Contrast-Enhanced Sonography of Thyroid Nodules Jue Jiang, MD, Lili Huang, MM, Hongli Zhang, MM, Wenqi Ma, MM, Xue Shang, MD, Qi Zhou, MD, Ya Gao, MD, Shanshan Yu, MD, Yanhua Qi, MD Department of Ultrasound, The Second Affiliated Hospital, Medical School of Xi’an Jiaotong University, Xi’an 710004, China Received 21 March 2014; accepted 22 July 2014

ABSTRACT: Purpose. To investigate the value of contrast-enhanced ultrasound (CEUS) in the differentiation of benign and malignant nodules. Methods. One hundred eighty-nine patients with 213 thyroid nodules were enrolled in this retrospective study. All patients underwent preoperative CEUS and were subsequently scheduled for surgery. The pathology results were obtained after surgery. The time-intensity curves were plotted with TomTec software. The quantitative parameters of the timeintensity curve, such as the maximum intensity of peak (IMAX), the rise time from 10% to 90% of the IMAX, and the time to peak, were compared between the benign and malignant nodules. Results. There were no significant differences in the rise time or the time to peak among thyroid papillary carcinoma, nodular goiter, and follicular adenoma. However, a significant difference was identified in the IMAX. Conclusions. A quantitative evaluation of CEUS is helpful to differentiate benign and malignant thyroid C 2014 Wiley Periodicals, Inc. J Clin Ultranodules. V sound 00:000–000, 2014; Published online in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/ jcu.22240 Keywords: contrast agents; cancer; goiter; follicular adenoma; time-intensity curve; quantitative parameter; thyroid; ultrasonography

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onventional two-dimensional ultrasound (US) can differentiate benign and malignant thyroid nodules only by their morphologic characteristics, which leads to limited differential diagnostic value, especially for tiny lesions. In recent years, with the increasingly widespread application of novel contrast agents, convenCorrespondence to: Q. Zhou C 2014 Wiley Periodicals, Inc. V

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tional two-dimensional US combined with contrast-enhanced US (CEUS) has been more widely performed. The quantitative evaluation of CEUS can quantitatively evaluate the blood perfusion characteristics of benign and malignant lesions to assess the angiogenesis situation.1 Furthermore, it has also been used to differentiate thyroid papillary microcarcinoma, nodular goiter, and follicular adenoma, thereby significantly improving the clinical differential diagnosis of benign and malignant thyroid nodules.2 However, CEUS requires greater diagnostic skill of physicians and is easily affected by a physician’s subjective consciousness. To date, related studies on the quantitative evaluation of CEUS for the differentiation of benign and malignant thyroid nodules have rarely been reported. Only one similar study has been reported by Nemec et al.3 In their study, 46 patients with solitary, scintigraphically nonfunctional thyroid nodules were enrolled to undergo preoperative CEUS. The time-intensity curves (TIC) of benign and malignant nodules were compared via peak and washout enhancements, and a receiver operating characteristic curve analysis was performed to assess the diagnostic accuracy. The results indicated a significant difference in enhancement between benign and malignant nodules. Furthermore, the sensitivity, specificity, and accuracy of the quantitative evaluation of CEUS for the differentiation between benign and malignant thyroid nodules were 76.9%, 84.8%, and 82.6%, respectively. In this study, the TIC pattern and several quantitative parameters (the maximum intensity of peak [IMAX], the rise time from 10% to 90% of the IMAX [RT], and the time to peak 1

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[TTP]) in benign and malignant thyroid nodules were further investigated in patients.

acquired, including the IMAX, the RT, and the TTP. Statistical Analysis

PATIENTS AND METHODS

Subjects Patients with thyroid nodules were recruited from March 2009 to March 2012 in the Second Affiliated Hospital of Xi’an Jiaotong University. A preoperative CEUS examination was performed on all patients who were subsequently scheduled for surgery. The pathology results were obtained after surgery. Informed consent was obtained from all of the patients. Materials and Methods An Acuson Sequoia 512 with a 15L8W broadband linear array probe produced by Siemens Company (Erlangen, Germany) was used for the examinations. A routine US examination of the thyroid nodules was first performed to select the appropriate section; ie, we attempted to choose the long-axis section of the thyroid to ensure that the complete lesion and surrounding normal tissues were displayed simultaneously within a section. For a large tumor, the short-axis section and the contralateral normal thyroid were used as a control. The location, number, boundary, shape, internal echogenicity, anteroposterior–transversediameter ratio, and calcification of the nodules and their surrounding lymph nodes were observed. Contrast pulse sequencing was subsequently performed with a probe frequency of 7.0 MHz and mechanical index of 0.32. The contrast agent used was Sonovue (Bracco Inc., Milan, Italy). The 2.4 ml of contrast was administered via a superficial vein, followed by 5 ml saline. The patients were asked to breathe quietly and to not swallow during the inspection; the dynamic contrast-enhanced process was then initiated. The images were observed and recorded for 2 minutes. Finally, the data were automatically collected and stored on the machine’s hard drive. The dynamic contrast-enhanced images were input into TomTec software (TomTec GmbH, Munich, Germany) for quantitative analysis. To avoid individual errors, the most significant contrast-enhanced lesions were chosen for comparison with the adjacent normal thyroid tissues. The contrast enhancement in the region of interest of the normal thyroid gland tissue was set at 100. The TICs were plotted with the software, and several quantitative parameters were 2

Statistical analysis was performed by using the SPSS 13.0 statistical software package. The data were expressed as the mean 6 SD. Continuous variables were examined with t tests; p < 0.05 was considered significant.

RESULTS

Clinical Data One hundred eighty-nine patients with thyroid nodules, who were 18–72 years old (mean, 46 years), were recruited in this study, which included 59 men and 130 women. There were a total of 213 nodules in these patients, with a diameter of 4–42 mm (mean, 15 6 4 mm), which included 107 nodules in the left lobes and 106 nodules in the right lobes. According to the pathologic classifications, the 2013 nodules comprised 68 thyroid papillary carcinomas, 98 nodular goiters, and 47 follicular adenomas were identified. TICs of Benign and Malignant Thyroid Nodules The TICs of the thyroid papillary carcinomas were predominately characterized by a slow signal increase, with the peak value lower than that of the surrounding normal thyroid tissues (Figure 1). The nodular goiters predominantly demonstrated a rapid signal increase and the same peak value as the surrounding normal thyroid tissues. The TICs of the follicular adenomas were predominately characterized by a rapid signal increase and a higher peak value than that of the surrounding normal thyroid tissues. Comparative Analysis of the Quantitative Parameters of Benign and Malignant Thyroid Nodules As shown in Table 1, the quantitative parameters of the TIC were analyzed. There was a significant difference in the IMAX between the benign and malignant nodules. However, no significant differences in the RT or the TTP were identified. To further illustrate the differences between the benign and malignant nodules, we categorized the thyroid nodules into thyroid papillary carcinoma, nodular goiter, and follicular adenoma. As shown JOURNAL OF CLINICAL ULTRASOUND

CEUS OF THE THYROID

FIGURE 1. Imaging and time-intensity curves of different thyroid nodules using contrast-enhanced ultrasound. (A, C, E) Sonograms show (A) papillary carcinoma, (C) nodular goiter, and (E) follicular adenoma. (B, D, and F) are time-intensity curve of (B) thyroid papillary carcinoma, (D) nodular goiter, and (F) follicular adenoma. The green curve represents the lesion, and the yellow curve represents the normal thyroid tissue. The curve of the nodular goiter was predominantly characterized by a rapid signal increase and the same peak value as in the surrounding normal thyroid tissues, whereas the follicular adenoma was predominately characterized by a rapid signal increase and a higher peak value than that of the surrounding normal thyroid tissues.

TABLE 1 Quantitative Parameters of Time-Intensity Curves in Thyroid Nodules Malignant Nodules

Benign Nodules

Parameter IMAX RT (s) TTP (s)

Nodular Goiter

Follicular Adenoma

Total

Thyroid Papillary Carcinoma

1036 4 12 6 1 14 6 1

132 6 19 13 6 1 14 6 1

121 6 17 13 6 1 14 6 1

84 6 9* 14 6 1 17 6 1

Abbreviations: IMAX, maximum intensity of peak; RT, rise time from 10% to 90% of IMAX; TTP, time to peak. *p < 0.05 versus benign nodules, t test.

in Table 1, there were also no significant differences in the RT or the TTP among thyroid papillary carcinoma, nodular goiter, and follicular adenoma, but a significant difference in the IMAX was identified. DISCUSSION

The CEUS quantitative analysis technique is currently becoming one of the newest technologies in China, and it can be used for the quantitative evaluation of blood perfusion in solid VOL. 00, NO. 00, MONTH 2014

organs. The kinetics of the microbubble echocontrast agent in the vessels is similar to its kinetics in red blood cells; therefore, the number of microbubbles that reach the organs and their access speed (ie, the acoustic contrastenhanced intensity and its variation with time) may reflect the state of microcirculation perfusion.4 When a lesion occurs in the organ, the local blood perfusion may change.5 Because the blood perfusion state of a thyroid nodule is related to its vessel number, structure, and distribution, the TICs and quantitative parameters of different thyroid nodules are different. The ascending and descending branches of the TIC will reflect the changes of microbubble velocity and flow capacity with time, and the peak of the TIC will reflect the amount of tumor vascular bed, which correlates well with the blood perfusion of tissues.6 In this study, the diameters of 40 of thyroid papillary carcinoma were less than 1 cm. In these cases, the arteriovenous fistula in the center of the tumor had not yet formed, and the peripheral new vessels were thin; thus, the thyroid papillary carcinoma presented the status of decreased blood flow.7 In thyroid papillary carcinoma greater than 3

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1 cm, necrosis, fibrosis, and calcification often occur, which result in a low microvessel density (MVD). Therefore, the TICs of thyroid papillary carcinomas demonstrated a slow inflow and a low peak value pattern, compared with that of the surrounding normal thyroid tissues. Nodular goiter has a primarily bilateral, diffuse distribution. It does not have a complete fibrous capsule, and the parenchymal part is predominantly normal thyroid tissue. Therefore, the blood supply and distribution of a nodular goiter are similar to those in a normal thyroid. The TICs of the nodular goiters exhibited a pattern of rapid inflow, which quickly reached its peak value and had the same peak value as the normal thyroid tissues. Because the blood supply of thyroid follicular adenoma is richer than it is in the surrounding normal thyroid tissues, and the vessel distribution is regular with few vessels destroyed by the tumor, the TICs of the follicular adenomas de4monstrated rapid inflow and a higher peak value pattern than did the surrounding normal thyroid tissues. Our study has demonstrated that there was a significant difference in the IMAX between benign and malignant nodules. This finding may be attributable to the differences in the MVD. Some scholars have demonstrated that the IMAX is positively correlated with the MVD.8 Nodular goiter is a nodular, hyperplastic lesion formed by focal proliferation as a result of iodine deficiency and iodine supplementation, involution, and recurrent attacks of illness.9 Although it is characterized by a proliferative phase and stationary phase of resin accumulation and is enwrapped by surrounding fibrous tissue layers, it has the same MVD as that of normal thyroid tissues.9 Furthermore, the MVD of thyroid papillary carcinoma is certified as low, whereas the MVD of thyroid follicular adenoma is considered high.10 Our results indicated that there were no significant differences in the RT or the TTP between thyroid papillary carcinoma, nodular goiter, and follicular adenoma. The potential reasons are as follows. First, an insufficient sample size resulted in the absence of a significant difference. Second, nodular goiter and follicular adenoma are not typically a single lesion but are often combined lesions that accompany

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Hashimoto’s thyroiditis, methylene inflammatory disease, and hyperthyroidism. In conclusion, a quantitative evaluation by using CEUS is helpful in differentiating between benign and malignant nodules.

REFERENCES 1. Greis C. Quantitative evaluation of microvascular blood flow by contrast-enhanced ultrasound (CEUS). Clin Hemorheol Microcirc 2011;49:137. 2. Bartolotta TV, Midiri M, Galia M, et al. Qualitative and quantitative evaluation of solitary thyroid nodules with contrast-enhanced ultrasound: initial results. Eur Radiol 2006;16:2234. 3. Nemec U, Nemec SF, Novotny C, et al. Quantitative evaluation of contrast-enhanced ultrasound after intravenous administration of a microbubble contrast agent for differentiation of benign and malignant thyroid nodules: assessment of diagnostic accuracy. Eur Radiol 2012;22:1357. 4. Schwarz KQ, Chen X, Bezante GP, et al. The Doppler kinetics of microbubble echo contrast. Ultrasound Med Biol 1996;22:453. 5. Kogan P, Johnson KA, Feingold S, et al. Validation of dynamic contrast-enhanced ultrasound in rodent kidneys as an absolute quantitative method for measuring blood perfusion. Ultrasound Med Biol 2011;37:900. 6. Brannigan M, Burns PN, Wilson SR. Blood flow patterns in focal liver lesions at microbubbleenhanced US. Radiographics 2004;24:921. 7. Pacella CM, Guglielmi R, Fabbrini R, et al. Papillary carcinoma in small hypoechoic thyroid nodules: predictive value of echo color Doppler evaluation. Preliminary results. J Exp Clin Cancer Res 1998;17:127. 8. Wei X, Li Y, Zhang S, et al. WITHDRAWN: Evaluation of microcirculation of thyroid cancer in Chinese females with breast cancer using contrastenhanced ultrasound (CEUS) combined with VEGF and microvessel density (MVD). Clin Hemorheol Microcirc 2013 March 11. [Epub ahead of print]. 9. Sahin M, Sengul A, Berki Z, et al. Ultrasoundguided fine-needle aspiration biopsy and ultrasonographic features of infracentimetric nodules in patients with nodular goiter: correlation with pathological findings. Endocr Pathol 2006;17:67. 10. Jebreel A, England J, Bedford K, et al. Vascular endothelial growth factor (VEGF), VEGF receptors expression and microvascular density in benign and malignant thyroid diseases. Int J Exp Pathol 2007;88:271.

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Contrast-enhanced sonography of thyroid nodules.

To investigate the value of contrast-enhanced ultrasound (CEUS) in the differentiation of benign and malignant nodules...
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