Abdominal Imaging
ª Springer Science+Business Media New York 2014 Published online: 20 August 2014
Abdom Imaging (2015) 40:333–342 DOI: 10.1007/s00261-014-0221-y
Triphasic and epithelioid minimal fat renal angiomyolipoma and clear cell renal cell carcinoma: qualitative and quantitative CEUS characteristics and distinguishing features Qing Lu, Cui-xian Li, Bei-jian Huang, Li-yun Xue, Wen-ping Wang Department of Ultrasound, Shanghai Institute of Medical Imaging, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Shanghai 200032, China
Abstract Purpose: To determine the contrast-enhanced ultrasonography (CEUS) characteristics of minimal fat renal angiomyolipoma (AML) (triphasic and epithelioid) and compare them to each other and to clear cell renal cell carcinoma (ccRCC) to explore their differential diagnostic clue. Methods: Qualitative and quantitative CEUS analyses were retrospectively conducted for epithelioid renal AMLs (EAMLs) (n = 15), triphasic minimal fat AMLs (TAMLs) (n = 25), and ccRCCs (n = 113). Enhancement patterns and features with CEUS were qualitatively evaluated. As for the quantitative parameters, rise times (RT), time to peak (TTP), and tumor-to-cortex enhancement ratio (TOC ratio) were compared among these renal tumor histotypes. Results: No significant differences were detected on conventional ultrasound in the three histotypes of renal tumor. On qualitative CEUS analysis, centripetal enhancement in cortical phase (73.3% in EAMLs, 84.0% in TAMLs vs. 18.6% in ccRCCs, p < 0.001 for both), homogeneous peak enhancement (100.0% in both EAMLs and TAMLs vs. 43.4% in ccRCCs, p < 0.001 for both), and iso-enhancement in parenchyma phase (53.3% in AMLs, 52.0% in TAMLs vs. 26.5% in ccRCCs, p = 0.034 and 0.013, respectively) were valuable traits for differentiating EAMLs and TAMLs from ccRCCs. Furthermore, with quantitative analysis, RT and TTP were much shorter in ccRCCs than those in EAMLs and TAMLs. However, all these qualitative and quantitative Qing Lu and Cui-xian Li have contributed equally to the work. Correspondence to: Bei-jian Huang; email: huang.beijian@zs-hospital. sh.cn
characteristics made no significant difference between EAMLs and TAMLs. In the differential diagnosis of EAMLs from TAMLs, pseudocapsule sign was valuable (40.0% in EAMLs vs. 0.0% in TAMLs, p < 0.001), and TOC ratio was much higher in EAMLs (166.01 ± 64.47%) than that in TAMLs (93.74 ± 46.56%)(p < 0.001), though they did make overlaps with ccRCCs. With either heterogeneous peak enhancement or the presence of pseudocapsule or TOC ratio >97.34% as the criteria to differentiate ccRCCs and EAMLs from TAMLs, the sensitivity and specificity were 80.0% and 87.5%, respectively. Conclusions: Qualitative and quantitative CEUS analyses are helpful in the differential diagnosis of ccRCCs, EAMLs, and TAMLs. Key words: Minimal fat—Epithelioid angiomyolipoma—Contrast agent—Renal cell carcinoma—Ultrasonography
Angiomyolipoma (AML), consisted of variable amounts of smooth muscle, fat, and vascular tissue, is the most common benign renal neoplasm. According to sporadic studies, minimal fat renal AMLs, predominantly composed of smooth muscle [1], can cause a significant diagnostic dilemma due to the similarity with clear cell renal cell carcinoma (ccRCC) on radiology [2]. Previous investigators have described some imaging findings of minimal fat renal AML, including homogeneous and prolonged enhancement on contrast-enhanced computed tomography (CECT) [3] and slow centripetal homogeneous enhancement on contrast-enhanced ultrasonography (CEUS) [4]. However, owing to its rarity, these studies have the limitation of small case populations.
334
Q. Lu et al.: Triphasic and epithelioid minimal fat renal AML and ccRCC
Furthermore, epithelioid AML (EAML), composed of atypical epithelioid cells, is highly cellular and contains little or no fat. Thus the term ‘‘minimal fat AML’’ includes EAML and triphasic minimal fat AML (TAML). Because of its malignant potential [5, 6], EAML requires surgical treatment, just like ccRCC’s treatment strategy; however, TAML usually does not require surgical intervention unless it causes symptoms [7]. It is crucial to distinguish TAML from ccRCC and EAML to avoid unnecessary operation. To our best knowledge, there have been no literatures concerning the CEUS images of renal EAMLs and the differential diagnosis of TAML, EAML, and ccRCC. Thus, we conducted qualitative and quantitative CEUS analyses of these histotypes renal tumors, retrospectively, to assess the clinical value of CEUS in their differentiation.
examination, all patients received an intravenous bolus injection of 1.2 mL contrast agent (Sonovue; Bracco, Milan, Italy) followed by a 5 mL of 0.9% saline flush. Imaging settings were as follows: the only one focus was set below the tumor; time gain compensation was applied to provide background tissue noise minimization; frame rate 12–15 fps; mechanical index less than 0.1. The timer, equipped with the ultrasonographic system, was started at the moment of intravenous injection of Sonovue. Then, the renal lesion perfusion was evaluated in real time until 2–3 min after the injection. During the first minute, patients were asked to take slight half-fill breath to minimize the influence of breath on the quantitative CEUS analysis. Video clips of real-time CEUS were recorded on hard disk for off-line analysis and transferred as DICOM-files.
Materials and methods
Qualitative imaging interpretation and analysis
Patients
Qualitative imaging analyses were performed on the ultrasonographic system monitor, without any imaging settings altered, by two experienced radiologists blinded to the histopathology in consensus. On conventional ultrasound, lesion location and color flow signal were recorded. Lesion echogenicity was divided into hypoechoic, isoechoic, and hyperechoic regions compared with renal cortex. According to the contour of the renal margin, the lesions were classified as exophytic when they caused contour deformity in the renal margin and conversely, if not, as nonexophytic. The CEUS kidney assessment was divided into three phases after the beginning of Sonovue injection: cortical phase (8–20 s), parenchymal phase (20–120 s), and late phase (>120 s) [4]. The following CEUS features were observed and analyzed: (1) for enhancement degree: since it was difficult for patients to slight half-fill breath for a long time, the quantitative analysis of enhancement degree in parenchyma phase could not be conducted because of the influence of strong motion caused by breath. hyper-, iso-, and hypo-enhancement of renal lesions was compared with adjacent renal cortex in parenchyma phase. (2) For enhancement pattern: centripetal enhancement referred to enhancement from the lesion periphery to the center; entire enhancement occurred when both the peripheral and central area of the lesion were enhanced synchronously. (3) For enhancement feature at peak: homogeneous enhancement was defined as the appearance of a lesion occupied by a full enhancement of contrast agent, regardless of various enhancement degrees. On the contrary, heterogeneous enhancement was defined as the appearance of an enhanced lesion with areas without any enhancement. (4) On contrast-enhanced imaging, the presence of a pseudocapsule sign was defined as an enhanced rim of peritumoral tissue that appeared in the cortical phase and became more distinct in the parenchymal or late phase [8, 9].
The study institutional ethics committee approval was obtained to retrospectively review images and patient medical records. From Jan. 2006 to Jun. 2013, 501 nonconsecutive patients with 417 lesions suspected renal cell carcinoma underwent radical or partial nephrectomy within 2 weeks after CEUS examination. 45 minimal fat renal AMLs and 316 ccRCCs were pathologically confirmed. Among the 45 minimal fat AMLs, 40 were solid and 5 were solid-cystic on conventional ultrasound. Due to the small number of cases, solid-cystic lesions (n = 5) were excluded from analysis. The minimal fat renal AMLs included 15 EAMLs (maximum diameter 1.0–6.5 cm; mean 3.4 ± 1.8 cm) and 25 TAMLs (maximum diameter 1.5–6.0 cm; mean 3.6 ± 1.5 cm). Among the 316 ccRCC lesions, 113 demonstrated as solid on conventional ultrasound (diameter range 1.0–5.5 cm; mean 3.2 ± 1.4 cm). Each patient had only one lesion. Thus, 40 minimal fat renal AMLs (15 EAMLs [11 women and 4 men, age range, 19–70 years, 46.6 ± 16.5 years] and 25 TAMLs [16 women and 9 men, age range, 19–70 years, 37.9 ± 14.9 years]) and 113 ccRCCs [46 women and 67 men, age range, 23–74 years, 46.3 ± 18.4 years] were included in our study.
Ultrasonographic examination All patients underwent both conventional ultrasound and CEUS with one of the two ultrasonographic systems: E9 (GE Healthcare, England; C1-5, 1-5 MHz) and IU22 (Philips Medical Systems, The Netherlands; C5-1, 1-5 MHz), both equipped with pulse inversion harmonics as contrast-specific mode. The renal lesions were scanned by gray-scale and color Doppler ultrasound to obtain the tumor location, size, echogenicity, color flow signal, and the best imaging plane to demonstrate both lesions and normal adjacent renal parenchyma. Then, for CEUS
335
Q. Lu et al.: Triphasic and epithelioid minimal fat renal AML and ccRCC
Quantitative CEUS analysis The quantitative analysis, conducted with SonoLiver (Bracco Research SA, Geneva, Switzerland and TomTec Imaging Systems GmbH, Unterschleissheim, Germany), included three consecutive steps [10]. First, unwanted images were excluded from processing, such as out-ofplane images and images preceding contrast arrival. Second, a representative image which serves as a reference position for motion compensation, equipped with SonoLiver to minimize the influence of slight breathe on the quantitative analysis, was selected where the renal lesion is well delineated, generally at peak enhancement. Last, two regions of interest (ROIs) were manually drawn on the reference frame (on the contrast-enhanced images) at approximately the same depth. Analysis ROI, representing the area in which quantitative analysis was computed, should encompass the major enhanced solid portion of the lesions, regardless of its shape. Reference ROI was drawn in adjacent renal cortex with homogeneous enhancement [10]. The quantitative parameter included (1) maximum intensity (Imax), defined as the intensity on peak enhancement; (2) rise time (RT), defined as the time that the agents reach from 10% to 90% of Imax; (3) time to peak (TTP), defined as the time the lesion go up to Imax. The two time-related parameters were associated with the wash-in speed of contrast agent and showed a good stability in different depth; however, Imax would get variation by the influence of depth [11], so it was normalized using tumor-to-cortex enhancement ratio (TOC ratio) (Imax of lesions/cortex) to ensure that the peak intensity was independent of technical or individual variability.
Classification of AML subtypes All specimens surgically acquired were reviewed by a pathologist with more than 15 years of experience in genitourinary pathology. The histologic composition of
the tumors, cystic change, and necrosis were evaluated. Also, available immunohistochemical stains were reviewed. Furthermore, the epithelioid cell and fat content were estimated as the percentage of area occupied by epithelioid cells and fat vacuoles, respectively. EAML is composed of pure or near-total epithelioid cells, allowing a less than 10% microscopic focal adipocytic component [12]. TAML is defined as AML composed of thick-walled blood vessels, smooth muscle, and tiny proportion of microscopic adipose tissue, without any macroscopic fat. Therefore, ‘‘minimal fat renal AML’’ included EAML and TAML.
Statistical analysis Statistical analyses were performed using SPSS v.19.0 (SPSS Inc., Chicago, IL, USA). Average data were presented as mean ± standard deviation. The v2 test was used to compare TAML, EAML, and ccRCC in terms of enhancement pattern, enhancement degree, and homogeneity at peak. An independent sample t test was applied to compare the difference of quantitative parameters, including RT, TTP, and TOC ratio. For the features that played a statistically significant role in the differentiation diagnosis, we calculated sensitivity and specificity. A p value of less than 0.05 was considered to indicate a statistically significant difference.
Results Lesion pathology At pathologic examination, spindle cells accounted for the major cellular portion in TAMLs. As for the EAMLs, they were consisted of predominant epithelioid cells (the proportion 390%), which had pleomorphic and hyperchromatic nuclei with densely eosinophilic cytoplasm. Immunohistochemical findings were positive for melanin (reactive with HMB45 antibody, and positive for melan A) and smooth muscle markers (positive for a-smooth muscle-specific actin), but not for epithelial markers (cyto-
Table 1. Comparison of minimal fat AMLs (EAML and TAML) and ccRCCs on conventional ultrasound
Location Right (%, n) Left (%, n) EchogenIcity Hypoechoic (%, n) Isoechoic (%, n) Hyperechoic (%, n) Exophytic Yes (%, n) No (%, n) Color flow signal None (%, n) Little/rich (%, n)
EAML
TAML
ccRCC
53.3%, (8/15) 36.7%, (7/15)
56.0%, (14/25) 44.0%, (11/25)
69.0%, (78/113) 31.0%, (35/113)
73.3%, (11/15) 26.7%, (4/15) 0.0%, (0/15)
72.0%, (18/25) 24.0%, (6/25) 4.0%, (1/25)
59.3%, (67/113) 21.2%, (24/113) 19.5%, (22/113)
73.3%, (11/15) 26.7%, (4/15)
56.0%, (14/25) 44.0%, (11/25)
61.6%, (69/113) 38.4%, (43/113)
20.0%, (3/15) 80.0%, (12/15)
32.0%, (8/25) 68.0%, (17/25)
27.4%, (31/113) 72.6%, (82/113)
AML, angiomyolipoma; EAML, epithelioid angiomyolipoma; TAML, triphasic minimal fat angiomyolipoma; CEUS, contrast-enhanced ultrasonography; ccRCC, clear cell renal cell carcinoma
336
Q. Lu et al.: Triphasic and epithelioid minimal fat renal AML and ccRCC
Table 2. Comparison of minimal fat AMLs (EAML and TAML) and ccRCCs with CEUS EAMLs Enhancement pattern in cortical phase Centripetal enhancement Entire enhancement Homogeneity at peak enhancement Homogeneous enhancement Heterogeneous enhancement EchogenIcity in parenchymal phase Hypo-enhancement Iso-enhancement Hyper-enhancement Pseudocapsule sign
TAMLs
ccRCCs
73.3% (11/15) 26.7% (4/15)
84.0% (21/25) 16.0% (4/25)
18.6% (21/113) 81.4% (92/113)
100.0% (15/15) 0.0% (0/15)
100.0% (25/25) 0.0% (0/25)
43.4% (49/113) 56.6% (64/113)
33.3% 53.3% 13.3% 40.0%
(5/15) (8/15) (2/15) (6/15)
24.0% 52.0% 24.0% 0.0%
(6/25) (13/25) (6/25) (0/25)
61.1% 26.5% 12.4% 34.5%
(69/113) (30/113) (14/113) (39/113)
AML, angiomyolipoma; EAML, epithelioid angiomyolipoma; TAML, triphasic minimal fat angiomyolipoma; CEUS, contrast-enhanced ultrasonography; ccRCC, clear cell renal cell carcinoma
Fig. 1. A 58-year-old man with a hypoechoic mass in the left kidney. The preoperative diagnosis was RCC, but histopathology showed triphasic angiomyolipoma with predominant smooth muscle cells and the proportion of fat component less than 10%. A Conventional sonography showed a 35*28 mm heterogeneously hypoechoic mass in the left kidney low pole.
B At 15 s after Sonovue injection, the mass centripetally enhanced simultaneously with the renal cortex. C At 22 s, the mass enhanced homogeneously at its peak and to the same degree as renal cortex. D The mass showed simultaneous washed out pattern, and at 79 s, it showed iso-enhancement compared to the renal cortex.
keratin, epithelial membrane antigen), which made the definite diagnosis. All the EAMLs and TAMLs contained less than 10% fat scattered throughout with no single fat
focus larger than 5 mm. Cystic change or necrosis was detected in 74 ccRCCs; however, neither of them was detected in both TAMLs and EAMLs.
Q. Lu et al.: Triphasic and epithelioid minimal fat renal AML and ccRCC
Features with conventional ultrasound All lesions appeared as solid on conventional ultrasound without any anechoic regions throughout the lesions. The appearance of each lesion on conventional ultrasound is summarized in Table 1. There were no significant differences of imaging features among these three histotypes of renal tumors on conventional ultrasound.
Qualitative CEUS features There were no technical failures, such as wiggly recording, or adverse effects from the contrast agent in our study. The qualitative enhancement features among ccRCCs, EAMLs, and TAMLs are summarized in Table 2. Centripetal enhancement in cortical phase was much more common in EAMLs and TAMLs (Figs. 1, 2, 3) than that in ccRCCs (Fig. 4) (p < .001 and
ª Springer Science+Business Media New York 2014 Published online: 20 August 2014
Abdom Imaging (2015) 40:333–342 DOI: 10.1007/s00261-014-0221-y
Triphasic and epithelioid minimal fat renal angiomyolipoma and clear cell renal cell carcinoma: qualitative and quantitative CEUS characteristics and distinguishing features Qing Lu, Cui-xian Li, Bei-jian Huang, Li-yun Xue, Wen-ping Wang Department of Ultrasound, Shanghai Institute of Medical Imaging, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Shanghai 200032, China
Abstract Purpose: To determine the contrast-enhanced ultrasonography (CEUS) characteristics of minimal fat renal angiomyolipoma (AML) (triphasic and epithelioid) and compare them to each other and to clear cell renal cell carcinoma (ccRCC) to explore their differential diagnostic clue. Methods: Qualitative and quantitative CEUS analyses were retrospectively conducted for epithelioid renal AMLs (EAMLs) (n = 15), triphasic minimal fat AMLs (TAMLs) (n = 25), and ccRCCs (n = 113). Enhancement patterns and features with CEUS were qualitatively evaluated. As for the quantitative parameters, rise times (RT), time to peak (TTP), and tumor-to-cortex enhancement ratio (TOC ratio) were compared among these renal tumor histotypes. Results: No significant differences were detected on conventional ultrasound in the three histotypes of renal tumor. On qualitative CEUS analysis, centripetal enhancement in cortical phase (73.3% in EAMLs, 84.0% in TAMLs vs. 18.6% in ccRCCs, p < 0.001 for both), homogeneous peak enhancement (100.0% in both EAMLs and TAMLs vs. 43.4% in ccRCCs, p < 0.001 for both), and iso-enhancement in parenchyma phase (53.3% in AMLs, 52.0% in TAMLs vs. 26.5% in ccRCCs, p = 0.034 and 0.013, respectively) were valuable traits for differentiating EAMLs and TAMLs from ccRCCs. Furthermore, with quantitative analysis, RT and TTP were much shorter in ccRCCs than those in EAMLs and TAMLs. However, all these qualitative and quantitative Qing Lu and Cui-xian Li have contributed equally to the work. Correspondence to: Bei-jian Huang; email: huang.beijian@zs-hospital. sh.cn
characteristics made no significant difference between EAMLs and TAMLs. In the differential diagnosis of EAMLs from TAMLs, pseudocapsule sign was valuable (40.0% in EAMLs vs. 0.0% in TAMLs, p < 0.001), and TOC ratio was much higher in EAMLs (166.01 ± 64.47%) than that in TAMLs (93.74 ± 46.56%)(p < 0.001), though they did make overlaps with ccRCCs. With either heterogeneous peak enhancement or the presence of pseudocapsule or TOC ratio >97.34% as the criteria to differentiate ccRCCs and EAMLs from TAMLs, the sensitivity and specificity were 80.0% and 87.5%, respectively. Conclusions: Qualitative and quantitative CEUS analyses are helpful in the differential diagnosis of ccRCCs, EAMLs, and TAMLs. Key words: Minimal fat—Epithelioid angiomyolipoma—Contrast agent—Renal cell carcinoma—Ultrasonography
Angiomyolipoma (AML), consisted of variable amounts of smooth muscle, fat, and vascular tissue, is the most common benign renal neoplasm. According to sporadic studies, minimal fat renal AMLs, predominantly composed of smooth muscle [1], can cause a significant diagnostic dilemma due to the similarity with clear cell renal cell carcinoma (ccRCC) on radiology [2]. Previous investigators have described some imaging findings of minimal fat renal AML, including homogeneous and prolonged enhancement on contrast-enhanced computed tomography (CECT) [3] and slow centripetal homogeneous enhancement on contrast-enhanced ultrasonography (CEUS) [4]. However, owing to its rarity, these studies have the limitation of small case populations.
334
Q. Lu et al.: Triphasic and epithelioid minimal fat renal AML and ccRCC
Furthermore, epithelioid AML (EAML), composed of atypical epithelioid cells, is highly cellular and contains little or no fat. Thus the term ‘‘minimal fat AML’’ includes EAML and triphasic minimal fat AML (TAML). Because of its malignant potential [5, 6], EAML requires surgical treatment, just like ccRCC’s treatment strategy; however, TAML usually does not require surgical intervention unless it causes symptoms [7]. It is crucial to distinguish TAML from ccRCC and EAML to avoid unnecessary operation. To our best knowledge, there have been no literatures concerning the CEUS images of renal EAMLs and the differential diagnosis of TAML, EAML, and ccRCC. Thus, we conducted qualitative and quantitative CEUS analyses of these histotypes renal tumors, retrospectively, to assess the clinical value of CEUS in their differentiation.
examination, all patients received an intravenous bolus injection of 1.2 mL contrast agent (Sonovue; Bracco, Milan, Italy) followed by a 5 mL of 0.9% saline flush. Imaging settings were as follows: the only one focus was set below the tumor; time gain compensation was applied to provide background tissue noise minimization; frame rate 12–15 fps; mechanical index less than 0.1. The timer, equipped with the ultrasonographic system, was started at the moment of intravenous injection of Sonovue. Then, the renal lesion perfusion was evaluated in real time until 2–3 min after the injection. During the first minute, patients were asked to take slight half-fill breath to minimize the influence of breath on the quantitative CEUS analysis. Video clips of real-time CEUS were recorded on hard disk for off-line analysis and transferred as DICOM-files.
Materials and methods
Qualitative imaging interpretation and analysis
Patients
Qualitative imaging analyses were performed on the ultrasonographic system monitor, without any imaging settings altered, by two experienced radiologists blinded to the histopathology in consensus. On conventional ultrasound, lesion location and color flow signal were recorded. Lesion echogenicity was divided into hypoechoic, isoechoic, and hyperechoic regions compared with renal cortex. According to the contour of the renal margin, the lesions were classified as exophytic when they caused contour deformity in the renal margin and conversely, if not, as nonexophytic. The CEUS kidney assessment was divided into three phases after the beginning of Sonovue injection: cortical phase (8–20 s), parenchymal phase (20–120 s), and late phase (>120 s) [4]. The following CEUS features were observed and analyzed: (1) for enhancement degree: since it was difficult for patients to slight half-fill breath for a long time, the quantitative analysis of enhancement degree in parenchyma phase could not be conducted because of the influence of strong motion caused by breath. hyper-, iso-, and hypo-enhancement of renal lesions was compared with adjacent renal cortex in parenchyma phase. (2) For enhancement pattern: centripetal enhancement referred to enhancement from the lesion periphery to the center; entire enhancement occurred when both the peripheral and central area of the lesion were enhanced synchronously. (3) For enhancement feature at peak: homogeneous enhancement was defined as the appearance of a lesion occupied by a full enhancement of contrast agent, regardless of various enhancement degrees. On the contrary, heterogeneous enhancement was defined as the appearance of an enhanced lesion with areas without any enhancement. (4) On contrast-enhanced imaging, the presence of a pseudocapsule sign was defined as an enhanced rim of peritumoral tissue that appeared in the cortical phase and became more distinct in the parenchymal or late phase [8, 9].
The study institutional ethics committee approval was obtained to retrospectively review images and patient medical records. From Jan. 2006 to Jun. 2013, 501 nonconsecutive patients with 417 lesions suspected renal cell carcinoma underwent radical or partial nephrectomy within 2 weeks after CEUS examination. 45 minimal fat renal AMLs and 316 ccRCCs were pathologically confirmed. Among the 45 minimal fat AMLs, 40 were solid and 5 were solid-cystic on conventional ultrasound. Due to the small number of cases, solid-cystic lesions (n = 5) were excluded from analysis. The minimal fat renal AMLs included 15 EAMLs (maximum diameter 1.0–6.5 cm; mean 3.4 ± 1.8 cm) and 25 TAMLs (maximum diameter 1.5–6.0 cm; mean 3.6 ± 1.5 cm). Among the 316 ccRCC lesions, 113 demonstrated as solid on conventional ultrasound (diameter range 1.0–5.5 cm; mean 3.2 ± 1.4 cm). Each patient had only one lesion. Thus, 40 minimal fat renal AMLs (15 EAMLs [11 women and 4 men, age range, 19–70 years, 46.6 ± 16.5 years] and 25 TAMLs [16 women and 9 men, age range, 19–70 years, 37.9 ± 14.9 years]) and 113 ccRCCs [46 women and 67 men, age range, 23–74 years, 46.3 ± 18.4 years] were included in our study.
Ultrasonographic examination All patients underwent both conventional ultrasound and CEUS with one of the two ultrasonographic systems: E9 (GE Healthcare, England; C1-5, 1-5 MHz) and IU22 (Philips Medical Systems, The Netherlands; C5-1, 1-5 MHz), both equipped with pulse inversion harmonics as contrast-specific mode. The renal lesions were scanned by gray-scale and color Doppler ultrasound to obtain the tumor location, size, echogenicity, color flow signal, and the best imaging plane to demonstrate both lesions and normal adjacent renal parenchyma. Then, for CEUS
335
Q. Lu et al.: Triphasic and epithelioid minimal fat renal AML and ccRCC
Quantitative CEUS analysis The quantitative analysis, conducted with SonoLiver (Bracco Research SA, Geneva, Switzerland and TomTec Imaging Systems GmbH, Unterschleissheim, Germany), included three consecutive steps [10]. First, unwanted images were excluded from processing, such as out-ofplane images and images preceding contrast arrival. Second, a representative image which serves as a reference position for motion compensation, equipped with SonoLiver to minimize the influence of slight breathe on the quantitative analysis, was selected where the renal lesion is well delineated, generally at peak enhancement. Last, two regions of interest (ROIs) were manually drawn on the reference frame (on the contrast-enhanced images) at approximately the same depth. Analysis ROI, representing the area in which quantitative analysis was computed, should encompass the major enhanced solid portion of the lesions, regardless of its shape. Reference ROI was drawn in adjacent renal cortex with homogeneous enhancement [10]. The quantitative parameter included (1) maximum intensity (Imax), defined as the intensity on peak enhancement; (2) rise time (RT), defined as the time that the agents reach from 10% to 90% of Imax; (3) time to peak (TTP), defined as the time the lesion go up to Imax. The two time-related parameters were associated with the wash-in speed of contrast agent and showed a good stability in different depth; however, Imax would get variation by the influence of depth [11], so it was normalized using tumor-to-cortex enhancement ratio (TOC ratio) (Imax of lesions/cortex) to ensure that the peak intensity was independent of technical or individual variability.
Classification of AML subtypes All specimens surgically acquired were reviewed by a pathologist with more than 15 years of experience in genitourinary pathology. The histologic composition of
the tumors, cystic change, and necrosis were evaluated. Also, available immunohistochemical stains were reviewed. Furthermore, the epithelioid cell and fat content were estimated as the percentage of area occupied by epithelioid cells and fat vacuoles, respectively. EAML is composed of pure or near-total epithelioid cells, allowing a less than 10% microscopic focal adipocytic component [12]. TAML is defined as AML composed of thick-walled blood vessels, smooth muscle, and tiny proportion of microscopic adipose tissue, without any macroscopic fat. Therefore, ‘‘minimal fat renal AML’’ included EAML and TAML.
Statistical analysis Statistical analyses were performed using SPSS v.19.0 (SPSS Inc., Chicago, IL, USA). Average data were presented as mean ± standard deviation. The v2 test was used to compare TAML, EAML, and ccRCC in terms of enhancement pattern, enhancement degree, and homogeneity at peak. An independent sample t test was applied to compare the difference of quantitative parameters, including RT, TTP, and TOC ratio. For the features that played a statistically significant role in the differentiation diagnosis, we calculated sensitivity and specificity. A p value of less than 0.05 was considered to indicate a statistically significant difference.
Results Lesion pathology At pathologic examination, spindle cells accounted for the major cellular portion in TAMLs. As for the EAMLs, they were consisted of predominant epithelioid cells (the proportion 390%), which had pleomorphic and hyperchromatic nuclei with densely eosinophilic cytoplasm. Immunohistochemical findings were positive for melanin (reactive with HMB45 antibody, and positive for melan A) and smooth muscle markers (positive for a-smooth muscle-specific actin), but not for epithelial markers (cyto-
Table 1. Comparison of minimal fat AMLs (EAML and TAML) and ccRCCs on conventional ultrasound
Location Right (%, n) Left (%, n) EchogenIcity Hypoechoic (%, n) Isoechoic (%, n) Hyperechoic (%, n) Exophytic Yes (%, n) No (%, n) Color flow signal None (%, n) Little/rich (%, n)
EAML
TAML
ccRCC
53.3%, (8/15) 36.7%, (7/15)
56.0%, (14/25) 44.0%, (11/25)
69.0%, (78/113) 31.0%, (35/113)
73.3%, (11/15) 26.7%, (4/15) 0.0%, (0/15)
72.0%, (18/25) 24.0%, (6/25) 4.0%, (1/25)
59.3%, (67/113) 21.2%, (24/113) 19.5%, (22/113)
73.3%, (11/15) 26.7%, (4/15)
56.0%, (14/25) 44.0%, (11/25)
61.6%, (69/113) 38.4%, (43/113)
20.0%, (3/15) 80.0%, (12/15)
32.0%, (8/25) 68.0%, (17/25)
27.4%, (31/113) 72.6%, (82/113)
AML, angiomyolipoma; EAML, epithelioid angiomyolipoma; TAML, triphasic minimal fat angiomyolipoma; CEUS, contrast-enhanced ultrasonography; ccRCC, clear cell renal cell carcinoma
336
Q. Lu et al.: Triphasic and epithelioid minimal fat renal AML and ccRCC
Table 2. Comparison of minimal fat AMLs (EAML and TAML) and ccRCCs with CEUS EAMLs Enhancement pattern in cortical phase Centripetal enhancement Entire enhancement Homogeneity at peak enhancement Homogeneous enhancement Heterogeneous enhancement EchogenIcity in parenchymal phase Hypo-enhancement Iso-enhancement Hyper-enhancement Pseudocapsule sign
TAMLs
ccRCCs
73.3% (11/15) 26.7% (4/15)
84.0% (21/25) 16.0% (4/25)
18.6% (21/113) 81.4% (92/113)
100.0% (15/15) 0.0% (0/15)
100.0% (25/25) 0.0% (0/25)
43.4% (49/113) 56.6% (64/113)
33.3% 53.3% 13.3% 40.0%
(5/15) (8/15) (2/15) (6/15)
24.0% 52.0% 24.0% 0.0%
(6/25) (13/25) (6/25) (0/25)
61.1% 26.5% 12.4% 34.5%
(69/113) (30/113) (14/113) (39/113)
AML, angiomyolipoma; EAML, epithelioid angiomyolipoma; TAML, triphasic minimal fat angiomyolipoma; CEUS, contrast-enhanced ultrasonography; ccRCC, clear cell renal cell carcinoma
Fig. 1. A 58-year-old man with a hypoechoic mass in the left kidney. The preoperative diagnosis was RCC, but histopathology showed triphasic angiomyolipoma with predominant smooth muscle cells and the proportion of fat component less than 10%. A Conventional sonography showed a 35*28 mm heterogeneously hypoechoic mass in the left kidney low pole.
B At 15 s after Sonovue injection, the mass centripetally enhanced simultaneously with the renal cortex. C At 22 s, the mass enhanced homogeneously at its peak and to the same degree as renal cortex. D The mass showed simultaneous washed out pattern, and at 79 s, it showed iso-enhancement compared to the renal cortex.
keratin, epithelial membrane antigen), which made the definite diagnosis. All the EAMLs and TAMLs contained less than 10% fat scattered throughout with no single fat
focus larger than 5 mm. Cystic change or necrosis was detected in 74 ccRCCs; however, neither of them was detected in both TAMLs and EAMLs.
Q. Lu et al.: Triphasic and epithelioid minimal fat renal AML and ccRCC
Features with conventional ultrasound All lesions appeared as solid on conventional ultrasound without any anechoic regions throughout the lesions. The appearance of each lesion on conventional ultrasound is summarized in Table 1. There were no significant differences of imaging features among these three histotypes of renal tumors on conventional ultrasound.
Qualitative CEUS features There were no technical failures, such as wiggly recording, or adverse effects from the contrast agent in our study. The qualitative enhancement features among ccRCCs, EAMLs, and TAMLs are summarized in Table 2. Centripetal enhancement in cortical phase was much more common in EAMLs and TAMLs (Figs. 1, 2, 3) than that in ccRCCs (Fig. 4) (p < .001 and
