findings included hypervascularization and vessel structure. CEUS features included focal early arterial contrast enhancement, contrast enhancement compared to surrounding cortical tissue (hyper- or hypoenhancement), and assessment of wash-out in the late phase.
Reference standard
All patients included in the analysis underwent imaging follow-up (12 patients with CECT, 10 patients with CE-MRI, two patients with both CECT and CE-MRI) and/or surgery with histopathologic confirmation of malignancy and clinical surveillance including paraclinical parameters (laboratory tests, tumor markers, etc.) served as reference standard. All patients were followed up for at least two years. Stable or diminishing lesion size after two years and regular findings on cross-sectional imaging were considered to indicate a benign cortical lesion. All radiological reports (CECT, CE-MRI) were approved by board-certified radiologists.
Cross-sectional imaging
Overall, 14/32 patients underwent multiphase CT examinations (non-enhanced, arterial, and venous/delayed phase) using a standard protocol on a 64–128-detector CT scanner (Siemens Medical Systems, Forchheim, Germany), a minimum slice thickness of 0.625–1 mm, and reconstruction interval of 2 mm. The contrast agent was bolus-injected into an antecubital vein at a flow rate of 3.5–4.5 mL/s using a dual-head power injector. Contrast medium (100–120 mL; Ultravist®, Bayer Healthcare, Berlin, Germany) with an iodine concentration of 370 mg/mL was administered, followed by a 50-mL saline flush. The acquisition direction was craniocaudal.
MRI was performed at 1.5 T or 3.0 T using phased-array body coils in 12/32 patients. The imaging protocols comprised T2-weighted (T2W) standard two-dimensional (2D) sequences with and without fat saturation (FS) and T1-weighted (T1W) unenhanced 2D sequences with and without FS (including in-phase/opposed-phase technique). T1W three-dimensional (3D) sequences with FS were acquired in breath-hold technique before and during arterial, portal venous, and venous phases following intravenous administration of gadubutrol acid (Gadovist, Bayer Pharma, Berlin Germany; body weight adapted; manual or automatic injection at approximately 1–2 mL/s flow rate followed by 40 mL saline flush).
Statistical analysis
Continuous variables were tested for normal distribution using the Kolmogorov–Smirnov test; variables not normally distributed are reported as median and interquartile range (IQR) and were compared using the Mann–Whitney U test. Categorical variables were compared using Student’s t-test or the χ2 test, as appropriate. CEUS findings and corresponding histopathological reports from each patient were analyzed retrospectively for diagnostic accuracy by testing sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV).
A two-sided significance level of α = 0.05 was defined to indicate statistical significance. All statistical analyses were performed using the SPSS software package (IBM Corp., Armonk, NY, USA).
Results
All 32 patients (59.4% women, median age = 56 years, age range = 47–70 years) were successfully examined by CEUS without any adverse reaction. Baseline characteristics of all study patients are summarized in Table 1. Eighteen patients had a history of renal disease, among them 15 with chronic renal insufficiency and three with atrophied/shrunken kidneys. One patient suffered from fever and fatigue. While 19 presumed renal pseudotumors were incidentally detected during routine US examinations in our institution, 13 patients were referred by external nephrologists or radiologists to elucidate unclear B-mode findings. Three patients had a history of cancer: one renal cell carcinoma in the contralateral kidney treated by nephrectomy; one synovial sarcoma of the shoulder; and one neuroendocrine tumor of the major duodenal papilla.
Baseline characteristics of all study patients.
Values are given as n/N (%) or median (IQR).
*Defined as glomerular filtration rate <15 mL/min/1.73 m2.
IQR, interquartile range.
Median kidney depth (measured from skin to superficial renal capsule) was 4.7 cm (IQR = 3.8–5.6 cm). Presumed developmental pseudotumors were distributed evenly between both sides with 17 lesions in the right kidney (upper pole = 2, mid-kidney = 10, lower pole = 5) and 15 lesions in the left kidney (upper pole = 3, mid-kidney = 9, lower pole = 3). Lesions had a median length of 25.5 mm (IQR = 19.3–34.0 mm) and width of 28.0 mm (IQR = 19.1–30.8 mm), and median lesion-to-regular-cortex ratio was 2.1 (IQR = 1.8–2.6 mm).
The presumed developmental pseudotumors were classified as prominent columns of Bertin (n = 22), dromedary/splenic hump (n = 4), and persistent renal lobulation (n = 6) by the two readers in consensus (Fig. 1). Overall, lesions were predominantly isoechogenic (n = 21), while five were hypoechogenic and six were hyperechogenic. Inhomogenicity were found in 11 lesions on B-mode US. Hypervascularization on CCDS was found in three lesions and irregular vessel structure compared to regular renal parenchyma in 11 cases (eight neoplasm, three developmental pseudotumor). CEUS findings revealed early enhancement in four cases (one pseudotumor, three neoplasms) and hyperenhancement in 4/23 pseudotumors and 6/9 neoplasms (Table 2). CEUS missed one case of an intraparenchymal oncocytoma showing no early enhancement, wash-out, or vessel abnormalities. Five lesions showed hypoenhancement compared to the regular cortical tissue. Lesion wash-out was present in three patients (two neoplasm, one pseudotumor).
Representative cases of developmental renal pseudotumors. (a) Enlarged column of Bertin (asterisk): seen as extension of renal cortical tissue, which could be mistaken for a focal renal mass. (b) Persistent fetal lobulation: a rare normal variant due to incomplete fusion of developing renal lobules. (c) Dromedary hump (arrowheads): focal bulges on the lateral border of the left kidney caused by splenic impression of superolateral aspect of left kidney.
Ultrasound findings in B-mode imaging, CCDS, and CEUS.
Values are given as n/N (%) or median (IQR).
*Compared to regular renal cortex/parenchyma.Bold indicates p-value <0.05.
CCDS, color-coded duplex sonography; CEUS, contrast-enhanced ultrasound; IQR, interquartile range.
Overall, in 32 patients with renal alterations classified as developmental pseudotumors, nine neoplastic lesions were found during imaging follow-up (seven renal cell carcinomas, one oncocytoma, one metanephric adenoma) and CEUS correctly identified eight of these malignant lesions while missing one intraparenchymal oncocytoma < 2 cm. Thus, 22/23 developmental renal pseudotumors were diagnosed correctly. Based on long-term follow-up and cross-sectional imaging as standard of reference, CEUS had 89% sensitivity (95% CI = 57–98), 96% specificity (95% CI = 80–99), a PPV of 89% (95% CI = 57–98), and an NPV of 96% (95% CI = 79–99) for ruling out renal malignancy in developmental pseudotumors.
Discussion
Over the last decade, CEUS has become an established imaging method in the characterization of focal renal lesions (11). The results of the present study show CEUS to have high specificity in the diagnosis of renal malignancy in patients with developmental renal pseudotumors. Therefore, CEUS appears to be a suitable additional imaging method to rule out renal malignancy in patients with inconclusive findings on B-mode sonography. CEUS is time-efficient as well as patient-friendly and has the potential to provide the diagnosis directly after plain B-mode US.
A major B-mode US criterion for the diagnosis of pseudotumor is isoechogenicity compared to surrounding cortical parenchyma (12). Nevertheless, differences in echogenicity due to altered acoustic reflectivity caused by different tissue orientations may occur (9). While a hypertrophic column of Bertin does not distort the outer renal contour, neoplastic lesions (both benign and malignant) > 2 cm may deform the outer cortical surface and could therefore be recognized with B-mode US or CCDS (6). However, smaller lesions in a pseudotumor with the same echogenicity as surrounding tissue may not lead to any deformity of the renal surface and can only be characterized by CEUS enhancement patterns.
Studies performed before the advent of CEUS show both CCDS and PDI to be useful diagnostic tools for the work-up of unclear renal B-mode findings, confirming pseudotumor by the demonstration of a vessel structure similar to that of normal renal tissue (12,13). In pseudotumors, vascular branching is normal, and there is no mass effect, while an irregular vessel structure can be found in focal renal lesions (Fig. 2). However, these US techniques have poor sensitivity in small lesions as well as obese or uncooperative patients or when overlying bowel gas is present. For these reasons, CCDS and PDI may not consistently allow confident characterization and final diagnosis. An irregular vessel structure on CCDS and CEUS was found in 8/9 patients in our cohort with neoplasia and regular vascularization in all pseudotumors. In comparing our findings with older studies, one must bear in mind that ultrasound image quality and US hardware as well as evaluation of vascular structure using microflow imaging have improved considerably over the last years.
Clear cell renal carcinoma (asterisk) mimicking a pseudotumor in a renal transplant. (a) B-mode US shows a homogenous, isoechoic focal lesion in the upper pole of a renal transplant in the right iliac fossa. (b) CCDS shows no blood flow inside the pseudotumor because intratumoral vessels are compressed. (c) 30 sec after contrast injection, CEUS shows strong contrast enhancement of the lesion with central necrosis, thus confirming a neoplasm. CCDS, color-coded duplex sonography; CEUS, contrast-enhanced ultrasound; SMI, superb microvascular imaging; US, ultrasound.
Instead of referring a patient for CT or MRI, CEUS can be used immediately to elucidate unclear B-mode US findings. CEUS allows accurate distinction between true tumors/neoplasms and pseudotumors by real-time imaging. After administration of ultrasound contrast agent, a pseudotumor with regular vascular architecture remains isoechoic to normal renal parenchyma in all phases of enhancement (Fig. 3) (7,9,14), while renal neoplasms show different contrast enhancement patterns with early enhancement in the arterial phase or late-phase wash-out. In the present study, CEUS showed findings indicating neoplasm, compared to developmental pseudotumors, such as early enhancement (33.3% vs. 4.3%) and hyperenhancement (66.6% vs. 17.4%). The value of CEUS in the evaluation of pseudotumors was demonstrated by Ascenti et al. (9), who showed full agreement of CEUS and CT/MRI in 24 patients. While the combined information provided by microflow imaging (for depiction of vessel structure) and contrast enhancement patterns on CEUS allows identification of neoplasm in pseudotumors, one neoplasm in the present study was missed by both CEUS (and CECT) representing with no imaging abnormalities such as early/late enhancement, wash-out, or irregular vessel structure on CEUS and CCDS. This neoplasm was detected by follow-up CE-MRI, and histopathology confirmed a small oncocytoma. The combination of quantitative CEUS and acoustic radiation force impulse elastography can provide relevant information to further characterize CT-indeterminate renal masses and to guide urological decision making by offering the possibility to differentiate RCC from oncocytoma and to differentiate RCC subtypes (15). Especially in obese patients, CEUS findings should be considered with caution since contrast enhancement and peak intensity could be of less quality and influence diagnostic performance (16). Therefore, the combination of CEUS with additional cross-sectional imaging is unavoidable. As demonstrated by Beyer et al. (17) in 83 patients, there are fewer false-negative results when CEUS is combined with CE-MRI in the characterization of focal liver lesions.
Representative case of a developmental pseudotumor (with prominent column of Bertin, arrowheads) detected by B-mode US (a) and further characterized by CCDS and CEUS. (a) Focal cortical thickening of the mid-portion of the right kidney identified by B-mode US. (b) Microflow imaging tool SMI shows regular vascular architecture in the area of interest. (c) Regular arterial inflow without early enhancement on CEUS after injection of 1.6 mL Sonovue (Bracco). (d) No wash-out is depicted until 3 min after microbubble injection; the pseudotumor remains isoechogenic in the late phase. CCDS, color-coded duplex sonography; CEUS, contrast-enhanced ultrasound; SMI, superb microvascular imaging; US, ultrasound.
The use of newer US postprocessing techniques such as time-intensity curve (TIC) analysis may improve diagnostic performance and inter-observer agreement in the characterization of renal pseudotumors. So far, no study has reported quantitative image analysis of renal pseudotumors. For the liver, standardized dynamic CEUS protocols to determine the perfusion/microcirculation of focal lesions using quantitative analysis have been demonstrated to be a fast and easy-to-use diagnostic tool (18). Furthermore, quantitative analysis of CEUS can show different enhancement features in real time for differentiation of histological renal tumor subtypes and may be helpful in differential diagnosis and preoperative evaluation. In the evaluation of unclear neoplasm within a pseudotumor, TIC can differentiate neoplasia from pseudotumors, which should have the same intensity curves as surrounding renal parenchyma, and the quantitative evidence improves radiologists’ diagnostic confidence. In case of shrunken kidney, hypertrophic renal parenchyma may mimic a pseudotumor in terms of earlier and stronger contrast enhancement (such as regular parenchyma compared to lower contrast enhancement in atrophic renal parenchyma), while microflow imaging and PDI potentially demonstrate a regular vessel structure within the normal parenchyma. Therefore, we recommend examiners to interpret CEUS findings in conjunction with prior Doppler US or microflow imaging when examining patients with developmental renal pseudotumors.
In addition to its diagnostic value, CEUS has the huge advantage that the microbubbles used as contrast agent are well tolerated. Two large multicenter studies reported very low adverse event rates of 0.020% and 0.009%, each with > 20,000 patients who underwent CEUS with sulfur hexafluoride microbubbles (19,20). While several studies report similar diagnostic performance for CEUS and cross-sectional imaging modalities in the assessment of renal tumors, an economic analysis found CEUS to be a cost-effective replacement for CE-MRI in the characterization of incidentally detected focal liver lesions (21). CEUS is safe and easy to perform and overcomes the limitations of gray-scale ultrasound and CCDS. Thus, CEUS has been integrated into daily clinical routine because it is cost-effective and rapidly generates additional images without radiation exposure. Moreover, it is a safe tool because the microbubble contrast agent has no cardiac or renal toxicity and can be used in patients with chronic renal failure and thyroid dysfunction.
With regard to CE-MRI, there is evidence that gadolinium deposition is steadily increasing with the number of CE-MRI examinations performed in a patient (22,23). Nevertheless, its long-term effects regarding a pathogenesis are yet unknown, while to date there are no definitive clinical findings are associated with gadolinium deposition in brain tissue (22,24).
Concerns about CT contrast agents are more serious and reported incidences of contrast-induced nephropathy are in the range of 2%–12% (25). Additionally, it must be borne in mind that CT examinations involve radiation exposure. This can be avoided when CEUS is used, which is especially important in young patients.
The present study has several limitations. We performed a retrospective, single-center study evaluating renal alterations using CEUS imaging. However, we used a standardized protocol with up-to-date CEUS technology for renal US and CEUS; therefore, a prospective approach would not have made much of a difference. The multifrequency ultra-wideband transducers used in this study cover the same bandwidth as two conventional transducers and thus provide superior sensitivity and resolution for both near and far field in both B-mode US and CEUS. It is thus possible to use one transducer across a wider range of patient types, potentially providing better imaging regardless of patient habitus and insonation conditions. This may increase detection of lesions and visualization of microbubbles.
In conclusion, the findings of the present study show an excellent performance of CCDS and CEUS in the diagnosis and rule-out of renal neoplasm in patients with developmental renal pseudotumors. Additional CEUS, in particular, has the potential to reduce further, invasive diagnostic procedures in cases with a poor quality of CCDS/PDI due to the patients’ anatomy or otherwise inconclusiveness of the tumor entity in native sonography.
Footnotes
Declaration of conflicting interests
The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: TF reports having received consultancy honoraria from Bracco and Canon Medical Imaging; AM reports receiving consultancy honoraria from Canon Medical and Hitachi; BH reports having received consultancy honoraria from Canon Medical Imaging; and MHL reports having received consultancy honoraria from Siemens Healthineers.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
