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Assessment of Diffuse Thyroid Disease by Strain Ratio in Ultrasound Elastography
Ultrasound in Med. & Biol., Vol. -, No. -, pp. 1–6, 2015 Copyright Ó 2015 World Federation for Ultrasound in Medicine & Biology Printed in the USA. All rights reserved 0301-5629/$ - see front matter
http://dx.doi.org/10.1016/j.ultrasmedbio.2015.07.012
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Original Contribution ASSESSMENT OF DIFFUSE THYROID DISEASE BY STRAIN RATIO IN ULTRASOUND ELASTOGRAPHY ZHI YANG,* HAIXIAN ZHANG,y KUN WANG,* GUANGHE CUI,* and FENGKUI FUz * Department of Ultrasonography, Binzhou Medical University Hospital, Binzhou, Shandong Province, China; y Department of Ultrasound, Huashan Hospital, Fudan University, Shanghai, China; and z Department of Radiology, The People’s Hospital of Binzhou, Binzhou, Shangdong Province, China (Received 9 January 2015; revised 8 July 2015; in final form 13 July 2015)
Abstract—The goal of this study was to explore the value of strain ratio from real-time elastography in the semiquantitative assessment of diffuse thyroid disease. Fifty-one patients with primary hyperthyroidism, 70 with Hashimoto’s thyroiditis, 8 with subacute thyroiditis and 43 with normal healthy thyroids were recruited to measure the strain ratio (SR) of thyroid tissue and sternocleidomastoid muscle (on the same side of the thyroid). SR values of all groups were subjected to statistical analysis. The SRs (mean ± standard deviation) of patients with hyperthyroidism, Hashimoto’s thyroiditis and subacute thyroiditis were 2.30 ± 1.08, 7.04 ± 7.74 and 24.09 ± 13.56, respectively. The SR of the control group was 1.76 ± 0.54. SR values ranked in ascending order were control group , hyperthyroidism group , Hashimoto’s thyroiditis group , subacute thyroiditis group. There were statistically significant (p , 0.05) differences in thyroid hardness between groups with different diffuse thyroid diseases. SR values of the hyperthyroidism and control groups did not statistically differ (p . 0.05). It is feasible to assess diffuse thyroid disease with strain ratios obtained with ultrasound elastography. (E-mail: jimmyyz0044@163. com) Ó 2015 World Federation for Ultrasound in Medicine & Biology. Key Words: Diffuse thyroid disease, Real-time elastography, Strain ratio, Ultrasound.
follicles. There are many phagocytes, including giant cells, in the tissue and a tough texture. In theory, differentiation with ultrasonic elastography is feasible because of the different pathologic features and hardness. Conventional ultrasonography has a certain value in the diagnosis of diffuse thyroid disease that has been recognized clinically to some extent (Kim et al. 2014). It is difficult to differentiate Hashimoto’s thyroiditis from hyperthyroidism by conventional ultrasonography owing to its complex diversity of clinical manifestations. Ultrasonic elastography, a new technology first proposed by Ophir et al. (1991), has been developed in recent years. Significant differences in the elastic coefficients of fats, mammary glands, fibrous tissues and non-invasive and invasive cancerous tissues have been revealed by clinical pathologic research. Therefore, there are also differences in the extent of deformation of various tissues under external force. These differences can be used to distinguish a variety of tissues and lesions with ultrasonic elastography. Ultrasonic elastography is currently used mainly on space-occupying lesions of superficial organs such as the mammary glands (Meng et al. 2011; Tozaki
INTRODUCTION Diffuse thyroid disease comprises mainly primary hyperthyroidism, Hashimoto’s thyroiditis and subacute thyroiditis. The pathology of primary hyperthyroidism is described as hyperplasia of tall columnar or cuboidal follicular epithelial cells, a decrease or the disappearance of colloid in follicular cavities, different degrees of lymphoid germinal center-associated lymphocytic infiltration among follicles and soft texture. In Hashimoto’s thyroiditis, marked infiltration of lymphocytes and plasma cells and fibrosis are observed microscopically. Most cases have lymphoid follicles with germinal centers. Widespread fibrosis and lymphocytic infiltration are observed in atrophy of the thyroid gland, as is a hard texture. There is a correlation with viral infection in cases of subacute thyroiditis that manifests as mild enlargement, swelling and destruction of thyroid
Address correspondence to: Zhi Yang, No. 661 Yellow River 2 Road, Binzhou, Shandong Province, 256603, China. E-mail: [email protected] Conflict of interest: No potential conflicts of interest are disclosed. 1
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et al. 2011), thyroid (Friedrich-Rust et al. 2012; Scacchi et al. 2009) and prostate (Brock et al. 2015; Xu et al. 2014). It is also used in the diagnosis of diffuse lesions in liver and kidney (Cui et al. 2014; FierbinteanuBraticevici et al. 2009; Rifai et al. 2011; Takahashi et al. 2010; Toshima et al. 2011), but studies of diffuse lesions of the thyroid are rare. Five-grade rating and strain ratio (SR) methods are available for the diagnosis of thyroid nodules by ultrasonic elastography. The five-grade rating system is based on the differences in color of focal areas. The SR method is a quantitative analysis of tissue hardness; the SR is the ratio of a lesion’s hardness to the hardness of the surrounding normal tissue. The five-grade rating and SR methods are limited in the diagnosis of diffuse thyroid disease as there is no normal thyroid tissue surrounding the lesion area for comparison. In this study, the ipsilateral sternocleidomastoid served as the reference, solving the problem of the lack of reference in the SR method applied to diffuse thyroid disease. The aim of this study was to explore the value of the strain ratio obtained by real-time elastography in the semi-quantitative assessment of diffuse thyroid disease. METHODS Informed written consent was obtained from all patients. The study was performed in accordance with the ethics guidelines of the Helsinki Declaration and was approved by the institutional review board of Binzhou Medical University Hospital, Binzhou, Shandong Province, China. Patients One hundred twenty-nine individuals seen in our outpatient department from May 2013 to March 2015 were screened. Among them, 51 cases were diagnosed as hyperthyroidism (8 men, 43 women; age range 16–80 y, mean 6 SD 43.2 6 10.6 y), 70 cases were diagnosed as Hashimoto’s thyroiditis (16 men, 54 women; 17–62 y, 40.1 6 13.4 y) and 8 cases were diagnosed as subacute thyroiditis (2 men, 6 women; 27–58 y, 37.8 6 9.3 y). All cases were confirmed by biopsy or clinical and experimental examination. The control group consisted of 43 healthy volunteers (10 men, 33 women; 20–60 y, 41.2 6 12.3 y) whose ultrasonic and thyroid function tests did not show abnormal results. Imaging and image analysis Ultrasound elastography images were obtained using a Preirus scanner (Hitachi Medical, Tokyo, Japan). A Model EUP-L73S probe with a center frequency of 7.0 MHz was used. The quantitative analysis function of diffuse tissue was loaded. With respect to the color codes
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of elastic images, blue indicated harder areas, red indicated softer areas and green indicated moderately hard areas. Patients were positioned supine with the head tilted back to fully expose the neck. The muscles of the neck were kept tension free, and the neck was smeared with couplant. A gray-scale ultrasound examination was performed with routine transverse and longitudinal scanning. The echogenicity and blood flow of glands were observed, and the thyroid and blood flow parameters of the bilateral superior thyroid artery were measured. The apparatus was then switched to elastography mode to scan longitudinal sections. Gray-scale and elastography images were displayed on the same screen. We confirmed that the range of the sampling frame included most of the thyroid tissue and ipsilateral sternocleidomastoid in the anterior triangle of the neck, avoiding the great vessels of the neck. The probe was placed on the cervical skin and made to vibrate slightly. Compressive and relaxation waveforms were display on the elastographic screen above and below the baseline of the waveform scale. The hardness of cervical tissues presented with stable layering. Two regions of interest (ROIs) for comparison were delineated to calculate the SR. The thyroid tissue was selected as ROI A (diameter: 8.97 6 2.67 mm) to be compared with ROI B (diameter: 4.87 6 1.83 mm), the sternocleidomastoid in front of the ipsilateral thyroid. The ROI should include as much of the tissue of the thyroid or sternocleidmastoid as possible. The mean strain of the thyroid was determined in the representative ROI from the thyroid tissue and expressed as A. The mean strain of the corresponding ROI of ipsilateral sternocleidomastoid was expressed as B. A and B should be in central region of the image, with SR 5 B/A (Aydin et al. 2014). The SRs of the two ROIs (Fig. 1) were obtained and recorded automatically by the built-in ultrasonic elastography analysis software. Patients were required to hold their breath when necessary to decrease error inelastic parameters and avoid the great vessels of the neck. Statistical analysis Statistical results were analyzed with SPSS Version 16.0 (SPSS, Chicago, IL, USA). The data were expressed as means 6 SD. The difference in SRs between the group with diffuse thyroid disease and the control group was evaluated by one-way analysis of variance and multiple comparisons between groups. Differences were considered statistically significant at p , 0.05. Receiver operating characteristic (ROC) curves were drawn by taking SR as the result, sensitivity as the vertical axis and 1 2 specificity as the horizontal axis. The cutoff point for diagnosis was determined by the highest critical point of Youden’s index (sensitivity 1 specificity 2 1).
Assessment of diffuse thyroid disease by strain ratio d Z. YANG et al.
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Fig. 1. Method for measuring SR. Two ROIs for comparison were delineated to calculate the SR. The yellow circle A is the local ROI on the thyroid tissue, The yellow circle B is the local ROI on the sternocleidomastoid in front of the ipsilateral thyroid. SR—B/A. SR 5 strain ratio; ROI 5 region of interest.
RESULTS The strain ratios of patients with hyperthyroidism, Hashimoto’s thyroiditis and subacute thyroiditis were 2.30 6 1.08, 7.04 6 7.74 and 24.09 6 13.56, respectively, whereas the SR of the control group was 1.76 6 0.54. SRs of the thyroid and ipsilateral sternocleidomastoid were ranked in ascending order as control group , hyperthyroidism group , Hashimoto’s thyroiditis group , subacute thyroiditis group. There were statistically significant differences in thyroid hardness between the diffuse thyroid disease groups (p , 0.05). The SRs of the hyperthyroidism and control groups did not statistically differ (Table 1, Fig. 2). In Figure 2, the log SR is plotted to reduce the level of scalar rating. Multiple comparisons revealed that there was no significant differences between the primary hyperthyroidism and control groups (p 5 0.648). However, the primary hyperthyroidism group significantly differed from the Hashimoto’s thyroiditis (p , 0.01) and subacute thyroiditis (p , 0.01) groups. The group with Hashimoto’s thyroiditis significantly differed from the control (p , 0.01) and subacute thyroiditis (p , 0.01) groups. To compare the primary hyperthyroidism group with the Hashimoto’s thyroiditis group, a ROC curve was plotted by taking SR as the result, sensitivity as the
vertical axis and 1 2 specificity as the horizontal axis (Fig. 3). The maximum of the area under the curve was 0.827. Determined with the highest critical point of Youden’s index (sensitivity 1 specificity 2 1), the diagnostic cutoff point was 3.65, sensitivity 58.6%, specificity 94.4% and diagnostic accuracy 74.2%. A ROC curve (Fig. 4) was also plotted to compare the Hashimoto’s thyroiditis group with the subacute thyroiditis group, and the maximum area under the curve was 0.931. The diagnostic cutoff point was 10.41, sensitivity 100%, specificity 85.7% and diagnostic accuracy 87.2%. DISCUSSION Since its introduction, ultrasonic elastography has been widely used in the assessment of fibrosis of abdominal organs (Cui et al. 2014; Fierbinteanu-Braticevici et al. 2009; Rifai et al. 2011; Takahashi et al. 2010; Table 1. Strain ratio ranges of different groups Strain ratio Group
Number of cases
Range
Mean 6 SD
Control Primary hyperthyroidism Hashimoto’s thyroiditis Subacute thyroiditis
43 51 70 8
0.66–2.70 1.11–5.54 1.41–17.64 10.41–73.00
1.76 6 0.54 2.30 6 1.08 7.04 6 7.74 24.09 6 13.56
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Fig. 2. Boxplot of strain ratios in different groups.
Toshima et al. 2011) and the differentiation between malignant and benign nodular lesions of minor organs such as the thyroid and mammary glands (FriedrichRust et al. 2012; Meng et al. 2011; Scacchi et al. 2009; Tozaki et al. 2011) and has attained clinical acceptance. Five-grade rating and SR methods are available for the diagnosis of thyroid nodules by ultrasonic elastography. Both methods can distinguish between malignant and benign thyroid nodules (Cantisani et al. 2012; Hong et al. 2009).
Fig. 3. Receiver operating characteristic curve of strain ratios for differential diagnosis of primary hyperthyroidism and Hashimoto’s thyroiditis. Diagonal segment is produced by ties.
Fig. 4. Receiver operating characteristic curve of strain ratios for differential diagnosis of Hashimoto’s thyroiditis and subacute thyroiditis. Diagonal segment is produced by ties.
However, interpretation of the results of color grading is easily affected by the subjective judgment of doctors. Different ratings may be assigned to the same image under the same conditions by different doctors, because the color grading depends on the pressure exerted by the operator and different observers judge the distribution of various colors differently. SR is a specific number, eliminating the effect of subjective judgment. This method is better than the grading method in the differentiation of malignant and benign nodules; it can provide quantitative information on thyroid nodules and improve diagnostic confidence (Sun et al. 2014; Wang et al. 2013). In our study, the ipsilateral sternocleidomastoid served as the reference. Key to this study was whether it is feasible to take the ipsilateral sternocleidomastoid as the reference for thyroid lesions. Also, such factors such as relative depth and relative stiffness are potential complicating factors affecting the stress ratio, as the strain will attenuate along with depth, and the stiffness of the ipsilateral sternocleidomastoid may also affect strain. In this research, we did not take those factors into consideration; therefore, further study is needed, as there may be an opportunity to improve the results by analyzing and compensating for this complication. It has been proved that the hardness of muscles differs under relaxed and tight conditions (Muraki et al. 2015; Yanagisawa et al. 2011). There is little difference between images of relaxed muscle bundles in real-time tissue elastography. In a previous study, the muscle-to-nodule
Assessment of diffuse thyroid disease by strain ratio d Z. YANG et al.
strain ratio could safely be used instead of the parenchymato-nodule strain ratio to differentiate benign and malignant thyroid nodules in situations in which the parenchyma-tonodule strain ratio could not be used (Aydin et al. 2014). In the method used in this study, we took the ipsilateral sternocleidomastoid as the reference for thyroid lesions. To avoid the measurement error, the ROI should include as much of the thyroid or the sternocleidmastoid tissue as possible so that the value is closer to the real strain of the thyroid or the sternocleidomastoid. The sternocleidomastoids of patients were relaxed in this study and correlated well in hardness with normal thyroid glands. It was feasible to take sternocleidomastoid as the reference for hardness of thyroid tissues with diffuse lesions. This method has also been proven to be practically feasible. Hardness in this study was ranked as follows: control thyroid group , hyperthyroidism group , Hashimoto’s thyroiditis group , subacute thyroiditis group. Comparisons of the control group with the Hashimoto’s thyroiditis group, the control group with the subacute thyroiditis group, the hyperthyroidism group with the Hashimoto’s thyroiditis group, the hyperthyroidism group with the subacute thyroiditis group and the Hashimoto’s thyroiditis group with the subacute thyroiditis group revealed notable differences in SRs. However, there was no statistically significant difference between the control and hyperthyroidism groups. It is easy to distinguish healthy thyroid tissue from tissue affected by primary hyperthyroidism, Hashimoto’s thyroiditis and subacute thyroiditis by conventional ultrasonography. The clinical features of subacute thyroiditis, such as fever, headache and thyroid tenderness, are not associated with other diffuse thyroid diseases, which facilitates the diagnosis. Transient hyperthyroidism occurs in some cases of Hashimoto’s thyroiditis when thyroid hormones are released into blood by the destruction of follicles by inflammation in the early stage. Ultrasonography reveals that the thyroid is diffusely enlarged with heterogeneous echogenicity and plentiful blood flow presenting the ‘‘fire sign,’’ and the peak systolic velocity of the superior thyroid artery is increased, which is similar to the ultrasound findings in primary hyperthyroidism. It is difficult to make a differential diagnosis by conventional ultrasonography. There were markedly statistically significant differences in hardness between the thyroid tissue and reference tissue in this study. When the cutoff point for differential diagnosis was 3.65, sensitivity was 57.6%, specificity was 93.8% and diagnostic accuracy was 76.9%. CONCLUSIONS The elasticity of tissue affected by diffuse thyroid disease and normal thyroid tissue is quantitatively reflected by SRs obtained with ultrasonic elastography,
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with ipsilateral muscle as the reference. The SR method overcomes the past disadvantages of evaluation criteria in elastography and can be a useful method for the diagnosis of diffuse thyroid disease.
REFERENCES Aydin R, Elmali M, Polat AV, Danaci M, Akpolat I. Comparison of muscle-to-nodule and parenchyma-to-nodule strain ratios in the differentiation of benign and malignant thyroid nodules: Which one should we use? Eur J Radiol 2014;83:e131–e136. Brock M, Roghmann F, Sonntag C, Sommerer F, Tian Z, L€oppenberg B, Palisaar RJ, Noldus J, Hanske J, von Bodman C. Fusion of magnetic resonance imaging and real-time elastography to visualize prostate cancer: A prospective analysis using whole mount sections after radical prostatectomy. Ultraschall Med 2015;36:355–361. Cantisani V, Ulisse S, Guaitoli E, De Vito C, Caruso R, Mocini R, D’Andrea V, Ascoli V, Antonaci A, Catalano C, Nardi F, Redler A, Ricci P, De Antoni E, Sorrenti S. Q-Elastography in the presurgical diagnosis of thyroid nodules with indeterminate cytology. PLoS One 2012;7:e50725. Cui G, Yang Z, Zhang W, Li B, Sun F, Xu C, Wang K. Evaluation of acoustic radiation force impulse imaging for the clinicopathological typing of renal fibrosis. Exp Ther Med 2014;7:233–235. Fierbinteanu-Braticevici C, Andronescu D, Usvat R, Cretoiu D, Baicus C, Marinoschi G. Acoustic radiation force imaging sonoelastography for noninvasive staging of liver fibrosisi. World J Gastroenterol 2009;15:5525–5532. Friedrich-Rust M, Romenski O, Meyer G, Dauth N, Holzer K, Gr€unwald F, Kriener S, Herrmann E, Zeuzem S, Bojunga J. Acoustic radiation force impulse-imaging for the evaluation of the thyroid gland: A limited patient feasibility study. Ultrasonics 2012;52: 69–74. Hong Y, Liu X, Li Z, Zhang X, Chen M, Luo Z. Real-time ultrasound elastography in the differential diagnosis of benign and malignant thyroid nodules. J Ultrasound Med 2009;28:861–867. Kim DW, Jung SJ, Ha TK, Park HK, Kang T. Comparative study of ultrasound and computed tomography for incidentally detecting diffuse thyroid disease. Ultrasound Med Biol 2014;40:1778–1784. Meng W, Zhang G, Wu C, Wu G, Song Y, Lu Z. Preliminary results of acoustic radiation force impulse (ARFI) ultrasound imaging of breast lesions. Ultrasound Med Biol 2011;37:1436–1443. Muraki T, Ishikawa H, Morise S, Yamamoto N, Sano H, Itoi E, Izumi SI. Ultrasound elastography-based assessment of the elasticity of the supraspinatus muscle and tendon during muscle contraction. J Shoulder Elbow Surg 2015;24:120–126. Ophir J, Cespedes EI, Ponnekenti H, Yazdi Y, Li X. Elastography: A quantitative method for imaging the elasticity of biological tissues. Ultrason Imaging 1991;13:111–134. Rifai K, Cornberg J, Mederacke I, Bahr MJ, Wedemeyer H, Malinski P, Bantel H, Boozari B, Potthoff A, Manns MP, Gebel M. Clinical feasibility of liver elastography by acoustic radiation force impulse imaging (ARFI). Dig Liver Dis 2011;43:491–497. Scacchi M, Andrioli M, Carzaniga C, Vitale G, Moro M, Poggi L, Pecori Giraldi F, Fatti LM, Cavagnini F. Elastosonographic evaluation of thyroid nodules in acromegaly. Eur J Endocrinol 2009;161:607–613. Sun J, Cai J, Wang X. Real-time ultrasound elastography for differentiation of benign and malignant thyroid nodules: A meta-analysis. Ultrasound Med 2014;33:495–502. Takahashi H, Ono N, Eguchi Y, Eguchi T, Kitajima Y, Kawaguchi Y, Nakashita S, Ozaki I, Mizuta T, Toda S, Kudo S, Miyoshi A, Miyazaki K, Fujimoto K. Evaluation of acoustic radiation force impulse elastography for fibrosis staging of chronic liver disease: A pilot study. Liver Int 2010;30:538–545. Toshima T, Shirabe K, Takeishi K, Motomura T, Mano Y, Uchiyama H, Yoshizumi T, Soejima Y, Taketomi A, Maehara Y. New method for assessing liver fibrosis based on acoustic radiation force impulse: A special reference to the difference between right and left liver. J Gastroenterol 2011;46:705–711.
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Tozaki M, Isobe S, Fukuma E. Preliminary study of ultrasonographic tissue quantification of the breast using the acoustic radiation force impulse (ARFI) technology. Eur J Radiol 2011;80:182–187. Wang H, Brylka D, Sun LN, Lin YQ, Sui GQ, Gao J. Comparison of strain ratio with elastography score system in differentiating malignant from benign thyroid nodules. Clin Imaging 2013;37:50–55.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2015.07.012
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Original Contribution ASSESSMENT OF DIFFUSE THYROID DISEASE BY STRAIN RATIO IN ULTRASOUND ELASTOGRAPHY ZHI YANG,* HAIXIAN ZHANG,y KUN WANG,* GUANGHE CUI,* and FENGKUI FUz * Department of Ultrasonography, Binzhou Medical University Hospital, Binzhou, Shandong Province, China; y Department of Ultrasound, Huashan Hospital, Fudan University, Shanghai, China; and z Department of Radiology, The People’s Hospital of Binzhou, Binzhou, Shangdong Province, China (Received 9 January 2015; revised 8 July 2015; in final form 13 July 2015)
Abstract—The goal of this study was to explore the value of strain ratio from real-time elastography in the semiquantitative assessment of diffuse thyroid disease. Fifty-one patients with primary hyperthyroidism, 70 with Hashimoto’s thyroiditis, 8 with subacute thyroiditis and 43 with normal healthy thyroids were recruited to measure the strain ratio (SR) of thyroid tissue and sternocleidomastoid muscle (on the same side of the thyroid). SR values of all groups were subjected to statistical analysis. The SRs (mean ± standard deviation) of patients with hyperthyroidism, Hashimoto’s thyroiditis and subacute thyroiditis were 2.30 ± 1.08, 7.04 ± 7.74 and 24.09 ± 13.56, respectively. The SR of the control group was 1.76 ± 0.54. SR values ranked in ascending order were control group , hyperthyroidism group , Hashimoto’s thyroiditis group , subacute thyroiditis group. There were statistically significant (p , 0.05) differences in thyroid hardness between groups with different diffuse thyroid diseases. SR values of the hyperthyroidism and control groups did not statistically differ (p . 0.05). It is feasible to assess diffuse thyroid disease with strain ratios obtained with ultrasound elastography. (E-mail: jimmyyz0044@163. com) Ó 2015 World Federation for Ultrasound in Medicine & Biology. Key Words: Diffuse thyroid disease, Real-time elastography, Strain ratio, Ultrasound.
follicles. There are many phagocytes, including giant cells, in the tissue and a tough texture. In theory, differentiation with ultrasonic elastography is feasible because of the different pathologic features and hardness. Conventional ultrasonography has a certain value in the diagnosis of diffuse thyroid disease that has been recognized clinically to some extent (Kim et al. 2014). It is difficult to differentiate Hashimoto’s thyroiditis from hyperthyroidism by conventional ultrasonography owing to its complex diversity of clinical manifestations. Ultrasonic elastography, a new technology first proposed by Ophir et al. (1991), has been developed in recent years. Significant differences in the elastic coefficients of fats, mammary glands, fibrous tissues and non-invasive and invasive cancerous tissues have been revealed by clinical pathologic research. Therefore, there are also differences in the extent of deformation of various tissues under external force. These differences can be used to distinguish a variety of tissues and lesions with ultrasonic elastography. Ultrasonic elastography is currently used mainly on space-occupying lesions of superficial organs such as the mammary glands (Meng et al. 2011; Tozaki
INTRODUCTION Diffuse thyroid disease comprises mainly primary hyperthyroidism, Hashimoto’s thyroiditis and subacute thyroiditis. The pathology of primary hyperthyroidism is described as hyperplasia of tall columnar or cuboidal follicular epithelial cells, a decrease or the disappearance of colloid in follicular cavities, different degrees of lymphoid germinal center-associated lymphocytic infiltration among follicles and soft texture. In Hashimoto’s thyroiditis, marked infiltration of lymphocytes and plasma cells and fibrosis are observed microscopically. Most cases have lymphoid follicles with germinal centers. Widespread fibrosis and lymphocytic infiltration are observed in atrophy of the thyroid gland, as is a hard texture. There is a correlation with viral infection in cases of subacute thyroiditis that manifests as mild enlargement, swelling and destruction of thyroid
Address correspondence to: Zhi Yang, No. 661 Yellow River 2 Road, Binzhou, Shandong Province, 256603, China. E-mail: [email protected] Conflict of interest: No potential conflicts of interest are disclosed. 1
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et al. 2011), thyroid (Friedrich-Rust et al. 2012; Scacchi et al. 2009) and prostate (Brock et al. 2015; Xu et al. 2014). It is also used in the diagnosis of diffuse lesions in liver and kidney (Cui et al. 2014; FierbinteanuBraticevici et al. 2009; Rifai et al. 2011; Takahashi et al. 2010; Toshima et al. 2011), but studies of diffuse lesions of the thyroid are rare. Five-grade rating and strain ratio (SR) methods are available for the diagnosis of thyroid nodules by ultrasonic elastography. The five-grade rating system is based on the differences in color of focal areas. The SR method is a quantitative analysis of tissue hardness; the SR is the ratio of a lesion’s hardness to the hardness of the surrounding normal tissue. The five-grade rating and SR methods are limited in the diagnosis of diffuse thyroid disease as there is no normal thyroid tissue surrounding the lesion area for comparison. In this study, the ipsilateral sternocleidomastoid served as the reference, solving the problem of the lack of reference in the SR method applied to diffuse thyroid disease. The aim of this study was to explore the value of the strain ratio obtained by real-time elastography in the semi-quantitative assessment of diffuse thyroid disease. METHODS Informed written consent was obtained from all patients. The study was performed in accordance with the ethics guidelines of the Helsinki Declaration and was approved by the institutional review board of Binzhou Medical University Hospital, Binzhou, Shandong Province, China. Patients One hundred twenty-nine individuals seen in our outpatient department from May 2013 to March 2015 were screened. Among them, 51 cases were diagnosed as hyperthyroidism (8 men, 43 women; age range 16–80 y, mean 6 SD 43.2 6 10.6 y), 70 cases were diagnosed as Hashimoto’s thyroiditis (16 men, 54 women; 17–62 y, 40.1 6 13.4 y) and 8 cases were diagnosed as subacute thyroiditis (2 men, 6 women; 27–58 y, 37.8 6 9.3 y). All cases were confirmed by biopsy or clinical and experimental examination. The control group consisted of 43 healthy volunteers (10 men, 33 women; 20–60 y, 41.2 6 12.3 y) whose ultrasonic and thyroid function tests did not show abnormal results. Imaging and image analysis Ultrasound elastography images were obtained using a Preirus scanner (Hitachi Medical, Tokyo, Japan). A Model EUP-L73S probe with a center frequency of 7.0 MHz was used. The quantitative analysis function of diffuse tissue was loaded. With respect to the color codes
Volume -, Number -, 2015
of elastic images, blue indicated harder areas, red indicated softer areas and green indicated moderately hard areas. Patients were positioned supine with the head tilted back to fully expose the neck. The muscles of the neck were kept tension free, and the neck was smeared with couplant. A gray-scale ultrasound examination was performed with routine transverse and longitudinal scanning. The echogenicity and blood flow of glands were observed, and the thyroid and blood flow parameters of the bilateral superior thyroid artery were measured. The apparatus was then switched to elastography mode to scan longitudinal sections. Gray-scale and elastography images were displayed on the same screen. We confirmed that the range of the sampling frame included most of the thyroid tissue and ipsilateral sternocleidomastoid in the anterior triangle of the neck, avoiding the great vessels of the neck. The probe was placed on the cervical skin and made to vibrate slightly. Compressive and relaxation waveforms were display on the elastographic screen above and below the baseline of the waveform scale. The hardness of cervical tissues presented with stable layering. Two regions of interest (ROIs) for comparison were delineated to calculate the SR. The thyroid tissue was selected as ROI A (diameter: 8.97 6 2.67 mm) to be compared with ROI B (diameter: 4.87 6 1.83 mm), the sternocleidomastoid in front of the ipsilateral thyroid. The ROI should include as much of the tissue of the thyroid or sternocleidmastoid as possible. The mean strain of the thyroid was determined in the representative ROI from the thyroid tissue and expressed as A. The mean strain of the corresponding ROI of ipsilateral sternocleidomastoid was expressed as B. A and B should be in central region of the image, with SR 5 B/A (Aydin et al. 2014). The SRs of the two ROIs (Fig. 1) were obtained and recorded automatically by the built-in ultrasonic elastography analysis software. Patients were required to hold their breath when necessary to decrease error inelastic parameters and avoid the great vessels of the neck. Statistical analysis Statistical results were analyzed with SPSS Version 16.0 (SPSS, Chicago, IL, USA). The data were expressed as means 6 SD. The difference in SRs between the group with diffuse thyroid disease and the control group was evaluated by one-way analysis of variance and multiple comparisons between groups. Differences were considered statistically significant at p , 0.05. Receiver operating characteristic (ROC) curves were drawn by taking SR as the result, sensitivity as the vertical axis and 1 2 specificity as the horizontal axis. The cutoff point for diagnosis was determined by the highest critical point of Youden’s index (sensitivity 1 specificity 2 1).
Assessment of diffuse thyroid disease by strain ratio d Z. YANG et al.
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Fig. 1. Method for measuring SR. Two ROIs for comparison were delineated to calculate the SR. The yellow circle A is the local ROI on the thyroid tissue, The yellow circle B is the local ROI on the sternocleidomastoid in front of the ipsilateral thyroid. SR—B/A. SR 5 strain ratio; ROI 5 region of interest.
RESULTS The strain ratios of patients with hyperthyroidism, Hashimoto’s thyroiditis and subacute thyroiditis were 2.30 6 1.08, 7.04 6 7.74 and 24.09 6 13.56, respectively, whereas the SR of the control group was 1.76 6 0.54. SRs of the thyroid and ipsilateral sternocleidomastoid were ranked in ascending order as control group , hyperthyroidism group , Hashimoto’s thyroiditis group , subacute thyroiditis group. There were statistically significant differences in thyroid hardness between the diffuse thyroid disease groups (p , 0.05). The SRs of the hyperthyroidism and control groups did not statistically differ (Table 1, Fig. 2). In Figure 2, the log SR is plotted to reduce the level of scalar rating. Multiple comparisons revealed that there was no significant differences between the primary hyperthyroidism and control groups (p 5 0.648). However, the primary hyperthyroidism group significantly differed from the Hashimoto’s thyroiditis (p , 0.01) and subacute thyroiditis (p , 0.01) groups. The group with Hashimoto’s thyroiditis significantly differed from the control (p , 0.01) and subacute thyroiditis (p , 0.01) groups. To compare the primary hyperthyroidism group with the Hashimoto’s thyroiditis group, a ROC curve was plotted by taking SR as the result, sensitivity as the
vertical axis and 1 2 specificity as the horizontal axis (Fig. 3). The maximum of the area under the curve was 0.827. Determined with the highest critical point of Youden’s index (sensitivity 1 specificity 2 1), the diagnostic cutoff point was 3.65, sensitivity 58.6%, specificity 94.4% and diagnostic accuracy 74.2%. A ROC curve (Fig. 4) was also plotted to compare the Hashimoto’s thyroiditis group with the subacute thyroiditis group, and the maximum area under the curve was 0.931. The diagnostic cutoff point was 10.41, sensitivity 100%, specificity 85.7% and diagnostic accuracy 87.2%. DISCUSSION Since its introduction, ultrasonic elastography has been widely used in the assessment of fibrosis of abdominal organs (Cui et al. 2014; Fierbinteanu-Braticevici et al. 2009; Rifai et al. 2011; Takahashi et al. 2010; Table 1. Strain ratio ranges of different groups Strain ratio Group
Number of cases
Range
Mean 6 SD
Control Primary hyperthyroidism Hashimoto’s thyroiditis Subacute thyroiditis
43 51 70 8
0.66–2.70 1.11–5.54 1.41–17.64 10.41–73.00
1.76 6 0.54 2.30 6 1.08 7.04 6 7.74 24.09 6 13.56
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Fig. 2. Boxplot of strain ratios in different groups.
Toshima et al. 2011) and the differentiation between malignant and benign nodular lesions of minor organs such as the thyroid and mammary glands (FriedrichRust et al. 2012; Meng et al. 2011; Scacchi et al. 2009; Tozaki et al. 2011) and has attained clinical acceptance. Five-grade rating and SR methods are available for the diagnosis of thyroid nodules by ultrasonic elastography. Both methods can distinguish between malignant and benign thyroid nodules (Cantisani et al. 2012; Hong et al. 2009).
Fig. 3. Receiver operating characteristic curve of strain ratios for differential diagnosis of primary hyperthyroidism and Hashimoto’s thyroiditis. Diagonal segment is produced by ties.
Fig. 4. Receiver operating characteristic curve of strain ratios for differential diagnosis of Hashimoto’s thyroiditis and subacute thyroiditis. Diagonal segment is produced by ties.
However, interpretation of the results of color grading is easily affected by the subjective judgment of doctors. Different ratings may be assigned to the same image under the same conditions by different doctors, because the color grading depends on the pressure exerted by the operator and different observers judge the distribution of various colors differently. SR is a specific number, eliminating the effect of subjective judgment. This method is better than the grading method in the differentiation of malignant and benign nodules; it can provide quantitative information on thyroid nodules and improve diagnostic confidence (Sun et al. 2014; Wang et al. 2013). In our study, the ipsilateral sternocleidomastoid served as the reference. Key to this study was whether it is feasible to take the ipsilateral sternocleidomastoid as the reference for thyroid lesions. Also, such factors such as relative depth and relative stiffness are potential complicating factors affecting the stress ratio, as the strain will attenuate along with depth, and the stiffness of the ipsilateral sternocleidomastoid may also affect strain. In this research, we did not take those factors into consideration; therefore, further study is needed, as there may be an opportunity to improve the results by analyzing and compensating for this complication. It has been proved that the hardness of muscles differs under relaxed and tight conditions (Muraki et al. 2015; Yanagisawa et al. 2011). There is little difference between images of relaxed muscle bundles in real-time tissue elastography. In a previous study, the muscle-to-nodule
Assessment of diffuse thyroid disease by strain ratio d Z. YANG et al.
strain ratio could safely be used instead of the parenchymato-nodule strain ratio to differentiate benign and malignant thyroid nodules in situations in which the parenchyma-tonodule strain ratio could not be used (Aydin et al. 2014). In the method used in this study, we took the ipsilateral sternocleidomastoid as the reference for thyroid lesions. To avoid the measurement error, the ROI should include as much of the thyroid or the sternocleidmastoid tissue as possible so that the value is closer to the real strain of the thyroid or the sternocleidomastoid. The sternocleidomastoids of patients were relaxed in this study and correlated well in hardness with normal thyroid glands. It was feasible to take sternocleidomastoid as the reference for hardness of thyroid tissues with diffuse lesions. This method has also been proven to be practically feasible. Hardness in this study was ranked as follows: control thyroid group , hyperthyroidism group , Hashimoto’s thyroiditis group , subacute thyroiditis group. Comparisons of the control group with the Hashimoto’s thyroiditis group, the control group with the subacute thyroiditis group, the hyperthyroidism group with the Hashimoto’s thyroiditis group, the hyperthyroidism group with the subacute thyroiditis group and the Hashimoto’s thyroiditis group with the subacute thyroiditis group revealed notable differences in SRs. However, there was no statistically significant difference between the control and hyperthyroidism groups. It is easy to distinguish healthy thyroid tissue from tissue affected by primary hyperthyroidism, Hashimoto’s thyroiditis and subacute thyroiditis by conventional ultrasonography. The clinical features of subacute thyroiditis, such as fever, headache and thyroid tenderness, are not associated with other diffuse thyroid diseases, which facilitates the diagnosis. Transient hyperthyroidism occurs in some cases of Hashimoto’s thyroiditis when thyroid hormones are released into blood by the destruction of follicles by inflammation in the early stage. Ultrasonography reveals that the thyroid is diffusely enlarged with heterogeneous echogenicity and plentiful blood flow presenting the ‘‘fire sign,’’ and the peak systolic velocity of the superior thyroid artery is increased, which is similar to the ultrasound findings in primary hyperthyroidism. It is difficult to make a differential diagnosis by conventional ultrasonography. There were markedly statistically significant differences in hardness between the thyroid tissue and reference tissue in this study. When the cutoff point for differential diagnosis was 3.65, sensitivity was 57.6%, specificity was 93.8% and diagnostic accuracy was 76.9%. CONCLUSIONS The elasticity of tissue affected by diffuse thyroid disease and normal thyroid tissue is quantitatively reflected by SRs obtained with ultrasonic elastography,
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with ipsilateral muscle as the reference. The SR method overcomes the past disadvantages of evaluation criteria in elastography and can be a useful method for the diagnosis of diffuse thyroid disease.
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