Contrast-Enhanced Ultrasonography versus Contrast-Enhanced Magnetic Resonance Imaging in the Diagnosis of Mediastinal Tumors

ARTICLE IN PRESS Ultrasound in Med. & Biol., Vol. 00, No. 00, pp. 111, 2020 Copyright © 2020 World Federation for Ultrasound in Medicine & Biology. All rights reserved. Printed in the USA. All rights reserved. 0301-5629/$ - see front matter

https://doi.org/10.1016/j.ultrasmedbio.2020.10.005


Original Contribution CONTRAST-ENHANCED ULTRASONOGRAPHY VERSUS CONTRAST-ENHANCED MAGNETIC RESONANCE IMAGING IN THE DIAGNOSIS OF MEDIASTINAL TUMORS TAGEDPJUHONG PAN,* WENWEI CHEN,* HAIDONG ZHANG,y XINGYUE HUANG,* and XIN HUANG*TAGEDEN

* Department of Ultrasound, Renmin Hospital of Wuhan University, Wuhan, China; and y Department of Radiology, Renmin Hospital of Wuhan University, Wuhan, China (Received 18 June 2020; revised 9 September 2020; in final from 7 October 2020)

Abstract—The aim of the study was to evaluate and compare contrast-enhanced ultrasound (CEUS) and contrast-enhanced magnetic resonance imaging (CE-MRI) with respect to their value in the differential diagnosis between benign and malignant mediastinal tumors. Forty-two patients with mediastinal tumor underwent CEUS and CE-MRI respectively. The sensitivity, specificity, diagnostic coincidence rate, positive predictive value (PPV) and negative predictive value of the two methods were compared. The value of different enhancement patterns in the differential diagnosis of benign and malignant mediastinal tumors was analyzed. SonoLiver software was used to obtain the dynamic vascular pattern curve (DVPC) of the lesions, and parameters such as arrival time (AT), rise time (RT), time to peak (TTP), maximum intensity/peak intensity (IMAX) and quality of fit (QOF) were extracted from timeintensity curves for quantitative analysis. We found that (i) the specificity of CEUS was higher than that of CE-MRI, and the PPV and diagnostic coincidence rate of CEUS were equal to those of CE-MRI; (ii) the enhancement patterns and DVPC of CEUS differed between the benign and malignant groups, while there was no difference in CE-MRI enhancement intensity; and (iii) AT, RT and TTP in the malignant groups were significantly shorter, while IMAX was significantly higher. In conclusion, the application of quantitative parameters and DVPC of CEUS is worth popularizing. CEUS can be used as an effective alternative and complementary examination for patients who cannot undergo CE-MRI. (E-mail: [email protected]) © 2020 World Federation for Ultrasound in Medicine & Biology. All rights reserved. Key Words: Ultrasonography, Microbubble, Mediastinal tumors, Contrast-enhanced magnetic resonance imaging, Dynamic vascular pattern curve.

mediastinal tumors. Complete surgical excision is attempted in most malignant mediastinal tumors, whereas some types such as malignant lymphoma and germ cell tumor may exhibit a promising pathologic complete response to chemotherapy and radiotherapy. Pre-operative neoadjuvant chemoradiotherapy can be very helpful for advanced thymic epithelial tumors, and non-small cell lung cancer is sensitive to targeted therapy (Saito et al. 2016). Therefore, accurate pre-operative qualitative diagnosis can limit surgery to those patients with mediastinal tumor who might benefit from multimodality treatment and avoid potentially futile surgery, related morbidity and unnecessary costs. Magnetic resonance imaging (MRI), with high soft tissue resolution and powerful 3-D imaging technology, has been the preferred imaging modality, providing an important basis for clinicians to diagnose mediastinal tumors (Ackman 2015; Carter et al. 2017). Nevertheless,

INTRODUCTION Patients with mediastinal tumor can present with an insidious onset of symptoms in the early stage, and the histopathological compositions of mediastinal tumors are often complex and diverse (Azizad et al. 2016). Early diagnosis is very important for the management and prognosis of mediastinal tumors. Traditionally, conventional imaging such as X-ray, color Doppler ultrasound and routine computed tomography (CT) scan might play an important role in determining size, location, extension and possible diagnosis of mediastinal tumors, but there are still limitations in the differential diagnosis of benign and malignant tumors. As we all know, it is feasible to perform a watch-and-wait approach for some benign Address correspondence to: Wenwei Chen, Department of Ultrasound, Renmin Hospital of Wuhan University, Wuhan 430030, China. E-mail: [email protected]

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for some mediastinal tumors, routine MRI scan cannot distinguish well the lesions from the surrounding normal tissue or further determine the nature of the lesions. As a pretreatment examination method for mediastinal tumors, contrast-enhanced (CE)-MRI is widely recommended by clinicians for its advantages: First, it has superior soft tissue contrast resolution and more imaging sequences, especially the specific short time inversionrecovery (STIR) sequence, which is often performed to increase the conspicuity of the mediastinal tumors and surrounding adipose tissue and is deemed to be an excellent indication. Second, there are no artifacts of thoracic bony structures. Third, the multiplanar imaging (transverse, sagittal and coronal imaging) capabilities of contrast-enhanced magnetic resonance imaging (CE-MRI) facilitate visualization of the entire morphology of lesions and their spatial relationship to the surrounding large vessels and heart intuitively, as well as their aberrant large feeding arteries, which are vital for surgical planning. However, CE-MRI still has some disadvantages. For example, it is contraband for claustrophobics and patients with magnetic metal implants. In addition, children and patients with dyspnea have difficulty cooperating with the examination, or the image quality is poor because of the patients’ breathing and motion artifacts. Furthermore, it is well known that gadolinium, as a contrast agent, is contraindicated in patients with severe hepatic and renal dysfunction (Martin 2008). Finally, contrast administration is associated with the risk of hypersensitivity reactions and accumulation/retention in the central nervous system and other body areas (Runge 2016). Therefore, a tolerableand reliable alternative examination is needed for such patients. In fact, contrast-enhanced ultrasound (CEUS) is tolerable, radiation free, inexpensive and readily available, and allows dynamic imaging with high spatial resolution. Encouragingly, in recent years, the application of CEUS technology in liver (Tan et al. 2020), kidney and heart (Tang et al. 2015), prostate and breast (Nielsen Moody et al., 2017) and thyroid (Zhang et al. 2016) has advanced and has been validated in the differentiation of malignant from benign tumors. CEUS for the diagnosis of retroperitoneal, mediastinal and peripheral lung tumors has been performed in our department for nearly 10 y, and many outstanding results have been obtained (Li et al. 2011; Wu et al. 2015). However, to date, there have been few comparative studies of CEUS and CE-MRI in the diagnosis of mediastinal tumors. The aim of the study described here was to explore and directly compare the capabilities of the two methods in the differential diagnosis of benign and malignant mediastinal tumors by comparing the rates of coincidence of the two methods with the pathologic results, the different enhancement patterns of the two methods and the quantitative parameters of CEUS and the dynamic vascular pattern curve (DVPC).

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METHODS Study participants This research was approved by the ethics committee of Renmin Hospital of Wuhan University. It was a single-center study in which data were acquired prospectively, and an analysis was performed retrospectively. The entry criteria of this study were (i) no contraindications for CEUS and CE-MRI examinations; (ii) receipt of written informed consent before the study; (iii) a definitive diagnosis based on histopathological findings from surgical resection or percutaneous biopsy; and (iv) no chemotherapeutic or radiotherapeutic treatment before examination. Exclusion criteria included (i) the presence of contraindications to CEUS or CE-MRI or performance of only one of the pre-treatment examinations; (ii) CEUS or CE-MRI image quality insufficient to meet the diagnostic criteria; and (iii) no definitive pathologic results. On the basis of these criteria, 42 hospitalized patients with mediastinal tumor in the Department of Thoracic Surgery and Oncology of our hospital were recruited for this study from January 2015 to October 2019. There were 25 men and 17 women with a mean age of 49.6 § 10.2 y (range: 2176 y). Contrast-enhanced ultrasound Conventional ultrasound (US) and CEUS were performed with Esaote MyLab Twice ultrasonic diagnostic equipment coupled to a linear array 3- to 9-MHz transducer and a convex array 2- to 5-MHz transducer, equipped with the real-time Contrast Tune Imaging (CnTI) module (Esaote, Genoa, Italy). Conventional US. First, conventional US was performed to determine tumor size, shape, border, location, internal echogenicity and relationships with adjacent structures. The color Doppler window was focused on the mediastinal tumors to detect blood flow signals. CEUS. The optimal sound window was selected to avoid the ribs and gas. In addition, the focus and depth were adjusted to best visualize the lesions. CEUS was performed on all patients using a low mechanical index (0.08) to avoid disruption of microbubbles. A 2.4-mL bolus of a US blood pool contrast agent (SonoVue, Bracco, Milan, Italy) was injected into the antecubital vein, followed by a 5-mL saline flush; at the same time, the timer was started. All parameters were kept constant for this procedure, and all tumors were observed continuously for up to 4 min. The dynamic image was digitally stored on the hard disk of the machine for later analysis of enhancement patterns and acquisition of the DVPC.

ARTICLE IN PRESS CEUS vs. CE-MRI in diagnosis of mediastinal tumors
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CEUS imaging analysis. Contrast enhancement intensity of the mediastinal masses was assessed visually by comparison with the enhancement intensity of the surrounding adipose tissue in the peak stage. Then the semiquantitative classification of enhancement pattern was determined. Contrast enhancement intensity of the lesions was assessed visually by comparison with the enhancement intensity of the surrounding adipose tissue when the contrast medium in the lesions reached its peak. CEUS enhancement intensity was categorized into four grades: high, equal, low and no enhancement. We determined whether there was perfusion defect and whether the enhancement distribution was homogeneous, as well as the pattern of contrast agent entering the lesions (centripetal: enhancement from the edge or periphery of the mass toward the center; centrifugal: enhancement from the center of the mass toward the periphery; or decentralized: obviously enhanced in one decentralized area of the mass) (Kong et al. 2020). CEUS quantification was performed using SonoLiver software (TomTec Imaging Systems, Unterschleissheim, Germany), and DVPCs of all 42 lesions were obtained. Five perfusion parameters were extracted from timeintensity curves (TICs), including IMAX (maximum intensity within the analysis regions of interest in the lesion as well as that in the reference surrounding adipose tissue), QOF (quality of fit between raw data and theoretical curve), AT (contrast agent arrival time), RT (rise time, time from 10% to 90% of IMAX) and TTP (time to peak). The study was conducted in accordance with the guidelines and introduction published by the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) (Dietrich et al. 2012; Sidhu et al. 2018).

Contrast-enhanced magnetic resonance imaging All MRI examinations were performed with a 3.0-T superconducting MR scanner (Discovery MR750 Plus, GE Healthcare, Little Chalfont, England), using a sensitivity eight-channel phased-array surface coil, with patients in the supine position throughout the examination. The scan range was extended from the thoracic inlet to the adrenal glands.

Routine MRI scan. Before CE-MRI, conventional T1- and T2-weighted sagittal, coronal and axial images were obtained, with sequences using the following parameters: FSE sequence T1 weighted image (WI) (TR350550 ms, TE812 ms); FR-FSE sequence T2 WI (TR 4000 ms, TE 90-120 ms); STIR sequence (TR 4000 ms, TE 40 ms, TI 150 ms); 5-mm section thickness, 1.5-mm intersection gap; 320 £ 320-mm field of view.

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CE-MRI. The LAVA-FLex sequence (3-DGRET1 WI) was adopted using the following parameters: TR 640 ms, TE 9 ms, flip angle 15˚, 5-mm section thickness, 1.5-mm intersection gap, 320 £ 320-mm field of view. Multihance (Gd-BOPTA injection, Shanghai Bracco Sine Pharmaceutical Corp. Ltd., Shanghai, China) was administered intravenously at the rate of 3 mL/s (total dose: 0.1 mmol/kg wt) by using a power injector (MEDRAD, Spectris Solaris EP MR Injection System), followed by a 20-mL saline flush at the same rate. CE-MRI images were sequentially obtained 0, 30, 60, 90, 120, 150, 180, 210, 240, 270 and 300 s after administration of contrast material. All images were imported into GE AW 4.5 workstation for analysis. CE-MRI imaging analysis. All scans were retrospectively evaluated to determine lesion size and range, shape, location, margin, signal, enhancement pattern and other related imaging characteristics. Semiqualitative classification was done by visual assessment of the enhancement intensity of the lesions in comparison with the signal intensity of that under the same sequence of routine MRI: grade 1 = no enhancement (i.e., was defined as the same intensity with reference to the lesions under the same sequence of routine MRI); grade 2 = slightly enhanced (i.e., minimal or moderate enhancement, defined as a lowintensity or iso-intensity with reference to the muscle of the chest wall in the post-enhancement images by visual inspection); and grade 3 = significantly enhanced (i.e., high-intensity with reference to the muscle of the chest wall in the post-enhancement images by visual inspection). All CEUS and CE-MRI images were evaluated by two experienced sonologists and two senior radiologists (all with more than 10 y of experience), respectively, who were blinded to other imaging studies and the patients’ clinical information, including histopathology results. Thereafter, the qualitative diagnosis was made, and the enhancement patterns of CEUS and CE-MRI were determined. If there was disagreement between them, the final determination was made after discussion. The results were checked and recorded by two graduate students. Statistical analysis Statistical analysis was performed with SPSS Version 18.0 (IBM, Armonk, NY, USA). The pathologic results were taken as the diagnostic gold standard, and the coincidence rate, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (PLR) and negative likelihood ratio (NLR) of CEUS and CE-MRI in the diagnosis of

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mediastinal tumors were calculated. The parametric Student t-test was used to test the difference between the two means if the measurement data followed the normal distribution, whereas the non-parametric MannWhitney U-test was applied if the data did not follow the normal distribution. Normally distributed data were expressed as the mean § standard deviation. The x2-test (McNemar test) was used to compare enumeration data, and the consistency of the two means was evaluated using the k coefficient. The MantelHaenszel test (MH x2) was used to compare the enhancement patterns of CEUS and CE-MRI between benign and malignant mediastinal tumors. Results were considered statistically significant at p < 0.05. RESULTS Pathologic results Results for all 42 patients, including 15 benign and 27 malignant tumors, were verified by pathologic examinations after surgical resection or percutaneous biopsy. Specific pathologic types are summarized in Table 1. CEUS and CE-MRI findings US and CEUS appearance. Anterior mediastinal tumors were found in 23 cases (54.8%), and localized superior, middle or posterior mediastinal masses in 9, 4 and 6 cases, respectively. Tumor size varied from 43.6 £ 35.9 to 100.0 £ 85.7 mm, and the average longest diameter was 68.5 § 29.6 mm. A total of 31 mediastinal masses appeared as hypo-echoic and 3 appeared as hyper-echoic parenchymal lesions; 7 mixed tumors presented as cystic part combined with solid lesions or floating dotted echoes on US; 5 lesions were finally diagnosed as malignant tumors, including immature teratomas, thymic carcinomas complicated with necrosis and a neuroendocrine carcinoma. The other 2 mixed lesions was determined to be a mature teratoma and a nodular goiter. Only 1 case, which

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appeared anechoic, was confirmed as a lymphangioma. Irregular masses with ill-defined borders were found in 15 cases and were incompletely or completely wrapping adjacent great vessels, and there were 2 cases with tracheal airway compression. Oval or circular masses with ill-defined borders were found in 8 cases, 2 of which exhibited expansive growth with invasion of adjacent chest wall, and 2 of which had mild expansive growth with incomplete involvement of adjacent vessels. Oval or circular masses with welldefined borders were found in 19 cases, 4 of which caused compression of the heart or the great vessels to different degrees. CEUS revealed centripetal enhancement in 11 malignant lesions and 4 benign lesions, centrifugal enhancement in 7 malignant lesions and 3 benign lesions and decentralized enhancement in 9 malignant lesions and 6 benign lesions. There were no statistically significant differences in enhancement distribution between the two groups. CE-MRI observations. All CE-MRI results revealed the same location, shape, range and margin as US and CEUS, but with more complicated signal findings. Most lesions displayed heterogeneous hypo-, isoor hyper-signals on T1 WI and mainly heterogeneous hyper-signals on T2 WI. Heterogeneous slight or significant enhancement was seen in 18 cases, homogeneous slight or significant enhancement in 13 and no obvious enhancement in 11; one of which was finally diagnosed as a lymphangioma, the others of which were found to be corresponding to the regions with nodular hyper-signals on T2 WI. The longest diameter of all 42 tumors measured by CE-MRI was similar to that measured with US and CEUS (71.3 § 30.5 mm vs. 68.5 § 29.6 mm). Three oval masses with ill-defined borders that were diagnosed as invasive tumors by CE-MRI exhibited obliteration of a fat plane between the tumor and adjacent structures and accompanying peripheral feeding arteries, which exhibited no obvious compression or invasion on US or CEUS.

Table 1. Histopathological composition of benign and malignant mediastinal tumors Histologic origin

Pathologic type (benign)

n

Pathologic type (malignant)

n

Mesenchymal tissue

Thymoma Nodular goiter Hamartoma Reactive lymph nodes Fibroma Lymphangioma Mature teratoma

3 1 1 2 1 1 2

Thymic carcinoma

4

Schwannoma Neurofibroma Eosinophilic granuloma Chronic lymphohistitis

1 1 1 1

Malignant mesothelioma Non-Hodgkin’s lymphoma Malignant fibrous histiocytoma Liposarcoma Immature teratoma Seminoma Neuroendocrine carcinoma

1 5 1 1 3 2 1

Metastatic tumor

9

Embryonic reproductive system Nervous system Other origin

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Table 2. Comparison of CEUS and CE-MRI in the diagnosis of mediastinal tumors with the gold standard of pathologic diagnosis Pathologic diagnosis (n)

CEUS Malignant Benign CE-MRI Malignant Benign

Total

k Coefficient

Malignant

Benign

18 9

3 12

21 21

0.429

24 3

5 10

29 13

0.573

CEUS = contrast-enhanced ultrasound; CE-MRI = contrast-enhanced magnetic resonance imaging.

Comparison of CEUS and CE-MRI in the diagnosis of mediastinal tumors Diagnostic coincidence rate and k coefficient. For the population with mediastinal tumors, all lesions were completely detected by CEUS and CE-MRI. Compared with the pathologic results as the gold standard, the diagnostic coincidence rate of CEUS was 71.4% (k coefficient = 0.429), and that of CE-MRI was 80.9% (k coefficient = 0.573). This was considered moderate agreement. The results are outlined in Table 2. Capability for differentiating malignant from benign mediastinal tumors. In this study, the diagnostic sensitivity of CEUS versus CE-MRI was 66.7% versus 88.9%, the specificity was 80.0% versus 66.7% and the NPV was 57.1% versus 76.9%, respectively (p < 0.05); the differences were statistically significant. There were no differences in PPV, PLR and NLR between CEUS and CE-MRI, as the PPV were 85.7% versus 82.8%, the PLR was 3.33% versus 2.67%, and the NLR was 0.42% versus 0.33%, respectively (p > 0.05) (Table 3). Enhancement patterns of CEUS and CE-MRI in benign and malignant mediastinal tumors On the basis of the histopathological results, all 42 lesions were divided into two groups, benign group and malignant group, and the difference in enhancement intensity between CEUS and CE-MRI in the two groups was statistically analyzed. Most malignant mediastinal tumors had high enhancement (Fig. 1), while benign

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mediastinal tumors presented with high, equal, no or low enhancement (Fig. 2). Compared with the signal intensity of the lesions under the same sequence of routine MRI, CE-MRI enhancement intensity was categorized into three grades: grade 1 = no enhancement; grade 2 = slight enhancement; and grade 3 = significant enhancement. Both benign and malignant mediastinal tumors manifested complete high enhancement in CE-MRI (Fig. 3). The distribution of CEUS enhancement intensity differed between the benign and malignant groups (MH x2 = 4.594, p = 0.032), indicating that the enhancement intensity of CEUS was differed between benign and malignant mediastinal tumors (Table 4). Nevertheless, there was no significant difference in the distribution of CE-MRI enhancement intensity (MH x2 = 0.071, p = 0.79), which indicated that there was no difference in CE-MRI enhancement intensity between benign and malignant mediastinal tumors (Table 4). Quantitative evaluation and DVPCs of CEUS The quantitative parameters extracted from CEUS standard TICs, which were obtained using Sonoliver software, indicated that there were differences in IMAX, AT, RT and TTP between the benign and malignant groups (p < 0.001), AT, RT and TTP were significantly shorter in the malignant group than in the benign groups and IMAX was significantly higher in the malignant group than in the benign group, while there was no difference in QOF between the two groups (Table 5). In fact, real-time dynamic images could not be obtained with CE-MRI, so it was difficult to obtain relevant quantitative parameters. Moreover, the DVPC obtained with Sonoliver software had the typical DVPC shape of a malignant mediastinal tumor, with a monophasic positive wave with a steep rise and steep drop (Fig. 4d), while the typical DVPC of a benign tumor was a monophasic negative wave with a slow rise and slow fall (Fig. 5d). In addition, on the DVP color parameter map, the internal color of a malignant tumor was a heterogeneous red, with the ’’mosaic sign’’ (Fig. 4ac), while that of the benign tumor was more of a homogeneous blue (Fig. 5ac). DISCUSSION Mediastinal tumors may manifest with localizing symptoms secondary to tumor invasion or compression of

Table 3. Capability of CEUS and CE-MRI for differentiating malignant from benign mediastinal tumors

CEUS CE-MRI

Sensitivity

Specificity

Accuracy

PPV

NPV

PLR

NLR

66.7 88.9

80.0 66.7

71.4 80.9

85.7 82.8

57.1 76.9

3.33 2.67

0.42 0.33

CEUS = contrast-enhanced ultrasound; CE-MRI = contrast-enhanced magnetic resonance imaging; PPV = positive predictive value; NPV = negative predictive value; PLR = positive likelihood ratio; NLR = negative likelihood ratio.

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Fig. 1. Patient 1 was a 22-y-old man. CEUS contrast medium reached its peak at 29 s, with high enhancement of the superior mediastinal tumor (a). Immunohistochemical results indicated non-Hodgkin’s lymphoma (T lymphoblastoma) (b). Patient 2 was a 76-y-old man with a mass located in the right anterior mediastinum. The CEUS contrast medium reached its peak at 21 s, with high enhancement (c). The histopathological section indicates squamous cell carcinoma. CEUS = contrast-enhanced ultrasound.

Fig. 2. Patient 3 was a 21-y-old man with a mass in the anterior mediastinum. The CEUS contrast agent reached its peak at 34 s, with low enhancement (a). The histopathological section indicates eosinophilic granuloma. Patient 4 was a 57-yold woman with a posterior mediastinal tumor. The CEUS contrast agent reached its peak at 39 s, with low enhancement (c). The histopathological section indicates schwannoma. CEUS = contrast-enhanced ultrasound.

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Fig. 3. Patient 5 was a 64-y-old woman with non-Hodgkin’s lymphoma (diffuse large B-cell type) in the right superior mediastinum (ac). Patient 4 was a 57-y-old woman with a schwannoma in the posterior mediastinum (df). Patient 6 was a 36-y-old woman with chronic inflammation of the mediastinal lymphatic tissue (gi). All three cases exhibited low signal intensity on T1 WI imaging (a, d, g), and all exhibited significant enhancement on contrast-enhanced T1 WI (CE-T1 WI) imaging (b, e, h).

surrounding structures (chest discomfort, thoracalgia, cough, hemoptysis, hoarseness, Horner syndrome, superior vena cava obstruction syndrome and sudden Table 4. Enhancement patterns of CEUS and CE-MRI between benign and malignant mediastinal tumors(n) Mediastinal tumors

CEUS High Equal Low No CE-MRI Significant Slight No

MantelHaenszel x2

p

Malignant

Benign

21 2 4 0

6 5 2 2

4.594

0.032

16 2 9

7 6 2

0.071

0.79

CEUS = contrast-enhanced ultrasound; CE-MRI = contrast-enhanced magnetic resonance imaging.

bronchospasm) (Bekele et al. 2013; Carro et al. 2019; Almeida and Heller 2020) or systemic symptoms, which typically result from release of excess hormones, antibodies or cytokines such as in hypercalcemia from parathyroid adenoma or myasthenia gravis in thymoma (Azizad et al. 2016). Nevertheless, some patients may have non-specific clinical manifestations such as fever, dyspnea and dysphagia. Although the majority of tumors may be asymptomatic in the early stage, and some tumors have found accidentally on X-rays obtained for routine health examinations (Trousse and Avaro 2010) or preoperative examinations for other systemic diseases, for example, cardiovascular disease in an echocardiography. Considering its germination and development in terms of histoembryology, the mediastinum contains tissues and organs that are derived from three germ layers (endoderm, mesoderm and ectoderm) and go on to form various physiologic systems in the human body, such as the cardiac

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Table 5. Comparison of CEUS quantitative parameters between benign and malignant mediastinal tumors (x§S) Pathologic category

n

IMAX (%)

QOF (%)

AT (s)

RT (s)

TTP (s)

Benign Malignant t p

15 27

161.4 § 13.1* 297.6 § 33.7 14.986 <0.001

87.5 § 8.5 85.3 § 7.0 0.902 0.373

15.8 § 2.9 11.3 § 3.4 4.497 <0.001

25.2 § 4.4 14.5 § 3.2 8.233 <0.001

37.7 § 4.1 25.6 § 3.6 10.004 <0.001

IMAX = maximum intensity (peak intensity); QOF = quality of fit; AT = Time of arrival; RT = Rise time; TTP = time to peak. * Mean § standard deviation.

Fig. 4. Representative dynamic enhancement pattern of contrast-enhanced ultrasound images of malignant mediastinal tumor (ac) and dynamic vascular pattern curve (DVPC) (d). The patient was a 43-y-old man with an anterior mediastinal seminoma, accompanied by a high level of human chorionic gonadotropin. The internal color filling the tumor was a heterogeneous red, with the “mosaic” sign. (a) Early phase of perfusion. (b) Peak enhancement. (c) Wash-out. (d) The DVPC was a monophasic positive wave with a steep rise and steep drop.

and great vessels of the circulatory system, the trachea of the respiratory system, the esophagus of the digestive system, nervous system and immune system, which ultimately determine the complex origin and variety of mediastinal tumors. This characteristic is also reflected in the manifold histopathological results for benign and malignant mediastinal tumors. The anatomic location, shape and range of all 42 cases determined from multiple sonographic views were all consistent with CE-MRI or surgical findings in the present study. But some researchers (Wang et al. 2019) reported that the measurements of the mediastinal masses on US were significantly underestimated compared with those obtained by CT or CE-MRI because of being limited by bony parts of the thorax and pulmonary air. This inconsistency might be that our study had excluded huge masses, which were difficult to fully display. Given the well-known superiority of CE-MRI in

detecting foci of tumoral neoangiogenesis (Brennan et al. 2009), CE-MRI visualized well peripheral feeding arteries in this study, which was beneficial to further diagnosis of invasive tumors. Bhalla and Marom (2019) suggested that CE-MRI was more accurate in diagnosing invasion of the mediastinum and chest wall compared with CT and ultrasonography (US), and this was also consistent with our research because of its competence in soft tissue. Compared with CE-MRI, CEUS can provide different, complementary information and correlative parameters of tumors, and its advantages are obvious. First, the ultrasound contrast agent is microbubbles metabolized through the pulmonary circulation, which means it is tolerable and without hepatorenal toxicity (Gummadi et al., 2018). Second, CEUS could be used to observe the whole process of enhancement dynamically in real time as well as in any plane. And third, as a real blood pool

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Fig. 5. Representative dynamic enhancement pattern of contrast-enhanced ultrasound images of benign mediastinal tumor (ac) and dynamic vascular pattern curve (DVPC) curve (d). The patient was a 49-y-old male with a thymoma (AB type) in the right lateral anterior mediastinum. The internal color filling the tumor was mostly a homogeneous blue. (a) Early phase of perfusion. (b) peak enhancement. (c) Wash-out. The DVPC was a monophasic negative wave with a slow rise and slow fall (d).

tracer, ultrasound contrast agent circulates systematically, yet will not infiltrate the extracellular matrix. Microcirculatory perfusion in mediastinal tumors can be observed dynamically by CEUS in real time, and the quantitative parameters of tumor blood supply can be analyzed by post-processing software. In this study, the coincidence rate, PLR and NLR of CEUS in the diagnosis of mediastinal tumors were equal to those of CEMRI, while the specificity was higher than that of CEMRI, with lower sensitivity and negative predictive value. There could be several reasons based on analysis: (i) Intermittent scanning at several points in time is often adopted by CE-MRI to collect images, which may lead to the omission of characteristic changes over time to a certain extent, while CEUS employs real-time observation and continuous video recording so that the perfusion, distribution and clearance of contrast medium in the masses can be observed fully and repeatedly by sonographers, which is beneficial in improving the coincidence rate in diagnosis. (ii) Compared with the lowmolecular-weight contrast agent used in CE-MRI, SonoVue, the second-generation ultrasound contrast agent used in CEUS, can pass well through the blood circulation including the terminal capillary bed, but will not infiltrate outside the blood vessels. It can significantly enhance the blood flow signal based on backscattering. Furthermore, the sensitivity and specificity of CEUS in visualizing tumor neovascularization, deep tissue and small and slow blood flow were improved. (iii) The

CEUS enhancement pattern of benign mediastinal tumors, often characterized as ’’slow wash-in and slow wash-out,’’ provides sufficient time for sonographers to observe and is helpful in accurately estimating the dynamic changes of the perfusion and further improving the diagnostic coincidence rate. In our study, through comparison of the enhancement levels of the two modalities, it was found that the distribution of CEUS enhancement intensity differed significantly between benign and malignant groups. Most of the malignant groups exhibited high enhancement, while in the benign groups, there were various levels such as high, equal, low and no enhancement. Wang et al. (2019) reported that most malignant mediastinal tumors exhibit complete high enhancement, whereas most benign lesions exhibit incomplete, partial low or no enhancement. These results suggest that the different enhancement intensities of CEUS have important implications for the further differential diagnosis of mediastinal tumors. However, there was no significant difference in degree of enhancement of CE-MR between benign and malignant tumors. Although malignant tumors such as non-Hodgkin’s lymphoma appeared significantly enhanced, in this study, some benign lesions, such as posterior mediastinal schwannoma, and chronic inflammation of lymphoid tissue also exhibited obvious enhancement. Presumably the reason might be that the contrast agent used in CE-MRI has a low molecular weight and, thus, can easily infiltrate the intercellular

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space through vascular endothelial cells and then gradually deposit in the fibrous extracellular matrix of the tumors. Therefore, both benign and malignant lesions with a great deal of extracellular matrix can exhibit obvious enhancement. In addition, the vessels in tumor or inflammatory tissue are often leaky or incomplete, which makes it easier for a contrast agent to extravasate into the extravascular extracellular space. In this extracellular space, the gadolinium-based contrast agent increases the signal intensity of T1-weighted images. In this way, tissues with increased perfusion and vessel leakage stand out with respect to normally perfused tissue, which enhances less. Mowatt et al. (2013) also pointed out in a systematic review that benign diseases such as proliferative benign prostatic hyperplasia and prostatitis also exhibit marked enhancement after contrast agent administration, making CE-MRI less specific in the transition zone of the prostate, especially in older men. Moreover, CE-MRI is not real-time imaging in fact and cannot really compare the dynamic intensity of intratumoral contrast agent in real time as does CEUS. In a systematic review, Fr€ ohlich et al. (2015) reported that dynamic CEUS is the most sensitive noninvasive real-time examination that can quantitatively estimate perfusion of the parenchyma of organ systems and can distinguish benign from malignant tumors. In our study, quantitative parameters of CEUS such as AT, RT, TTP, IMAX and QOF, for all 42 cases of mediastinal tumor, were measured from the TIC using Sonoliver software and compared between benign and malignant groups. It was found that the time-dependent parameters, such as AT, RT and TTP, were significantly shorter in malignant group than in the benign group, indicating that the contrast medium entered malignant tumors faster and reached peak intensity rapidly, which may be related to the fact that the malignant tumors always have greater neovascularization, yet the neovascular smooth muscle is usually underdeveloped and sometimes composed of only endothelial cells. Furthermore, there are even arteriovenous shunts in some malignant tumors. All of these factors contribute significantly to a low-vascular-resistance circulation and fast wash-in as well as rapid peak perfusion of contrast medium. In addition, IMAX, which represents the maximum relative intensity of the lesions, was significantly higher in the malignant group than in the benign group, which was considered to be related to the larger diameter and density of blood vessels in malignant tumors than in benign lesions and the possibility that malignant tumors might release large quantities of angiogenic factor to stimulate the formation of peripheral and internal invasive capillaries to increase oxygen diffusion and nutrients permeated from the surrounding tissues to maintain their proliferation, progression and metastasis (Kong et al. 2020). Therefore, the perfusion

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of contrast agent in malignant tumors was characterized by a rapid flow rate and large volume of microbubbles. However, there was no significant difference in QOF between the two groups, and the QOF of all the lesions was higher than 75%, which guarantees the reliability of curve fitting of TIC. The DVP mode of Sonoliver software can display the perfusion distribution of the lesions, and reflect the distribution characteristics of contrast media at each point in the process of enhancement with color images (red and blue). At the same time, the enhancement pattern of the lesions and the dynamic change in intensity relative to the reference area can be reflected in the form of a curve, which makes the contrast between the lesions and the surrounding adipose tissue more intuitive than TICs. The results of the present study indicated that the typical DVPC of malignant mediastinal tumors was a monophasic positive wave with a steep rise and drop. As illustrated in Figure 4, the entire process resulted in high enhancement of inhomogeneity and fast wash-in and wash-out. This result may be associated with the greater neovascularization of malignant tumors and with uneven distribution, larger diameter and/or arteriovenous shunt. In conformity with our results, Li et al. (2014) reported that the DVPC of retroperitoneal malignant tumors was a monophasic wave with a downward opening, which was above the baseline, first up and then down, until close to the baseline. However, in our study the typical DVPC of benign mediastinal tumors was a monophasic negative wave with a slow rise and slow fall. As can be seen clearly in the dynamic color parameter map of the DVP mode of type AB thymoma in Figure 5, the entire process revealed low homogeneity enhancement, slow wash-in and slow washout, similar to the result verified by Kong et al. (2020) that CEUS of benign thymoma revealed homogeneous late enhancement. This might be explained by the less vascular distribution, more mature vascular smooth muscle as well as well-developed endothelial function and more stable hemodynamics in benign tumors. Several limitations of this study have to be considered. First, acquisition of mediastinal images with ultrasonography is often restricted by bony parts of the thorax and pulmonary air, so it is difficult to visualize small lesions with high quality through limited available acoustic windows. Therefore, there was a certain selection bias because our population included only patients with large lesions, the vast majority of which (76.2%, 32/42) were located in the superior or anterior mediastinum adjacent to the chest wall. Transesophageal echocardiography, which might provide more details (Li et al. 2016) in detecting tumors in the middle or posterior mediastinum with high quality, should be included to make the conclusions more convincing in future studies.

ARTICLE IN PRESS CEUS vs. CE-MRI in diagnosis of mediastinal tumors
J. PAN et al.

Second, this study examined a single center’s experience. Given the small number of patients and the variability in mediastinal tumor type, there was no subgrouping of benign and malignant tumors, and there was a lack of statistical analysis of the CEUS characteristics of lesions originating from different tissues, so further detailed investigations including larger numbers of patients with mediastinal tumors might be necessary. CONCLUSIONS The coincidence rate of CEUS in the diagnosis of mediastinal tumors was equivalent to that of CE-MRI. In contrast, the specificity of CEUS was significantly higher than that of CE-MRI. In addition, there were some differences in CEUS enhancement intensity and the DVPC between benign and malignant mediastinal tumors. Moreover, this study reported significant differences in quantitative parameters (IMAX, AT, RT and TTP), which might contribute to discrimination of malignant from benign mediastinal tumors and would be worth popularizing. Therefore, CEUS may be a helpful option, especially as an excellent effective alternative and complementary examination in patients with contraindications to CE-MRI. Conflict of interest disclosure—The authors declare that they have no competing interests.

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