|Year : 2015 | Volume
| Issue : 1 | Page : 41-45
Contrast-enhanced ultrasound in the diagnosis of solitary thyroid nodules
Zhang Yuan, Jiang Quan, Zhang Yunxiao, Chen Jian, He Zhu
Department of Ultrasound, Shanghai Pudong New Area People's Hospital, Pudong, Shanghai, China
|Date of Web Publication||16-Apr-2015|
Department of Ultrasound, Shanghai Pudong New Area People's Hospital, Pudong, Shanghai
Source of Support: None, Conflict of Interest: None
Objectives: The aim was to study the patterns of solitary thyroid nodule with real-time contrast-enhanced ultrasound (CEUS) and assess its value in differentiating between malignant and benign thyroid nodules.
Materials and Methods: Seventy-eight patients with solitary thyroid nodule (37 malignant, 41 benign) underwent real-time CEUS. The patterns of their enhancement were assessed from six aspects: Degree of enhancement, process of enhancement, homogeneity of enhancement, completeness of enhancement, boundary of the enhanced lesions, and shape of the enhanced lesions.
Results: Contrast-enhanced patterns were significantly different between benign and malignant thyroid nodules (P < 0.05), except for process of enhancement. The shape of most malignant lesions was irregular (94.59%), the boundary was unclear (86.49%) and had no significantly enhanced (78.38%). Most malignant lesions became inhomogeneously (78.38%) and incompletely enhanced (70.27%).
Conclusions: The patterns of real-time CEUS are significantly different between benign and malignant thyroid nodules, and have important clinical value.
Keywords: Contrast-enhanced ultrasonography, thyroid nodule, diagnosis, contrast-enhancement patterns
|How to cite this article:|
Yuan Z, Quan J, Yunxiao Z, Jian C, Zhu H. Contrast-enhanced ultrasound in the diagnosis of solitary thyroid nodules. J Can Res Ther 2015;11:41-5
| > Introduction|| |
Thyroid nodules are commonly encountered lesions and have been observed in 50% of autopsied patients.  The estimated annual incidence rate of 0.1% in the ultrasonography (US) suggests 300,000 newly diagnosed nodules as of 2005.  Although only 1 of 20 clinically identified nodules is malignant,  it is important to exclude the presence of a malignant thyroid lesion. ,
Previous studies have demonstrated the feasibility of contrast-enhanced ultrasonography (CEUS) for the differentiation of benign and malignant thyroid nodules.  Nemec et al. reported that the complete CEUS data of 42 patients (73.8%) benign and (26.2%) malignant nodules revealed a significant difference in enhancement between benign and malignant nodules. Furthermore, CEUS demonstrated sensitivity of 76.9%, specificity of 84.8% and accuracy of 82.6%. Quantitative analysis of CEUS using a microbubble contrast agent allows the differentiation of benign and malignant thyroid nodules and may potentially serve, in addition to grey-scale and Doppler ultrasound, as an adjunctive tool in the assessment of patients with thyroid nodules.  Hornung et al. reported that CEUS represents a highly sensitive method for the detection of the microvascularization of thyroid carcinomas. Future studies should compare these findings to benign pathologies in order to establish CEUS as a standard diagnostic procedure in the preoperative evaluation of suspicious thyroid nodules.  Zhang reported that contrast-enhanced US enhancement patterns were different in benign and malignant lesions. Ring enhancement was predictive of benign lesions, whereas heterogeneous enhancement was helpful for detecting malignant lesions. 
Our study focused on exploring the observed indicators of contrast-enhancement patterns of solitary thyroid nodules, and was designed to evaluate the diagnostic value between malignant and benign thyroid nodules.
| > Materials and methods|| |
The study was approved by the ethics committee of our hospital, and patients informed consent was obtained. From January 2012 to April 2013, 78 patients with thyroid nodules, 32 males and 46 females, average age (39.9 9ra. 5) years, minimum age 25 years, maximum 65 years, the diameter of nodule, size range: 9 ng mm, mean: (18.2 8ne. 5) mm, all of them were solitary lesions. Histology revealed that 37 patients had malignant tumors with 28 cases of papillary carcinoma and 9 cases of follicular carcinoma. It also showed that 41 cases of them were benign lesions with34 cases of thyroid adenoma and 7 cases of nodular goiter. All lesions were not diffuse thyroid disease, and were confirmed by surgical excision.
Siemens Sequoia 512 color Doppler ultrasound system unit (probe model 15 L8WS, with the band width of 8fdt MHz) was used to taking in a contrast pulse sequencing (CPS) ultrasound imaging mode. SonoVue (Bracco, Italy) 25 mg of lyophilized powder and 5 ml of 0.9% sodium chloride solution were configured into a suspension, and mixed uniformity. The Patients' necks were hyperextended to expose the thyroid area. Scanning was performed by one experienced sonographer, who was asked to evaluate the nodule location, size and Doppler flow signals. The standard view of CEUS was the section which showed the most abundant blood flow signals within the lesion by power Doppler and the whole thyroid nodule and as much of the surrounding thyroid as possible. Focus was located in the trailing edge of the lesion, and the gain was adjusted to display only the boundaries of the lesion. Then, CPS was started and 2.5 ml of US contrast agent was injected intravenously through the ulnar vein, followed by injection of 5 ml of normal saline flush. During the investigation, the position of the probe was fixed and the patient was asked to avoid swallowing and breath holding. The real-time dynamic images were stored in the ultrasonic instrument.
Real-time CEUS of thyroid nodules persist 3 min. The contrast-enhancement patterns of the lesions were assessed from the following six aspects: (1) Degree of enhancement: (category 1: enhancement was lower than the surrounding gland; category 2: lesion enhancement was similar to the surrounding gland; category 3: enhancement was greater than in the surrounding gland); (2) method of enhancement: centripetal enhancement and non-concentric (diffuse, eccentric) enhancement; (3) homogeneity of enhancement: inhomogeneous enhancement [Figure 1] and homogeneous enhancement; (4) completeness of enhancement: incomplete enhancement [Figure 2] and complete enhancement; the so-called complete enhancement refers that the entire lesion were filled with contrast medium, while incomplete enhancement refers that the lesion appear region without contrast agent filling in. (5) boundary of the enhanced lesions: blurred [Figure 3] and well-defined; (6) shape of the enhanced lesions: irregular [Figure 4] and regular.
|Figure 1: Contrast-enhanced ultrasound images of a 45-year-old male patient with a thyroid nodule of the left thyroid lobe, and images demonstrate homogeneous enhancement or heterogeneous enhancement|
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|Figure 2: Contrast-enhanced ultrasound images of a 38-year-old female patient with a thyroid nodule of the right thyroid lobe, and images demonstrate incomplete enhancement|
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|Figure 3: Contrast-enhanced ultrasound images of a 40-year-old female patient with a thyroid nodule of the left thyroid lobe, and images demonstrate boundary of the enhanced lesions: Blurred|
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|Figure 4: Contrast-enhanced ultrasound images of a 39-year-old female patient with a thyroid nodule of the right thyroid lobe, and images demonstrate shape of the enhanced lesions: Irregular|
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The contrast-enhancement patterns between malignant and benign solitary thyroid nodules were calculated by χ2 test using statistical software SAS 8.0, taking P < 0.05 to be a statistically significant difference.
| > Results|| |
The difference of contrast-enhancement patterns between malignant and benign about 78 cases of solitary thyroid nodules was shown in [Table 1]. All nodules were perfused with contrast agent. The differences of contrast-enhancement patterns between malignant and benign thyroid nodules in five aspects were statistically significant (P < 0.05), including degree of enhancement, homogeneity of enhancement, completeness of enhancement, boundary of the enhanced lesions, shape of the enhanced lesions, except for the anatomical pattern of enhancement (P > 0.05). Most contrast-enhancement patterns of malignant lesions were irregular (94.59%), blurred (86.49%), no significant enhancement (78.38%), inhomogeneous enhancement (78.38%) and incomplete enhancement (70.27%).
|Table 1: The difference of contrast enhancement patterns between malignant and benign about 78 cases of solitary thyroid nodules|
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The diagnostic value of contrast-enhancement patterns of malignant thyroid nodules were shown in [Table 2]. The differences in five aspects were statistically significant. Moreover, the specificity of no significantly enhancement and incomplete enhancement were extremely high with a percentage of 95.12% and 90.24% respectively, while the sensitivity of irregular lesions was 94.59%.
|Table 2: The diagnostic value of contrast enhancement patterns of malignant thyroid nodules (%)|
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| > Discussion|| |
Tumors are the typical lesions which depend on blood vessels. Recently, color Doppler and power Doppler have been the most commonly used methods to detect blood vessels of tumors. Their larger blood vessels can be displayed by Doppler ultrasound, but the micro-vessels with low speed and flow can't. SonoVue is stabilized microbubble preparation containing sulfur hexafluoride with an average diameter of 2.5 μm. Microbubble can flow in the microcirculation and resonate at a low mechanical index. The microvascular perfusion of the tumor can be displayed clearly by using low energy acoustic emission and pulse inversion harmonic imaging. CEUS has made a major improvement in the diagnosis and differential diagnosis of focal liver lesions. Previously, Bartolotta studied 18 cases of solitary thyroid nodule by CEUS, and the results showed that the diagnosis of thyroid nodules was feasible.  Our study focused on exploring the observed indicators of contrast-enhancement patterns of solitary thyroid nodules, and designed to evaluate diagnostic value between malignant and benign thyroid nodules.
The evaluation of solitary malignant and benign thyroid nodule with contrast-enhanced ultrasound
There are few reports on the studies of thyroid nodules with real-time CEUS at the moment. Most of the studies focused on exploring the morphological characterization and quantitative parameters of time/intensity curve. ,,,,,, This study focused on exploring the diagnostic efficacies and assessment indexes of the solitary thyroid nodule with real-time CEUS, and assessed in six aspects. The diagnostic criteria of suspicious malignant nodules was no significant, incomplete, inhomogeneous, blurred and irregular enhancement comparing with histology. The results showed the differences of contrast enhancement patterns between malignant and benign thyroid nodules in five aspects were statistically significant (P < 0.05), except method of enhancement. In the process of CEUS, the contrast enhancement patterns such as no significant, incomplete, inhomogeneous, blurred and irregular enhancement strongly suggested malignancy. No significant enhancement was the better specificity index in the diagnosis of malignant nodules, and irregular shape of the enhanced lesions was the better sensitivity index.
The possible pathological basis of thyroid nodules with contrast-enhanced ultrasound
In this study, 78.38% of malignant thyroid nodules showed no significant enhancement, and 95.12% of benign nodules were significantly enhancement. Bartolotta  investigated that enhancement patterns of thyroid nodules with SonoVue and found that enhancement patterns of thyroid nodules were closely related to lesion size. The size of malignant thyroid nodules <1 cm showed no significant enhancement. The size of malignant thyroid nodules between 1 and 2 cm displayed a small amount of contrast media in lesions, while the size of malignant thyroid nodules bigger than 2 cm demonstrated significantly enhancement. In our study, 37 cases of malignant lesions the size of 2 lesions was less than 1 cm, and 27 lesions were 1-2 cm, while only 8 lesions were bigger than 2 cm. Therefore, in our result, most malignant thyroid nodules showed no significant enhancement. This maybe because that when the tumor is small, they do not form a large number of tumor vascular bed, and the blood supply is not abundant, so they displayed no significant enhancement, [Figure 5] and [Figure 6]. Zheng et al. reported that thirty-five thyroid carcinoma presented three enhancement patterns with CEUS. Type I: twenty-three lesions enhanced in a pattern of ring with centripetal fill-in, however, the central part of no contrast agent filling. Type II: five lesions enhanced regularly and homogeneously. Type III: seven lesions enhanced irregularly and homogeneously.  The pathological sections of thyroid cancers revealed the number of sinusoids in cancerous tissue was higher than that in benign lesions, suggesting that malignant nodules enhanced less than benign nodules, which may be due to the following three aspects: (1) Although there were a large number of neovascularization in cancerous tissue, its malignant invasive growth would undermine the organizational structure, including a large number of blood vessels and hence the necrotic blood vessels in the lesions were more than the neovascularization. (2) Micro-thrombus might be existed in malignant lesions, and leaded to vascular stenosis or occlusion. (3) Most malignant blood vessels were in low efficacy, namely not all of the tumor blood vessels were in the open state and functional status, and the degree of contrast-enhancement depended on not only the number of blood vessels, shape, etc., but also the effectiveness of tumor blood vessels. The anatomy of vascular pathology in thyroid cancer was more complex, and generally, the neovascularization of malignant lesions were divided into peripheral and the central zone, and the vascular distribution of them was different. The blood vessels in the peripheral zone of the lesions were relatively dense, and the tumors invaded outward easily, these might be cause of the blurred and irregular enhancement. The blood vessels were relatively sparse in the central zone prone to incomplete or complete necrosis, neovascularization of the entire lesion were non-uniformity distribution, intricate disorders, these might be caused incomplete, inhomogeneous enhancement.
|Figure 5: histologic micrograph of a 42-year-old male patient with thyroid cancer, tumor size 1.5 cm, and it showed a small amount of vascular|
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|Figure 6: histologic micrograph of a 35-year-old female patient with thyroid cancer, tumor size 1.9 cm, and it displayed a small amount of vascular|
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The problems and shortcomings of this study of thyroid nodules with contrast-enhanced ultrasound
Thyroid nodules with real-time CEUS perfused rapidly and briefly. It was difficult to determine the contrast enhancement patterns of the lesions with the naked eye during the rapid process. In this study, the cine clips of CEUS were reviewed and analyzed repeatedly by experienced sonographer in order to assess the contrast-enhancement pattern accurately. In addition, this study explored only the lesion characterization of angiographic perfusion, and didn't involve washout period. Thus, the diagnostic indexes couldn't reflect the whole process and needed to be improved and supplemented further. The study did not include the more common clinical cystic nodules and multiple nodules, the contrast-enhancement patterns of them remained to have an in-depth study.
The study also found the contrast-enhancement pattern between malignant and benign thyroid nodules might be overlapped. Some contrast-enhancement patterns of benign nodules were malignant behavior, such as some benign nodules were inhomogeneous enhancement (14.63%), incomplete enhancement (9.76%), blurred (19.51%), irregular (12.20%), and the pathology of these benign nodules were nodular goiter by retrospective analysis, the reason might be nodular goiter experienced proliferative phase, and the follicular surrounded by fibrous tissue in the long process between proliferation and withdrawal alternately. Because of different phases of disease development, as well as various parts of nodular imbalance in hyperplasia and degeneration, vascular characterization was different in different periods of nodular hyperplasia. ,
| > Conclusion|| |
The differences of contrast-enhancement patterns between malignant and benign thyroid nodules in five aspects were significant, such as degree of enhancement, homogeneity of enhancement, completeness of enhancement, boundary of the enhanced lesions, shape of the enhanced lesions. These contrast-enhancement patterns contributed to the differential diagnosis of solitary thyroid nodule. However, the contrast-enhancement pattern between malignant and benign thyroid nodules might be overlapped, in the actual clinical work, medical history, baseline ultrasound and other imaging examination findings should be analyzed and determined comprehensively to improve diagnostic accuracy.
| > Acknowledgements|| |
This study was supported by the Shanghai Pudong New Area Health Plan Board of Health Science and Technology Project(No.PW2014A-23); Shanghai Pudong New Area Leading Talents Training Plan (No.PWR12012-02); Shanghai Health Bureau research projects (No. 20134059); Shanghai Pudong Science and Technology Innovation Fund (No. PKJ2012-Y56).
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
[Table 1], [Table 2]